MD Anderson Surgical Oncology Handbook, The, 4th Edition PDF

Editors: Feig, Barry W .; Berger, David H.
; Fuhrman, George
M.
Title: MD A nderson Surgical Oncology Handbook, The, 4th
Edition
Copyr i ght 2006 Li ppi ncott Wi l l i ams & Wi l ki ns
> F ro nt o f Bo o k > Edit o rs
Editors
Barry W . Feig M.D.
M. D. Ander son Cancer Center , Depar tment of Sur gical Oncology,
Houston, Texas
David H. Berger M.D.
Houston, Texas
George M. Fuhrman M.D.
Houston, Texas
Secondary Edi tor

Brian Brow n
Acqui si ti ons Edi tor
Julia Seto
Managi ng Edi tor
Dave Murphy
Pr oject Manager
Benjamin Rivera
Manufactur i ng Manager
A dam Glazer
Associ ate Di r ector of Mar keti ng
Stephen Druding
Cover Desi gner
TechBooks
Compositor
R.R. Donnelley, Craw fordsville

Pr inter
Contributors
Eddie K. A bdalla MD, FA CS
Assi stant Pr ofessor
Depar tment of Sur gical Oncology, The Univer sity of Texas, M. D.
Ander son Cancer Center , Houston, Texas
Syed A . A hmad MD
Assi stant Pr ofessor of Sur ger y
Division of Sur gical Oncology, Depar tment of Sur ger y, Univer sity of
Cincinnati Medical Center , Bar r ett Cancer Center , Cincinnati, Ohio
Daniel A lbo MD, PhD
Michael E. DeBakey Depar tment of Sur ger y, Baylor College of
Medicine; Chief, Section of G ener al Sur ger y and Sur gical Oncology,
Depar tment of Sur ger y, Michael E. DeBakey VA Medical Center ,
Houston, Texas
W addah B. A l-Refaie MD
Fel l ow
Division of Sur ger y, Depar tment of Sur gical Oncology, The
Univer sity of Texas, M. D. Ander son Cancer Center , Houston, Texas
Keith D. A mos MD
Fel l ow
Robert H. I. A ndtbacka MD, CM
Fel l ow and Cl i ni cal Speci al i st
Gildy V. Babiera MD, FA CS

Chad M. Barnett PharmD
Cl i ni cal Phar macy Speci al i st
Division of Phar macy, The Univer sity of Texas M. D. Ander son
Cancer Center , Houston, Texas
David H. Berger MD
Pr ofessor and Vi ce Chai r
Michael E. DeBakey Depar tment of Sur ger y, Baylor College of
Medicine, Oper ative Car e Line Executive, Michael E. DeBakey VA
Medical Center , Houston, Texas
Shanda H. Blackmon MD, MPH
Instr uctor
Thor acic & Car diovasc Sur ger y Depar tment, The Univer sity of Texas,
M. D. Ander son Cancer Center , Houston, Texas
Richard J. Bold MD
Associ ate Pr ofessor of Sur ger y
Depar tment of Sur ger y, Univer sity of Califor nia Davis; Chief,
Division of Sur gical Oncology, Univer sity of Califor nia Davis Cancer
Center , Sacr amento, Califor nia
Michael Bouvet MD
Pr ofessor
Depar tment of Sur ger y, Univer sity of Califor nia San Diego, La Jolla,
Califor nia
George J. Chang MD
Depar tment of Sur ger y Oncology, The Univer sity of Texas M. D.
Judy L. Chase PharmD, FA SHP
Coor di nator
Clinical Phar macy Ser vices, Division of Phar macy, The Univer sity of
Texas M. D. Ander son Cancer Center , Houston, Texas
Eugene A . Choi MD
Fel l ow
Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.

Janice N. Cormier MD, MPH
Keith A . Delman MD
Division of Sur gical Oncology, Depar tment of Sur ger y, Winship
Cancer Institute, Emor y Univer sity, Atlanta, G eor gia
Colin P. N. Dinney MD
Pr ofessor
Depar tments of Ur ology and Cancer Biology, Chair man, Depar tment
of Ur ology, The Univer sity of Texas M. D. Ander son Cancer Center ,
Houston, Texas
Barry W . Feig MD, FA CS
Pr ofessor of Sur ger y
Jules A . Feledy Jr. MD
Depar tment of Reconstr uctive and Micr ovascular Sur ger y, The
Metr opolitan Institute F or Plastic Sur ger y, Washington, DC
W ayne A . I. Frederick MD
Associ ate Pr ofessor
Depar tment of Sur ger y, Howar d Univer sity; Associate Dir ector ,
Howar d Univer sity Cancer Center , Howar d Univer sity Hospital,
Washington, DC
George M. Fuhrman MD
Pr ogram Di r ector G eneral Sur ger y Resi dency
Atlanta Medical Center , Atlanta, G eor gia
Jeffrey E. Gershenw ald MD
Depar tments of Sur gical Oncology and Cancer Biology, The
Univer sity of Texas M. D. Ander son Cancer Center , Houston, Texas

Ricardo J. Gonzalez MD
Fel l ow
A na M. Grau MD
Depar tment of Sur ger y, Mehar r y Medical College and Vander bilt
Univer sity, Depar tment of Sur ger y, Nashville G ener al Hospital at
Mehar r y and Vander bilt Univer sity Medical Center , Nashville,
Tennessee
Mouhammed A . Habra MD
Fel l ow
Depar tment of Endocr ine Neoplasia and Hor monal Disor der s, The
Matthew M. Hanasono MD
Depar tment of Plastic Sur ger y, The Univer sity of Texas M. D.
Kelly L. Herne MD
Vol unteer faci l ty
Depar tment of Der matology, The Univer sity of Texas Houston
Medical School, Houston, Texas
W ayne L. Hofstetter MD
Depar tment of Thor acic and Car diovascular Sur ger y, The Univer sity
of Texas M. D. Ander son Cancer Center , Houston, Texas
F. Christopher Holsinger MD, FA CS
Depar tment of Head and Neck Sur ger y, The Univer sity of Texas M.
D. Ander son Cancer Center , Houston, Texas
Kelly K. Hunt MD
Pr ofessor of Sur ger y, Chi ef
Sur gical Br east Section, Depar tment of Sur gical Oncology, Associate
Medical Dir ector , Nellie B. Connally Br east Center , The Univer sity of
Rosa F. Hw ang MD
Sharon Renae Hymes MD
Depar tment of Der matology, The Univer sity of Texas M. D. Ander son
Cancer Center , Houston, Texas
Jeffrey E. Lee MD, FA CS
Jeffrey T. Lenert CDR, MC, USNR
Depar tment of Sur ger y, Unifor med Ser vices Univer sity of Health
Sciences; Staff Sur gical Oncologist, Depar tment of Sur ger y, National
Naval Medical Center , Bethesda, Mar yland
Paul F. Mansfield MD, FA CS
Division of Sur ger y, Depar tment of Sur gical Oncology, The
Ian E. McCutcheon MD
Pr ofessor
Depar tment of Neur osur ger y, The Univer sity of Texas M. D.
Funda Meric-Bernstam MD
Kenneth A . New kirk MD

Depar tment of Otolar yngology-Head and Neck Sur ger y, MEDSTARG eor getown Univer sity Medical Center , Washington, DC
A lexander A . Parikh MD
Division of Sur gical Oncology, Vander bilt Univer sity Medical Center ,
Nashville, Tennessee
Timothy M. Paw lik MD, MPH
Depar tment of Sur ger y, Johns Hopkins School of Medicine, Johns
Hopkins Hospital, Baltimor e, Mar yland
Nancy D. Perrier MD
Associ ate Pr ofessor of Sur ger y
James A . Reilly Jr. MD, FA CS
Sur gi cal Oncol ogi st, Di r ector Br east Car e Center
Depar tment of Sur ger y, Nebr aska Methodist Hospital, Omaha,
Nebr aska
Geoffrey L. Robb MD, FA CS
Pr ofessor and Chai r
Depar tment of Plastic Sur ger y, The Univer sity of Texas, M. D.
Emily K. Robinson MD
Depar tment of Sur ger y, The Univer sity of Texas M. D. Ander son
Cancer Center ; Medical Dir ector , Memor ial Her mann Cancer Center ,
Memor ial Her mann Hospital Texas, Medical Center , Houston, Texas
Steven E. Rodgers MD, PhD
Fel l ow
Jorge E. Romaguera MD
Pr ofessor
Depar tment of Lymphoma and Myeloma, The Univer sity of Texas M.
Brian M. Slomovitz MD, MS
Cl i ni cal Fel l ow
Depar tment of G ynecologic Oncology, The Univer sity of Texas M. D.
Pamela T. Soliman MD
Cl i ni cal Fel l ow
Carmen C. Solorzano MD
Depar tment of G ener al Sur ger y, Rush Univer sity; Dir ector ,
Depar tment of Endocr ine Sur ger y F ellowship, Rush Univer sity
Medical Center , Chicago, Illinois
Francis R. Spitz MD
Depar tment of Sur ger y, Hospital of Univer sity of Pennsylvania,
Philadelphia, Pennsylvania
Jeffrey J. Sussman MD, FA CS
Depar tment of Sur ger y, Univer sity of Cincinnati, Cincinnati, Ohio
Eva Thomas MD
Depar tment of Br east Medical Oncology, The Univer sity of Texas M.
George P. Tuszynski PhD
Pr ofessor
Depar tment of Neur oscience, Temple Univer sity, Philadelphia,
Pennsylvania
Douglas S. Tyler MD
Pr ofessor of Sur ger y, Chi ef Sur gi cal Oncol ogy, Vi ce Chai r man (VA
Ser vi ces)
Depar tment of Sur ger y, Duke Univer sity Medical Center , Dur ham,
Nor th Car olina
A ra A . Vaporciyan MD
Depar tment of Thor acic & Car diovascular Sur ger y, The Univer sity of
Gauri R. Varadhachary MD
Depar tment of G astr ointestinal Medical Oncology, The Univer sity of
Thomas N. W ang MD, PhD
Associ ate Pr ofessor, Attendi ng Physi ci an
Depar tment of Sur ger y, Medical College of G eor gia, Augusta,
G eor gia
Jeffrey D. W ayne MD
Depar tment of Sur ger y-Sur gical Oncology, Nor thwester n Univer sity
F einber g School of Medicine; Attending Physician, Depar tment of
Sur ger y, Nor thwester n Memor ial Hospital, Chicago, Illinois
Judith K. W olf MD
Christopher G. W ood MD
Depar tments of Ur ology and Cancer Biology, The Univer sity of
Texas, M. D. Ander son Cancer Center , Houston, Texas
Jonathan Scott Zager MD
Fel l ow
Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

M.
Edition
> F ro nt o f Bo o k > De dic a t io n
Dedication
To our w ives (Barbara, A drianne, and Laura) and families, for
their support, enthusiasm, and patience through our many
years of training and continued long hours spent in the care of
patients w ith cancer.

M.
Edition
> F ro nt o f Bo o k > F o re w o rd
Foreword
What ar e the components of contemporar y sur gi cal car e for the
pati ent bur dened by cancer ? The answer to thi s questi on i s to be
found i n the di sci pl i ne of sur gi cal oncol ogy, whi ch i s ar guabl y mor e
of a cogni ti ve than a techni cal sur gi cal speci al ty. Other than several
sur gi cal pr ocedur es that ar e onl y i nfr equentl y per for med outsi de of
cancer center s (such as tr i segmentectomy, hemi pel vec-tomy, and
r egi onal pancr eatectomy), the speci al ty of sur gi cal oncol ogy focuses
on i ntegrati ng sur ger y wi th other modal i ti es of cancer tr eatment
such as radi ati on oncol ogy and systemi c chemotherapy appr oaches.
Thi s i ntegrati on i s achi eved vi a the cr uci bl e of pr ospecti ve cl i ni cal
tr i al s that have emer ged as the hal l mar k of cl i ni cal sci enti fi c
r esear ch i n oncol ogy. To be effecti ve, the sur gi cal oncol ogi st must
under stand the natural bi ol ogy of sol i d tumor s i ncl udi ng thei r
i ncepti on, pr ol i ferati on, and di ssemi nati on. Such an under standi ng
al so i mpl i es a mor e than passi ng awar eness of the under l yi ng basi c
and transl ati onal sci ence that i s cur r entl y pushi ng the fr onti er s of
our under standi ng i n oncol ogy fur ther and fur ther.
In addi ti on to knowl edge about the natural bi ol ogy of tumor s, the
sur gi cal oncol ogi st must be i nti matel y awar e of the di agnosti c
opti ons i n the i ni ti al eval uati on of the tumor and the stagi ng
systems by whi ch a gi ven tumor can be descr i bed, pr ognosi s
ascer tai ned, and therapeuti c al gor i thms accessed. The appl i cabl e
tr eatments and thei r i ndi cati ons, r i sks, and benefi ts ar e cr i ti cal l y
i mpor tant as par t of thi s cogni ti ve ar mamentar i um. Mor eover, i n
thi s era of managed car e and cost contai nment, outcomes and
r esear ch-defi ned sur vei l l ance strategi es ar e al so a par t of the
knowl edge base of the practi ci ng sur gi cal oncol ogi st.
The tar geted audi ence of, The M. D. Ander son Sur gical Oncology
Handbook, now i n i ts four th edi ti on, i ncl udes sur geons-i n-trai ni ng
as wel l as sur geons of al l speci al ti es who ar e i n practi ce. Other
heal thcar e pr ofessi onal s wi l l no doubt fi nd thi s conci se manual to be
of use as a r eady r efer ence as wel l , i n much the same manner as

the fi r st and second edi ti ons of thi s book has been uti l i zed by the
oncol ogy communi ty at l ar ge. The cr edi t for thi s cur r ent handbook
bel ongs to the pr esent and for mer sur gi cal oncol ogy fel l ows at The
Uni ver si ty of Texas M. D. Ander son Cancer Center. These effor ts,
coupl ed wi th your own i nter est, wi l l hel p ensur e that the sol i d
tumor oncol ogy pati ent r ecei ves the best possi bl e mul ti modal i ty
car e avai l abl e. We hope that you fi nd thi s handbook useful i n thi s
cr i ti cal effor t.
Raphael E. Pol l ock M.D., Ph.D.
Head, Di vi si on of Sur ger y, Pr ofessor and Chai r man, Depar tment of
Sur gi cal Oncol ogy, M. D. Ander son Cancer Center, Houston, Texas

M.
Edition
> F ro nt o f Bo o k > P re fa c e
Preface
The M. D. Ander son Sur gical Oncology Handbook was wr i tten i n an
attempt to document the phi l osophi es and practi ces of the
Depar tment of Sur gi cal Oncol ogy at the M. D. Ander son Cancer
Center. The pur pose of the book i s to outl i ne basi c management
appr oaches based on our exper i ence wi th sur gi cal oncol ogy
pr obl ems at M. D. Ander son. The book i s i ntended to ser ve as a
practi cal gui de to the establ i shed sur gi cal oncol ogy pr i nci pl es for
tr eati ng cancer as i t i nvol ves each or gan system i n the body. Thi s
four th edi ti on has i ncl uded new chapter s on basi c sci ence and the
tr eatment of tumor s of unknown pr i mar y or i gi n. In addi ti on,
updated i nfor mati on has been added on new tr eatments and
pr ocedur es i ncl udi ng l ymphati c mappi ng for br east cancer and
mel anoma, hyper ther mi c i sol ated l i mb per fusi on for extr emi ty
mel anoma and sar coma, cr yosur ger y for l i ver tumor s, as wel l as
many other new advances i n tr eatment.
Thi s book i s wr i tten by cur r ent and for mer sur gi cal oncol ogy fel l ows
at M. D. Ander son. Al though the tar get audi ence for the fi r st edi ti on
was the sur gi cal house staff and sur gi cal oncol ogy trai nees, we
found that ther e was a si gni fi cantl y wi der appeal for the book acr oss
mul ti pl e di sci pl i nes and at var i ous l evel s of trai ni ng and exper i ence.
We have, ther efor e, wi dened the scope of the four th edi ti on to
r each thi s br oader gr oup. The author s r epr esent var i ous trai ni ng
pr ograms, and they have spent at l east two year s at the M. D.
Ander son Cancer Center studyi ng onl y sur gi cal oncol ogy. The
di ver si ty of author s al l ows us to pr esent the cur r ent opi ni ons and
practi ces of the M. D. Ander son Depar tment of Sur gi cal Oncol ogy,
al ong wi th other opi ni ons and tr eatment opti ons practi ced i n our
far-rangi ng sur gi cal trai ni ng. Al though ther e i s no seni or wel l known name associ ated wi th the book, the author s r epr esent 160
year s of sur gi cal trai ni ng; we have not, however, become dogmati c
and unyi el di ng i n our medi cal practi ces.
Thi s handbook i s not meant to encompass al l aspects of oncol ogy i n

mi nute detai l . Rather, i t i s an attempt to addr ess commonl y
encounter ed as wel l as contr over si al i ssues i n sur gi cal oncol ogy.
Whi l e other author s pr esent thei r opi ni ons and appr oaches as fi r ml y
establ i shed, we have tr i ed to poi nt out contr over si es and show
al ter nati ve appr oaches to these pr obl ems besi des our own.
We woul d l i ke to thank the sur gi cal staff at the M. D. Ander son
Cancer Center for thei r assi stance wi th the content of thi s book and
for thei r devoted teachi ng i n the hospi tal cl i ni cs, war ds, and
operati ng r ooms. In addi ti on, we woul d par ti cul ar l y l i ke to thank the
pati ents seen and tr eated at M. D. Ander son for thei r war mth and
appr eci ati on of our car e, as wel l as for thei r pati ence and
under standi ng of the l ear ni ng pr ocess.
B. W. F.
D. H. B.
G . M. F.

M.
Edition
> Ta ble o f C o nt e nt s > 1 - No ninva s iv e Bre a s t C a nc e r
1
Noninvasive Breast Cancer
Robert H. I. A ndtbacka
Funda Meric-Bernstam
Emily K. Robinson
Kelly K. Hunt
Noni nvasi ve br east cancer compr i ses two separate enti ti es: ductal
car ci noma i n si tu (DCIS) and l obul ar car ci noma i n si tu (LCIS). DCIS
i s defi ned as a pr ol i ferati on of epi thel i al cel l s confi ned to the
mammar y ducts, wher eas LCIS i s defi ned as a pr ol i ferati on of
epi thel i al cel l s confi ned to the l obul es. Nei ther DCIS nor LCIS has
demonstrabl e evi dence of i nvasi on thr ough the basement
membrane. Because they ar e noni nvasi ve, DCIS and LCIS do not
pose a r i sk of metastasi s.
Ductal Carcinoma in Situ

Epidemiology
Befor e the i ntr oducti on of scr eeni ng mammography, most cases of
DCIS r emai ned undetected unti l they for med a pal pabl e mass.
Wi despr ead use of r outi ne scr eeni ng mammography has r esul ted i n
a 10-fol d i ncr ease i n the r epor ted i nci dence of DCIS si nce the mi d1980s. In the Uni ted States, the i nci dence i s now 10 to 20 per
100,000 woman-year s, and some have esti mated that mor e than
58,000 new cases of DCIS wi l l be di agnosed i n 2006. The r epor ted
pr eval ence of DCIS has i ncr eased as the qual i ty and sensi ti vi ty of
mammography have i mpr oved, and DCIS cur r entl y accounts for 20%
to 44% of al l new scr een-detected br east neopl asms i n Nor th
Amer i ca, wi th 1 case of DCIS detected per 1,300 scr eeni ng
mammograms.
The medi an age r epor ted for pati ents wi th DCIS ranges fr om 47 to
63 year s, si mi l ar to that r epor ted for pati ents wi th i nvasi ve
car ci noma. Some studi es have r epor ted a tr end towar d a l ower
medi an age when DCIS i s detected dur i ng scr eeni ng exami nati ons.
The fr equency of a fami l y hi stor y of br east cancer among fi r stdegr ee r el ati ves of pati ents wi th DCIS (i .e., 10% 35% ) i s the same
as that r epor ted for women wi th i nvasi ve br east mal i gnanci es.
Other r i sk factor s for DCIS ar e the same as those for i nvasi ve
br east cancer and i ncl ude ol der age, pr ol i ferati ve br east di sease,
nul l i par i ty, and ol der age at the ti me of fi r st ful l -ter m pr egnancy.
Pathology
DCIS i s a pr ol i ferati on of mal i gnant cel l s that have not br eached the
ductal basement membrane and ar i se fr om ductal epi thel i um i n the
r egi on of the ter mi nal l obul ar-ductal uni t. DCIS pr obabl y r epr esents
one stage i n the conti nuum of hi stol ogi c pr ogr essi on fr om atypi cal
ductal hyper pl asi a to i nvasi ve car ci noma. DCIS compr i ses a
heter ogeneous gr oup of l esi ons wi th var i abl e hi stol ogi c ar chi tectur e,
mol ecul ar and cel l ul ar character i sti cs, and cl i ni cal behavi or.
Mal i gnant cel l s pr ol i ferate to obl i terate the ductal l umen, and ther e
may be an associ ated br eakdown of the myoepi thel i al cel l l ayer of
the basement membrane sur r oundi ng the
ductal l umen. Al so, DCIS has been l i nked wi th changes i n the
sur r oundi ng str oma r esul ti ng i n fi br obl ast pr ol i ferati on, l ymphocyte
i nfi l trati on, and angi ogenesi s. Al though the pr ocess i s poor l y
under stood, most i nvasi ve ductal car ci nomas ar e bel i eved to ar i se
fr om DCIS.
Classification of Ductal Carcinoma In Situ

DCIS i s general l y cl assi fi ed as one of fi ve subtypescomedo, sol i d,
cr i br i for m, mi cr opapi l l ar y, and papi l l ar ybased on di ffer ences i n the
ar chi tectural patter n of the cancer cel l s and nucl ear featur es.
Cr i br i for m, comedo, and mi cr opapi l l ar y ar e the most common
subtypes, al though two or mor e patter ns coexi st i n up to 50% of
cases.
The i denti fi cati on of factor s i ndi cati ve of aggr essi ve bi ol ogy has l ed
to a fundamental change i n the way noni nvasi ve br east cancer i s
cl assi fi ed. The ol d cl assi fi cati on system, a str i ctl y descr i pti ve
hi stol ogi c nomencl atur e, has been abandoned i n favor of a system
that i ncor porates these pr ognosti c factor s and strati fi es l esi ons
based on thei r l i kel i hood of r ecur r ence. Lagi os et al . (1989)

i denti fi ed hi gh nucl ear grade and comedo necr osi s as factor s
pr edi cti ve of l ocal r ecur r ence. At 8 year s, pati ents whose tumor s
had a hi gh nucl ear grade and comedo necr osi s had a 20% l ocal
r ecur r ence rate after br east conser vati on sur ger y and i r radi ati on,
compar ed wi th 5% for those pati ents whose tumor s di d not have
necr osi s and wer e a l ower nucl ear grade. Subsequentl y, Si l ver stei n
et al . (1995) devel oped the Van Nuys cl assi fi cati on i n whi ch thr ee
r i sk gr oups wer e di sti ngui shed based on the pr esence or absence of
hi gh nucl ear grade and comedo-type necr osi s: (1) nonhi gh-grade
DCIS wi thout comedo-type necr osi s, (2) nonhi gh-grade DCIS wi th
comedo-type necr osi s, and (3) hi gh-grade DCIS wi th or wi thout
comedo-type necr osi s. Si l ver stei n et al . found 31 cases of l ocal
r ecur r ence among 238 pati ents who under went br east-conser vi ng
sur ger y; the l ocal r ecur r ence rate was 3.8% i n gr oup 1, 11.1% i n
gr oup 2, and 26.5% i n gr oup 3. The 8-year actuar i al di sease-fr ee
sur vi val rate was 93% for gr oup 1, 84% for gr oup 2, and 61% for
gr oup 3. Other cl assi fi cati on systems have al so been pr oposed;
however, no si ngl e cl assi fi cati on system has been uni ver sal l y
accepted.
Multifocality
Mul ti focal DCIS i s general l y defi ned as DCIS pr esent i n two or mor e
foci separated by 5 mm i n the same br east quadrant. Most
i nvesti gator s bel i eve that mul ti focal di sease i n fact r epr esents
i ntraductal spr ead fr om a si ngl e focus of DCIS. By car eful ser i al
subsecti oni ng, Hol l and et al . (1990) demonstrated that mul ti focal
l esi ons that appear ed to be separate usi ng tradi ti onal pathol ogi cal
techni ques actual l y or i gi nated fr om the same focus i n 81 of 82
mastectomy speci mens.
Multicentricity
Mul ti centr i c DCIS i s defi ned as DCIS pr esenti ng as a separate focus
outsi de the i ndex quadrant. The r epor ted i nci dence of
mul ti centr i ci ty may depend on the extent of the pathol ogi cal r evi ew
and ther efor e var i es fr om 18% to 60% , but i s mor e l i kel y to be
ar ound 30% to 40% . Because mammar y l obul es ar e not
constrai ned by the ar ti fi ci al l y i mposed quadrant segr egati ons,
cur sor y pathol ogi cal exami nati on may i ncor r ectl y i nter pr et
conti guous i ntraductal spr ead as mul ti centr i ci ty. Appr oxi matel y 96%
of al l l ocal r ecur r ences after tr eatment of DCIS occur i n the same
quadrant as the i ndex l esi on, i mpl i cati ng r esi dual untr eated di sease
rather than mul ti centr i ci ty, and rai si ng questi ons about the
i mpor tance of mul ti centr i ci ty. The i nci dence of detecti on of DCIS i s
hi gher i n autopsy studi es than i n the general popul ati on, suggesti ng
that not al l DCIS l esi ons become cl i ni cal l y si gni fi cant.
Microinvasion
The Amer i can Joi nt Commi ttee on Cancer (AJCC) stagi ng system
(Si ngl etar y et al ., 2002) defi nes mi cr oi nvasi on as i nvasi on of br east
cancer cel l s thr ough the basement membrane at one or mor e foci ,
none of whi ch exceeds a di mensi on of 1 mm. A br east cancer wi th
mi cr oi nvasi on i s cl assi fi ed as a T1mi c tumor, wher eas DCIS i s
cl assi fi ed as T0. Mi cr oi nvasi on upstages the cancer fr om stage 0 to
stage 1 i n the AJCC stagi ng system.
The i nci dence of mi cr oi nvasi on i n DCIS var i es accor di ng to the si ze
and extent of the i ndex l esi on. Lagi os et al . (1989) r epor ted a 2%
i nci dence of mi cr oi nvasi on i n pati ents wi th DCIS measur i ng l ess
than 25 mm i n di ameter, compar ed wi th a 29% i nci dence of
mi cr oi nvasi on i n i ndex l esi ons l ar ger than 26 mm. The i nci dence of
mi cr oi nvasi on i s al so hi gher i n pati ents wi th hi gh-grade or comedotype DCIS tumor s wi th necr osi s and i n pati ents wi th DCIS tumor s
who pr esent wi th a pal pabl e mass or ni ppl e di schar ge. Some
i nvesti gator s have questi oned whether i t i s useful to di sti ngui sh
pur e DCIS fr om DCIS wi th mi cr oi nvasi on. By defi ni ti on, DCIS does
not have the abi l i ty to metastasi ze to axi l l ar y l ymph nodes or
di stant si tes, wher eas DCIS wi th mi cr oi nvasi on does. Axi l l ar y
metastasi s has been r epor ted i n 0% to 20% of pati ents wi th
mi cr oi nvasi ve DCIS. In addi ti on, pati ents wi th mi cr oi nvasi ve DCIS
have been shown to have a wor se pr ognosi s. Mi r z a et al . (2000)
r epor ted the l ong-ter m r esul ts of br east-conser vi ng therapy i n DCIS
and ear l y-stage (T1) br east cancer and noted that the 20-year
di sease-speci fi c sur vi val rates wer e better among pati ents wi th
DCIS than among pati ents wi th DCIS wi th mi cr oi nvasi on or T1
i nvasi ve tumor s. Pati ents wi th mi cr oi nvasi on and those wi th T1
tumor s had si mi l ar sur vi val rates. In a r etr ospecti ve study of 1,248
ser i al l y secti oned DCIS tumor s, de Mascar el et al . (2002) r epor ted a
10.1% i nci dence of axi l l ar y metastases i n cases of DCIS wi th a
cl uster of mi cr oi nvasi ve cel l s. Pati ents wi th DCIS had a better 10year di stant metastasi s-fr ee sur vi val rate than pati ents wi th
mi cr oi nvasi ve DCIS (98% and 91% , r especti vel y). The overal l
sur vi val rate was al so better i n pati ents wi th DCIS (96.5% vs.
88.4% ). The metastasi s-fr ee and overal l sur vi val rates wer e wor se
i n pati ents wi th i nvasi ve ductal car ci noma than i n pati ents wi th

mi cr oi nvasi ve DCIS. These r esul ts suggest that DCIS wi th
mi cr oi nvasi on shoul d be character i zed as a smal l i nvasi ve tumor
wi th a good outcome and that the therapeuti c appr oach for these
pati ents shoul d be si mi l ar to that for pati ents wi th i nvasi ve cancer.
However, fur ther study i s needed to i nvesti gate the bi ol ogy of
mi cr oi nvasi on.
Diagnosis
Clinical Presentation
Befor e the advent of r outi ne mammography, most pati ents wi th
DCIS pr esented wi th a pal pabl e mass, ni ppl e thi ckeni ng or
di schar ge, or Paget di sease of the ni ppl e. Occasi onal l y, DCIS was an
i nci dental fi ndi ng i n an other wi se beni gn bi opsy speci men. The
pal pabl e l esi ons wer e l ar ge, and up to 25% demonstrated associ ated
foci of i nvasi ve di sease. Now that scr eeni ng mammography i s mor e
pr eval ent, most cases of DCIS ar e di agnosed wi th of the ai d of
mammography al one when the tumor i s sti l l cl i ni cal l y occul t.
Pati ents wi th abnor mal i ti es detected by mammography shoul d al so
under go i magi ng of the contral ateral br east because 0.5% to 3.0%
of pati ents have synchr onous occul t abnor mal i ti es or cancer s i n the
contral ateral br east. Mammographi c i mages shoul d be compar ed
wi th pr evi ous i mages, i f avai l abl e, to establ i sh i nter val changes.
Mammographic Features
On a mammogram, DCIS can pr esent as mi cr ocal ci fi cati ons, a softti ssue densi ty, or both. Mi cr ocal ci fi cati ons ar e the most common
mammographi c mani festati on of DCIS (80% 90% ). DCIS accounts
for 80% of al l br east car ci nomas pr esenti ng wi th cal ci fi cati ons. Any
i nter val change fr om a pr evi ous mammogram i s associ ated wi th
mal i gnancy i n 15% to 20% of cases and most often i ndi cates i n si tu
di sease. Hol l and et al . (1990) descr i bed two di ffer ent cl asses of
mi cr ocal ci fi cati ons: (1) l i near branchi ng-type mi cr ocal ci fi cati ons,
whi ch ar e mor e often associ ated wi th hi ghnucl ear-grade, comedotype l esi ons; and (2) fi ne, granul ar cal ci fi cati ons, whi ch ar e
pr i mar i l y associ ated wi th mi cr opapi l l ar y or cr i br i for m l esi ons of
l ower nucl ear grade that do not show necr osi s. Al though the
mammographi c mor phol ogy of mi cr ocal ci fi cati ons suggests the
ar chi tectural type of DCIS, i t i s not al ways r el i abl e. Hol l and et al .
al so demonstrated that the mammographi c fi ndi ngs si gni fi cantl y

under esti mated the pathol ogi cal extent of di sease, par ti cul ar l y i n
cases of mi cr opapi l l ar y DCIS. Lesi ons wer e mor e than 2 cm l ar ger
by hi stol ogi c exami nati on than by mammographi c esti mati on i n 44%
of cases of mi cr opapi l l ar y l esi ons, compar ed wi th onl y 12% of cases
of the pur e comedo subtype. However, when magni fi cati on vi ews
wer e used i n the mammographi c exami nati on, the extent of di sease
was under esti mated i n onl y 14% of cases of mi cr opapi l l ar y tumor s.
Hence, magni fi cati on vi ews i ncr ease the i mage r esol uti on and ar e
better abl e to detect the mi cr ocal ci fi cati on shape, number, and
extent when compar ed wi th mammography al one and shoul d be used
r outi nel y i n the eval uati on of suspi ci ous mammographi c fi ndi ngs.
Other Imaging Modalities

Mammography r emai ns the standar d for radi ographi c eval uati on of
DCIS. The r ol e of other i magi ng modal i ti es, such as ul trasound and
magneti c r esonance i magi ng (MRI), has yet to be establ i shed for
DCIS. Ul trasound i s benefi ci al i n the eval uati on of a pal pabl e l esi on
and the assessment of r egi onal l ymph node basi ns, but i t i s not as
r el i abl e i n r outi ne br east scr eeni ng. Contrast-enhanced MRI i s al so
ver y sensi ti ve i n the detecti on of DCIS and i nvasi ve
cancer, but i t l acks speci fi ci ty. DCIS has a nonspeci fi c appearance
and nonspeci fi c ki neti c enhancement cur ves that can mi mi c
fi br ocysti c changes and other beni gn fi ndi ngs. The cost and
accessi bi l i ty of MRI al so make i t l ess feasi bl e as an effecti ve
scr eeni ng method. However, ther e i s evi dence that pati ents at hi gh
r i sk for br east cancer or those women wi th ver y nodul ar br easts
may benefi t fr om scr eeni ng wi th MRI.
Diagnostic Biopsy
Ster eotacti c cor e-needl e or vacuum-assi sted bi opsy i s the pr efer r ed
method for di agnosi ng DCIS. Cal ci fi cati ons that appear fai ntl y on
mammograms or that ar e deep i n the br east and cl ose to the chest
wal l may be di ffi cul t to tar get wi th ster eotacti c bi opsy. In addi ti on,
use of ster eotacti c bi opsy i n pati ents above the wei ght l i mi t of the
ster eotacti c system (about 135 kg [297 l b]) and i n pati ents wi th
smal l br easts may be i mpossi bl e. Pati ents who cannot r emai n pr one
or who cannot cooperate for the durati on of the pr ocedur e ar e al so
not good candi dates for ster eotacti c bi opsy. Bl eedi ng di sor der s and
the concomi tant use of anti coagul ants ar e r el ati ve
contrai ndi cati ons. Bi opsy speci mens shoul d be radi ographed to
document the sampl i ng of suspi ci ous mi cr ocal ci fi cati ons. Car e

shoul d be taken to mar k the bi opsy si te wi th a metal l i c cl i p i n the
event that al l mi cr ocal ci fi cati ons ar e r emoved wi th the bi opsy
pr ocedur e.
Because ster eotacti c cor e-needl e and vacuum-assi sted bi opsy
speci mens r epr esent onl y a sampl e of an abnor mal i ty obser ved on
mammography, the r esul ts ar e subject to sampl i ng er r or. Invasi ve
car ci noma i s found on exci si onal bi opsy i n 20% of pati ents i n whom
DCIS was di agnosed by a ster eotacti c cor e-needl e bi opsy. If the
cor e-needl e bi opsy r esul ts ar e di scor dant wi th the fi ndi ngs of
i magi ng studi es, an exci si onal bi opsy shoul d be per for med to
confi r m the di agnosi s. After di agnosi s usi ng ster eotacti c cor e-needl e
bi opsy, 30% to 50% of pati ents wi th atypi cal ductal hyper pl asi a and
20% of pati ents wi th radi al scar ar e found to have a coexi stent
car ci noma near the si te of the bi opsy. Ther efor e, when the fi nal
pathol ogi cal studi es fr om cor e-needl e bi opsy pr ocedur es i ndi cate
ei ther of these di agnoses, thi s shoul d be fol l owed by a sur gi cal
exci si onal bi opsy.
Pati ents who ar e not candi dates for ster eotacti c bi opsy or who have
ster eotacti c bi opsy r esul ts that ar e i nconcl usi ve or di scor dant wi th
the mammographi c fi ndi ngs shoul d under go exci si onal bi opsy. Thi s
techni que i s per for med wi th the assi stance of pr eoperati ve needl e
l ocal i z ati on of the mammographi c abnor mal i ty or of the pr evi ousl y
pl aced metal l i c cl i p mar ki ng the bi opsy si te. Speci men radi ography
i s essenti al to confi r m the r emoval of mi cr ocal ci fi cati ons of i nter est.
The exci si onal bi opsy shoul d be per for med wi th the ai m of obtai ni ng
a mar gi n-negati ve r esecti on that can ser ve as a defi ni ti ve sur ger y.
Treatment
The di agnosi s of DCIS i s fol l owed by a mastectomy or br eastconser vi ng sur ger y (al so r efer r ed to as segmental mastectomy,
l umpectomy, or wi de l ocal exci si on) per for med wi th needl e
l ocal i z ati on. Most pati ents who under go br east-conser vi ng sur ger y
r ecei ve postoperati ve radi ati on therapy to i mpr ove l ocal contr ol .
Postoperati ve endocr i ne therapy wi th tamoxi fen shoul d al so be
consi der ed for those pati ents whose tumor s ar e estr ogen r eceptor
posi ti ve.
Mastectomy Versus Breast-conserving

Therapy
Tradi ti onal l y, DCIS has been tr eated wi th mastectomy. However,

because br east-conser vi ng techni ques for i nvasi ve di sease have
been shown to be effecti ve l ocal therapy, the practi ce of tr eati ng a
noni nvasi ve condi ti on wi th a sur gi cal pr ocedur e mor e radi cal than
that used to tr eat i ts i nvasi ve counter par t has been questi oned. The
rati onal e for per for mi ng total mastectomy i n pati ents wi th DCIS i s
based on the hi gh i nci dence of mul ti focal i ty and mul ti centr i ci ty, as
wel l as on the r i sk of occul t i nvasi on associ ated wi th the di sease.
Thus, mastectomy r emai ns the standar d wi th whi ch other pr oposed
therapeuti c modal i ti es shoul d be compar ed. However, no pr ospecti ve
tr i al s have compar ed outcomes after mastectomy wi th those after
br east-conser vi ng sur ger y i n pati ents wi th DCIS. A r etr ospecti ve
r evi ew by Bal ch et al . (1993) documented a l ocal r el apse rate of
3.1% and a mor tal i ty rate of 2.3% after mastectomy for DCIS. The
cancer-r el ated mor tal i ty rate fol l owi ng mastectomy for DCIS was
1.7% i n a ser i es r epor ted by Fowbl e (1989) and ranged fr om 0% to
8% i n a r evi ew by Vezer i di s and Bl and (1994).
In one of the l ar gest studi es compar i ng br east-conser vi ng therapy
wi th mastectomy, Si l ver stei n et al . (1992) exami ned 227 cases of
DCIS wi thout mi cr oi nvasi on. In thi s nonrandomi zed study, pati ents
wi th tumor s smal l er than 4 cm wi th mi cr oscopi cal l y cl ear mar gi ns
under went br east-conser vi ng sur ger y and radi ati on therapy,
wher eas pati ents wi th tumor s l ar ger than 4 cm or wi th posi ti ve
mar gi ns under went mastectomy. The rate of di sease-fr ee sur vi val at
7 year s was 98% i n the mastectomy gr oup compar ed wi th 84% i n
the br east-conser vi ng sur ger y gr oup (p = 0.038), wi th no di ffer ence
i n overal l sur vi val rates. In a meta-anal ysi s, Boyages et al . (1999)
r epor ted a r ecur r ence rate of 22.5% , 8.9% , and 1.4% fol l owi ng
br east-conser vi ng sur ger y al one, br east-conser vi ng sur ger y wi th
radi ati on therapy, and mastectomy, r especti vel y. In pati ents who
under went br east-conser vi ng sur ger y al one, appr oxi matel y 50% of
the r ecur r ences wer e i nvasi ve cancer s. Al though r ecur r ence rates
ar e hi gher i n pati ents who under go br east-conser vi ng sur ger y than
i n pati ents who under go mastectomy, no sur vi val advantage has
been shown for the l atter gr oup.
Technique of Breast-conserving Surgery

The goal of br east-conser vi ng sur ger y i s to r emove al l suspi ci ous
cal ci fi cati ons and obtai n negati ve sur gi cal mar gi ns. Because DCIS i s
usual l y nonpal pabl e, br east-conser vi ng sur ger y i s most often
per for med wi th mammographi c needl e l ocal i z ati on. Intraoperati ve
or i entati on of the speci men wi th two or mor e mar ki ng sutur es i s
cr i ti cal for mar gi n anal ysi s. In addi ti on, speci men radi ography i s
essenti al to confi r m the r emoval of al l mi cr ocal ci fi cati ons. In
pati ents wi th extensi ve cal ci fi cati ons, bracketi ng of the
cal ci fi cati ons wi th two or mor e wi r es may assi st i n the exci si on of
al l suspi ci ous cal ci fi cati ons.
After whol e-speci men radi ography, the speci men shoul d be i nked
and then ser i al l y secti oned for pathol ogi cal exami nati on to eval uate
the mar gi n status and extent of di sease. Chagpar et al . (2003)
demonstrated that i ntraoperati ve mar gi n assessment wi th the use of
secti oned-speci men radi ography enabl ed r e-exci si ons to be
per for med at the same sur ger y i f the mi cr ocal ci fi cati ons extended to
the cut edge of the speci men, mi ni mi z i ng the need for second
pr ocedur es for mar gi n contr ol . After the i ntraoperati ve mar gi ns ar e
deemed adequate, the boundar y of the r esecti on cavi ty i s mar ked
wi th radi opaque cl i ps to ai d i n the pl anni ng of postoperati ve
radi ati on therapy and i n mammographi c fol l ow-up.
The i ntraoperati ve goal of br east-conser vi ng sur ger y i s to obtai n
tumor-fr ee mar gi ns of 1 cm i f possi bl e. Thi s goal i s based on the
data pr ovi ded by Hol l and et al . (1990), whi ch demonstrated that up
to 44% of l esi ons extended mor e than 2 cm fur ther on hi stol ogi c
exami nati on than that esti mated by mammography. However, i n
most women, a 1-cm mar gi n i s not cosmeti cal l y feasi bl e. Ther efor e,
what consti tutes an adequate mar gi n for DCIS r emai ns
contr over si al . Most sur geons advocate r e-exci si on for posi ti ve
sur gi cal mar gi ns, and many sur geons advocate r e-exci si on for cl ose
mar gi ns, usi ng var yi ng thr eshol ds of l ess than 1, 2, or 5 mm.
Neuschatz et al . (2002) r epor ted that r esi dual tumor was found on
r e-exci si on i n 41% of pati ents wi th DCIS wi th 0- to 1-mm mar gi ns,
31% of pati ents wi th 1- to 2-mm mar gi ns, and 0% of pati ents wi th
gr eater than 2-mm mar gi ns. Lesi on si ze was another pr edi ctor of
r esi dual DCIS.
Radiation Therapy
Most pati ents wi th DCIS who under go br east-conser vi ng sur ger y
r ecei ve postoperati ve radi ati on therapy. Thr ee pr ospecti ve
randomi zed studi es have eval uated the r ol e of radi ati on therapy
fol l owi ng br east-conser vi ng sur ger y for DCIS. In the Nati onal
Sur gi cal Adjuvant Br east and Bowel Pr oject (NSABP) B-17 tr i al , 818
women wi th l ocal i zed DCIS wer e randomi zed to br east-conser vi ng
sur ger y or br east-conser vi ng sur ger y pl us radi ati on therapy after
mar gi n-negati ve r esecti ons. At a fol l ow-up ti me of 12 year s,

radi ati on therapy was associ ated wi th a r educti on i n the cumul ati ve
i nci dence of noni nvasi ve i psi l ateral br east tumor s fr om 14.6% to
8.0% and wi th a r educti on i n the i nci dence of i nvasi ve i psi l ateral
br east tumor s fr om 16.8% to 7.7% . Ther e was no di ffer ence i n the
12-year overal l sur vi val rate i n the two gr oups, wi th 86% of women
al i ve i n the br east-conser vi ng sur ger y gr oup and 87% al i ve i n the
br east-conser vi ng sur ger y pl us radi ati on therapy gr oup. However,
58% of al l deaths occur r ed befor e any br east cancer event, and the
death of 12 pati ents (3.0% ) i n the br east-conser vi ng sur ger y gr oup
and 15 pati ents (3.6% ) i n the br east-conser vi ng sur ger y pl us
radi ati on therapy gr oup was attr i buted to i nvasi ve br east cancer.
The overal l benefi t of radi ati on therapy for pati ents wi th DCIS was
al so obser ved i n the Eur opean Or gani z ati on for Resear ch and
Tr eatment of Cancer 10853 tr i al (Jul i en et al ., 2000). In thi s tr i al ,
1,010 women wi th DCIS wer e randomi zed to br east-conser vi ng
sur ger y or br east-conser vi ng sur ger y pl us radi ati on therapy. At a
medi an fol l ow-up ti me of 4.25 year s, radi ati on therapy was
associ ated wi th a r educti on i n the i nci dence of noni nvasi ve
i psi l ateral br east tumor s fr om 8.8% to 5.8% and wi th a r educti on i n
the i nci dence of i nvasi ve i psi l ateral br east tumor s fr om 8.0% to
4.8% . The l ower r ecur r ence rates i n thi s tr i al when compar ed wi th
those i n the NSABP B-17 wer e attr i buted to the shor ter fol l ow-up
ti me.
A thi r d tr i al , whi ch was conducted by the Uni ted Ki ngdom
Coor di nati ng Commi ttee on Cancer Resear ch, al so confi r med the
benefi ts of radi ati on therapy for l ocal contr ol (Houghton et al .,
2003). After a medi an fol l ow-up ti me of 4.4 year s, ther e was a
r educti on i n the i nci dence of noni nvasi ve i psi l ateral br east tumor s
fr om 7% to 3% and a r educti on i n the i nci dence of i nvasi ve
i psi l ateral tumor s fr om 6% to 3% . The concl usi on fr om these thr ee
pr ospecti ve randomi zed tr i al s i s that the addi ti on of radi ati on
therapy fol l owi ng br east-conser vi ng therapy for DCIS r esul ts i n an
appr oxi matel y 50% r el ati ve r educti on i n br east cancer r ecur r ence.
Br east-conser vi ng sur ger y al one (i .e., wi thout radi ati on therapy)
has been suggested to be suffi ci ent i n a sel ect subgr oup of pati ents
wi th DCIS. Ini ti al data that suppor ted the use of br east-conser vi ng
sur ger y al one i n the tr eatment of DCIS came fr om a study by Lagi os
et al . (1989) i n whi ch 79 pati ents wi th mammographi cal l y detected
DCIS under went mar gi n-negati ve exci si on al one. After a fol l ow-up
ti me of 124 months, the l ocal r ecur r ence rate was 16% overal l
33% for the subgr oup of pati ents wi th hi gh-grade l esi ons and
comedo necr osi s ver sus onl y 2% for the pati ents wi th l ow- or
i nter medi ate-grade l esi ons.
Subsequentl y, Si l ver stei n et al . (1996) devel oped the Van Nuys
Pr ognosti c Index (VNPI) by combi ni ng thr ee stati sti cal l y si gni fi cant
pr edi ctor s of l ocal r ecur r ence: tumor si ze, mar gi n wi dth, and
pathol ogi cal cl assi fi cati on. Thi s i ndex was r ecentl y modi fi ed to
i ncl ude pati ent age as a stati sti cal l y si gni fi cant pr edi ctor of l ocal
r ecur r ence and i s now r efer r ed to as the Uni ver si ty of Souther n
Cal i for ni a (USC)/VNPI (Si l ver stei n, 2003). Numer i cal val ues rangi ng
fr om 1 (best pr ognosi s) to 3 (wor st pr ognosi s) ar e assi gned for each
of the four pr edi ctor s. A si ze scor e of 1, 2, and 3 i s gi ven to smal l
tumor s (15 mm), i nter medi ate tumor s (1640 mm), and l ar ge
tumor s (41 mm), r especti vel y. Mar gi n wi dth i s assi gned a scor e of
1 i f 10 mm or gr eater, 2 i f 1 to 9 mm, and 3 i f l ess than 1 mm. The
pathol ogi cal cl assi fi cati on i s 1 for nonhi gh-grade DCIS wi thout
necr osi s, 2 for nonhi gh-grade DCIS wi th necr osi s, and 3 for hi ghgrade DCIS wi th or wi thout necr osi s. Pati ent age i s assi gned a scor e
of 1 for gr eater than 60 year s, 2 for 40 to 60 year s, and 3 for l ess
than 40 year s. The sum of these r esul ts i s the USC/VNPI scor e, wi th
4 bei ng the l owest possi bl e scor e and 12 the hi ghest possi bl e scor e.
The USC/VNPI scor es of 706 pati ents wi th DCIS tr eated wi th br eastconser vi ng therapy wi th or wi thout radi ati on therapy wer e
r etr ospecti vel y deter mi ned, and outcomes wer e compar ed by usi ng
l ocal r ecur r ence as the endpoi nt. Among pati ents wi th a USC/VNPI
scor e of 4, 5, or 6, the addi ti on of radi ati on therapy di d not appear
to confer an advantage over exci si on al one for l ocal r ecur r ence-fr ee
sur vi val . In contrast, for pati ents wi th a USC/VNPI scor e of 7, 8, or
9, the absol ute 12-year l ocal r ecur r ence-fr ee sur vi val rate was 12%
hi gher among those who under went radi ati on therapy and
exci si on than among those who under went exci si on al one (73% vs.
61% ). Al though pati ents wi th a USC/VNPI scor e of 10, 11, or 12
showed the gr eatest benefi t wi th the addi ti on of radi ati on therapy,
l ocal r ecur r ence rates sti l l exceeded 40% i n 8 year s r egar dl ess of
i r radi ati on. Based on the USC/VNPI scor e, Si l ver stei n (2003)
pr oposed the fol l owi ng tr eatment schema for DCIS: wi de l ocal
exci si on al one for pati ents wi th a USC/VNPI scor e of 4 to 6, exci si on
pl us radi ati on therapy for pati ents wi th a USC/VNPI scor e of 7 to 9,
and mastectomy for pati ents wi th a USC/VNPI scor e of 10 to 12. The
USC/VNPI scor e may be a useful adjunct i n therapeuti c deci si on
maki ng; however, i ts val i di ty has yet to be tested pr ospecti vel y.
As i ndi cated by the USC/VNPI scor e, mar gi n wi dth i s an i ndependent

pr ognosti c factor for r ecur r ence. Si l ver stei n et al . (1999) eval uated
the r ol e of postoperati ve radi ati on therapy for pati ents wi th mar gi nnegati ve r esecti ons i n a r etr ospecti ve anal ysi s of 469 pati ents. Thi s
study compar ed pati ents wi th DCIS tr eated wi th br east-conser vi ng
sur ger y wi th and wi thout radi ati on therapy. They found that
postoperati ve radi ati on therapy di d not l ower the l ocal r ecur r ence
rate among pati ents wi th mar gi ns that wer e at l east 10 mm. In
contrast, even on r eanal ysi s of the NSABP B-17 data, al l pati ent
cohor ts benefi ted fr om radi ati on therapy, r egar dl ess of the cl i ni cal
or mammographi c tumor character i sti cs. F ur ther mor e, Wong et al .
(2003) r epor ted that a pr ospecti ve si ngl e-ar m tr i al of no radi ati on
therapy i n pati ents wi th grade 1 to 2 DCIS that was no mor e than
2.5 cm and exci sed wi th 1 cm or gr eater mar gi ns conducted at the
Dana-Far ber /Har var d Cancer Center was ter mi nated after a medi an
fol l ow-up of 3.3 year s because of the number of l ocal r ecur r ences
obser ved, 2.5% per pati ent-year cor r espondi ng to a 5-year rate of
12.5% .
Two pr ospecti ve studi es ar e cur r entl y i nvesti gati ng the r ol e of
obser vati on, tamoxi fen, and radi ati on therapy after br eastconser vi ng therapy i n good-r i sk pati ents. In the Easter n
Cooperati ve Oncol ogy G r oup E-5194 tr i al , pati ents wi th DCIS no
mor e than 2.5 cm and l ow or i nter medi ate grade, or DCIS no mor e
than 1 cm and hi gh grade and mar gi ns of at l east 3 mm, under go
br east-conser vi ng sur ger y al one. Tamoxi fen use i s al l owed for 5
year s postoperati vel y. In the Radi ati on Therapy Oncol ogy G r oup
9804 tr i al , pati ents wi th DCIS no mor e than 2.5 cm, l ow or
i nter medi ate grade, and mar gi ns of at l east 3 mm ar e randoml y
assi gned to postoperati ve radi ati on therapy or obser vati on wi th the
opti on of tamoxi fen use i n each gr oup. In both of these tr i al s, the
pr i mar y outcome wi l l be l ocal r ecur r ence. These tr i al s wi l l pr ovi de
val uabl e i nfor mati on about obser vati on al one i n pati ents who
under go br east-conser vi ng sur ger y for good-r i sk DCIS.
Some have esti mated that appr oxi matel y 20% of al l women
under goi ng br east-conser vi ng sur ger y who woul d benefi t fr om
radi ati on therapy do not r ecei ve i t as par t of thei r tr eatment. The
rates of radi ati on therapy use have been shown to var y, dependi ng
on the r egi on of the countr y that the pati ent l i ves i n and the age of
the pati ent. Al so, many pati ents choose mastectomy over br eastconser vi ng sur ger y for DCIS because they ar e not abl e to compl ete
6 weeks of dai l y radi ati on therapy because of soci al consi derati ons.
Other pati ents who ar e candi dates for
br east-conser vi ng sur ger y choose to under go a mastectomy because

of concer ns about posti r radi ati on compl i cati ons. In pati ents not
r ecei vi ng radi ati on therapy, l ocal r ecur r ences i n the br east tend to
occur i n the i mmedi ate vi ci ni ty of the br east-conser vi ng cavi ty.
Hence, the i mpact of whol e br east i r radi ati on i n r educi ng l ocal
r ecur r ence may be l i mi ted to the i mmedi ate sur r oundi ng ar ea of
i ni ti al i nvol vement. Based on thi s, some have suggested that
equi val ent l ocal contr ol can be achi eved by radi ati ng onl y the ti ssue
sur r oundi ng the r esecti on cavi ty. Accel erated par ti al br east
i r radi ati on i s a techni que wher e hi gh-dose radi ati on i s del i ver ed
onl y to the ar ea at hi ghest r i sk for r ecur r ence. The tr eatment i s
compl eted over 4 to 5 days, wher eas conventi onal whol e br east
exter nal beam radi ati on therapy r equi r es 5 to 6 weeks. Several
methods of accel erated par ti al br east i r radi ati on have been
descr i bed, i ncl udi ng brachytherapy vi a mul ti pl e catheter s pl aced i n
the br east par enchyma, l ocal i zed confor mal exter nal beam radi ati on
therapy, brachytherapy vi a bead or seed i mpl ants, si ngl e-dose
i ntraoperati ve radi ati on therapy, and brachytherapy vi a a bal l oon
catheter i nser ted i nto the cavi ty after br east-conser vi ng sur ger y.
The NSABP r ecentl y i ni ti ated the B-39 tr i al , i n whi ch pati ents wi th
no mor e than 3-cm i nvasi ve stage I or II br east cancer or DCIS wi l l
be randomi zed to adjuvant whol e br east exter nal beam radi ati on
therapy or accel erated par ti al br east i r radi ati on after under goi ng
mar gi n-negati ve br east-conser vi ng sur ger y. Pati ents wi l l r ecei ve
chemotherapy and endocr i ne therapy when appr opr i ate. The pr i mar y
endpoi nt wi l l be l ocal tumor contr ol , and the secondar y endpoi nts
ar e di sease-fr ee and overal l sur vi val , cosmeti c r esul ts, and
tr eatment toxi ci ty. Thi s tr i al wi l l pr ovi de val uabl e i nfor mati on about
the potenti al r ol e for accel erated par ti al br east i r radi ati on.
Endocrine Therapy
Two pr ospecti ve randomi zed tr i al s have eval uated the effect of
tamoxi fen on outcome i n pati ents tr eated wi th br east-conser vi ng
sur ger y for DCIS. In the NSABP B-24 tr i al , 1,804 women wi th DCIS
wer e randoml y assi gned to br east-conser vi ng sur ger y and radi ati on
therapy fol l owed by ei ther tamoxi fen at 20 mg per day or a pl acebo
for 5 year s. Si xteen per cent of the women i n thi s study had posi ti ve
r esecti on mar gi ns. Women who r ecei ved tamoxi fen had fewer br east
cancer events at 7 year s' fol l ow-up than di d the pl acebo gr oup
(10.0% vs. 16.9% ). Among those who r ecei ved tamoxi fen, the rate
of i psi l ateral i nvasi ve br east cancer was 2.6% at 7 year s compar ed
wi th 5.3% i n the contr ol gr oup. Tamoxi fen al so decr eased the 7year cumul ati ve i nci dence of contral ateral br east neopl asms
(i nvasi ve and noni nvasi ve) to 2.3% compar ed wi th 4.9% i n the
contr ol gr oup. The benefi t of tamoxi fen therapy al so extended to
pati ents wi th posi ti ve mar gi ns or mar gi ns of unknown status. Ther e
was no di ffer ence i n the 7-year overal l sur vi val rate, whi ch was
95% i n both the tamoxi fen and the pl acebo gr oups. Most deaths
occur r ed befor e r ecur r ence devel oped and wer e not necessar i l y
r el ated to br east cancer. A subanal ysi s based on estr ogen r eceptor
status i ndi cated that women wi th estr ogen r eceptor-posi ti ve DCIS
who r ecei ved tamoxi fen had a 59% r educti on i n thei r r el ati ve r i sk
of br east cancer events when compar ed wi th those who r ecei ved the
pl acebo. Among pati ents wi th
estr ogen r eceptor-negati ve DCIS, ther e was no added benefi t fr om
tamoxi fen.
In a second pr ospecti ve randomi zed tr i al (Uni ted Ki ngdom
Coor di nati ng Commi ttee on Cancer Resear ch), pati ents under went
br east-conser vi ng sur ger y and wer e randomi zed to no adjuvant
tr eatment, adjuvant radi ati on therapy or tamoxi fen, or adjuvant
radi ati on therapy pl us tamoxi fen. Pati ents wi th posi ti ve mar gi ns
wer e excl uded fr om thi s tr i al , and onl y 10% of the women wer e
younger than 50 year s ol d, compar ed wi th 33% i n the NSABP B-24
tr i al . After a medi an fol l ow-up ti me of 4.4 year s, Houghton et al .
(2003) r epor ted that radi ati on therapy had the gr eatest i mpact on
r educi ng i psi l ateral br east cancer events, wher eas tamoxi fen added
to radi ati on therapy di d not r esul t i n a si gni fi cant addi ti onal
benefi t. The r el ati vel y shor t fol l ow-up ti me and compl ex desi gn of
thi s tr i al makes i nter pr etati on of the r esul ts i n di r ect compar i son to
the NSABP B-24 tr i al di ffi cul t.
The deci si on of whether to use adjuvant tamoxi fen for pati ents wi th
DCIS shoul d be made on an i ndi vi dual basi s. The use of tamoxi fen
has been associ ated wi th vasomotor symptoms, deep vei n
thr ombosi s, pul monar y embol us, and i ncr eased cataract for mati on.
The r i sk of endometr i al cancer among pati ents who r ecei ve the dr ug
i s two to seven ti mes the nor m. Tamoxi fen may be associ ated wi th
i ncr eased rates of str oke and beni gn ovar i an cysts. Ther efor e, the
effects of tamoxi fen to r educe i psi l ateral br east tumor s and to
pr event contral ateral br east di sease shoul d be wei ghed agai nst the
r i sk of tamoxi fen use i n each pati ent. In addi ti on, tamoxi fen shoul d
be r eser ved for pati ents wi th estr ogen r eceptor-posi ti ve tumor s.
Ar omatase i nhi bi tor s have been shown to be benefi ci al i n the
adjuvant tr eatment of i nvasi ve br east cancer i n postmenopausal

women. These agents have fewer car di ovascul ar si de effects than
tamoxi fen and may be benefi ci al i n the adjuvant tr eatment of
pati ents wi th DCIS fol l owi ng br east-conser vi ng sur ger y. Two ongoi ng
randomi zed pr ospecti ve cl i ni cal tr i al sNSABP B-35 and the
Inter nati onal Br east Cancer Inter venti on Study (IBIS-II)ar e
compar i ng tamoxi fen wi th anastr ozol e fol l owi ng br east-conser vi ng
sur ger y i n pati ents wi th a di agnosi s of DCIS. Resul ts fr om these
tr i al s shoul d deter mi ne the r ol e of ar omatase i nhi bi tor s i n the
adjuvant tr eatment of DCIS.
Axillary Node Staging

Because DCIS i s a noni nvasi ve di sease, l ymph node i nvol vement i s
not expected. Thus, the r ol e for axi l l ar y l ymph node di ssecti on i s
l i mi ted, and node di ssecti on shoul d not be per for med on a r outi ne
basi s. In cases wher e pati ents have l ar ge tumor s (>4 cm) or
extensi ve mi cr ocal ci fi cati ons, a focus of i nvasi on can be mi ssed
because of l i mi ted pathol ogi cal sampl i ng, and such pati ents ar e at
r i sk for l ymph node metastasi s. Hence, pati ents who under go
mastectomy for l ar ge, hi gh-grade DCIS shoul d be consi der ed for
i ntraoperati ve l ymphati c mappi ng and senti nel l ymph node
di ssecti on because i t i s not possi bl e to per for m l ymphati c mappi ng
after a mastectomy i f i nvasi ve cancer i s found i n the mastectomy
speci men. Pati ents wi th l ar ge, hi gh-grade, or pal pabl e DCIS who ar e
under goi ng br east-conser vi ng sur ger y ar e al so potenti al candi dates
for i ntraoperati ve l ymphati c
mappi ng and senti nel l ymph node di ssecti on (di scussed i n detai l i n
Chapter 2). Di agnosi s of DCIS wi th the use of ster eotacti c cor eneedl e bi opsy i s associ ated wi th a 20% rate of concomi tant i nvasi ve
cancer on fi nal pathol ogi cal exami nati on, fur ther emphasi z i ng the
i mpor tance of senti nel l ymph node di ssecti on at the ti me of
mastectomy for l ar ge, hi gh-grade l esi ons. In a study by Cox et al .
(1998), the combi nati on of hematoxyl i n-eosi n stai ni ng and
i mmunohi stochemi str y r eveal ed that 6% of pati ents wi th newl y
di agnosed DCIS had metastati c di sease i n the senti nel nodes.
Kl auber-DeMor e et al . (2000) found that senti nel l ymph nodes wer e
posi ti ve for cancer among 12% of pati ents wi th DCIS consi der ed to
be at hi gh r i sk for i nvasi on and among 10% of pati ents who had
DCIS wi th mi cr oi nvasi on. Thi s r i sk must be wei ghed agai nst the r i sk
of l ymphedema associ ated wi th senti nel node di ssecti on i n each
pati ent.
Predictors of Local Relapse

Ther e ar e several featur es of DCIS that ar e associ ated wi th a l ess
favorabl e cl i ni cal cour se. Tradi ti onal pathol ogi cal var i abl es, such as
l ar ge tumor si ze (>3 cm), hi gh nucl ear grade, comedo-type
necr osi s, and i nvol ved mar gi ns of exci si on, ar e associ ated wi th a
gr eater r i sk of l ocal r ecur r ence, as pr evi ousl y di scussed. Invol ved
mar gi ns of r esecti on consti tute the most i mpor tant i ndependent
pr ognosti c var i abl e for pr edi cti ng l ocal r el apse. As descr i bed
pr evi ousl y, the USC/VNPI combi nes four si gni fi cant pr edi ctor s of
l ocal r ecur r ence: tumor si ze, mar gi n wi dth, pathol ogi cal
cl assi fi cati on, and pati ent age. In addi ti on to a young pati ent age
(<50 year s of age), a fami l y hi stor y of br east cancer i s associ ated
wi th an i ncr eased r i sk of l ocal r ecur r ence; however, these factor s
ar e not consi der ed contrai ndi cati ons for br east-conser vi ng therapy.
Mol ecul ar mar ker s, such as over expr essi on of HER-2/neu, nm23,
heat shock pr otei n, and metal l othi onei n; l ow expr essi on of p21
Waf1 and Bcl 2; and DNA aneupl oi dy have been associ ated wi th hi ghgrade comedo l esi ons, but thei r i mpor tance as i ndependent
pr ognosti c var i abl es i n DCIS has not been cl ar i fi ed.
Treatment and Outcome of Local Recurrence

The overal l sur vi val rate i n pati ents wi th DCIS i s excel l ent. In the
NSABP B-17 tr i al , onl y 27 deaths (3.3% ) attr i butabl e to br east
cancer had occur r ed after a medi an fol l ow-up ti me of 12 year s. In
the NSABP B-24 tr i al , 0.8% of the pati ents di ed as a consequence of
thei r br east cancer after 7 year s of fol l ow-up. In both tr i al s, and i n
other studi es, appr oxi matel y 50% of al l l ocal r ecur r ences wer e
i nvasi ve cancer s. The management of l ocal r ecur r ence depends on
the therapy the pati ent r ecei ved for the pr i mar y cancer. In cases of
l ocal r ecur r ence i n pati ents who under went br east-conser vi ng
sur ger y wi thout radi ati on therapy, r e-exci si on wi th negati ve
mar gi ns and postoperati ve radi ati on therapy consti tute tr eatment
opti ons. For pati ents who have r ecur r ent br east cancer after
r ecei vi ng br east-conser vi ng sur ger y and radi ati on therapy,
mastectomy i s usual l y the pr efer r ed tr eatment. If the r ecur r ent
tumor i s i nvasi ve, stagi ng of the axi l l ar y nodes i s per for med wi th
l ymphati c mappi ng and senti nel l ymph node di ssecti on or wi th
axi l l ar y l ymph node di ssecti on.
The pr ognosi s after tr eatment of l ocal r ecur r ence depends on
whether the r ecur r ence i s i nvasi ve or noni nvasi ve. Si l ver stei n et al .
(1998) found that among pati ents wi th i nvasi ve r ecur r ent di sease,
the 8-year di sease-speci fi c mor tal i ty rate was 14.4% , and the
di stant di sease pr obabi l i ty was 27.1% . In a fol l ow-up study, Romer o
et al . (2004) r epor ted a 10-year di sease-speci fi c mor tal i ty rate of
15% i n pati ents wi th i nvasi ve r ecur r ent di sease. Al though most
pati ents wi th r ecur r ent di sease after DCIS do sur vi ve, an i nvasi ve
r ecur r ence i s a ser i ous event. Pati ents wi th DCIS shoul d under go
l ong-ter m fol l ow-up for both r ecur r ent di sease and devel opment of
new i psi l ateral or contral ateral pr i mar y tumor s.
Surveillance
Fol l owi ng br east-conser vi ng sur ger y, a mammogram shoul d be
obtai ned to detect r esi dual mi cr ocal ci fi cati ons. In addi ti on, a
mammogram shoul d be obtai ned 4 to 6 months after the compl eti on
of radi ati on therapy to establ i sh a new basel i ne. Fol l ow-up of
pati ents after br east-conser vi ng sur ger y wi th or wi thout radi ati on
therapy shoul d i ncl ude annual or bi annual physi cal exami nati on and
annual mammography for the fi r st 5 year s, wi th an annual physi cal
exami nati on and mammogram ther eafter. Both pati ents who under go
br east-conser vi ng therapy and those who under go mastectomy
shoul d be moni tor ed cl osel y for new pr i mar y cancer s i n the
contral ateral br east. The r i sk of devel opment of a new pr i mar y
cancer i n the contral ateral br east after tr eatment of DCIS i s two to
fi ve ti mes gr eater than the r i sk of devel opment of a fi r st pr i mar y
br east cancer and i s appr oxi matel y the same as the r i sk of
devel opment of a new contral ateral pr i mar y cancer after i nvasi ve
cancer.
Current Management of Ductal Carcinoma In

Situ at The University of Texas M. D.
Anderson Cancer Center
An al gor i thm for the cur r ent tr eatment of DCIS at M. D. Ander son
Cancer Center i s outl i ned i n F i gur e 1.1. Pati ents di agnosed wi th a
mammographi c abnor mal i ty under go contral ateral mammography,
and the mammograms ar e compar ed wi th pr evi ous i mages, i f
avai l abl e. In cases i n whi ch DCIS i s suspected, magni fi cati on vi ews
ar e r outi nel y used to del i neate the abnor mal i ty fur ther. Ul trasound
i s al so fr equentl y used to assess tumor si ze, mul ti centr i ci ty, and
nodal status. Di agnosti c bi opsy i s per for med by usi ng a vacuumassi sted ster eotacti c cor e-needl e bi opsy techni que. When DCIS i s
di agnosed, the pathol ogi cal eval uati on detai l s the tumor type and
grade, as wel l as any evi dence of mi cr oi nvasi on. The status of both
the estr ogen and the pr ogester one r eceptor s i s deter mi ned and
r epor ted.
The choi ce of sur gi cal therapy i s based on several factor s, i ncl udi ng
tumor si ze and grade, mar gi n wi dth, mammographi c appearance,
and pati ent pr efer ence. The benefi ts and r i sks of br east-conser vi ng
sur ger y and mastectomy shoul d be di scussed i n detai l wi th each
pati ent. Most pati ents wi th DCIS ar e candi dates for br eastconser vi ng therapy, and the choi ce of thi s l ocal tr eatment does not
i nfl uence thei r overal l sur vi val . Mastectomy i s i ndi cated i n pati ents
wi th di ffuse, mal i gnant-appear i ng cal ci fi cati ons i n the br east and
per si stent posi ti ve mar gi ns after attempts at sur gi cal exci si on.
Al though tumor si ze i s not an absol ute i ndi cati on for
mastectomy, mastectomy i s often pr efer r ed for pati ents wi th l ar ge

(>4 cm i n di ameter ), hi gh-grade DCIS. Ther e ar e few data avai l abl e
on the effi cacy of br east-conser vi ng sur ger y for DCIS wi th i ndex
l esi ons gr eater than 4 cm i n di ameter. Mastectomy may al so be a
better choi ce when a pati ent's anxi ety over the possi bi l i ty of
r ecur r ence outwei ghs the i mpact a mastectomy woul d have on her
qual i ty of l i fe. Immedi ate br east r econstr ucti on shoul d be
consi der ed for al l pati ents who r equi r e or el ect mastectomy.
Intraoperati ve mar gi n assessment wi th secti oned-speci men
radi ography i s used for most pati ents under goi ng br east-conser vi ng
sur ger y and for pati ents wi th extensi ve cal ci fi cati ons under goi ng
ski n-spar i ng mastectomy. Re-exci si on i s usual l y r ecommended for
pati ents who have mar gi ns l ess than 2 mm on fi nal pathol ogi cal
exami nati on after br east-conser vi ng sur ger y.
F i gur e 1.1. Management of l obul ar car ci noma i n si tu (LCIS) and

ductal car ci noma i n si tu (DCIS) at M. D. Ander son. 1 Exci si onal
bi opsy i s per for med for pati ents wi th LCIS detected by cor eneedl e bi opsy anal ysi s. Exci si on i s per for med wi th the i ntent of
achi evi ng negati ve mar gi ns i n pati ents wi th pl eomor phi c LCIS.
2 A pathol ogy r evi ew i s per for med, whi ch i ncl udes deter mi ni ng
the tumor si ze, hi stol ogi c type, and nucl ear grade; r ul i ng out an
i nvasi ve component; deter mi ni ng the l ymph node status i f l ymph
node sur ger y was per for med; and deter mi ni ng the estr ogen and
pr ogester one r eceptor status. 3 Candi dates for br east-conser vi ng
sur ger y ar e those wi th uni centr i c di sease, whose rati o of tumor
si ze to br east si ze al l ows for an acceptabl e cosmeti c r esul t wi th
r esecti on mar gi ns gr eater than or equal to 2 mm. Note: Cl i ni cal
tr i al s ar e consi der ed the pr efer r ed tr eatment opti ons for el i gi bl e
pati ents. U/S, ul trasound.
Pati ents who under go mastectomy for DCIS r outi nel y under go
i ntraoperati ve l ymphati c mappi ng and senti nel l ymph node
di ssecti on. In pati ents who under go br east-conser vi ng sur ger y,
senti nel l ymph node di ssecti on i s per for med on an i ndi vi dual basi s
and pr i mar i l y r eser ved for cases wher e the DCIS i s pal pabl e or hi gh
grade or exhi bi ts comedo-type necr osi s.
Adjuvant radi ati on therapy i s r ecommended to r educe the r i sk of
l ocal r ecur r ence i n pati ents who under go br east-conser vi ng sur ger y.
Br east-conser vi ng sur ger y al one (wi thout radi ati on therapy) i s
consi der ed for sel ected pati ents wi th smal l (<1 cm i n di ameter ),
l ow-grade l esi ons that have been exci sed wi th mar gi ns of at l east 5
mm and who can be obser ved di l i gentl y for r ecur r ence. Par ti al
br east i r radi ati on i s offer ed on pr otocol onl y. Tamoxi fen i s offer ed
for 5 year s to women wi th estr ogen r eceptor-posi ti ve DCIS who do
not have a hi stor y of venous thr omboembol i sm or str oke.
Fol l owi ng sur gi cal r esecti on, pati ents under go annual physi cal and
cl i ni cal br east exami nati ons. Other or gani z ati ons, such as the
Nati onal Compr ehensi ve Cancer Networ k, r ecommend a physi cal
exami nati on ever y 6 months for 5 year s and annual l y ther eafter.
Whether thi s i mpr oves the detecti on of r ecur r ence and outcome i s
not known. Pati ents who r ecei ve br east-conser vi ng sur ger y and
radi ati on therapy under go a di agnosti c mammogram 6 months after
the compl eti on of radi ati on therapy and annual bi l ateral
mammograms ther eafter. If a mastectomy i s per for med,
the pati ent i s fol l owed wi th an annual di agnosti c contral ateral

mammogram.
Al l pati ents wi th DCIS ar e consi der ed for cl i ni cal tr i al s, whi ch ar e
the pr efer r ed tr eatment opti ons for el i gi bl e pati ents.
Lobular Carcinoma in Situ

LCIS was fi r st descr i bed as a di sti nct pathol ogi cal enti ty i n 1941.
Dur i ng the era that fol l owed, the tr eatment of LCIS was the same as
that of i nvasi ve car ci nomaradi cal mastectomy. Haagensen i s
cr edi ted wi th al ter i ng the tr eatment phi l osophy for LCIS. In thei r
r evi ew of 211 cases, Haagensen et al . (1978) noted a 17%
i nci dence of subsequent i nvasi ve car ci nomas among women i n whom
di sease was di agnosed as LCIS and tr eated by obser vati on al one
(wi thout sur ger y). The r i sk of devel opi ng a subsequent car ci noma
was equal for both br easts, and onl y si x pati ents di ed of br east
cancer. Haagensen concl uded that cl ose obser vati on for LCIS
al l owed for ear l y detecti on of subsequent mal i gnancy, wi th
associ ated hi gh cur e rates. Haagensen's rati onal e for obser vati on as
a tr eatment phi l osophy for LCIS was based on hi s vi ew that pati ents
wi th LCIS wer e at i ncr eased r i sk for i nvasi ve br east cancer but that
LCIS i tsel f di d not pr ogr ess i nto a mal i gnancy. However, mor e r ecent
wor k has i ndi cated that cer tai n types of LCIS may be i ndol ent
pr ecur sor s of i nfi l trati ng cancer and that sur gi cal r esecti on shoul d
be consi der ed i n sel ected subtypes of LCIS.
Epidemiology
The i nci dence of LCIS i s di ffi cul t to esti mate because the di agnosi s
i s most often made fol l owi ng a pur el y i nci dental fi ndi ng. LCIS i s
often not detectabl e by pal pati on, gr oss pathol ogi cal exami nati on,
or mammography. Eval uati on of mammographi c abnor mal i ti es has
found LCIS to be pr esent i n 0.5% to 1.3% of br east cor e-needl e
bi opsy speci mens and 0.5% to 3.9% of exci si onal br east bi opsy
speci mens.
Tradi ti onal l y, LCIS has been mor e commonl y r epor ted i n
pr emenopausal women than i n postmenopausal women. In
Haagensen's ser i es descr i bed pr evi ousl y, 90% of the pati ents wer e
pr emenopausal . In a r evi ew of the Sur vei l l ance, Epi demi ol ogy, and
End Resul ts pr ogram database, Li et al . (2002) r epor ted that fr om
1978 to 1998 the i nci dence of LCIS i ncr eased i n al l age gr oups, but
that i t i ncr eased the most i n women 50 to 79 year s ol d. The
i ncr ease i n i nci dence i n women 40 to 49 year s ol d conti nued to the

1987 to 1989 ti me per i od and then stabi l i zed, wher eas the
i nci dence i n women age 50 year s or ol der i ncr eased thr oughout the
study per i od. Dur i ng the 1996 to 1998 ti me per i od, the i nci dence of
LCIS was the hi ghest i n women 50 to 59 year s ol d (11.47/100,000
per son-year s) fol l owed by women 60 to 69 year s ol d (8.14/100,000
per son-year s). The r eason for thi s i ncr ease i n LCIS i s bel i eved to be
mul ti factor i al and par ti al l y the r esul t of i ncr eased use of scr eeni ng
mammography; ther efor e, an i ncr eased number of bi opsi es wer e
per for med for mammographi cal l y detected br east abnor mal i ti es.
Estr ogen has been hypothesi zed to pl ay an i mpor tant r ol e i n the
pathogenesi s of LCIS; thus, the i ncr eased use of hor mone
r epl acement therapy i n postmenopausal
women may al so account for the i ncr eased i nci dence of LCIS i n
women age 50 year s or ol der.
The theor y that LCIS r epr esents a mar ker of i ncr eased r i sk of
i nvasi ve br east car ci noma has tradi ti onal l y been suppor ted by the
fact that the mean age at di agnosi s i s 10 to 15 year s younger than
that for i nvasi ve cancer. However, as the i nci dence of LCIS has
i ncr eased i n women 50 year s of age and ol der, the i nci dence of
i nfi l trati ng l obul ar car ci noma i n thi s age gr oup has i ncr eased
concur r entl y, wher eas women younger than 50 year s ol d have not
exper i enced an i ncr ease i n i nvasi ve l obul ar car ci noma. Recentl y,
some have suggested that LCIS i s mor phol ogi cal l y and bi ol ogi cal l y
mor e heter ogeneous than pr evi ousl y r epor ted. Al though cl assi c LCIS
may not be associ ated wi th i nvasi ve l obul ar car ci noma, cases of
l ar ger, mor e pl eomor phi c LCIS l esi ons may r epr esent cl onal
pr ol i ferati on of cel l s that may pr ogr ess to i nvasi ve l obul ar
car ci noma. Mol ecul ar anal ysi s of LCIS and i nvasi ve l obul ar
car ci noma has r eveal ed l oss of or decr eased expr essi on of the cel l
sur face adhesi on mol ecul e E-cadher i n i n both tumor types. Thi s
contrasts wi th ductal car ci noma, i n whi ch E-cadher i n expr essi on i s
usual l y mai ntai ned. LCIS and i nvasi ve ductal car ci noma have al so
been shown to exhi bi t si mi l ar l oss of heter oz ygosi ty. In addi ti on, i n
an anal ysi s of 180 pati ents wi th LCIS tr eated wi th br east-conser vi ng
therapy, F i sher et al . (2004) r epor ted that ei ght of ni ne pati ents
(89% ) wi th i nvasi ve i psi l ateral br east car ci noma r ecur r ence had a
r ecur r ence of the l obul ar type. These data fur ther str engthen the
theor y that LCIS i s not onl y a mar ker for i ncr eased r i sk of i nvasi ve
br east cancer, but al so a di r ect pr ecur sor of i nvasi ve l obul ar
car ci noma.
Pathology
LCIS i s character i zed by an i ntraepi thel i al pr ol i ferati on of the
ter mi nal l obul ar-ductal uni t. The cel l s ar e sl i ghtl y l ar ger and pal er
than those that l i ne the nor mal aci ni , but the l obul ar ar chi tectur e
r emai ns i ntact. The cel l s have a homogeneous mor phol ogy and do
not di spl ay pr omi nent chr omati n. The cytopl asm-to-nucl eus rati o i s
nor mal , wi th i nfr equent mi toses and no necr osi s. The pr ol i ferati ng
cel l s do not penetrate the basement membrane. Recentl y, a
pl eomor phi c var i ant of LCIS wi th l ar ger nucl ei , central necr osi s, and
cal ci fi cati ons was descr i bed. Thi s var i ant may be mor e pr one to
pr ogr essi ng to i nvasi ve l obul ar car ci noma.
The di agnosi s of LCIS i nvol ves the di ffer enti ati on of LCIS fr om other
for ms of beni gn di sease and fr om i nvasi ve l esi ons. In the absence of
compl ete r epl acement of the l obul ar uni t, atypi cal l obul ar
hyper pl asi a i s the desi gnated pathol ogi cal ter m. Papi l l omatosi s i n
the ter mi nal ducts may r esembl e LCIS but l acks the character i sti c
i nvol vement of the aci ni . DCIS may extend r etr ograde i nto the
aci ni , but i t has a mor e character i sti c anapl asti c cel l mor phol ogy
and general l y expr esses E-cadher i n. LCIS i s contai ned wi thi n the
basement membrane and i s thus di sti ngui shed fr om i nvasi ve l obul ar
car ci noma.
Numer ous studi es have documented that LCIS i s mul ti focal and
mul ti centr i c. If di l i gentl y sought, foci can be found el sewher e i n the
br east i n al most al l cases. In addi ti on, LCIS i s i denti fi ed i n the
contral ateral br east i n 50% to 90% of cases. Thus, the pr esence of
LCIS r efl ects a phenotypi c mani festati on of a general i zed
abnor mal i ty pr esent thr oughout both br easts. As a r esul t, the
tr eatment of LCIS shoul d be di r ected not onl y at the i ndex l esi on,
but al so at both br easts.
Diagnosis
Because LCIS i s usual l y not detectabl e by physi cal exami nati on or
mammography, i t i s most commonl y di agnosed as an i nci dental
fi ndi ng i n a br east bi opsy speci men. Ther efor e, the cl i ni cal
pr esentati on of pati ents wi th LCIS i s si mi l ar to that of pati ents
r equi r i ng br east bi opsy for fi br oadenoma, beni gn ductal di sease,
DCIS, or i nvasi ve br east cancer. Pati ents di agnosed wi th LCIS shoul d
under go bi l ateral di agnosti c mammography to excl ude other
mammographi c abnor mal i ti es. Ul trasound i s al so useful i n

eval uati ng suspi ci ous fi ndi ngs.
Treatment
Surgery
The opti mal cl i ni cal management of pati ents di agnosed wi th LCIS
wi th the use of a cor e-needl e bi opsy r emai ns contr over si al . In the
past, many sur geons opted to obser ve such pati ents because a
di agnosi s of LCIS was consi der ed a mar ker for i ncr eased r i sk of
br east cancer rather than a pr ecur sor of i nvasi ve cancer. However,
r ecent studi es by Ar pi no et al . (2004) and other s have r epor ted a
0% to 10% r i sk of synchr onous i nvasi ve br east cancer and a 0% to
50% r i sk of synchr onous DCIS i n pati ents di agnosed wi th LCIS by
cor e-needl e bi opsy speci mens. Hence, pati ents wi th LCIS di agnosed
by cor e-needl e bi opsy speci mens ar e now r ecommended to under go
sur gi cal exci si on to r ul e out synchr onous i nvasi ve cancer and DCIS.
In contrast wi th DCIS, ther e i s a l ack of pr ospecti ve randomi zed
tr i al s eval uati ng adjuvant tr eatment fol l owi ng sur gi cal exci si on of
LCIS. Most of the pati ents di agnosed wi th LCIS si nce the mi d-1970s
have under gone cl i ni cal obser vati on al one based on the
r ecommendati ons of Haagensen et al . (1978). In a study of pati ents
who under went obser vati on al one after mar gi n negati ve sur gi cal
exci si on of LCIS, F i sher et al . (2004) r epor ted an overal l 14.4%
i psi l ateral and 7.8% contral ateral br east cancer r ecur r ence rate
after 12 year s. Near l y 85% of i psi l ateral br east tumor r ecur r ences
wer e detected by mammography, and the r i sk of i psi l ateral
r ecur r ence was appr oxi matel y 1.6% per year. Mor e than 96% of al l
i psi l ateral r ecur r ences occur r ed i n the same quadrant as the
or i gi nal LCIS. Ni ne of 26 (34.6% [5.0% of the total ]) pati ents wi th
i psi l ateral r ecur r ence had an i nvasi ve tumor, an i nci dence that was
si mi l ar to that i n pati ents wi th contral ateral br east tumor
r ecur r ence (5.6% of the total ). However, the contral ateral
r ecur r ences occur r ed l ater. Onl y 2 of the 180 pati ents i n the study
di ed fr om br east cancer, r esul ti ng i n a br east cancer-speci fi c
mor tal i ty rate of 1.1% at 12 year s of fol l ow-up ti me. The fr ee
exci si on mar gi ns wer e bel i eved to have contr i buted to the l ow rate
of i nvasi ve i psi l ateral r ecur r ence. In another study of 100 pati ents
wi th LCIS, Ottesen et al . (2000) r epor ted a 13% i nvasi ve i psi l ateral
br east cancer r ecur r ence rate and a 16% overal l r ecur r ence rate. In
thi s study, mar gi n status was not eval uated, and the i nvasi ve
i psi l ateral br east tumor r ecur r ence rate was mor e than doubl e that
obser ved by F i sher et al . (2004). Hence, compl ete exci si on of LCIS
wi th negati ve mar gi ns may r esul t i n decr eased occur r ence of
i nvasi ve br east cancer. However, at the pr esent ti me, the data ar e
i nsuffi ci ent to r ecommend r e-exci si on to achi eve negati ve mar gi ns
for LCIS. F ur ther study of the var i ous LCIS subtypes i s needed to
deter mi ne whether pati ents wi th some subtypes woul d i ndeed
benefi t fr om r e-exci si on.
Contral ateral mi r r or-i mage br east bi opsy, a pr ocedur e advocated for
pati ents wi th LCIS i n the past, has fal l en out of favor because a
mi r r or-i mage bi opsy negati ve for LCIS does not el i mi nate the need
for cl ose obser vati on of the r emai ni ng br east ti ssue i n the
contral ateral br east. A vi abl e therapeuti c opti on for LCIS i s bi l ateral
pr ophyl acti c mastectomy. Thi s appr oach i s usual l y r eser ved for
pati ents who have addi ti onal r i sk factor s for br east cancer or who
exper i ence extr eme anxi ety r egar di ng the obser vati on and/or
chemopr eventi on opti ons. Because LCIS poses no r i sk of r egi onal
metastasi s, axi l l ar y node di ssecti on i s not r equi r ed. Immedi ate
br east r econstr ucti on shoul d be offer ed for pati ents who under go
pr ophyl acti c mastectomy for LCIS.
Endocrine Therapy and Chemoprevention

Another tr eatment opti on for pati ents wi th a di agnosi s of LCIS i s
chemopr eventi on wi th tamoxi fen. In the NSABP P-1 br east cancer
pr eventi on tr i al , F i sher et al . (1998) obser ved a 56% decr ease i n
the i nci dence of i nvasi ve br east cancer s i n a subset of women wi th
LCIS who r ecei ved tamoxi fen as compar ed wi th women wi th LCIS
who under went obser vati on al one. The annual haz ar d rate of
i nvasi ve cancer was 5.69 per 1,000 women who r ecei ved tamoxi fen
compar ed wi th 12.99 per 1,000 women who di d not. Postmenopausal
women wi th LCIS wer e el i gi bl e to be randomi zed between tamoxi fen
and ral oxi fene i n the NSABP P-2 tr i al , whi ch cl osed to accr ual i n
2004 (the Study of Tamoxi fen And Ral oxi fene). The fi r st r esul ts
fr om thi s tr i al ar e expected i n 2006.
Radiation Therapy
Adjuvant radi ati on therapy has not been eval uated speci fi cal l y for
the tr eatment of LCIS, and data ar e cur r entl y i nsuffi ci ent to
r ecommend thi s tr eatment on a r outi ne basi s. If synchr onous DCIS
or i nvasi ve br east cancer i s found i n an exci sed LCIS speci men, the
pati ent wi l l benefi t fr om radi ati on therapy and shoul d r ecei ve
tr eatment accor di ng to the gui del i nes for DCIS or i nvasi ve br east
cancer.
Surveillance
Fol l owi ng br east-conser vi ng therapy for LCIS, pati ents shoul d
under go annual or bi annual physi cal exami nati ons wi th bi l ateral
br east exami nati ons. They shoul d al so under go annual bi l ateral
di agnosti c mammography. Use of scr eeni ng ul trasound i n pati ents
wi th LCIS i s bei ng eval uated. Al so, pati ents who under go a bi l ateral
mastectomy wi th or wi thout r econstr ucti on shoul d under go an
annual physi cal exami nati on, and any suspi ci ous l esi ons shoul d be
eval uated wi th ul trasound and bi opsy anal ysi s.
Current Treatment of Lobular Carcinoma In

Situ at M. D. Anderson Cancer Center
The al gor i thm for tr eatment of pati ents wi th LCIS at M. D. Ander son
i s outl i ned i n F i gur e 1.1. Pati ents found to have LCIS by bi opsy
anal ysi s ar e eval uated wi th bi l ateral di agnosti c mammography i f not
per for med pr i or to obtai ni ng the bi opsy speci men. The new
mammograms ar e compar ed wi th pr evi ous i mages, i f avai l abl e.
Suspi ci ous l esi ons ar e fur ther eval uated wi th ul trasound, and
addi ti onal cor e-needl e bi opsy speci mens ar e obtai ned when
appr opr i ate.
Pati ents found to have a suspi ci ous abnor mal i ty on mammography
or ul trasound under go br east-conser vi ng therapy wi th exci si on of
the abnor mal i ty under needl e l ocal i z ati on. If they ar e found to have
synchr onous DCIS or i nvasi ve br east cancer, subsequent tr eatment
i s admi ni ster ed accor di ng to the gui del i nes for these tumor s. Reexci si on to attai n negati ve mar gi ns i s not r outi nel y per for med i n
pati ents found to have i sol ated cl assi cal LCIS i n an exci sed
speci men. If necessar y, r e-exci si on i s per for med to achi eve negati ve
mar gi ns i n pati ents wi th a di agnosi s of pl eomor phi c LCIS. Bi l ateral
pr ophyl acti c mastectomy i s r eser ved for pati ents wi th addi ti onal r i sk
factor s for br east cancer and pati ents who exper i ence extr eme
anxi ety r egar di ng the obser vati on and/or chemopr eventi on opti ons.
Pati ents who under go br east-conser vi ng therapy for LCIS do not
r outi nel y r ecei ve radi ati on therapy but ar e offer ed tamoxi fen i f they
ar e sui tabl e candi dates for anti estr ogen therapy.
After br east-conser vi ng sur ger y, pati ents under go annual physi cal
exami nati ons and bi l ateral di agnosti c mammography. Fol l owi ng a

bi l ateral pr ophyl acti c mastectomy wi th or wi thout r econstr ucti on,
pati ents ar e al so eval uated wi th the use of annual physi cal
exami nati ons, and any suspi ci ous l esi ons ar e i nvesti gated by usi ng
ul trasound and bi opsy anal ysi s when appr opr i ate.
Al l pati ents wi th LCIS ar e consi der ed for cl i ni cal tr i al s, whi ch ar e
the pr efer r ed tr eatment opti ons for el i gi bl e pati ents.
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M.
Edition
> Ta ble o f C o nt e nt s > 2 - Inva s iv e Bre a s t C a nc e r
2
Invasive Breast Cancer
Jonathan S. Zager
Carmen C. Solorzano
Eva Thomas
Barry W . Feig
Gildy V. Babiera
Epidemiology
Br east cancer i s a l eadi ng heal th concer n i n the Uni ted States
because i t i s the second most common cause of death among
Amer i can women (after l ung cancer ) and the l eadi ng cause of death
among women ages 40 to 50 year s. In 2005, appr oxi matel y 212,930
new cases wi l l be di agnosed, and near l y 40,870 br east cancerr el ated deaths wi l l occur. In the Uni ted States, whi te femal es have
the hi ghest i nci dence of br east car ci noma, and the i nci dence
i ncr eases wi th i ncr easi ng age. For an Amer i can woman, the l i feti me
r i sk of bei ng di agnosed wi th br east cancer i s 1 i n 7 or 14% , and the
l i feti me r i sk of dyi ng fr om br east cancer i s appr oxi matel y 3.4% .
Accor di ng to the Nati onal Cancer Insti tute's Sur vei l l ance,
Epi demi ol ogy, and End Resul ts Pr ogram, the i nci dence of br east
cancer i ncr eases rapi dl y dur i ng the four th decade of l i fe. After
menopause, the i nci dence conti nues to i ncr ease but at a much
sl ower rate, peaki ng i n the seventh and ei ghth decades of l i fe and
sl owl y l evel i ng off after 80 year s of age. The overal l i nci dence of
br east cancer i n al l races has i ncr eased over the l ast two decades
fr om appr oxi matel y 110 to 130/100,000 pati ents (al l races) to 114
to 140/100,000 pati ents fr om 1990 to 2000. F r om 1990 to 2001,
sur vi val rates i mpr oved steadi l y and si gni fi cantl y for women wi th
l ocor egi onal di sease i n al l age gr oups, and the age-adjusted br east
cancer mor tal i ty rate for whi te women i n the Uni ted States dr opped.
However, for Afr i can Amer i can women, the 5-year r el ati ve sur vi val
rates ar e l ower than those for whi te women for l ocal i zed di sease
(90% vs. 97% ), r egi onal di sease (66% vs. 79% ), and metastati c
di sease (15% vs. 23% ).
The rate of di agnosi s of r egi onal di sease decr eased i n the l ate
1980s i n the Uni ted States among women ol der than 40 year s. Thi s
decr ease l i kel y r efl ects the i ncr eased use of mammography i n the
ear l y 1980s. In contrast, the i ncr ease i n sur vi val rates i n the same
ti me per i od, par ti cul ar l y for women wi th r egi onal di sease, l i kel y
r efl ects i mpr ovements i n systemi c adjuvant therapy. Ther efor e, both
scr eeni ng mammography and i mpr oved therapy have pr obabl y
contr i buted to the r ecent decl i ne i n br east cancer mor tal i ty rates i n
the Uni ted States.
Risk Factors
The most i mpor tant r i sk factor for the devel opment of br east cancer
i s gender. The femal e-to-mal e rati o for br east cancer i s 100:1.
Ther efor e, thi s chapter focuses on r i sk factor s among women.
Si ngl etar y ni cel y summar i zed r i sk factor s for br east cancer i n a
2003 r evi ew ar ti cl e, and a si mpl i fi ed ver si on i s pr ovi ded i n Tabl e
2.1.
Table 2.1. Risk factors for breast cancer

and associated relative risks
Risk Factor
Category at Risk
Relative
Risk
Germline
mutations
BRCA-1 and
younger than 40
years old
BRCA-1 and 60
69 years old
200
15
Lobular
Proliferative
breast disease
carcinoma in situ
Ductal carcinoma
in situ
16.4
17.3
Personal history
of breast cancer
Invasive breast
cancer
6.8
Ionizing radiation
exposure
Hodgkin disease
5.2
Family history
First-degree
relative with
premenopausal
breast cancer
First-degree
relative with
postmenopausal
breast cancer
3.3
1.8
Age at first
childbirth
Hormone
replacement
therapy with
estrogen and
progesterone
Older than 30
years
Current user for
at least 5 years
1.71.9
1.3
Early menarche
Younger than 12
years
1.3
Late menopause
Older than 55
years
1.21.5
Singletary SE. Rating the risk factors for breast

cancer. Ann Surg 2003;237: 474.
G eneti c al terati ons pr edi sposi ng i ndi vi dual s to br east and ovar i an
cancer have r ecei ved much attenti on r ecentl y. Al though these gene
mutati ons ar e i nher i ted, onl y 5% to 10% of br east cancer s ar e
bel i eved to r esul t fr om an i nher i ted mutated gene. Autosomal
domi nant condi ti ons associ ated wi th an i ncr eased r i sk of br east
cancer i ncl ude Li -F raumeni syndr ome, BRCA-1 and BRCA-2
mutati ons, Mui r-Tor r e syndr ome, Cowden di sease, and Peutz-Jegher s
syndr ome (Tabl e 2.2). Al though autosomal domi nant, these
condi ti ons do not al ways exhi bi t 100% penetrance. Another
i nher i ted condi ti on that may be associ ated wi th br east cancer i s the
autosomal r ecessi ve di sor der ataxi a-tel angi ectasi a.
The most common geneti c anomal i es associ ated wi th an i ncr eased
r i sk of br east cancer ar e the BRCA-1 and BRCA-2 genes. The BRCA1 gene i s found on the l ong ar m of chr omosome 17q, and the BRCA2 gene i s found on chr omosome 13. Both BRCA-1 and BRCA-2
mutati ons ar e associ ated wi th an i ncr eased r i sk of ovar i an cancer,
but the r i sk i s hi gher i n BRCA-1. The r i sk of devel opi ng br east or
ovar i an cancer di ffer s wi th the exact si te of
the BRCA-1 mutati on on chr omosome 17q but ranges fr om 37% to
87% by age 70 for br east cancer and fr om 11% to 42% by age 60
for ovar i an cancer.
Table 2.2. Autosomal dominant conditions

associated with possible development of
breast cancer
Syndrome Defect
Associated
Condition or
Increased Risk for
Mutation of
chromosome
17q
Malignancies of the
breast, ovaries, and
possibly prostate
and colon
BRCA-2
Mutation of
chromosome
13q
Malignancies of the
breast (including
male), ovaries,
prostate, larynx,
and pancreas
LiFraumeni
Mutation in
the p53
gene on
chromosome
17p
Malignancies of the
breast, brain, and
adrenal glands;
soft-tissue sarcomas
Mutation in
DNA
mismatch
repair
genes
(hMLH1 and
hMSH2) on
chromosome
2p
Malignancies of the
breast and
gastrointestinal (GI)
and genitourinary
tracts; sebaceous
tumors (i.e.,
hyperplasia,
adenoma,
epithelioma,
carcinoma),
keratoacanthoma
Mutation in
the PTEN
Malignancies of the
breast, colon,
uterus, thyroid,
BRCA-1
Muir-Torre
Cowden
disease
PeutzJeghers
gene on
chromosome
10q
lung, and bladder;

hamartomatous
polyps in GI tract
Mutation in
the STK11
gene on
chromosome
19p
Malignancies of the
breast and
pancreas;
mucocutaneous
melanin deposition,
hamartomas of the
GI tract
A per sonal hi stor y of br east cancer i s a si gni fi cant r i sk factor for

the devel opment of cancer i n the contral ateral br east. The i nci dence
of contral ateral br east cancer i s 0.5% to 1.0% per year of fol l owup.
Exposur e to i oni z i ng radi ati on for the tr eatment of Hodgki n di sease
has been associ ated wi th a mar kedl y i ncr eased r i sk of br east cancer
i f the exposur e was befor e age 30 (r el ati ve r i sk i s 5.2). The r i sk i s
l ess i n the fi r st 15 year s after tr eatment than after 15 year s.
Nonpr ol i ferati ve br east di seases such as adenosi s, fi br oadenomas,
apocr i ne changes, duct ectasi a, and mi l d hyper pl asi a car r y no
i ncr eased r i sk of br east cancer. However, pr ol i ferati ve br east
di seases ar e associ ated wi th br east cancer to var i ous degr ees.
Moderate or fl or i d hyper pl asi a wi thout atypi a, papi l l omas, and
scl er osi ng adenosi s car r y a sl i ghtl y i ncr eased r i sk of br east cancer
(1.5 to 2 ti mes that of the general popul ati on). Atypi cal ductal or
l obul ar hyper pl asi a i s associ ated wi th a moderatel y i ncr eased r i sk of
devel opi ng br east cancer (4 to 5 ti mes). Lobul ar car ci noma i n si tu i s
associ ated wi th a hi gh r i sk of br east cancer (8 to 10 ti mes). These
r i sks appl y equal l y to both br easts, even i f the br east di sease was
uni l ateral .
Age i s an i mpor tant r i sk factor for the devel opment of br east cancer.
The r i sk that br east cancer wi l l devel op i n a whi te Amer i can woman
i n a si ngl e year i ncr eases fr om 1:207 at l ess than age 39 year s to
1:13 between ages 60 and 79.

A fami l y hi stor y of br east cancer i ncr eases a woman's r i sk of br east
cancer. The hi ghest r i sk i s associ ated wi th the pr esence of br east
cancer i n a young fi r st-degr ee r el ati ve wi th bi l ateral br east cancer.
The overal l r i sk depends on the number of r el ati ves wi th cancer,
thei r ages at di agnosi s, and whether the di sease was uni l ateral or
bi l ateral . For exampl e, a 30-year-ol d woman whose si ster had
bi l ateral br east cancer befor e age 50 has a cumul ati ve pr obabi l i ty of
br east cancer by age 70 of 55% . Thi s pr obabi l i ty decr eases to 8%
for a 30-year-ol d woman whose si ster devel oped uni l ateral br east
cancer after age 50.
A number of endogenous endocr i ne factor s have al so been
i mpl i cated as r i sk factor s i n br east cancer. The r i sk of br east cancer
for women who exper i ence menopause after age 55 i s twi ce that of
women who exper i ence menopause befor e age 44. Al though age at
menar che i s i mpor tant, age at onset of r egul ar menses may have a
l ar ger effect on r i sk. Women who began to have r egul ar ovul ator y
cycl es befor e age 13 have a four fol d gr eater r i sk than those whose
menar che occur r ed after age 13 and who had a 5-year del ay to the
devel opment of r egul ar cycl es. The cumul ati ve durati on of
menstr uati on may al so be i mpor tant. Women who menstr uate for
mor e than 30 year s ar e at gr eater r i sk than those who menstr uate
for l ess than 30 year s. Age at fi r st chi l dbi r th has a gr eater effect on
r i sk than the number of pr egnanci es. For exampl e, a woman who
had her fi r st chi l d befor e age 19 has hal f the r i sk of a nul l i par ous
woman. Women who have thei r fi r st chi l d between 30 and 34 year s
of age have the same r i sk as nul l i par ous women, and women who
have thei r fi r st chi l d after age 35 have a gr eater r i sk than
nul l i par ous women. These obser vati ons i ndi cate that the hor monal
mi l i eu at di ffer ent ti mes i n a woman's l i fe may affect her r i sk of
br east cancer.
Exogenous hor mone r epl acement therapy i s known to i ncr ease a
woman's r i sk of br east cancer (r el ati ve r i sk after 5 year s of
tr eatment i s 1.3). However, the benefi ts associ ated wi th hor mone
r epl acement therapy i ncl ude i ncr eased bone densi ty and fewer
postmenopausal symptoms. Ther efor e, tr eati ng physi ci ans shoul d
thor oughl y di scuss wi th thei r pati ents the r i sks and benefi ts of thi s
therapy.
Pathology
Invasi ve car ci nomas of the br east tend to be hi stol ogi cal l y
heter ogeneous tumor s. The vast major i ty of these tumor s ar e

adenocar ci nomas that ar i se fr om the ter mi nal ducts. Ther e ar e fi ve
common hi stol ogi c var i ants of mammar y adenocar ci noma:
1. Infiltr ating ductal car cinoma accounts for 75% of al l br east
cancer s. Thi s l esi on i s character i zed by the absence of speci al
hi stol ogi c featur es. It i s har d on pal pati on and gr i tty when
transected. It i s associ ated wi th var i ous degr ees of fi br oti c
r esponse. Often ther e i s associ ated ductal car ci noma i n si tu
(DCIS) wi thi n the speci men. Infi l trati ng ductal car ci nomas
commonl y metastasi ze to axi l l ar y l ymph nodes. The pr ognosi s
for pati ents wi th these tumor s i s poor er than that for pati ents
wi th some of the other hi stol ogi c subtypes (i .e., muci nous,
col l oi d, tubul ar, and medul l ar y). Di stant metastases ar e found
most often i n the bones, l ungs, l i ver, and brai n.
2. Infiltr ating lobular car cinoma i s seen i n 5% to 10% of br east
cancer cases. Cl i ni cal l y, thi s l esi on often has an ar ea of i l l defi ned thi ckeni ng wi thi n the br east. Mi cr oscopi cal l y, smal l cel l s
i n a si ngl e- or Indi an-fi l e patter n ar e character i sti cal l y seen.
Infi l trati ng l obul ar cancer s tend to gr ow ar ound ducts and
l obul es. Mul ti centr i ci ty and bi l ateral i ty ar e obser ved mor e
fr equentl y i n i nfi l trati ng l obul ar car ci noma than i n i nfi l trati ng
ductal car ci noma. The pr ognosi s for l obul ar car ci noma i s si mi l ar
to that for i nfi l trati ng ductal car ci noma. In addi ti on to
metastasi z i ng to axi l l ar y l ymph nodes, l obul ar car ci noma i s
known to metastasi ze to unusual si tes (e.g., meni nges and
ser osal sur faces) mor e often than do other for ms of br east
cancer.
3. Tubular car cinoma accounts for onl y 2% of br east car ci nomas.
The di agnosi s of tubul ar car ci noma i s made onl y when mor e than
75% of the tumor demonstrates tubul e for mati on. Axi l l ar y nodal
metastases ar e uncommon wi th thi s type of tumor. The pr ognosi s
for pati ents wi th tubul ar car ci noma i s consi derabl y better than
that for pati ents wi th other types of br east cancer.
4. Medullar y car cinoma accounts for 5% to 7% of br east cancer s.
Hi stol ogi cal l y, the l esi on i s character i zed by poor l y di ffer enti ated
nucl ei , a syncyti al gr owth patter n, a wel l -ci r cumscr i bed bor der,
i ntense i nfi l trati on wi th smal l l ymphocytes and pl asma cel l s, and
l i ttl e or no DCIS. The pr ognosi s for pati ents wi th pur e medul l ar y
car ci noma i s favorabl e; however, mi xed var i ants wi th i nvasi ve
ductal components wi l l have pr ognoses si mi l ar to i nvasi ve ductal

car ci noma.
5. Mucinous or colloid car cinoma consti tutes appr oxi matel y 3% of
br east cancer s. It i s character i zed by an abundant accumul ati on
of extracel l ul ar muci n sur r oundi ng cl uster s of tumor cel l s.
Col l oi d car ci noma i s sl ow gr owi ng and tends to be bul ky. If a
br east car ci noma i s pr edomi nantl y muci nous, the pr ognosi s i s
favorabl e.
Rar e hi stol ogi c types of br east mal i gnancy i ncl ude papi l l ar y,
apocr i ne, secr etor y, squamous cel l and spi ndl e cel l car ci nomas, and
car ci nosar coma. Infi l trati ng ductal car ci nomas occasi onal l y have
smal l ar eas contai ni ng one or mor e of these speci al hi stol ogi c types.
Tumor s wi th these mi xed hi stol ogi c appearances behave si mi l ar l y to
pur e i nfi l trati ng ductal car ci nomas.
Staging
Typi cal l y, br east cancer i s staged usi ng the Amer i can Joi nt
Commi ttee on Cancer (AJCC) gui del i nes. The AJCC TNM br east
cancer stagi ng system was updated i n 2003 and publ i shed i n the
si xth edi ti on of the AJCC Cancer Staging Manual. The most r ecent
TNM cl assi fi cati ons and stage gr oupi ngs for br east cancer ar e
summar i zed i n Tabl e 2.3.
Diagnosis
History and Physical Examination
The di agnosi s of br east cancer has under gone a dramati c evol uti on
si nce the mi d-1980s. Pr evi ousl y, 50% to 75% of al l br east cancer s
wer e detected by sel f-exami nati on. Subsequent to the wi despr ead
avai l abi l i ty of mammographi c scr eeni ng pr ograms, ther e has been a
shi ft towar d the di agnosi s of cl i ni cal l y occul t, nonpal pabl e l esi ons.
Despi te thi s tr end, eval uati on of a woman for br east cancer
conti nues to be based on a car eful hi stor y and physi cal
exami nati on.
The hi stor y i s di r ected at assessi ng cancer r i sk and establ i shi ng the
pr esence or absence of symptoms i ndi cati ve of br east di sease and
shoul d i ncl ude age at menar che, menopausal status, pr evi ous
pr egnancy, and use of oral contracepti ves or postmenopausal
r epl acement estr ogens. A per sonal hi stor y of br east cancer and
other cancer s tr eated wi th radi ati on or chemotherapy (e.g., Hodgki n
di sease) i s i mpor tant. In addi ti on, the fami l y hi stor y of br east
cancer or ovar i an cancer i n fi r st-degr ee r el ati ves (i .e., mother or
si ster ) shoul d be establ i shed. After the r i sk for br east cancer has
been deter mi ned, the pati ent shoul d be assessed for speci fi c
symptoms. Br east pai n and ni ppl e di schar ge ar e often, but not
al ways, associ ated wi th beni gn pr ocesses such as fi br ocysti c di sease
and i ntraductal papi l l oma. Mal ai se, bony pai n, and wei ght l oss ar e
rar e but may i ndi cate metastati c di sease.
Physi cal exami nati on by the heal th car e pr ovi der must constantl y
take i nto consi derati on the comfor t and emoti onal wel l -bei ng of the
pati ent. Exami nati on i s i ni ti ated by car eful vi sual i nspecti on wi th
the pati ent si tti ng upr i ght. Ni ppl e changes, gr oss asymmetr y, and
obvi ous masses ar e al l noted. The ski n must be car eful l y i nspected
for subtl e changes; these can range fr om sl i ght di mpl i ng to the
mor e dramati c peau d'or ange, war m or er ythematous appearance
associ ated wi th l ocal l y advanced or i nfl ammator y br east cancer. In
l ar ge or ptoti c br easts, the br easts shoul d be l i fted to faci l i tate
i nspecti on of the i nfer i or por ti on of the br east and i nframammar y
fol d. After car eful i nspecti on and wi th the pati ent r emai ni ng i n the
si tti ng posi ti on, the per i cl avi cul ar r egi ons ar e exami ned for
potenti al nodal di sease. Both axi l l ae ar e then car eful l y pal pated. If
pal pabl e, nodes shoul d be character i zed as to thei r number, si ze,
and mobi l i ty. Exami nati on of the axi l l a al ways i ncl udes pal pati on of
the axi l l ar y tai l of the br east; assessment of thi s ar ea i s often
over l ooked once the pati ent i s pl aced i n a supi ne posi ti on. Pal pati on
of the br east par enchyma i tsel f i s accompl i shed wi th the pati ent
supi ne and the i psi l ateral ar m pl aced over the head. The subar eol ar
ti ssues and each quadrant of both br easts ar e systemati cal l y
pal pated. Masses ar e
noted wi th r espect to thei r si ze, shape, l ocati on, consi stency, and
mobi l i ty.
Table 2.3. Current AJCC TNM classification

and stage grouping for breast carcinoma
Classification
and Stage
Definition
Grouping
Primary tumor (T)
TX
Primary tumor cannot be

assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
Tis (DCIS)
Ductal carcinoma in situ
Tis (LCIS)
Lobular carcinoma in situ
Tis (Paget)
Paget disease of the nipple

with no tumor
Note: Paget disease associated
with a tumor is classified
according to the size of the
tumor.
T1
T1mic
Tumor 2 cm or less in greatest

dimension
Microinvasion 0.1 cm or less in
greatest dimension
Tumor more than 0.1 cm but
T1a
not more than 0.5 cm in

greatest dimension
T1b
Tumor more than 0.5 cm but

not more than 1 cm in greatest
dimension
T1c
Tumor more than 1 cm but not

more than 2 cm in greatest
dimension
T2
Tumor more than 2 cm but not

more than 5 cm in greatest
dimension
T3
Tumor more than 5 cm in

greatest dimension
Tumor of any size with direct
extension to
T4
T4a
T4b
1. chest wall or
2. skin, only as described as
follows
Extension to chest wall, not
including pectoralis muscle
Edema (including peau
d'orange) or ulceration of the
skin of the breast, or satellite
skin nodules confined to the

same breast
T4c
Both T4a and T4b
T4d
Inflammatory carcinoma
Regional lymph nodes (N)
NX
Regional lymph nodes cannot

be assessed (e.g., previously
removed)
N0
No regional lymph node

metastasis
N1
Metastasis in movable
ipsilateral axillary lymph
node(s)
N2
Metastases in ipsilateral
axillary lymph nodes fixed or
matted, or in clinically
apparent ipsilateral internal
mammary nodes in the absence
of clinically evident axillary
lymph node metastasis
N2a
Metastasis in ipsilateral axillary

lymph nodes fixed to one
another (matted) or to other
structures
N2b
N3
Metastasis only in clinically

mammary nodes and in the
absence of clinically evident
axillary lymph node metastasis
Metastasis in ipsilateral
infraclavicular lymph node(s),
or in clinically apparent
ipsilateral internal mammary
lymph node(s) and in the
presence of clinically evident
axillary lymph node
metastasis; or metastasis in
ipsilateral supraclavicular
lymph node(s) with or without
axillary or internal mammary
lymph node involvement
N3a
infraclavicular lymph node(s)
and axillary lymph node(s)
N3b
internal mammary lymph
node(s) and axillary lymph
node(s)
N3c
supraclavicular lymph node(s)
Regional
lymph nodes
(pN)
pNX
Regional lymph nodes cannot

be assessed (e.g., previously
removed, not removed for
pathological study)
pN0

metastasis histologically, no
additional examination for
isolated tumor cells
pN0(i-)

metastasis histologically,
negative IHC
pN0(i+)

positive IHC, no IHC cluster
greater than 0.2 mm
pN0(mol-)

negative molecular findings
(RT-PCR)
pN0(mol+)

positive molecular findings (RT-
PCR)
pN1mi
Micrometastasis (greater than

0.2 mm, none greater than 2.0
mm)
pN1
Metastasis in 1 to 3 axillary
lymph nodes, and/or in internal
mammary nodes with
microscopic disease detected
by sentinel lymph node
dissection but not clinically
apparent
pN1a
lymph nodes
pN1b
Metastasis in internal
mammary nodes with
apparent
pN1c
lymph nodes and in internal
mammary lymph nodes with
apparent
pN2
lymph nodes, or in clinically
apparent internal mammary
lymph nodes in the absence of
pN2a
lymph nodes (at least one
tumor deposit greater than 2.0
mm)
pN2b
Metastasis in clinically
apparent internal mammary
lymph nodes in the absence of
pN3
Metastasis in 10 or more
axillary lymph nodes, or in
infraclavicular lymph nodes, or
in clinically apparent ipsilateral
internal mammary lymph nodes
in the presence of 1 or more
positive axillary lymph nodes;
or in more than 3 axillary
lymph nodes with clinically
negative microscopic
metastasis in internal
mammary lymph nodes; or in
ipsilateral supraclavicular
lymph nodes
pN3a
Metastasis in 10 or more
axillary lymph nodes (at least
one tumor deposit greater than
2.0 mm), or metastasis to the
infraclavicular lymph nodes
pN3b
Metastasis in clinically
mammary lymph nodes in the
presence of 1 or more positive
axillary lymph nodes; or in
more than 3 axillary lymph
nodes and in internal
mammary lymph nodes with
apparent
pN3c
supraclavicular lymph nodes
Distant metastasis (M)

MX
Distant metastasis cannot be

assessed
M0
No distant metastasis
M1
Distant metastasis
DCIS, ductal carcinoma in situ; LCIS, lobular
carcinoma in situ; IHC, immunohistochemistry;

RT-PCR, reverse transcriptase-polymerase
chain reaction.
Adapted from American Joint Committee on
Cancer (AJCC). AJCC Cancer Staging Manual.
6th ed. 2002.
Cr i ti cal anal ysi s of physi cal exami nati ons has shown that the exams
ar e often i nadequate for di ffer enti ati ng beni gn and mal i gnant br east
masses. Var i ous ser i es have i denti fi ed a 20% to 40% er r or rate,
even among exper i enced exami ner s. Because of the hi gh rate of
i naccuracy, any per si stent br east mass r equi r es addi ti onal
eval uati on. F ur ther mor e, for the di ffer enti ati on of a l ocal l y
advanced or i nfl ammator y br east car ci noma, a mul ti di sci pl i nar y
team consi sti ng of a medi cal oncol ogi st, sur geon, and radi ati on
oncol ogi st shoul d be consul ted to obtai n a consensus as to the
pati ent's cl i ni cal pr esentati on and the most appr opr i ate tr eatment
r egi men.
Evaluation of Palpable Lesions

The choi ce of i ni ti al di agnosti c eval uati on after the detecti on of a
br east mass shoul d be i ndi vi dual i zed for each pati ent accor di ng to
age, per cei ved cancer r i sk, and character i sti cs of the l esi on. For
most pati ents, mammographi c eval uati on i s an i mpor tant i ni ti al
step. Mammography i n thi s setti ng ser ves two pur poses, to assess
the r i sk of mal i gnancy for the pal pabl e l esi on and to scr een both
br easts for other nonpal pabl e l esi ons. Bi l ateral synchr onous cancer s
occur i n appr oxi matel y 3% of al l cases; at l east hal f of these l esi ons
ar e nonpal pabl e.
For a pal pabl e l esi on, mammograms may r eveal the stel l ate or
spi cul ated appearance typi cal of mal i gnancy. Cal ci fi cati ons, ni ppl e
changes, and axi l l ar y adenopathy may al so be vi sual i zed. The
pr esence or absence of these mammographi c fi ndi ngs can pr edi ct
mal i gnancy wi th an accuracy of 70% to 80% . Mammography i s l east
accurate i n younger pati ents wi th dense br easts; for thi s r eason, i t
i s rar el y used i n pati ents younger than the age of 30 year s for
scr eeni ng.
After mammographi c eval uati on, pal pabl e masses suspected to be
mal i gnant shoul d under go fi ne-needl e aspi rati on (F NA) bi opsy or,
pr eferabl y, cor e-needl e bi opsy. Some cl i ni ci ans advocate needl e
bi opsy at the ti me of i ni ti al eval uati on (i .e., befor e mammography).
For most pati ents bei ng tr eated at M. D. Ander son Cancer Center
(MDACC), bi opsy i s defer r ed unti l after mammographi c exami nati on
i s compl eted because a needl e-punctur e hematoma wi l l occasi onal l y
obscur e futur e radi ographi c eval uati on. For young pati ents wi th
dense br easts for whom mammography i s not i deal , needl e bi opsy
wi th or wi thout the ai d of ul trasonography i s the pr i mar y mode of
eval uati on. However, i f the l esi on can be vi sual i zed under
ul trasound, i t i s pr eferabl e to per for m needl e bi opsy wi th ul trasound
gui dance to confi r m that the needl e i s wi thi n the abnor mal i ty.
F NA wi th a 22-gauge needl e al l ows for accurate di ffer enti ati on
between cysti c and sol i d masses and pr ovi des mater i al for cytol ogi c
exami nati on but does not establ i sh an i nvasi ve component i f a
br east cancer di agnosi s i s made. Cysti c l esi ons cannot be
di ffer enti ated fr om sol i d l esi ons by mammography but ar e ver y wel l
character i zed by ul trasonography. Beni gn br east cysts typi cal l y yi el d
nonbl oody fl ui d and become nonpal pabl e after aspi rati on. Bl oody or
ser ous fl ui d shoul d be submi tted for cytol ogi c anal ysi s. The
i nci dence of mal i gnancy among br east cysts i s
appr oxi matel y 1% and i s l i mi ted al most excl usi vel y to cysts that
yi el d bl oody or ser ous fl ui d or have a r esi dual mass after aspi rati on.
Aspi rati on i s often curati ve; onl y one i n fi ve br east cysts wi l l r ecur,
and most of these ar e obl i terated wi th a second drai nage. If
per si stent, however, exci si on i s usual l y r ecommended.
For sol i d l esi ons, several passes thr ough the l esi on wi th the syr i nge
under constant negati ve pr essur e wi l l typi cal l y yi el d ampl e mater i al
for cytol ogi c eval uati on. The mater i al i s evacuated onto a
mi cr oscopi c sl i de and i mmedi atel y fi xed i n 95% ethanol . Mul ti pl e
studi es have demonstrated that F NA i s si mpl e, safe, and accurate i n
eval uati ng beni gn and mal i gnant br east masses. However, for
l esi ons i nter pr eted as mal i gnant, cytol ogi c eval uati on i s unabl e to
di ffer enti ate between i n si tu and i nvasi ve car ci noma. Cor e-needl e
bi opsy al l ows the pathol ogi st to di sti ngui sh i nvasi ve and i n si tu
car ci noma by pr ovi di ng a cor e of ti ssue for hi stopathol ogi cal
eval uati on.
Al though physi cal exami nati on, mammography, and needl e bi opsy
al l car r y a r i sk of er r or when used al one, the combi nati on of these
thr ee modal i ti es i s extr emel y accurate i n pr edi cti ng whether a
pal pabl e l esi on i s beni gn or mal i gnant. For l esi ons wi th equi vocal or
contradi ctor y r esul ts, open bi opsy i s the defi ni ti ve test. The MDACC
appr oach to pal pabl e and nonpal pabl e br east masses ar e outl i ned i n
F i gur es 2-1 and 2-2.
Evaluation of Nonpalpable Lesions

Because of the i ncr easi ng avai l abi l i ty of mammographi c scr eeni ng
pr ograms, the di agnosti c rate of nonpal pabl e br east cancer has r i sen
rapi dl y i n the Uni ted States. Si nce 1997, the Amer i can Cancer
Soci ety, the Nati onal Cancer Insti tute, and the Amer i can Col l ege of
Radi ol ogy have r el eased updated gui del i nes for br east cancer
scr eeni ng that ar e i n l ar ge par t based on new data publ i shed i n
1997. Each or gani z ati on r ecommends that women begi n r egul ar
scr eeni ng mammography i n thei r for ti es.
Mammographi c si gns of mal i gnancy can be di vi ded i nto two mai n
categor i es: mi cr ocal ci fi cati ons and densi ty changes.
Mi cr ocal ci fi cati ons can be cl uster ed or scatter ed. Densi ty changes
i ncl ude di scr ete masses, ar chi tectural di stor ti ons, and asymmetr i es.
The most pr edi cti ve mammographi c fi ndi ngs of mal i gnancy ar e
spi cul ated masses wi th associ ated ar chi tectural di stor ti on, cl uster ed
mi cr ocal ci fi cati ons i n a l i near or branchi ng ar ray, and
mi cr ocal ci fi cati ons associ ated wi th a mass. The Amer i can Col l ege of
Radi ol ogy devel oped the Br east Imagi ng Repor ti ng and Data System,
whi ch categor i zes mammographi c fi ndi ngs as fol l ows: I = negati ve
(no fi ndi ngs); II = beni gn appearance; III = pr obabl y beni gn
appearance (<2% chance of mal i gnancy); IV = fi ndi ngs suspi ci ous
for br east cancer (fur ther di vi ded i nto IVa, mi l dl y suspi ci ous, and
IVb, moderatel y suspi ci ous); and V = fi ndi ngs hi ghl y suspi ci ous for
br east cancer (>90% chance of br east cancer ).
Once scr eeni ng mammography demonstrates a suspi ci ous l esi on,
fur ther eval uati on i s necessar y for di agnosi s. For l esi ons i nter pr eted
as pr obabl y beni gn (i .e., wel l -defi ned, sol i tar y masses), car eful
counsel i ng and r epeat mammography i n 6 months may be
under taken i n pati ents at l ow r i sk for br east cancer. For cer tai n
l esi ons, ul trasonography may i denti fy a subset
of cysti c l esi ons that wi l l not r equi r e bi opsy. Ul trasonography may

al so be used to gui de fi ne-needl e or cor e-needl e bi opsy. For
suspi ci ous l esi ons, some for m of bi opsy i s r equi r ed. Ul trasoundgui ded bi opsy i s not useful for eval uati ng mi cr ocal ci fi cati ons
because they ar e typi cal l y not sonographi cal l y vi si bl e. However,
mammography-gui ded ster eotacti c br east bi opsy i s a useful

techni que for obtai ni ng ti ssue for di agnosi s fr om nonpal pabl e
l esi ons and mi cr ocal ci fi cati ons. The MDACC appr oach to nonpal pabl e
br east masses i s outl i ned i n F i gur e 2.1.
F i gur e 2.1. Uni ver si ty of Texas M. D. Ander son Cancer Center

al gor i thm for the wor kup of a pal pabl e br east mass.
F i gur e 2.2. Uni ver si ty of Texas M. D. Ander son Cancer Center

al gor i thm for the wor kup of a nonpal pabl e br east mass. BIRADS,
Br east Imagi ng Repor ti ng and Data System.
Ti ssue sampl i ng can be obtai ned wi th the Mammotome (Ethi con

Endo Sur ger y, Ci nci nnati , OH) devi ce, whi ch i s used at
MDACC i n conjuncti on wi th ster eotacti c gui ded i magi ng to obtai n
mul ti pl e cor e-needl e bi opsi es vi a a vacuum-assi sted cutti ng devi ce
pl aced thr ough a smal l 1/4-i n i nci si on r emovi ng or sampl i ng the
l esi on i n questi on and often some sur r oundi ng ti ssue.
Breast Biopsy Technique

When cor e-needl e bi opsy or F NA i s i mpossi bl e or i nappr opr i ate,
exci si onal br east bi opsy may be per for med. Exci si onal bi opsy may
ser ve both di agnosti c and l ocal tr eatment pur poses. The enti r e
suspi ci ous mass and a sur r oundi ng 1-cm r i m of nor mal ti ssue shoul d
be exci sed. An exci si onal bi opsy such as thi s wi l l ful fi l l the
r equi r ements for l umpectomy and avoi d subsequent r e-exci si on.
For ei ther pal pabl e or nonpal pabl e suspi ci ous l esi ons, pl anni ng an
opti mal open bi opsy mandates car eful consi derati on of at l east thr ee
i ssues. F i r st, the bi opsy si te may r equi r e futur e r e-exci si on for
br east conser vati on tr eatment. Second, the bi opsy si te must be abl e
to be i ncor porated i nto a futur e mastectomy i nci si on i f thi s for m of
tr eatment i s chosen. Thi r d, the bi opsy must be constr ucted i n a
cosmeti cal l y opti mal manner wi thout compr omi si ng oncol ogi c
pr i nci pl es. Al l br east bi opsi es shoul d be per for med wi th the
assumpti on that the tar get l esi on i s mal i gnant.
Bi opsi es ar e typi cal l y per for med i n an outpati ent setti ng.
Cur vi l i near i nci si ons ar e often used to take advantage of decr eased
l i nes of tensi on al ong Langer 's l i nes. Radi al scar s ar e general l y
avoi ded except i n the extr eme medi al (l ower ) aspect of the br east,
wher e mastectomy i nci si ons become radi al l y or i ented or i n the
extr eme l ateral posi ti on at the 2 or 3 o'cl ock posi ti on, wher e l ess
ski n wi l l need to be sacr i fi ced for a ski n-spar i ng mastectomy.
Ci r cumar eol ar i nci si ons have an obvi ous cosmeti c advantage but
may l ead to sacr i fi ce of ar eol ar ti ssue i f r e-exci si on i s r equi r ed.
Al though a smal l amount of per i pheral tunnel i ng i s acceptabl e to
mai ntai n an i nci si on wi thi n a potenti al mastectomy scar, extr eme
tunnel i ng to the per i pher y of the br east fr om a central per i ar eol ar
i nci si on must be avoi ded. Si tuati ng the i nci si on wel l away fr om the
abnor mal i ty for cosmeti c r easons not onl y makes i t vi r tual l y
i mpossi bl e to i denti fy the tumor bed i f r e-exci si on i s r equi r ed, but
al so r esul ts i n the r emoval of an i nor di nate amount of br east ti ssue.
Ther efor e, the i nci si on shoul d general l y be pl aced di r ectl y over the
mal i gnant l esi on to avoi d excessi ve ti ssue r emoval that may
compr omi se cosmeti c outcome or to pr event bei ng unabl e to l ocate
the tumor bed i f r e-exci si on i s r equi r ed. Pati ents who under go
br east-conser vi ng sur ger y shoul d have a separate axi l l ar y i nci si on
that i s not conti guous wi th the br east i nci si on. Separati ng these
i nci si ons pr ovi des a better cosmeti c outcome (the axi l l ar y drai n wi l l
cause the bi opsy cavi ty to become di stor ted i f they ar e not
separated).
For nonpal pabl e l esi ons, pr eoperati ve needl e l ocal i z ati on wi th a
sel f-r etai ni ng hook wi r e i s r equi r ed. Thi s pr ocedur e r equi r es car eful
communi cati on between the radi ol ogi st and the sur geon. For most
l esi ons, the l ocal i z i ng needl e i s pl aced under mammographi c
gui dance i nto the br east vi a the shor test di r ect path to the l esi on.
The sel f-r etai ni ng wi r e i s pl aced thr ough the needl e, and then the
needl e may or may not be r emoved at the di scr eti on of the sur geon.
Postl ocal i z ati on mammograms of the wi r e ar e
r evi ewed to confi r m that the wi r e i s wi thi n the tar geted ar ea.
Exci si onal bi opsy i s then per for med by exci si ng br east ti ssue ar ound
the wi r e ti p. For super fi ci al l esi ons, an el l i pse of ski n at the poi nt of
wi r e i nser ti on may be r emoved en bl oc wi th the under l yi ng br east
ti ssue. Postexci si on speci men radi ographs ar e essenti al to confi r m
the l ocal i zed tar get was r emoved. Often, the entr y si te of the wi r e
i s not di r ectl y over the tar geted l esi on, and thi s trajector y shoul d
be accounted for when the i nci si on i s pl aced on the br east.
Once the bi opsy speci men has been exci sed, i t must be handl ed
car eful l y. The sur geon shoul d note the or i entati on of the exci sed
br east ti ssue and then hand del i ver the speci men to the pathol ogy
depar tment. The l ateral , medi al , super i or, i nfer i or, super fi ci al , and
deep mar gi ns shoul d be i nked i n a col or-coded manner. Mater i al
shoul d be pr ocessed for r eceptor anal ysi s and fl ow cytometr y.
Cl osur e of the bi opsy i nci si on r equi r es meti cul ous hemostasi s. Deep
par enchymal sutur es often cause cosmeti cal l y unpl easi ng di stor ti on
of the r esi dual br east and shoul d be avoi ded. Drai ns ar e not used i n
the br east. The ski n i s cl osed wi th a subcuti cul ar sutur e, and a l i ght
dr essi ng i s pl aced.
Pretreatment Evaluation
Once the di agnosi s of br east cancer has been made, appr opr i ate
tr eatment pl anni ng i nvol ves eval uati ng the extent of di sease both
l ocal l y i n the br east and r egi onal nodes and of di stant si tes
(typi cal l y to the l ung, l i ver, and bone). For pati ents wi th stage I or
stage II br east cancer, thi s eval uati on i s usual l y l i mi ted to a
compl ete hi stor y and physi cal exami nati on, a chest radi ograph, and
eval uati on of ser um l i ver chemi str i es. The r outi ne use of bone scans
i n asymptomati c pati ents wi th appar ent ear l y-stage br east cancer
car r i es an extr emel y l ow yi el d; several studi es have demonstrated
onl y a 2% i nci dence of posi ti ve scan r esul ts i n thi s setti ng. In
contrast, up to 25% of asymptomati c pati ents wi th appar ent stage
III cancer have posi ti ve bone scan r esul ts; thus, r outi ne scanni ng i n
thi s popul ati on appear s wor thwhi l e. In the absence of i ncr eased
ser um l i ver chemi str i es or pal pabl e hepatomegal y, l i ver i magi ng i s
not used r outi nel y i n the pr eoperati ve eval uati on of pati ents wi th
ear l y-stage di sease.
Ul trasound i s r outi nel y used at MDACC to eval uate the axi l l ar y
nodal basi n and any suspi ci ous i nfracl avi cul ar, supracl avi cul ar, or
i nter nal mammar y adenopathy. Suspi ci ous nodes can be sampl ed by
ul trasound-gui ded F NA. Posi ti ve r esul ts i nfl uence the deci si on on

how to pr oceed wi th fur ther therapy. Pati ents wi th posi ti ve axi l l ar y
nodal F NAs can be schedul ed for an axi l l ar y l ymph node di ssecti on
(ALND) at the ti me of l umpectomy or mastectomy, ther efor e
avoi di ng senti nel l ymph node (SLN) bi opsy and a second sur ger y, or
they can be r efer r ed to the medi cal oncol ogi st for systemi c
neoadjuvant chemotherapy.
Treatment
Many of the cur r ent r ecommendati ons r egar di ng therapy for
i nvasi ve br east cancer have been i nfl uenced by the r esul ts of
randomi zed, pr ospecti ve cl i ni cal tr i al s per for med by the Nati onal
Sur gi cal Adjuvant Br east and Bowel Pr oject (NSABP). A summar y of
sel ected tr i al s i s pr esented i n Tabl e 2.4.
Early-Stage Breast Cancer (T1, T2, N0, N1)

Appr oxi matel y 75% of pati ents wi th br east cancer pr esent wi th
tumor s l ess than 5 cm i n di ameter and no evi dence of fi xed or
matted nodes. These pati ents wi th ear l y-stage br east cancer ar e
general l y tr eated (a) wi th br east conser vati on and radi ati on therapy
or total mastectomy wi th or wi thout r econstr ucti on and (b) wi th
eval uati on of the r egi onal nodes i n the for m of ALND or SNL bi opsy.
Breast Conservation Versus Mastectomy

Many pati ents wi th br east cancer can be effecti vel y tr eated wi th
br east-conser vi ng therapy (BCT). Si nce 1970, seven pr ospecti ve
randomi zed tr i al s compar i ng br east conser vati on strategi es wi th
radi cal or modi fi ed radi cal mastectomy have fai l ed to demonstrate
any sur vi val benefi t to the mor e aggr essi ve appr oach. Among these
tr i al s, the two most wi del y known wer e conducted by Har r i s et al .
(1992) at the Nati onal Cancer Insti tute i n Mi l an, Ital y, and by
F i sher et al . (1995) i n conjuncti on wi th the NSABP i n the Uni ted
States. The Mi l an tr i al was l i mi ted to pati ents wi th stage I br east
cancer (tumor l ess than 2 cm and negati ve axi l l ar y l ymph nodes)
and compar ed radi cal mastectomy wi th a br east conser vati on
strategy i nvol vi ng quadrantectomy, ALND, and radi ati on therapy. No
si gni fi cant di ffer ences i n l ocal contr ol , di sease-fr ee sur vi val , or
overal l sur vi val rate have been noted, even i n the most r ecent
fol l ow-up of these studi es al most 20 year s after thei r i ncepti on.
NSABP B-06 exami ned women wi th pr i mar y tumor s up to 4 cm i n
di ameter and N0 or N1 nodal status. Pati ents wer e randoml y

assi gned to modi fi ed radi cal mastectomy, l umpectomy wi th ALND, or
l umpectomy and ALND pl us radi ati on therapy. Hi stol ogi cal l y
negati ve mar gi ns wer e r equi r ed i n the br east conser vati on gr oups.
Di sease-fr ee and overal l sur vi val rates di d not di ffer si gni fi cantl y
among the thr ee gr oups, but the l ocal r ecur r ence rate was mar kedl y
r educed at 10 year s by radi ati on therapy (12% wi th radi ati on
therapy vs. 53% wi thout radi ati on therapy). These r esul ts uphel d
br east conser vati on as an appr opr i ate tr eatment for pati ents wi th
stage I or stage II br east cancer and made i t cl ear that radi ati on
therapy i s r equi r ed as an i ntegral par t of any br east conser vati on
strategy.
The cur r ent standar d for BCT at MDACC for l ocal contr ol of the
br east i s exci si on of the tumor wi th negati ve mar gi ns fol l owed by
radi ati on therapy at the appr opr i ate ti me. The use of systemi c
therapy i s based on age, tumor si ze, nodal i nvol vement, and
r eceptor status and i s gi ven befor e (neoadjuvant) or after
(adjuvant) sur ger y. A radi ati on oncol ogi st sees the pati ents after
compl eti on of sur ger y or adjuvant chemotherapy to deter mi ne
radi ati on dosi metr y and si mul ati on, and radi ati on therapy i s begun
3 to 4 weeks after sur ger y. A dose of 50 G y i s gi ven to the whol e
br east, and then 10 G y i s gi ven to the operati ve si te as a boost
usi ng tangenti al por ts and computer i zed dosi metr y.
The use of par ti al br east radi ati on therapy for BCT i nstead of whol e
br east i r radi ati on wi th a boost to the tumor si te i s
cur r entl y bei ng i nvesti gated. Advantages of par ti al br east

i r radi ati on i ncl ude shor ter tr eatment (5 days vs. 6 weeks); l ess
scatter radi ati on to the l ungs, hear t, and cor onar y vessel s; and l ess
ski n bur ni ng and desquamati on. Numer ous studi es ar e i n pr ogr ess
to eval uate the dosi metr y, si de effect pr ofi l es, and effi cacy of
par ti al br east i r radi ati on. Unti l the r esul ts of these studi es ar e
known, par ti al br east i r radi ati on shoul d be consi der ed exper i mental
and be per for med under pr otocol onl y. The del i ver y methods for
par ti al br east i r radi ati on cur r entl y under i nvesti gati on ar e radi ati on
therapy thr ough brachytherapy catheter s pl aced i ntraoperati vel y or
postoperati vel y and thr ee-di mensi onal confor mal radi ati on gi ven
exter nal l y to the br east postoperati vel y.
Table 2.4. Summary of selected NSABP

therapeutic trials for invasive breast cancer
Trial
Treatment
Outcome
NSABP
B-04
Total mastectomy
vs. total
mastectomy with
XRT vs. radical
mastectomy
No significant
difference in
disease-free or
overall survival
rates
NSABP
B-06
Total mastectomy
vs. lumpectomy
vs. lumpectomy
with XRT
No significant
difference in
disease-free or
overall survival
rates; addition of
XRT to
lumpectomy
reduced local
recurrence rate
from 39% to 10%
NSABP
B-13
Surgery alone vs.

surgery plus
adjuvant
chemotherapy in
node-negative
patients with
estrogen receptornegative tumors
Improved
disease-free
survival rate for
adjuvant
chemotherapy
group
Surgery alone vs.

surgery plus
adjuvant
tamoxifen in
node-negative
patients with
estrogen receptorpositive tumors
Improved
disease-free
survival rate for
adjuvant
tamoxifen group
NSABP
B-18
Neoadjuvant
chemotherapy
with doxorubicin,
cyclophosphamide,
or both for 4
cycles vs. the
same regimen
given
postoperatively
No significant
difference in
overall survival or
disease-free
survival rates
(53% and 70% at
9 years in the
postoperative
group and 69%
and 55% in the
preoperative
group)
NSABP
B-21
Lumpectomy plus
tamoxifen vs.
lumpectomy plus
tamoxifen plus
XRT vs.
lumpectomy plus
XRT for nodenegative tumors
<1 cm
Combination of
XRT and
tamoxifen was
more effective
than either alone
in reducing
ipsilateral breast
tumor recurrence
NSABP
B-14
NSABP
B-27
Neoadjuvant
chemotherapy
comparing AC 4
cycles then
surgery vs. AC
4 cycles,
docetaxel 4
cycles then
surgery vs.
surgery between 4
cycles of AC and 4
cycles of
docetaxel
Groups I and III

were combined
and compared
with group II;
clinical and
pathological
complete
response rates
increased
significantly
among patients
who received
preoperative AC
and docetaxel
NSABP
B-32
SLN biopsy
followed by
axillary dissection
vs. SLN biopsy
alone for clinically
node-negative
patients
SLN identification
rate was similar
in both groups,
accuracy was high
for both, negative
predictive value
was high for both
NSABP, National Surgical Adjuvant Breast and

Bowel Project; XRT, radiation therapy; AC,
doxorubicin (Adriamycin), cyclophosphamide;
SLN, sentinel lymph node.
Al though BCT and mastectomy r esul t i n equi val ent sur vi val rates for
pati ents wi th stage I or stage II di sease, the deci si on to conser ve
the br east must be made i ndi vi dual l y. Of utmost i mpor tance for the
success of BCT i s the pati ent's moti vati on and commi tment to
pr eser ve the br east and pr event advanced r ecur r ences: dai l y

outpati ent radi ati on tr eatments over 5 to 6 weeks ar e r equi r ed.
Mor e i mpor tant i s l ong-ter m fol l ow-up of the pr eser ved br east to
detect br east cancer r ecur r ences. Other factor s that must be
consi der ed i n maki ng the choi ce between mastectomy and br east
conser vati on sur ger y, ar e outl i ned i n Tabl e 2.5.
For extr emel y smal l br easts, the cosmeti c r esul t may be
unacceptabl e fol l owi ng l ocal exci si on, especi al l y for pati ents wi th
si zeabl e tumor s. For l ar ge or pendul ous br easts, l ack of uni for mi ty
i n radi ati on dosi ng may r esul t i n unattracti ve fi br osi s and
r etracti on. Pati ents may benefi t fr om mastectomy pl us
r econstr ucti on and per haps sur gi cal augmentati on or r educti on of
the
contral ateral br east. Pati ents wi th l ar ger tumor s mi ght al so be best
ser ved by mastectomy because of the poor cosmeti c outcome that
r esul ts when a l ar ge ar ea of the br east and the defect ar e r emoved.
Ver y l i ttl e data exi st i n a pr ospecti ve randomi zed setti ng for the
feasi bi l i ty of BCT i n pati ents wi th l ar ge tumor s. Khanna et al .
i nvesti gated the outcomes for 68 pati ents who under went BCT
wi thout the use of pr eoperati ve (neoadjuvant) chemotherapy for 4to 12-cm tumor s. The mean tumor di ameter was 5 cm, and the
medi an fol l ow-up was 48 months. The actuar i al l ocor egi onal
r ecur r ence rate was 8.5% , and no r ecur r ence occur r ed i n pati ents
who had negati ve sur gi cal mar gi ns. No si gni fi cant di ffer ence i n
di sease-fr ee sur vi val rates was noted for pati ents who under went
BCT and those who under went mastectomy. Ni nety-four per cent of
the pati ents who under went BCT r epor ted a favorabl e cosmeti c
outcome. Al ter nati vel y, a mor e attracti ve appr oach to tr eati ng T3
tumor s, or for pati ents wi th unfavorabl e br easttumor rati os, may
be neoadjuvant chemotherapy, whi ch may shr i nk the tumor to the
poi nt wher e br east conser vati on i s feasi bl e or cosmeti cal l y opti mal .
Table 2.5. Absolute and relative

contraindications to breast-conserving
therapy
Absolute contraindications
Prior radiotherapy to the breast or chest wall

Radiotherapy use during pregnancy
Diffuse suspicious or malignant-appearing
microcalcifications
Multicentric disease
Positive pathologial margin after multiple
attempts to obtain negative margins
Relative contraindications
Multifocal disease requiring two or more
separate surgical incisions
Active connective tissue disease involving the
skin (especially scleroderma and lupus)
Tumor size >5 cm (controversial)
Focally positive margins after multiple attempts
to obtain negative margins
Adapted from National Comprehensive Cancer
Network Guidelines, 2005.
Al though, ther e does not appear to be any di ffer ence i n overal l
sur vi val for pati ents who under go mastectomy or BCT for ear l ystage br east cancer. Ther e does appear to be a di ffer ence i n
r ecur r ence rates between the two sur gi cal tr eatment opti ons.
Attempts have been made to i denti fy pati ents wi th a hi gh rate of
l ocal r ecur r ence after BCT on the basi s of the hi stol ogy of the
pr i mar y tumor. To date, ther e have been no documented si gni fi cant
di ffer ences i n l ocal r ecur r ence by hi stol ogi c subtype. The r i sk of
l ocal r ecur r ence has been shown to be hi gher for women younger
than 35 year s and for women whose tumor s ar e gr eater than 2 cm
i n di ameter, r egar dl ess of l ymph node status. For pati ents wi th
posi ti ve l ymph nodes, nucl ear grade i s al so si gni fi cantl y cor r el ated
wi th r ecur r ence. The l ocal r ecur r ence rates for BCT quoted i n the
major publ i shed studi es (notabl y, the Mi l an study, NSABP B-06, and
the Dani sh Br east Cancer Cooperati ve G r oup study) range fr om
2.6% to 18% , whi ch i s sl i ghtl y hi gher than the range quoted for
mastectomy (2.3% to 13% ). In the Mi l an study, the 20-year cr ude

i nci dence rate for r ecur r ence was si gni fi cantl y hi gher for BCT than
for mastectomy (8.8% vs. 2.3% ) (p <0.001). However, ther e was no
si gni fi cant di ffer ence i n overal l sur vi val rates between BCT and
mastectomy i n any of these studi es. The ul ti mate goal of BCT for
pati ents wi th ear l y-stage br east cancer i s to pr ovi de an opti mal
cosmeti c r esul t wi thout compr omi si ng l ocal contr ol . Cl ear l y, a
mul ti di sci pl i nar y effor t coupl ed wi th car eful pati ent sel ecti on i s
cr i ti cal for the successful outcomes of BCT.
Locally Advanced Breast Cancer

Local l y advanced br east cancer encompasses tumor s wi th a br oad
range of bi ol ogi cal behavi or s. Thi s categor y i ncl udes tumor s that
ar e l ar ge or have extensi ve r egi onal l ymph node i nvol vement
wi thout evi dence of di stant metastati c di sease at i ni ti al
pr esentati on. These tumor s fal l i nto the categor y of stage III
di sease accor di ng to the AJCC system. Appr oxi matel y 10% to 20%
of al l pati ents wi th br east cancer have stage III di sease, whi ch
i ncl udes T3 tumor s wi th N1, N2, or N3 di sease; T4 tumor s wi th any
N cl assi fi cati on; or any T cl assi fi cati on wi th N2 or N3 r egi onal l ymph
node i nvol vement. Appr oxi matel y 25% to 30% of stage III br east
cancer s ar e i noperabl e at the ti me of di agnosi s.
Many l ocal l y advanced br east cancer s ar e di scover ed by a pati ent or
her spouse. The r emai ni ng ar e di scover ed dur i ng r outi ne physi cal
exami nati on. On occasi on, a di scr ete mass may not be pr esent;
rather, ther e i s a di ffuse i nfi l trati on of the br east ti ssue. These
pati ents pr esent wi th a br east that i s asymmetr i c, i mmobi l e, and
di ffer ent i n consi stency fr om the contral ateral br east. Seventy-fi ve
per cent of pati ents wi th stage III di sease wi l l have cl i ni cal l y
pal pabl e axi l l ar y or supracl avi cul ar l ymph nodes at the ti me of
di agnosi s. Thi s cl i ni cal fi ndi ng i s confi r med on pathol ogi cal
exami nati on i n 66% to 90% of pati ents. Of the pati ents wi th
posi ti ve nodes, 50% wi l l have mor e than four nodes i nvol ved. When
appr opr i ate stagi ng i s per for med, 20% of pati ents wi th stage III
di sease ar e found to have di stant metastases at pr esentati on.
Di stant metastases ar e al so the most fr equent for m of tr eatment
fai l ur e and usual l y appear wi thi n 2 year s of the i ni ti al di agnosi s.
Both F NA and cor e-needl e bi opsy can be used to confi r m br east
cancer i n these pati ents. These pr ocedur es ar e usual l y easi l y
per for med because of the l ar ge tumor si ze at pr esentati on. The
Hal sted radi cal mastectomy, whi ch was i ni ti al l y bel i eved to be the
tr eatment of choi ce for l ocal l y advanced br east cancer, has been
pr oven to be i nadequate for l ocal contr ol and l ong-ter m pati ent

sur vi val . In 1942, Haagensen r epor ted a 53% l ocal r ecur r ence rate
and a 0% 5-year overal l sur vi val rate among 1,135 pati ents wi th
stage III br east cancer who had under gone a Hal sted radi cal
mastectomy.
The fai l ur e of sur ger y al one to contr ol stage III br east cancer l ed to
the use of radi ati on therapy as a si ngl e-agent tr eatment modal i ty i n
thi s gr oup of pati ents. However, the r esul ts wi th
radi ati on therapy wer e i n some cases i nfer i or to those seen wi th
sur ger y al one. The 5-year overal l sur vi val and l ocal r ecur r ence
rates seen wi th radi ati on therapy al one have ranged fr om 10% to
30% and fr om 25% to 70% , r especti vel y.
Sur ger y pl us radi ati on therapy for l ocal l y advanced br east cancer
al so r esul ts i n poor overal l r esul ts. The l ack of effi cacy of the
combi nati on of two l ocal tr eatment modal i ti es confi r med that stage
III br east cancer i s a systemi c di sease. Al though l ocal contr ol
i ncr eased sl i ghtl y (but i nsi gni fi cantl y) wi th sur ger y pl us radi ati on
therapy, the 5-year overal l sur vi val rate was unchanged, and
pati ents conti nued to di e of di stant metastases.
In the ear l y 1970s, systemi c combi nati on chemotherapy was added
to the l ocal tr eatments for l ocal l y advanced br east cancer. Ini ti al
pr otocol s wer e desi gned to admi ni ster the chemotherapy after l ocal
tr eatment, but thi s sequence of tr eatment does not al l ow for
assessment of the effi cacy of the chemotherapy because al l
measurabl e di sease i s r emoved befor e admi ni strati on of the dr ugs.
The cur r ent practi ce i s to admi ni ster i nducti on chemotherapy befor e
any l ocal tr eatment. Thi s sequence al l ows for r educti on of the i ni ti al
tumor bur den befor e sur ger y, tr eatment of the potenti al systemi c
di sease wi thout del ay, and assessment of the r esponse of the tumor
to the tr eatment bei ng r ender ed.
Several cancer tr eatment center s have r epor ted exper i ences wi th
combi ned modal i ty therapy for l ocal l y advanced di sease. Al though
the pr otocol s di ffer among i nsti tuti ons wi th r espect to the speci fi c
chemotherapy r egi mens and the type of l ocal tr eatment, the studi es
have used i nducti on neoadjuvant chemotherapy fol l owed by l ocal
tr eatment (i .e., sur ger y, radi ati on therapy, or both) and subsequent
adjuvant chemotherapy. Many pati ents wi th l ocal l y advanced br east
cancer ar e now bei ng tr eated wi th thi s chemotherapy sandwi ch
appr oach.
Pati ents wi th l ocal l y advanced br east cancer ar e typi cal l y tr eated
wi th an anthracycl i ne-based r egi men and a taxane befor e sur ger y or

sandwi ched ar ound sur ger y. If postoperati ve chemotherapy i s
pl anned, i t shoul d pr ecede radi ati on therapy to avoi d i nter r upti ng
the tr eatment of systemi c di sease because di stant metastases ar e
the most fr equent for m of tr eatment fai l ur e. Adjuvant hor monal
therapy i s r outi nel y offer ed to al l pati ents wi th r eceptor-posi ti ve
tumor s once they have compl eted systemi c and l ocor egi onal
therapy.
Inflammatory Breast Cancer

Infl ammator y br east cancer i s a rar e, vi r ul ent for m of l ocal l y
advanced br east cancer. It r epr esents 1% to 6% of al l br east
cancer s and pr esents as er ythema, war mth, and edema of the
br east. Rapi d onset of symptoms (wi thi n 3 months) i s necessar y to
make the di agnosi s of i nfl ammator y car ci noma. The ti me cour se
di sti ngui shes i t fr om l ocal l y advanced br east cancer wi th secondar y
l ymphati c i nvasi on, whi ch usual l y pr ogr esses sl owl y over mor e than
3 months. Pai n i s al so pr esent i n hal f of pati ents wi th i nfl ammator y
br east cancer. Confusi on of the physi cal fi ndi ngs as symptoms of an
i nfecti ous pr ocess often r esul ts i n del ays i n di agnosi s and
tr eatment. Tumor embol i ar e often seen i n the subder mal
l ymphati cs on mi cr oscopi c exami nati on. Bi opsy for di agnosi s shoul d
i ncl ude a segment of i nvol ved ski n because a domi nant
mass i s usual l y not pal pabl e on physi cal exami nati on. Ul ti matel y,
the di agnosi s of i nfl ammator y br east car ci noma i s based on the
cl i ni cal eval uati on, whi ch i ncl udes the ti meframe for whi ch the si gns
and symptoms appear.
Infl ammator y car ci noma, si mi l ar to other for ms of l ocal l y advanced
br east cancer, i s a systemi c di sease. In a study of i nfl ammator y
car ci noma, l ocal therapy as the onl y tr eatment modal i ty r esul ted i n
poor outcomes; the medi an sur vi val was l ess than 2 year s, and the
5-year overal l sur vi val rate was 5% . The use of mul ti modal i ty
therapy i n these pati ents has i mpr oved l ocal contr ol and overal l
sur vi val rate over l ocal therapy al one. Standar d tr eatment i s
anthracycl i ne and then taxane-based chemotherapy, ei ther both
befor e sur ger y or sandwi ched ar ound sur ger y. Radi ati on i s
admi ni ster ed after compl eti on of al l sur ger y and systemi c therapy.
Pati ents whose di sease pr ogr esses dur i ng chemotherapy pr oceed to
pr eoperati ve radi ati on therapy or, i f the cancer i s operabl e, sur ger y.
Axillary Lymph Node Dissection

ALND i s sti l l the gol d standar d of car e when eval uati ng the drai ni ng
nodal basi n for l ymph node metastases. Al though ALND appear s to
contr i bute l i ttl e to overal l pati ent sur vi val , i t i s i mpor tant for
stagi ng and l ocal contr ol . ALND pr ovi des i nfor mati on wi th pr ognosti c
and tr eatment i mpl i cati ons for women under goi ng br east
conser vati on sur ger y or modi fi ed radi cal mastectomy. The r ol e of
the r outi ne use of ALND has been r edefi ned i n the past decade by
the wi despr ead use and devel opment of the SLN bi opsy techni que.
Never thel ess, an ALND i s sti l l consi der ed appr opr i ate as a fi r st l i ne
of tr eatment for l ocal contr ol and stagi ng of the axi l l ar y l ymph
nodes, par ti cul ar l y i n cer tai n si tuati ons such as (a) F NA bi opsypr oven axi l l ar y l ymph node metastases or (b) when ther e ar e
suspi ci ous and pal pabl e nodes i n the axi l l a.
The i nci dence of axi l l ar y l ymph node metastases i ncr eases as the
pr i mar y tumor gr ows. A substanti al pr opor ti on of pati ents wi th
appar ent ear l y-stage br east cancer pr esent wi th axi l l ar y nodal
metastases. In one study, 17% of pati ents wi th cl i ni cal l y staged
T1N0 di sease had hi stol ogi cal l y posi ti ve nodes; thi s fi gur e r ose to
27% for pati ents wi th cl i ni cal l y T2N0 staged di sease. Other studi es
have found that 10% of pati ents wi th tumor s smal l er than 0.5 cm
have posi ti ve axi l l ar y l ymph nodes. Tumor s 0.5 to 1.0 cm ar e
associ ated wi th posi ti ve axi l l ar y l ymph nodes i n 13% to 22% of
pati ents, and 1.1- to 2.0-cm tumor s ar e associ ated wi th l ymph node
metastases i n up to 30% of pati ents.
The contr i buti on of ALND to l ocal contr ol i s smal l but measurabl e. In
NSABP B-04, whi ch compar ed radi cal mastectomy wi th si mpl e
mastectomy (wi thout ALND) wi th and wi thout i r radi ati on, 40% of
pati ents wi th cl i ni cal l y negati ve axi l l ae had posi ti ve nodes at radi cal
mastectomy, and 1% of these pati ents eventual l y exper i enced
r ecur r ence i n the axi l l a. In pati ents wi th unoperated axi l l ae (si mpl e
mastectomy gr oup), 18% eventual l y devel oped cl i ni cal adenopathy
that r equi r ed del ayed ALND; four of these pati ents eventual l y
exper i enced r ecur r ence i n the axi l l a despi te del ayed ALND. No
sur vi val di sadvantage was seen for pati ents under goi ng del ayed
ver sus i mmedi ate ALND. Radi ati on was l ess effecti ve than ALND i n
pr eventi ng eventual r ecur r ence
i n the axi l l a, especi al l y among pati ents wi th cl i ni cal l y posi ti ve
nodes.
In addi ti on to contr i buti ng to l ocal contr ol , ALND pr ovi des stagi ng
and pr ognosti c i nfor mati on because nodal status i s a major

pr edi ctor of outcome. For al l pati ents wi th node-negati ve cancer, a
10-year sur vi val rate of at l east 70% may be anti ci pated. For
pati ents wi th 1 to 3 posi ti ve nodes thi s rate dr ops to 40% , and for
pati ents wi th 4 to 10 posi ti ve nodes the rate dr ops to l ess than
20% . Mi cr ometastati c nodal di sease (l ess than 2 mm i n di ameter )
car r i es a better pr ognosi s than macr ometastati c di sease.
The cur r ent standar d of car e i s an anatomi c l evel I or l evel II ALND
for al l pati ents wi th stage I or stage II br east cancer. For pati ents
wi th i nvasi ve br east cancer who ar e under goi ng BCT, ALND shoul d
be per for med vi a a separate axi l l ar y i nci si on that does not extend
anter i or to the pectoral i s fol d. ALND shoul d consi st of en bl oc
r emoval of l evel s I and II nodal ti ssue, and i f l evel III nodes ar e
gr ossl y or pathol ogi cal l y i nvol ved, r emoval of these nodes shoul d be
i ncl uded i n the ALND. However, r emoval of cl i ni cal l y negati ve l evel
III l ymph nodes i s of l i ttl e benefi t wi th r espect to stagi ng because
onl y 1% to 3% of stage I or stage II pati ents show l evel III
i nvol vement i n the absence of l evel I or l evel II di sease. Level III
di ssecti ons car r y a substanti al l y hi gher r i sk of subsequent
l ymphedema, especi al l y i f radi ati on therapy i s al so used. The l evel I
or l evel II ALND shoul d pr eser ve the l ong thoraci c and thoracodor sal
ner ves and avoi d str i ppi ng of the axi l l ar y vei n. A cl osed-sucti on
drai n i s pl aced and r emoved after the drai nage has suffi ci entl y
decr eased.
Pati ents wi th ear l y-stage di sease wi th a l ow r i sk of axi l l ar y l ymph
node i nvol vement may not r equi r e a ful l ALND, and SLN bi opsy may
be the best way to stage the axi l l ar y l ymph node i n these pati ents.
The best appr oach for pati ents wi th T1 tumor s mi ght be SLN bi opsy
to detect l ymph node metastases because SLN bi opsy pr ovi des
pr ognosti c i nfor mati on wi th pr esumabl y l ess mor bi di ty and hel ps
for mul ate a tr eatment strategy. Al though thi s appr oach may seem
r easonabl e, no nati onal consensus has cur r entl y been r eached
r egar di ng the use of SLN bi opsy.
Sentinel Lymph Node Biopsy

Identi fyi ng pati ents wi th metastases i n the axi l l ar y l ymph nodes
wi th ALND i s extr emel y i mpor tant for pr ognosi s, r egi onal tr eatment,
and l ocal contr ol . But because br east cancer si ze on pr esentati on
has become pr ogr essi vel y smal l er due to the wi despr ead use of
scr eeni ng mammography, the pr obabi l i ty of nodal i nvol vement has
al so decr eased. In addi ti on, the compl i cati ons associ ated wi th the
r outi ne use of ALND to deter mi ne axi l l ar y metastases has made i t
i ncr easi ngl y har d to justi fy thi s pr ocedur e i n cer tai n pati ent
popul ati ons. The chal l enge i s to use ALND onl y i n pati ents wi th
nodal metastases. A newer appr oach that enabl es sel ecti ve
l ymphadenectomy i s l ymphati c mappi ng and SLN bi opsy. The SLN i s
often defi ned as the fi r st l ymph node to r ecei ve l ymphati c drai nage
fr om a pr i mar y br east cancer and, ther efor e, the node most l i kel y to
contai n metastati c tumor cel l s. When SLN bi opsy i s per for med by an
exper i enced team consi sti ng of a sur geon, nucl ear medi ci ne
physi ci an, pathol ogi st, and operati ng r oom nur ses and techni ci ans,
the fi ndi ng of a tumor-fr ee SLN
al most i nvar i abl y i ndi cates that the pati ent has node-negati ve
br east cancer and need not under go fur ther axi l l ar y di ssecti on.
However, SLN bi opsy shoul d not be under taken unti l the team has
consi stentl y documented a hi gh rate of SLN i denti fi cati on and l ow
rate of fal se-negati ve SLNs.
SLN bi opsy i s an unstandar di zed standar d of car e. Contr over sy
exi sts as to whether the dye or radi oi sotope shoul d be i njected
i ntrapar enchymal l y, i ntrader mal l y, or subar eol ar l y; whether i t
shoul d be i njected the day befor e or the day of sur ger y; the dose of
the radi oi sotope; and whether bl ue dye, radi oi sotope, or both
shoul d be used. The pl ethora of l i teratur e on SLN bi opsy i n br east
cancer and the techni ques and i di osyncrasi es of thi s method exi st.
Most r epor ted studi es state: successful SLN detecti on i n 94% to
98% of pati ents, an accuracy rate of 97% to 100% , and a fal senegati ve rate of 0% to 15% .
SLN bi opsy can be per for med usi ng radi ol abel ed col l oi d, vi tal bl ue
dye, or both. Pr eoperati ve l ymphosci nti graphy, al though not
mandator y, can be used to i denti fy the SLN and document patter ns
of l ymphati c drai nage. A handhel d gamma counter, the ai d of vi si bl e
bl ue dye, or both can be used i ntraoperati vel y to l ocate the SLN.
SLN bi opsy may be unsuccessful i n pati ents wi th cer tai n cl i ni cal
pr esentati ons: (a) pal pabl e axi l l ar y adenopathy, (b) medi al
hemi spher e l ocati on of the pr i mar y tumor wher e pr eoperati ve
l ymphosci nti graphy di d not i denti fy an axi l l ar y SLN, (c) pr evi ous
axi l l ar y sur ger y because the l ymphati c drai nage fr om the pr i mar y
may be di stor ted, and (d) l ar ge bi opsy cavi ty (l ar ger than 6 cm)
because the l ymphati c drai nage fr om the sur r oundi ng br east ti ssue
may not be the same as that of the pr i mar y tumor.
An i mpor tant questi on i s the cl i ni cal si gni fi cance of SLN posi ti vi ty
as i ndi cated by i mmunohi stochemi cal anal ysi s but not by r outi ne
hematoxyl i n and eosi n stai ni ng. A better under standi ng of the

natural hi stor y of the di sease woul d hel p deter mi ne whether
subsequent axi l l ar y di ssecti on, axi l l ar y radi ati on therapy, or
adjuvant chemotherapy i s needed i n pati ents wi th mi cr ometastasi s
i n the SLN. Several r egi onal and nati onal studi es (Amer i can Col l ege
of Sur geons Oncol ogy G r oup Z0010/Z0011) ar e bei ng conducted to
addr ess the i ssues associ ated wi th thi s new techni que. The NSABP
B-32 i s a pr ospecti ve randomi zed phase III tr i al to assess whether
SLN bi opsy r esul ts i n the same pr ognosi s, r egi onal contr ol , and
overal l sur vi val rate as does ALND for i nvasi ve br east cancer s.
Pati ents wi th cl i ni cal l y negati ve nodes wer e randoml y assi gned to
SLN bi opsy wi th i mmedi ate ALND or to SLN bi opsy al one. In both
gr oups, a SLN was i denti fi ed i n 97% of pati ents, 26% of whom wer e
SLN posi ti ve. In 61.5% of the SLN-posi ti ve pati ents, the posi ti ve
SLNs wer e the onl y posi ti ve nodes. In the gr oups assi gned to SLN
bi opsy wi th i mmedi ate ALND, the fal se-negati ve rate was 9.7% , the
negati ve pr edi cti ve val ue was 96.1% , and the accuracy was 97.2% .
The i nvesti gator s concl uded that the rate of SLN i denti fi cati on was
si mi l ar i n both gr oups and that overal l accuracy and the negati ve
pr edi cti ve val ue wer e hi gh i n both gr oups.
Two other gr oups of pati ents that mi ght be consi der ed for SLN
bi opsy at the ti me of thei r defi ni ti ve sur ger y, but that ar e sti l l
rather contr over si al , ar e those r ecei vi ng total mastectomy for
noni nvasi ve cancer and hi gh-r i sk pati ents r ecei vi ng pr ophyl acti c
mastectomy. These two gr oups of pati ents may be at hi gh r i sk for
har bor i ng an occul t i nvasi ve cancer. Per for mi ng an SLN bi opsy at
the ti me of mastectomy may pr ecl ude the pati ent fr om havi ng to
under go a second operati on and an axi l l ar y l ymph node di ssecti on i n
the event that an occul t i nvasi ve cancer i s di scover ed after
hi stopathol ogi cal eval uati on of the mastectomy speci men.
Breast Reconstruction
For pati ents not under goi ng br east conser vati on, br east
r econstr ucti on shoul d be consi der ed a standar d opti on of cancer
therapy. Reconstr ucti on may i nvol ve autol ogous ti ssue, syntheti c
i mpl ants, or both. Al though sati sfactor y r esul ts can be obtai ned wi th
ei ther i mmedi ate or del ayed r econstr ucti on, MDACC physi ci ans favor
i mmedi ate r econstr ucti on for most pati ents, par ti cul ar l y those
unl i kel y to under go postmastectomy radi ati on therapy. Immedi ate
r econstr ucti on car r i es a substanti al psychol ogi cal benefi t for many
women and often al l ows a better cosmeti c r esul t. The i ni ti ati on of
adjuvant chemotherapy i s not si gni fi cantl y del ayed, and concer ns

that l ocal r ecur r ence may go undetected i n a r econstr ucted br east
ar e not wel l founded, especi al l y for T1 and T2 l esi ons. However, i f
the pati ent i s known to r equi r e postmastectomy radi ati on, the
pati ent i s often counsel ed to del ay the r econstr ucti on. Chapter 24
expands on the techni cal detai l s and potenti al opti ons for br east
r econstr ucti on.
At MDACC, al most hal f of the pati ents wi th br east cancer tr eated
wi th mastectomy under go i mmedi ate r econstr ucti on. Al though the
method of r econstr ucti on i s i ndi vi dual i zed, pedi cl ed or fr ee
transver se r ectus abdomi ni s myocutaneous fl aps ar e the most
commonl y used. Contral ateral augmentati on or r educti on may be
per for med to maxi mi ze symmetr y. For pati ents wi th bi l ateral br east
cancer who desi r e mastectomy or pati ents wi th a per cei ved hi gh r i sk
for a contral ateral second pr i mar y l esi on, si mul taneous
contral ateral pr ophyl acti c mastectomy wi th bi l ateral i mmedi ate
r econstr ucti on i s a vi abl e opti on. Counsel i ng r egar di ng the
possi bi l i ty of postmastectomy radi ati on and i ts subsequent
compl i cati ons to the r econstr ucted br east shoul d al ways be
di scussed wi th the pati ent.
MDACC physi ci ans typi cal l y per for m a ski n-spar i ng mastectomy i n
pati ents under goi ng i mmedi ate br east r econstr ucti on because
pr eser vati on of br east ski n al l ows for a mor e natural contour to the
r econstr ucted br east. No i ncr eased r i sk of l ocal r ecur r ence has been
obser ved for pati ents tr eated wi th ski n-spar i ng techni ques.
Current Treatment Standards for Systemic

Adjuvant Therapy
For node-posi ti ve and node-negati ve br east cancer pati ents,
deci si ons r egar di ng adjuvant chemotherapy must be i ndi vi dual i zed.
Cur r ent standar ds ar e based l ar gel y on pati ent age, l evel of
estr ogen r eceptor s expr essed by the tumor, si ze of the pr i mar y
tumor, and hi stol ogi c status of the axi l l a. Other factor s to consi der
ar e overal l heal th status, HER-2/neu oncogene ampl i fi cati on, and
nucl ear grade. G eneral gui del i nes r egar di ng the use of adjuvant
chemotherapy ar e pr esented i n Tabl e 2.6.
Cur r ent standar ds favor the use of mul ti dr ug combi nati on

chemotherapy i n al l pati ents except those wi th the most favorabl e
pr esentati on (i .e., node negati ve and pr i mar y tumor l ess than 1

cm). Resul ts fr om the Ear l y Br east Cancer Tr i al i sts Col l aborati ve
G r oup (EBCTCG ) i n 1995 and agai n i n 2000 i ndi cated that mul ti dr ug
chemotherapy si gni fi cantl y r educes di sease r ecur r ence and death i n
both node-posi ti ve and node-negati ve pati ents, r egar dl ess of stage,
menopausal status, r eceptor status, or pati ent age.
Table 2.6. Adjuvant chemotherapy

recommendations for patients with invasive b
carcinoma on the basis of axillary nodal sta
menopausal status, estrogen receptor expres
and tumor size
Nodal,
Menopausal, Tumor
Therapy
and ER
Size
Status
Comments
Positive node
Premenopausal
Negative
Any
Multidrug
combination
chemotherapy
Four to 8 c
of
anthracyclin
and taxane
combination
sequence a
the standar
for all node
positive
patients,
(CMF, CAF, or
AC; AC + Ta
Positive
regardless
ER or
menopausa
status; this
adjuvant
therapy has
been shown
prolong ove
survival
Multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)
+ tamoxifen
Addition of
tamoxifen t
chemothera
prolongs ov
survival
Multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)
Twenty per
reduction in
recurrence
11% reduct
in mortality
patients ag
50 to 69;
minimal dat
for patients
70
Tamoxifen 20
mg QD with
Combinatio
Postmenopausal
Negative
Positive
or without
multidrug
combination
chemotherapy
(CMF, CAF, or
AC; AC + T)
chemothera
and tamoxi
results in
longer over
survival tha
tamoxifen a
None;
consider
tamoxifen or
AI for
contralateral
risk reduction
Overall surv
after local
treatment a
is >90%; lo
toxicity and
beneficial
effects of
tamoxifen o
may justify
use
Consider
multidrug
combination
chemotherapy
(CMF, CAF, or
AC)
Prognostic
factors, suc
grade and H
2/neu statu
may be use
in selecting
patients for
chemothera
Negative node
Pre- or postmenopausal
Positive or
negative
<1
cm
1
cm
and
<2
cm
Negative
2
cm
Positive
1
cm
Multidrug
combination
chemotherapy
(CMF, CAF, or
AC)
Tamoxifen
with or
without
multidrug
combination
chemotherapy
(CMF, CAF, or
AC)
Reduction i
risk of
recurrence
equal to tha
observed in
node-positi
disease
Chemothera
is
recommend
for women
high-grade
tumors or T
lesions;
tamoxifen o
therapy is
recommend
for tumors
2 cm; decis
about the
addition of
cytotoxic
therapy for
pre- or
postmenopa
women sho
be made on
basis of
estrogen
receptor lev
performanc
status, and
tumor facto
ER, estrogen receptor; CMF, cyclophosphamide,

methotrexate, 5-fluorouracil; CAF; cyclophosphamid
doxorubicin (Adriamycin), 5-fluorouracil; AC,
doxorubicin (Adriamycin), cyclophosphamide; T,
taxane; QD, every day; AI, aromatase inhibitor.
a Addition of the taxane paclitaxel to 4 cycles of AC
treatment alternative.
Numer ous chemotherapy r egi mens ar e effecti ve i n the adjuvant
setti ng. The EBCTCG has shown that combi nati on chemotherapy i s
mor e effecti ve than si ngl e agents. Si x months of CMF
(cyl cophosphami de, methotr exate, and 5-fl uor ouraci l ) was the
standar d for many year s and i s sti l l used by some oncol ogi sts. The
anthracycl i nes doxor ubi ci n and epi r ubi ci n have become the mai nstay
of adjuvant chemotherapy. Thr ee months of the anthracycl i ne
r egi men AC (adr i amyci n and cycl ophosphami de) was shown to be
equi val ent to 6 months of CMF and i s ther efor e a commonl y used
r egi men i n the Uni ted States. However, the thr ee-dr ug
anthracycl i ne r egi mens FAC (5-fl uor ouraci l , adr i amyci n, and
cycl ophosphami de) and F EC ar e super i or to CMF and ar e thus
pr obabl y super i or to AC. Hence, the thr ee-dr ug r egi mens ar e
pr efer r ed at MDACC. For node-negati ve pati ents, acceptabl e
effecti ve adjuvant chemotherapy opti ons i ncl ude CMF, AC, FAC, and
F EC.
The taxanes pacl i taxel and docetaxel pl us anthracycl i nes have been
compar ed wi th anthracycl i nes al one i n node-posi ti ve pati ents. Thr ee
l ar ge randomi zed tr i al s have demonstrated a l onger di sease-fr ee
sur vi val ti me among node-posi ti ve pati ents who r ecei ved taxane
pl us anthracycl i ne. Thus, i t i s wi del y accepted that node-posi ti ve
pati ents shoul d r ecei ve AC, FAC, or F EC i n sequence or i n
combi nati on wi th pacl i taxel or docetaxel .
Chemotherapy i s typi cal l y gi ven ever y 3 weeks, al though emer gi ng
data have demonstrated si mi l ar effi cacy wi th weekl y or ever y-2week (dose dense) chemotherapy. The EBCTCG meta-anal ysi s has
shown that l ess than 3 months of chemotherapy i s i nsuffi ci ent and
mor e than 6 months i s unnecessar y. Stem cel l transpl ant has not
been shown to i mpr ove the overal l sur vi val rate and shoul d be used
onl y i n the context of a cl i ni cal tr i al .
Tamoxi fen, whi ch was or i gi nal l y r ecommended for the tr eatment of
postmenopausal women wi th estr ogen r eceptor-posi ti ve br east
cancer, i s now i ndi cated for a much br oader range of pati ents.
Regar dl ess of pati ent age or menopausal status, when used for the
standar d 5 year s, tamoxi fen i s associ ated wi th a 47% r educti on i n
the r i sk of br east cancer r ecur r ence and a 26% r educti on i n the r i sk
of death. Tamoxi fen therapy i s general l y wel l tol erated; tr eatmentl i mi ti ng adver se effects devel op i n l ess than 5% of pati ents. In
addi ti on to i ts anti tumor pr oper ti es, tamoxi fen i ncr eases bone
densi ty and r educes ser um chol ester ol l evel s. However, tamoxi fen
al so i ncr eases the i nci dence of endometr i al cancer and
thr omboembol i c events. Standar d tr eatment wi th tamoxi fen i s 5
year s. A meta-anal ysi s of fi ve randomi zed cl i ni cal tr i al s showed that
pati ents who wer e tr eated wi th tamoxi fen for 3 to 5 year s had a
gr eater r educti on i n r ecur r ence than di d pati ents tr eated for 1 to 2
year s (22% 8% vs. 7% 11% ). Data
fr om NSABP B-14 i ndi cated that 10 year s of tamoxi fen use offer no
sur vi val advantage over 5 year s. Tamoxi fen and chemotherapy
together achi eve an addi ti ve sur vi val benefi t.
The ar omatase i nhi bi tor s anastr ozol e, l etr ozol e, and exemestane
wor k by i nhi bi ti ng the ar omatase enz yme that catal yzes the
conver si on of adr enal cor ti coster oi ds to estr ogens and ther efor e
decr eases the pr oducti on of estr ogens i n postmenopausal women
onl y. The effi cacy and si de effect pr ofi l es of anastr ozol e and
tamoxi fen wer e compar ed i n postmenopausal women i n the ATAC
(Ar i mi dex, Tamoxi fen Al one or i n Combi nati on) tr i al , the l ar gest
br east cancer therapeuti c tr i al ever conducted. The r esul ts of the
tr i al demonstrated that i n adjuvant endocr i ne therapy for
postmenopausal pati ents wi th ear l y-stage br east cancer, anastr ozol e
r esul ted i n a hi gher di sease-fr ee sur vi val rate (86.9% vs. 84.5% ),
l onger ti me to r ecur r ence, and l ower i nci dence of contral ateral
br east cancer. The r esul ts al so demonstrated that the i nci dence of
endometr i al cancer, vagi nal bl eedi ng and di schar ge, cer ebr ovascul ar
events, venous thr omboembol i c events, and hot fl ashes occur r ed
si gni fi cantl y l ess fr equentl y wi th anastr ozol e, wher eas
muscul oskel etal di sor der s and fractur es occur r ed l ess fr equentl y
wi th tamoxi fen. As a r esul t of the ATAC tr i al , anastr ozol e i s now the
pr efer r ed hor mone therapy for postmenopausal pati ents wi th
r eceptor-posi ti ve br east cancer.

For pati ents al r eady taki ng tamoxi fen, r ecent studi es have
exami ned the r ol e of swi tchi ng fr om tamoxi fen to the ar omatase
i nhi bi tor exemestane after 2 to 3 year s of tamoxi fen or the
ar omatase i nhi bi tor, and l etr ozol e after 5 year s of tamoxi fen. Both
tr i al s demonstrated that swi tchi ng to the ar omatase i nhi bi tor s
i ncr eased the di sease-fr ee sur vi val rate. It i s uncl ear when an
ar omatase i nhi bi tor shoul d be i ni ti ated, and ongoi ng tr i al s ar e
compar i ng the ti mi ng and sequence of tamoxi fen and ar omatase
i nhi bi tor s.
Ther e i s no r ol e for ar omatase i nhi bi tor s i n pr emenopausal women,
and tamoxi fen r emai ns the gol d standar d for these pati ents.
Ongoi ng tr i al s ar e exami ni ng the useful ness of ovar i an abl ati on i n
addi ti on to tamoxi fen i n pr emenopausal pati ents, but ther e i s
cur r entl y no data to suppor t the r outi ne use of ovar i an abl ati on
outsi de of a cl i ni cal tr i al .
Systemic Neoadjuvant Therapy

The use of neoadjuvant chemotherapy has i ts or i gi ns i n the
management of i noperabl e l ocal l y advanced br east cancer. F ur ther
rati onal e for usi ng neoadjuvant therapy i ncl udes the potenti al to
downsi ze tumor s and subsequentl y be abl e to offer mor e pati ents
BCT, the abi l i ty to assess the i n vi vo r esponse to chemotherapeuti c
agents, and the theor eti cal ear l y tr eatment of di stant
mi cr ometastati c di sease. The di sadvantages of usi ng neoadjuvant
chemotherapy i ncl ude the possi bl e del ay of curati ve sur ger y,
psychosoci al factor s, subopti mal cl i ni cal and radi ol ogi c assessment
of the pr i mar y tumor, and the potenti al l oss of pr ognosti c
i nfor mati on.
The NSABP B-18 tr i al demonstrated that neoadjuvant chemotherapy
for operabl e pr i mar y br east cancer al l owed mor e pati ents to
successful l y under go br east conser vati on sur ger y and cor r el ated
cl i ni cal and pathol ogi cal r esponse to pr ognosi s.
However, i t al so demonstrated that ther e was no sur vi val advantage
wi th neoadjuvant chemotherapy over standar d adjuvant
chemotherapy. Ther efor e, i f the pati ent's pr i mar y tumor si ze at
i ni ti al pr esentati on pr ecl udes a good br east conser vati on outcome,
but the pr i mar y tumor has the potenti al to be downsi zed by
neoadjuvant chemotherapy and the woman desi r es br east
conser vati on sur ger y rather than mastectomy, neoadjuvant
chemotherapy shoul d be offer ed. Ther e i s sti l l potenti al for a hi gher

r i sk of r ecur r ence wi th conser vati ve sur ger y than wi th mastectomy,
r egar dl ess of whether neoadjuvant or adjuvant therapy i s used, and
thi s r i sk shoul d be di scussed wi th the pati ent.
The effect of di ffer ent chemotherapy r egi mens on tumor r esponse
can best be measur ed i n the neoadjvuant setti ng because thi s may
cor r el ate to pr ognosi s and to conti nued i mpr ovement of br eastconser vi ng sur ger y rates. The r esul ts fr om NSABP B-27 cl ear l y
demonstrated that four cycl es of AC pr eoperati vel y or four cycl es of
AC fol l owed by sur ger y wi th four cycl es of docetaxel postoperati vel y
was not as effi caci ous i n obtai ni ng a cl i ni cal or pathol ogi cal
compl ete r esponse as both four cycl es of AC fol l owed by four cycl es
of docetaxel i n the neoadjuvant setti ng. The addi ti on of docetaxel to
AC i ncr eased the cl i ni cal compl ete r esponse rate by 50% and near l y
doubl ed the pathol ogi cal compl ete r esponse rate compar ed wi th AC
al one.
At MDACC, the use of FAC or pacl i taxel i n the neoadjuvant setti ng
was eval uated. Pati ents wer e randoml y assi gned to r ecei ve
neoadjuvant FAC or pacl i taxel and then have l ocal therapy fol l owed
by addi ti onal FAC, XRT, (wi th or wi thout tamoxi fen) i f they wer e
postmenopausal and had r eceptor-posi ti ve tumor s. At 4 year s, the
di sease-fr ee sur vi val rate was not si gni fi cantl y di ffer ent between
the FAC and pacl i taxel gr oups (83% vs. 86% ), but the pathol ogi cal
compl ete r esponse rate was si gni fi cantl y better i n the FAC gr oup
(16.4% vs. 8.1% ).
Another tr i al exami ni ng a di ffer ent neoadjuvant chemotherapy
r egi men was the Aber deen tr i al . In thi s tr i al , the pati ents r ecei ved
four doses of CVAP (cycl ophosphami de, vi ncr i sti ne, doxor ubi ci n, and
pr edni sone) and then wer e exami ned for a cl i ni cal r esponse. Those
wi thout a compl ete r esponse went on to r ecei ve four doses of
docetaxel , and those wi th a compl ete r esponse wer e randoml y
assi gned to r ecei ve four mor e doses of CVAP or four cycl es of non
cr oss-r esi stant chemotherapy docetaxel . Thi s study demonstrated
the rate of br east-conser vi ng sur ger y was i mpr oved for those who
r ecei ved the noncr oss-r esi stant docetaxel (CVAP fol l owed by
docetaxel ) (67% ) compar ed wi th those who r ecei ved CVAP fol l owed
by mor e CVAP (48% ).
F i nal l y, the use of neoadjuvant chemotherapy pr ovi des r esear cher s
wi th oppor tuni ti es to i mpr ove chemotherapy use and pati ent
outcomes based on tumor r esponse. Newer techni ques such as
mi cr oar ray gene pr ofi l i ng ar e bei ng used to devel op a method of
cl assi fyi ng gene pr ofi l es associ ated wi th par ti cul ar tumor s that may
cor r el ate wi th pathol ogi cal compl ete r esponse. These data may
eventual l y i denti fy whi ch pati ents wi l l benefi t fr om a par ti cul ar
r egi men or whi ch pati ents can be spar ed systemi c therapy.
Trastuzumab
Trastuz umab (Her cepti n) i s a monocl onal anti body that tar gets the
HER-2/neu oncogene, whi ch codes for a gr owth factor that i s
over expr essed i n 25% to 30% of br east cancer s. The anti body wor ks
by bi ndi ng to the HER-2 gr owth factor r eceptor s pr esent on the
sur face of the cancer cel l s and ther eby downr egul ates the r eceptor s.
The effects of trastuz umab ar e r estr i cted to pati ents wi th HER2/neu-over expr essi ng tumor s. Trastuz umab i s effecti ve as a si ngl e
agent, but i t acts syner gi sti cal l y wi th numer ous chemotherapeuti c
agents, i ncl udi ng taxanes and vi nor el bi ne. For thi s r eason,
trastuz umab pl us chemotherapy i s the standar d of car e for pati ents
wi th HER-2/neu-ampl i fi ed, metastati c tumor s. Trastuz umab i s now
bei ng eval uated i n ear l i er-stage br east cancer.
In the neoadjuvant setti ng, trastuz umab pl us nonanthracycl i necontai ni ng chemotherapy has been shown i n var i ous smal l tr i al s to
i nduce a compl ete pathol ogi cal r esponse i n 19% to 35% of pati ents.
One of four ongoi ng tr i al s cur r entl y l ooki ng at the effecti veness of
an adjuvant r egi men contai ni ng trastuz umab pl us chemotherapy,
NSABP B-31 i s exami ni ng the use of doxor ubi ci n and
cycl ophosphami de fol l owed by pacl i taxel wi th or wi thout
trastuz umab. Resear cher s at MDACC exami ned the effi cacy of
neoadjuvant trastuz umab pl us pacl i taxel and F EC i n tr eati ng
operabl e HER-2/neu-posi ti ve br east cancer s and compar ed these
pati ents wi th pati ents who r ecei ved onl y pacl i taxel and F EC. The
r esul ts demonstrated that trastuz umab-based neoadjuvant therapy
r esul ted i n a si gni fi cantl y hi gher pathol ogi cal compl ete r esponse
rate. Because ther e have been r epor ts of congesti ve hear t fai l ur e i n
pati ents tr eated wi th trastuz umab, neoadjuvant or adjuvant
trastuz umab shoul d be used onl y i n the setti ng of cl i ni cal tr i al s unti l
the l ong-ter m car di ac safety data ar e known.
Surgical Considerations after Neoadjuvant

Chemotherapy
Ther e ar e numer ous factor s to consi der befor e usi ng neoadjuvant
chemotherapy to tr eat br east cancer. (a) Wi l l admi ni ster i ng
neoadjuvant chemotherapy conver t an other wi se l ar ge tumor

r equi r i ng mastectomy i nto one manageabl e by BCT? If not, then
neoadjuvant chemotherapy may not be desi rabl e because a
mastectomy wi l l need to be per for med ei ther way, and much of the
i nfor mati on (e.g., tumor si ze and l ymph node i nvol vement wi th
metastases) useful i n deter mi ni ng whether ther e i s a r ol e for
fur ther tr eatment wi th radi ati on may be l ost. (b) The tumor i n the
br east must be car eful l y l ocal i zed wi th a cl i p or per manent mar ker
befor e chemotherapy to ensur e pr oper l ocal i z ati on of the tumor
dur i ng sur ger y i n the event that the chemotherapy pr oduces a
compl ete cl i ni cal r esponse. (c) How much ti ssue shoul d be r emoved
dur i ng sur ger y after chemotherapy i s compl eted? The answer i s
debatabl e, but general l y al l gr oss di sease pl us any other suspi ci ous
ar eas wi th a r i m of nor mal -appear i ng ti ssue shoul d be r emoved. (d)
How shoul d the nodal basi n after neoadjuvant chemotherapy be
managed? One opti on i s to scr een the axi l l a befor e chemotherapy
wi th ul trasound or SLN bi opsy. If ther e ar e
ei ther cl i ni cal l y suspi ci ous nodes or nodes that appear to har bor
di sease, SLN bi opsy or ul trasound-gui ded F NA of the nodes i n
questi on coul d be per for med befor e the star t of chemotherapy to
confi r m metastases. If the r esul t of the bi opsy i s posi ti ve, then a
for mal ALND shoul d be per for med dur i ng defi ni ti ve sur ger y. A
negati ve ul trasound-gui ded F NA or SLN bi opsy r esul t pr oduces mor e
of a di l emma. In thi s si tuati on, whether to per for m SLN bi opsy or
ALND after chemotherapy i s uncl ear and i s cur r entl y bei ng
i nvesti gated by the Amer i can Col l ege of Sur geons Oncol ogy G r oup.
At MDACC, oncol ogi sts r outi nel y per for m SLN bi opsy after
neoadjuvant chemotherapy dur i ng defi ni ti ve sur ger y i f the pati ents
wer e cl i ni cal l y node negati ve by physi cal and ul trasound
exami nati ons pr i or to i ni ti ati ng chemotherapy.
Follow-Up After Primary Treatment of

Invasive Breast Cancer
After pr i mar y therapy for i nvasi ve br east cancer, pati ents must be
made awar e of the l ong-ter m r i sk for r ecur r ent or metastati c
di sease. Al though most studi es r epor t that r ecur r ences occur wi thi n
5 year s after pr i mar y therapy, r ecur r ences can occur mor e than 20
year s after pr i mar y therapy.
The publ i shed Amer i can Soci ety of Cl i ni cal Oncol ogy gui del i nes for
fol l ow-up i ndi cate that ther e i s no sur vi val advantage to r outi ne
l aborator y and radi ographi c studi es because ear l y detecti on of
metastati c di sease rar el y affects the overal l sur vi val rate. Instead,
pati ents shoul d meet wi th thei r doctor s for di scussi on of new
symptoms, physi cal exams, and year l y mammograms. Schedul ed
fol l ow-up vi si ts shoul d be under taken ever y 4 months for year s 1
and 2, ever y 6 months for year s 3 thr ough 5, and ever y 12 months
ther eafter. Monthl y sel f-exami nati on of the br easts i s al so
r ecommended. Mammography i s done 6 months after the compl eti on
of BCT to al l ow sur ger y- and radi ati on-i nduced changes to stabi l i ze,
and then year l y. For pati ents who have under gone mastectomy, a
contral ateral mammogram i s obtai ned year l y. Routi ne bone scans,
skel etal sur veys, and computed tomographi c scans of the abdomen
and brai n yi el d an extr emel y l ow rate of occul t metastases i n
other wi se asymptomati c pati ents and i s not cost-effecti ve for
pati ents wi th ear l y-stage br east cancer.
Locally Recurrent Breast Cancer

The ti me cour se, cl i ni cal si gni fi cance, and pr ognosi s of l ocal l y
r ecur r ent br east cancer var y dramati cal l y between pati ents
under goi ng BCT and those under goi ng mastectomy. Local r ecur r ence
rates of 5% to 10% at 8 to 10 year s have been r epor ted for
pati ents wi th conser ved br easts. Local r ecur r ence typi cal l y occur s
over a pr otracted ti me and i s associ ated wi th systemi c metastases i n
l ess than 10% of pati ents. Local r ecur r ence fol l owi ng l umpectomy i s
curabl e i n most cases; 50% to 63% of pati ents wi th l ocal r ecur r ence
wi l l r emai n di sease-fr ee 5 year s after sal vage mastectomy.
In contrast, l ocal chest wal l r ecur r ence fol l owi ng mastectomy
typi cal l y occur s wi thi n the fi r st 2 to 3 year s after sur ger y. It i s
associ ated wi th di stant metastases i n as many as two thi r ds of
pati ents and r esul ts i n eventual death for many. One thi r d of
pati ents wi th chest wal l r ecur r ence wi l l have concur r ent di stant
metastati c di sease, and wi thi n 1 year, hal f wi l l have di stant di sease.
The medi an sur vi val i n thi s setti ng i s 2 to 3 year s.
Al though uncl ear, pati ents wi th an appar entl y i sol ated l ocal
r ecur r ence after BCT can often be tr eated wi thout systemi c
cytotoxi c chemotherapy dependi ng on the stage at pr esentati on.
Any pati ent wi th a l ocal r ecur r ence, especi al l y chest wal l
r ecur r ences after mastectomy, shoul d under go compl ete r estagi ng
after detecti on of the r ecur r ence. For pati ents wi th a pur el y l ocal
r ecur r ence, sur gi cal exci si on pl us radi ati on therapy pr ovi des better
l ocal contr ol than does ei ther modal i ty al one.
Metastatic Breast Cancer

Metastati c br east cancer general l y cannot be cur ed, and tr eatment
i s mai nl y pal l i ati ve. The medi an sur vi val after detecti on of di stant
metastases i s 2 year s, but some pati ents l i ve for many year s. Other
than trastuz umab-based chemotherapy, chemotherapy rar el y
pr ol ongs sur vi val and i s di r ected at i mpr ovi ng tumor-r el ated
symptoms and sl owi ng the spr ead of the tumor. The most common
si te of di stant metastati c spr ead i s the osseous skel eton; other
common si tes ar e the soft ti ssues, l ymph nodes, l ungs, pl eura, and
l i ver. Cer tai n subtypes of br east cancer pr esent di ffer ent patter ns of
metastases. For exampl e, pati ents wi th rapi dl y gr owi ng, hor mone
r eceptor-negati ve, and poor l y di ffer enti ated tumor s ar e l i kel y to
have metastases to vi sceral or gans (e.g., l i ver, l ungs, brai n),
wher eas pati ents wi th sl owl y gr owi ng, hor mone r eceptor-posi ti ve,
and wel l -di ffer enti ated tumor s ar e l i kel y to devel op metastases to
bone and soft ti ssues and ar e l ess l i kel y to exhi bi t ear l y l i fethr eateni ng mani festati ons.
For pati ents wi th metastases, the deci si on to tr eat wi th systemi c
chemotherapy or hor monal therapy r ests on several i ssues: the si te
and extent of the di sease, hor mone r eceptor status, di sease-fr ee
i nter val , age, and menopausal status. Pati ents wi th sl owl y gr owi ng,
l i mi ted, and nonl i fe-thr eateni ng metastati c di sease and hor mone
r eceptor-posi ti ve or known hor mone-r esponsi ve tumor s ar e
general l y offer ed hor monal therapy as the fi r st therapeuti c
modal i ty. Because al l hor monal mani pul ati ons used today have a
better therapeuti c rati o than do cytotoxi c therapi es, the practi cal
r esul t of sequenti al hor monal therapi es i s that pati ents can be
acti vel y tr eated wi th few systemi c si de effects. When hor monal
therapy i s no l onger effecti ve, these pati ents pr oceed to
chemotherapy. For pati ents wi th mor e extensi ve (i .e., symptomati c)
or l i fe-thr eateni ng di sease and for al l pati ents wi th hor mone
r eceptor-negati ve br east cancer, combi nati on chemotherapy i s the
fi r st tr eatment of choi ce. Anthracycl i nes (e.g., doxor ubi ci n) and
taxanes (e.g., pacl i taxel , docetaxel ) ar e cur r entl y the most effecti ve
anti tumor agents agai nst metastati c br east cancer.
The choi ce of i ni ti al chemotherapy depends on the pati ent's age,
per for mance status, pr i or neoadjuvant and adjuvant chemotherapy,
and di sease-fr ee i nter val . Anthracycl i nes or taxanes ar e opti ons, as
ar e capeci tabi ne, vi nor el bi ne, and gemci tabi ne. Because metastati c
br east cancer i s i ncurabl e wi th standar d therapi es, enr ol l ment i n
cl i ni cal tr i al s i s al ways encouraged. Tar geted agents agai nst
epi der mal gr owth factor r eceptor, vascul ar endothel i al gr owth factor,
and other tumor-r el ated pr otei ns ar e acti vel y

under i nvesti gati on. Trastuz umab-based chemotherapy i s the
standar d of car e for those wi th HER-2/neu-ampl i fi ed tumor s;
however, for al l other pati ents, combi nati on chemotherapy has not
been shown to pr ol ong sur vi val over sequenti al si ngl e agents, and i t
i s associ ated wi th mor e i ntense si de effects. Thus, outsi de of a
cl i ni cal tr i al , pati ents wi th metastati c br east cancer ar e typi cal l y
tr eated wi th sequenti al si ngl e agents.
Breast Cancer and Pregnancy

The i nci dence of br east cancer, whi ch accounts for 2.8% of br east
mal i gnanci es, detected dur i ng pr egnancy i s 2 per 10,000 gestati ons.
The di agnosi s of br east cancer i s typi cal l y mor e di ffi cul t i n a
pr egnant woman because of a l ow l evel of suspi ci on based on a
general l y young pati ent age, the r el ati ve fr equency of nodul ar
changes i n the br east dur i ng pr egnancy, and the i ncr ease i n br east
densi ty dur i ng pr egnancy that r ender s mammographi c i magi ng l ess
accurate. For these and other r easons, di agnosi s of br east cancer
dur i ng pr egnancy i s fr equentl y del ayed. Thi s del ay, rather than
speci fi c di ffer ences i n the bi ol ogy of br east cancer between
pr egnant and nonpr egnant women, l i kel y expl ai ns the r el ati vel y
poor pr ognosi s for women wi th br east cancer detected dur i ng
pr egnancy. When matched for tumor stage, pr egnant women wi th
br east cancer appear to have a si mi l ar pr ognosi s as nonpr egnant
pati ents wi th br east cancer.
Because the accuracy of mammography i s l i mi ted i n thi s setti ng, al l
per si stent and suspi ci ous br east masses di scover ed dur i ng
pr egnancy shoul d under go eval uati on by F NA, cor e-needl e bi opsy, or
exci si onal bi opsy pl us an ul trasound exami nati on. Exci si onal bi opsy
under l ocal anesthesi a i s safe at any ti me dur i ng pr egnancy.
Inci si onal bi opsy i s not r ecommended for di agnosi s because of the
possi bi l i ty of the pati ents devel opi ng a fi stul a. Al though
contr over si al , when cancer i s di agnosed, mammography can sti l l be
per for med i n the gravi d femal e when the fetus i s shi el ded
adequatel y. Once a di agnosi s of mal i gnancy i s establ i shed,
tr eatment deci si ons ar e i nfl uenced by the speci fi c tr i mester of
pr egnancy. For women who want to compl ete thei r pr egnanci es, the
goal shoul d be curati ve tr eatment of the br east cancer wi thout
i njur y to the fetus. Ter mi nati on of pr egnancy i n the hope of
mi ni mi z i ng hor monal sti mul ati on of the tumor does not al ter
mater nal sur vi val and i s not r ecommended.
Sur gi cal tr eatment of gestati onal br east cancer i s general l y

i denti cal to that of nongestati onal br east cancer. Ther e i s no
evi dence that extra-abdomi nal sur gi cal pr ocedur es ar e associ ated
wi th pr ematur e l abor or that the typi cal l y used anestheti c agents
ar e teratogeni c. Modi fi ed radi cal mastectomy as pr i mar y therapy can
be under taken at any poi nt dur i ng pr egnancy wi thout undue r i sk to
the mother or fetus. For cancer detected dur i ng the thi r d tr i mester,
del ayi ng pr i mar y tr eatment for up to 4 weeks to al l ow for del i ver y
befor e sur ger y i s acceptabl e. If modi fi ed radi cal mastectomy i s
under taken dur i ng pr egnancy, br east r econstr ucti on shoul d not be
per for med si mul taneousl y; a symmetr i c r esul t i s i mpossi bl e unti l
the postpar tum appearance of the contral ateral br east i s known.
For women desi r i ng br east conser vati on, tr eatment i s compl i cated
by the fact that radi ati on therapy i s contrai ndi cated
dur i ng pr egnancy. For cancer s detected dur i ng the thi r d tr i mester,
l umpectomy and axi l l ar y di ssecti on can be per for med safel y usi ng
general anesthesi a, and radi ati on therapy can be del ayed unti l after
del i ver y. Longer del ays may be detr i mental to mater nal outcome,
al though the ti me l i mi t wi thi n whi ch radi ati on therapy must be
car r i ed out to mi ni mi ze the r i sk of l ocal r ecur r ence i s unknown.
It may be necessar y to admi ni ster cytotoxi c adjuvant chemotherapy
dur i ng pr egnancy, whi ch may rai se fear s of congeni tal
mal for mati ons. Most studi es have demonstrated no i ncr eased r i sk of
fetal mal for mati on associ ated wi th chemotherapy admi ni ster ed
dur i ng the second and thi r d tr i mester s. In contrast, chemotherapy
admi ni strati on dur i ng the fi r st tr i mester i s associ ated wi th an
i ncr eased i nci dence of spontaneous abor ti on and congeni tal
mal for mati on, especi al l y when methotr exate i s used.
Cystosarcoma Phyllodes
Cystosar coma phyl l odes r epr esents an uncommon fi br oepi thel i al
br east neopl asm and accounts for onl y 0.5% to 1% of br east
car ci nomas. These tumor s can occur i n women of al l ages, i ncl udi ng
adol escents and the el der l y, but most ar i se i n women between 35
and 55 year s of age. Cystosar coma phyl l odes ar e typi cal l y qui te
l ar ge and have a mean di ameter of 4 to 5 cm. Because phyl l odes
tumor s and fi br oadenomas ar e mammographi cal l y i ndi sti ngui shabl e,
the deci si on to per for m exci si onal bi opsy i s usual l y based on l ar ge
tumor si ze, a hi stor y of rapi d gr owth, and pati ent age. Pr edi cti ng
the behavi or of these tumor s on the basi s of hi stopathol ogi cal
featur es such as hi sti otype (beni gn vs. i ndeter mi nate vs.

mal i gnant), mar gi n status, str omal over gr owth, and si ze has been
di ffi cul t par tl y because of thei r rar i ty. Common si tes of metastases
fr om mal i gnant cystosar coma phyl l odes ar e l ung, bone, and
medi asti num.
Appr opr i ate tr eatment for phyl l odes tumor s i s compl ete sur gi cal
exci si on. Br east conser vati on sur ger y wi th appr opr i ate mar gi ns i s
the pr efer r ed pr i mar y therapy. The i nci dence of l ocal r ecur r ence
ranges fr om 5% to 15% for beni gn tumor s and 20% to 30% for
mal i gnant tumor s. Local r ecur r ences ar e typi cal l y sal vageabl e wi th
total mastectomy and do not affect the overal l sur vi val rate. For al l
phyl l odes tumor s, the l ow i nci dence of axi l l ar y nodal metastases
(l ess than 1% ) obvi ates l ymphadenectomy. The r epor ted rates of
di stant metastasi s for pati ents wi th mal i gnant tumor s range fr om
25% to 40% . The pr esence of str omal over gr owth may be the
str ongest pr edi ctor of di stant metastasi s and ul ti mate outcome. To
date, no r ol e for radi ati on therapy, chemotherapy, or hor monal
therapy has been establ i shed for thi s di sease.
Recommended Reading
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Col l aborati ve G r oup. Lancet 1998;352:930.
Anonymous. Tamoxi fen for ear l y br east cancer : an over vi ew of
the randomi zed tr i al s. Ear l y Br east Cancer Tr i al i sts Col l aborati ve
G r oup. Lancet 1998;351:1451.
Bar navon Y, Wal l ack MK. Management of the pr egnant pati ent
wi th car ci noma of the br east. Sur g G ynecol Obstet
1990;171:347.
Baum M, Buzdar A, Cuz i ck J, et al . The ATAC (Ar i mi dex,
Tamoxi fen Al one or i n Combi nati on) Tr i al i sts G r oup. Anastr ozol e
al one or i n combi nati on wi th tamoxi fen ver sus tamoxi fen al one
for adjuvant tr eatment of postmenopausal women wi th ear l y-
stage br east cancer : r esul ts of the ATAC (Ar i mi dex, tamoxi fen
al one or i n combi nati on) tr i al effi cacy and safety update
anal yses. Cancer 2003;98:1802.
Braun S, Pantel K, Mul l er P, et al . Cytokerati n-posi ti ve cel l s i n
the bone mar r ow and sur vi val of pati ents wi th stage I, II, or III
br east cancer. N Engl J Med 2000;342:525.
Cady B. A contemporar y vi ew of axi l l ar y di ssecti on. Br east Dis
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Chaney AW, Pol l ack A, McNeese MD, et al . Pr i mar y tr eatment of
cystosar coma phyl l odes of the br east. Cancer 2000;89:1502.
F i sher B, Ander son S, Redmond CK, et al . Reanal ysi s and r esul ts
after 12 year s of fol l ow-up i n a randomi zed cl i ni cal tr i al
compar i ng total mastectomy wi th l umpectomy wi th or wi thout
i r radi ati on i n the tr eatment of br east cancer. N Engl J Med
1995;333:1456.
F i sher B, Br yant J, Wol mar k N, et al . Effect of pr eoperati ve
chemotherapy on the outcome of women wi th operabl e br east
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F i sher B, Redmond C, F i sher ER, et al . Ten-year r esul ts of a
randomi zed cl i ni cal tr i al compar i ng radi cal mastectomy and total
mastectomy wi th or wi thout radi ati on. N Engl J Med
1985;312:674.
G i ul i ano AE. Senti nel l ymph node di ssecti on i n br east cancer.
Pr oc Am Soc Clin Oncol 2001;530.
G r eco M, Agr esti R, Casci nel l i N, et al . Br east cancer pati ents
tr eated wi thout axi l l ar y sur ger y: cl i ni cal i mpl i cati ons and bi ol ogi c
anal ysi s. Ann Sur g 2000;232:1.
G r odstei n F, Mei r S, G raham C, et al . Postmenopausal hor mone
therapy and mor tal i ty. N Engl J Med 1997;336:1769.
Har r i s JR, Li ppman ME, Ver onesi U, et al . Br east cancer. N Engl J
Med 1992;327:319, 390, 473.

Hender son IC. Ri sk factor s for br east cancer devel opment. Cancer
1993;71(suppl 6):2128.
Hor tobagyi G N. Tr eatment of br east cancer. N Engl J Med
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the MammoSi te br east brachytherapy appl i cator i n women wi th
ear l y-stage br east cancer tr eated wi th br east-conser vi ng therapy.
Int J Radiat Oncol Biol Phys 2003;55:289.
Khanna MM, Mar k RJ, Si l ver stei n MJ, et al . Br east conser vati on
management of br east tumor s 4 cm or l ar ger. Ar ch Sur g
1992;9:1038.
Krag D, Weaver D, Ashi kaga T, et al . The senti nel node i n br east
cancer : a mul ti center val i dati on study. N Engl J Med
1998;339:941.
Kuer er HM, Hunt KK, Newman LA, et al . Neoadjuvant
chemotherapy i n women wi th i nvasi ve br east car ci noma:
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McG ui r e WL, Cl ar k G M. Pr ognosti c factor s and tr eatment deci si ons
i n axi l l ar y node-negati ve br east cancer. N Engl J Med
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postmenopausal women. Am J Sur g 2004;188:136.

M.
Edition
> Ta ble o f C o nt e nt s > 3 - M e la no m a
3
Melanoma
Timothy M. Paw lik
Jeffrey E. Gershenw ald
Epidemiology
The i nci dence of i nvasi ve cutaneous mel anoma i n the Uni ted States
has been r i si ng by an average of 3% per year. An esti mated 68,780
cases of i nvasi ve mel anoma wi l l be di agnosed i n the Uni ted States
i n 2006. For Amer i cans, the cur r ent esti mated l i feti me r i sk of
devel opi ng mel anoma i s 1 i n 74; an esti mated 10,710 peopl e wi l l
di e of mel anoma i n 2006. The i nci dence of mel anoma has been
i ncr easi ng faster than that of any other cancer. The major
envi r onmental r i sk factor, exposur e to ul travi ol et B (UV-B)
radi ati on, i s r efl ected i n geographi c and ethni c patter ns of
mel anoma rates. Al though ther e i s some evi dence that the i ncr ease
i n mel anoma i nci dence has abated ver y r ecentl ypossi bl y as a
r esul t of i ncr eased ear l y detecti on, changes i n r ecr eati onal
behavi or, and i ncr eased sun pr otecti oni t i s uncl ear when the
mel anoma epi demi c wi l l peak and how geographi c patter ns wi l l
change over ti me. Ther e have been changes i n the di str i buti on and
stage of mel anoma at di agnosi s, wi th an i ncr ease i n thi nner l esi ons.
At pr esent, many mel anomas seen at many i nsti tuti ons ar e l ess
than 1 mm thi ck.
Risk Factors
Identi fyi ng r i sk factor s and esti mati ng an i ndi vi dual 's r i sk of
devel opi ng mel anoma ar e i mpor tant. Strati fyi ng pati ents by r i sk can
be cl i ni cal l y useful i n deter mi ni ng pr i mar y pr eventi on strategi es and
i n di r ecti ng the l evel of scr eeni ng. Pati ents i denti fi ed as bei ng at
hi gh r i sk for mel anoma shoul d be r ecr ui ted to pr eventi on tr i al s.
Mul ti pl e factor s can pl ace a pati ent at r i sk for devel opi ng

mel anoma:
1. Skin type: Peopl e wi th a whi te raci al backgr ound have at l east
ten ti mes the mel anoma i nci dence of Afr i can Amer i cans and
seven ti mes the mel anoma i nci dence of Amer i can Hi spani cs. In
addi ti on, whi te pati ents who ar e fai r or who have r ed hai r, l i ght
ski n, or bl ue eyes have a par ti cul ar pr opensi ty to be at
i ncr eased r i sk for mel anoma.
2. Age: The i nci dence of mel anoma i ncr eases wi th age. Data have
shown that the i nci dence of mel anoma i s si mi l ar i n women and
men younger than 50 year s and hi gher i n men than i n women
ol der than 50 year s.
3. G ender : In general , the i nci dence of mel anoma i s hi gher i n men
than i n women. Speci fi cal l y, a man's r i sk of mel anoma
devel opment over hi s l i feti me i s 1.7 ti mes a woman's r i sk.
4. Tanning bed use: The use of a tanni ng bed mor e than ten ti mes
per year i s associ ated wi th a doubl i ng i n the r i sk of mel anoma
for pati ents age 30 year s or ol der. Young pati ents who use
tanni ng booths mor e than ten ti mes per year have
mor e than seven ti mes the mel anoma r i sk of pati ents who do not
use tanni ng booths.
5. Pr evious melanoma: The r i sk of devel opi ng a second mel anoma
i n a pati ent who has had a mel anoma i s 3% to 7% ; thi s r i sk i s
mor e than 900 ti mes that of the general popul ati on.
6. Sunlight exposur e: Occasi onal or r ecr eati onal exposur e to
sunl i ght, especi al l y a hi stor y of sever e bl i ster i ng sunbur n, has
been associ ated wi th i ncr eased r i sk of mel anoma. Ther e i s a
cor r el ati on between the number of sever e and pai nful sunbur n
epi sodes and the r i sk of mel anoma; pati ents who have a hi stor y
of ten or mor e sever e sunbur ns ar e mor e than twi ce as l i kel y to
devel op a mel anoma compar ed wi th pati ents who have no hi stor y
of sunbur ns. It i s i mpor tant to note that even sunbur ns after the
age of 20 year s may be associ ated wi th an i ncr eased r i sk of
mel anoma. The effects of sunl i ght have been attr i buted to
exposur e to UV-B radi ati on, whi ch, accor di ng to hypotheti cal
mechani sms of mel anoma i nducti on, may account for
appr oxi matel y two-thi r ds of mel anomas.
7. Benign nevi: Al though a beni gn nevus i s most l i kel y not a
pr ecur sor of mel anoma, the pr esence of l ar ge number s of nevi

has been consi stentl y associ ated wi th an i ncr eased r i sk of
mel anoma. Per sons wi th mor e than 50 nevi , al l of whi ch ar e
gr eater than 2 mm i n di ameter, have 5 to 17 ti mes the
mel anoma r i sk of per sons wi th fewer nevi .
8. F amily histor y: A fami l y hi stor y of mel anoma i ncr eases a
per son's r i sk of mel anoma by thr ee to ei ght ti mes. Per sons who
have two or mor e fami l y member s wi th mel anoma ar e at a
par ti cul ar l y hi gh r i sk for devel opi ng mel anoma.
9. G enetic pr edisposition: Speci fi c geneti c al terati ons have been
i mpl i cated i n the pathogenesi s of mel anoma. At l east four
di sti nct genesl ocated on chr omosomes 1p, 6q, 7, and 9may
pl ay a r ol e i n mel anoma. A tumor suppr essor gene l ocated on
chr omosome 9p21 i s pr obabl y i nvol ved i n fami l i al and sporadi c
cutaneous mel anoma. Del eti ons or r ear rangements of
chr omosomes 10 and 11 ar e al so wel l documented i n cutaneous
mel anoma. Mor e r ecentl y, geneti c r esear ch has i denti fi ed
speci fi c var i ants that confer suscepti bi l i ty to cutaneous
mal i gnant mel anoma. Var i ants outsi de the codi ng r egi on of the
CDKN2A gene ar e associ ated wi th mel anoma pr edi sposi ti on. A
mutati on i n the 5 untransl ated end of CDKN2A generates a
novel upstr eam i ni ti ati on codon that abr ogates expr essi on of
p16, whi ch i s necessar y for tumor suppr essi on.
Another geneti c al terati on that may pl ay a r ol e i s mutati on i n
the B-RAF gene. RAF pr otei ns ar e a fami l y of ser i ne/thr eoni nespeci fi c pr otei n ki nases that for m par t of a si gnal i ng modul e that
r egul ates cel l pr ol i ferati on, di ffer enti ati on, and sur vi val . In
mammal s, ther e ar e thr ee i sofor ms: A-RAF, B-RAF, and C-RAF.
Recentl y, i t was shown that the B-RAF i sofor m i s mutated i n a
hi gh pr opor ti on (60% 70% ) of mel anomas. The major i ty of the
mutati ons that have been found i n B-RAF ar e somati c changes
pr esumed to be i nduced by envi r onmental factor s. Most studi es
have concl uded that
B-RAF i s not a mel anoma pr edi sposi ti on gene. Rather, some
i nvesti gator s have pr oposed a model i n whi ch B-RAF pl ays a key
r ol e i n pr otecti ng agai nst pr ogr essi on i n the ear l y stages of the
di sease. One mutati on, a gl utami c-aci d-for-val i ne substi tuti on at
posi ti on 600 (V600E), accounts for mor e than 90% of the B-RAF
mutati ons i n mel anoma. Thi s mutati on causes acti vati on of
downstr eam effector s of the mi togen-acti vated pr otei n ki nasesi gnal i ng cascade, l eadi ng to mel anoma tumor pr ogr essi on by an
unknown mechani sm.
10. Atypical mole and melanoma syndr ome: Pr evi ousl y known as
dyspl asti c nevus syndr ome, atypi cal mol e and mel anoma
syndr ome i s character i zed by the pr esence of l ar ge number s of
atypi cal mol es (dyspl asti c nevi ) that r epr esent a di sti nct
cl i ni copathol ogi cal type of mel anocyti c l esi on. They can be
pr ecur sor s of mel anoma and/or mar ker s of i ncr eased mel anoma
r i sk. Al though the actual fr equency of an atypi cal mol e
pr ogr essi ng to mel anoma i s smal l , pati ents wi th atypi cal mol e
and mel anoma syndr ome shoul d be obser ved cl osel y, and fami l y
member s shoul d al so be scr eened.
Cl i ni cal featur es of mel anoma i ncl ude var i egated col or, i r r egul ar
rai sed sur face, i r r egul ar per i meter, and sur face ul cerati on. A bi opsy
shoul d be per for med on any pi gmented l esi on that under goes a
change i n si ze, confi gurati on, or col or. The so-cal l ed ABCDEs of
ear l y di agnosi s ar e an easy mnemoni c devi ce to hel p physi ci ans and
l ayper sons r emember the ear l y si gns of mal i gnant mel anoma. A
denotes l esi on asymmetr y, B bor der i r r egul ar i ty, C col or var i egati on,
D di ameter gr eater than 6 mm, and E a l esi on that i s evol vi ng or
enl ar gi ng.
When a pati ent pr esents wi th a l esi on suggesti ve of mel anoma, a
thor ough physi cal exami nati on must be per for med, wi th par ti cul ar
emphasi s on the ski n, al l nodal basi ns, and subcutaneous ti ssues.
Chest radi ography and l i ver functi on studi es shoul d be per for med i f
i nvasi ve mel anoma i s confi r med. F ur ther eval uati on i s based on
pathol ogi cal fi ndi ngs. In general , we di scourage r outi ne extensi ve
eval uati on wi th computed tomography or posi tr on emi ssi on
tomography (PET) because thei r yi el d i n the absence of symptoms,
abnor mal l aborator y fi ndi ngs, or abnor mal fi ndi ngs on chest
radi ography i s ver y l ow i n pati ents wi th pr i mar y mel anoma.
Melanoma BIOPSY
The choi ce of bi opsy techni que var i es accor di ng to the anatomi cal
si te, si ze, and shape of the l esi on. Defi ni ti ve therapy must be
consi der ed i n choosi ng a bi opsy techni que. Ei ther an exci si onal
bi opsy or an i nci si onal bi opsy usi ng a scal pel or punch i s acceptabl e.
An exci si onal bi opsy al l ows the pathol ogi st to most accuratel y
deter mi ne the thi ckness of the l esi on. For exci si onal bi opsi es, a
nar r ow mar gi n of nor mal -appear i ng ski n (13 mm) i s taken wi th the
speci men. An el l i pti cal i nci si on i s used to faci l i tate cl osur e. The
bi opsy i nci si on shoul d be or i ented to faci l i tate l ater wi de l ocal
exci si on (e.g., l ongi tudi nal l y on extr emi ti es) and mi ni mi ze the need
for a ski n graft to pr ovi de wound cl osur e. We r eser ve punch bi opsy
for l esi ons that ar e l ar ge, ar e l ocated on anatomi cal ar eas wher e
maxi mum pr eser vati on of sur r oundi ng ski n i s
i mpor tant, or can be compl etel y exci sed wi th a 6-mm punch. Punch
bi opsi es shoul d be per for med at the most rai sed or dar kest ar ea of
the l esi on. F ul l -thi ckness bi opsy i nto the subcutaneous ti ssue must
be per for med to per mi t pr oper mi cr ostagi ng of the l esi on (see the T
Stagi ng secti on l ater i n thi s chapter ).
Shave bi opsi es ar e di scouraged i f a di agnosi s of mel anoma i s bei ng
consi der ed. F i ne-needl e aspi rati on bi opsy may be used to document
nodal and extranodal mel anoma metastases but shoul d not be used
to di agnose pr i mar y mel anomas. In general , we send al l pi gmented
l esi ons for per manent-secti on exami nati on and per for m defi ni ti ve
sur ger y at a l ater ti me.
Pathology
Al though the pathol ogi cal anal ysi s pr i mar i l y consi sts of mi cr oscopi c
exami nati on of hematoxyl i n-eosi nstai ned tumor, several
mel anocyti c cel l mar ker s may al so be useful i n confi r mi ng the
di agnosi s of mel anoma. Two anti bodi es wi del y used i n
i mmunohi stochemi cal eval uati ons ar e S-100 and HMB-45. S-100 i s
expr essed not onl y by mor e than 90% of mel anomas, but al so by
several other tumor s and some nor mal ti ssues, i ncl udi ng dendr i ti c
cel l s. In contrast, the monocl onal anti body HMB-45 i s r el ati vel y
speci fi c (yet not as sensi ti ve) for pr ol i ferati ve mel anocyti c cel l s and
mel anoma. It i s ther efor e an excel l ent confi r mator y stai n for
neopl asti c cel l s when the di agnosi s of mel anoma i s bei ng
consi der ed. Recentl y, anti -MART-1 stai ni ng has al so been shown to
be useful i n the di agnosi s of mel anoma.
The major types of mel anoma ar e as fol l ows:
1. Super ficial spr eading melanomas consti tute the major i ty of
mel anomas (appr oxi matel y 70% ) and general l y ar i se i n a pr eexi sti ng nevus.
2. Nodular melanomas ar e the second most common type (15%
30% ). Nodul ar mel anomas pr ogr ess to i nvasi veness mor e qui ckl y
than other types; however, when depth of the mel anoma i s

contr ol l ed for, nodul ar mel anomas ar e associ ated wi th the same
pr ognosi s as other l esi ons.
3. Lentigo maligna melanomas consti tute a smal l per centage of
mel anomas (4% 10% ). These l esi ons occur i n sun-exposed
ar eas and ar e r el ated to sun exposur e. Lenti go mal i gna
mel anomas ar e typi cal l y l ocated on the faces of ol der whi te
women. Many year s can el apse befor e a l enti go mal i gna
mel anoma becomes i nvasi ve. In general , l enti go mal i gna
mel anomas ar e l ar ge (>3 cm at di agnosi s), fl at l esi ons and ar e
uncommon i n i ndi vi dual s younger than 50 year s. Al though these
l esi ons have tradi ti onal l y been bel i eved to be l ess aggr essi ve,
the pr ognosi s of pati ents wi th l enti go mal i gna mel anoma
ul ti matel y depends on the depth of i nvasi on.
4. Acr al lentiginous melanomas occur on the pal ms (pal mar ), sol es
(pl antar ), or beneath the nai l beds (subungual ), al though not al l
pal mar, pl antar, and subungual mel anomas ar e acral l enti gi nous
mel anomas. These mel anomas account for onl y 2% to 8% of
mel anomas i n whi te pati ents but for a substanti al l y hi gher
pr opor ti on of mel anomas (35% 60% ) i n dar ker-ski nned
pati ents. They ar e often l ar ge, wi th an average di ameter of
appr oxi matel y 3 cm.
5. Amelanotic melanomas ar e mel anomas that occur wi thout
pi gmentati on changes. These l esi ons ar e uncommon and ar e
mor e di ffi cul t to di agnose because of thei r l ack of pi gmentati on.
Factor s such as change i n si ze, asymmetr y, and i r r egul ar bor der s
suggest mal i gnancy and shoul d pr ompt a bi opsy.
Staging
The mel anoma stagi ng system has been r evi sed numer ous ti mes as
under standi ng of the di sease has evol ved. In 2002, the Amer i can
Joi nt Commi ttee on Cancer (AJCC) publ i shed a r evi sed stagi ng
system for cutaneous mel anoma i n the si xth edi ti on of the AJCC
Cancer Staging Manual. The r evi si ons r efl ect the r esul ts of an
extensi ve sur vi val anal ysi s of pr ognosti c factor s that was conducted
usi ng data fr om near l y 30,000 mel anoma pati ents. Featur es of the
r evi sed system i ncl ude new strata for pr i mar y tumor thi ckness,
i ncor porati on of pr i mar y tumor ul cerati on as an i mpor tant stagi ng
cr i ter i on i n both the tumor (T) and node (N) cl assi fi cati ons, r evi si on
of the N cl assi fi cati on to r efl ect the i mpor tance of r egi onal nodal
tumor bur den, and new categor i es for stage IV di sease (Tabl es 3.1
and 3.2).
T Classification
Br esl ow tumor thi ckness and tumor ul cerati on ser ve as the
domi nant pr ognosti c factor s i n the T cl assi fi cati on. A thi r d
pr ognosti c factorCl ar k l evel of i nvasi oni s i mpor tant for pati ents
wi th thi n (T1) pr i mar y l esi ons.
Br esl ow tumor thi ckness, measur ed i n mi l l i meter s, i s deter mi ned by
usi ng an ocul ar mi cr ometer to measur e the total ver ti cal hei ght of
the mel anoma fr om the granul ar l ayer to the ar ea of deepest
penetrati on. Cl ar k l evel of i nvasi on i s deter mi ned by usi ng an ocul ar
mi cr ometer to deter mi ne the depth of penetrati on i nto the der mi s.
Consi stent and uni for m data now suppor t the concl usi on that
measur ement of Br esl ow tumor thi ckness i s mor e r epr oduci bl e than
measur ement of Cl ar k l evel of i nvasi on and that Br esl ow tumor
thi ckness i s the mor e accurate pr edi ctor of outcome. Mor eover, the
AJCC Mel anoma Task For ce has adopted the Br esl ow depth val ues of
1, 2, and 4 mm as cut-offs for the T categor i es (Tabl e 3.1).
However, Cl ar k l evel of i nvasi on r emai ns an i mpor tant pr ognosti c
factor for pati ents wi th T1 l esi ons (Tabl e 3.1).
Pr i mar y tumor ul cerati on i s hi stopathol ogi cal l y defi ned as the
absence of an i ntact epi der mi s over l yi ng a por ti on of the pr i mar y
tumor. Impor tantl y, ul cerated mel anomas ar e associ ated wi th a
si gni fi cantl y wor se pr ognosi s than nonul cerated mel anomas of the
same thi ckness. In the T categor y of the AJCC stagi ng system, the
l etter a si gni fi es a nonul cerated l esi on, whi l e b si gni fi es an
ul cerated l esi on. Ul cerated pr i mar y mel anomas ar e cl assi fi ed i n the
same stage as nonul cerated l esi ons of the next hi gher T categor y
(e.g., T1b and T2a l esi ons ar e both stage Ib) (Tabl e 3.2).
N Classification
In both the pr evi ous ver si on of the AJCC stagi ng system and the
new, r evi sed ver si on, r egi onal nodal tumor bur den i s the most
i mpor tant pr edi ctor of sur vi val i n pati ents wi thout di stant
di sease. The descr i pti on of the nodal tumor bur den, however, was
mar kedl y r efi ned i n the l atest stagi ng system. Thi s change r efl ects
the i ncr easi ng use of cutaneous l ymphosci nti graphy, l ymphati c
mappi ng, and senti nel l ymph node bi opsy (SLNB), whi ch have
si gni fi cantl y enhanced the abi l i ty to detect nodal metastases i n the
r egi onal nodal basi n.
Table 3.1. 2002 American Joint Committee on

cancer TNM classification for cutaneous
melanoma
T
Thickness
Classification
Ulceration Status
T1
1.0 mm
a: Without
ulceration and
level II/III
b: With ulceration
or level IV/V
1.012.0 mm
a: Without
ulceration
b: With ulceration
2.014.0 mm
a: Without
ulceration
b: With ulceration
>4.0 mm
a: Without
ulceration
b: With ulceration
T2
T3
T4
No. of
N
Metastatic
Classification
Nodes
Nodal Metastatic
Mass
1 node
a:
Micrometastasis a
b:
Macrometastasis b
N2
23 nodes
a:
Micrometastasis
b:
Macrometastasis
c: In-transit
met(s)/satellite(s)
without
metastatic nodes
N3
4 or more metastatic nodes, or

matted nodes, or in-transit
met(s)/satellite(s) with metastatic
node(s)
N1
M
Site
Classification
Serum Lactate
Dehydrogenase
Level
M1a
Distant skin,
subcutaneous,
or nodal
metastases
Normal
M1b
Lung
metastases
Normal
All other
visceral
metastases
M1c
Any distant
metastasis
Normal
Elevated
Micrometastases are diagnosed after sentinel or

elective lymphadenectomy.
b Macrometastases are defined as clinically
detectable nodal metastases confirmed by
therapeutic lymphadenectomy or nodal metastases
that exhibit gross extracapsular extension.
Adapted from Balch CM, Buzaid AC, Soong SJ, et
al. Final version of the American Joint Committee
on Cancer staging system for cutaneous
melanoma. J Clin Oncol 2001;19:36353648, with
permission.
Table 3.2. 2002 American Joint Committee

on cancer stage groupings for cutaneous
melanoma
Clinical
Staginga
Pathological
Staging b
Tis
N0
M0
Tis
N0
M0
IA
T1a
N0
M0
T1a
N0
M0
T1b
N0
M0
T1b
N0
M0
T2a
N0
M0
T2a
N0
M0
T2b
N0
M0
T2b
N0
M0
T3a
N0
M0
T3a
N0
M0
T3b
N0
M0
T3b
N0
M0
T4a
N0
M0
T4a
N0
M0
IIC
T4b
N0
M0
T4b
N0
M0
III c
Any
T
N1
N2
N3
M0
T14a
N1a
M0
T14a
N2a
M0
T14b
N1a
M0
T14b
N2a
M0
T14a
N1b
M0
T14a
N2b
M0
IB
IIA
IIB
IIIA
IIIB
IIIC
IV
a
Any
T
Any
N
Any
M1
T1
4a/b
N2c
M0
T14b
N1b
M0
T14b
N2b
M0
Any T
N3
M0
Any T
Any
N
Any
M1
Clinical staging includes microstaging of the

primary melanoma and clinical and/or
radiologic evaluation for metastases. By
convention, it should be used after complete
excision of the primary melanoma with clinical
assessment for regional and distant
metastases.
b Pathological staging includes microstaging of
the primary melanoma and pathological
information about the regional lymph nodes
gained after partial or complete
lymphadenectomy. Pathological stages 0 and 1A
are the exceptions; patients with this stage of
disease do not require pathological evaluation
of the lymph nodes.
c There are no stage III subgroups for clinical
staging.
Adapted from Balch CM, Buzaid AC, Soong SJ,
et al. Final version of the American Joint
Committee on Cancer staging system for

cutaneous melanoma. J Clin Oncol
2001;19:36353648, with permission.
In the new stagi ng system, both the actual number of l ymph nodes
and the tumor bur den (mi cr oscopi c vs. macr oscopi c) wi thi n the node
ar e taken i nto account. Pati ents who have cl i ni cal l y negati ve l ymph
nodes but pathol ogi cal l y documented nodal
metastases ar e defi ned as havi ng mi cr oscopi c or cl i ni cal l y occul t
nodal metastases (desi gnated by the l etter a i n the N categor y of
the new stagi ng system). In contrast, pati ents wi th cl i ni cal evi dence
of nodal metastases that i s confi r med on pathol ogi cal exami nati on
ar e defi ned as havi ng macr oscopi c or cl i ni cal l y appar ent nodal
metastases (desi gnated by the l etter b i n the N categor y of the new
stagi ng system). Sur vi val rates for pati ents wi th macr oscopi c nodal
di sease ar e si gni fi cantl y wor se than rates for pati ents wi th
mi cr oscopi c nodal di sease. Data fr om the Wor l d Heal th Or gani z ati on
(WHO) Mel anoma Pr ogram showed that pati ents who under went
wi de l ocal exci si on and concomi tant el ecti ve r egi onal l ymph node
di ssecti on and wer e found on pathol ogi cal r evi ew to have
mi cr oscopi c nodal di sease far ed si gni fi cantl y better than pati ents
who under went wi de l ocal exci si on fol l owed by therapeuti c
l ymphadenectomy per for med when nodal di sease became cl i ni cal l y
evi dent (5-year sur vi val rates, 48.2% vs. 26.6% , p = 0.04).
Mul ti pl e studi es have demonstrated that the number of
pathol ogi cal l y i nvol ved l ymph nodes i s a domi nant and i ndependent
pr edi ctor of outcome i n pati ents wi th mel anoma. In the anal ysi s on
whi ch the new AJCC stagi ng system i s based, the best pr ognosti c
gr oupi ng of posi ti ve nodes was one ver sus two to thr ee ver sus four
or mor e. These cut-offs for number of posi ti ve nodes have ther efor e
been i ncor porated i nto the N cl assi fi cati on of the AJCC stagi ng
system.
Inter esti ngl y, the pr esence of tumor ul cerati on, a domi nant
pr ognosti c factor wi thi n the T cl assi fi cati on system, has al so been
shown to be an i ndependent adver se pr ognosti c factor i n pati ents
wi th r egi onal nodal di sease. In fact, ul cerati on of the pr i mar y tumor
was the onl y pr i mar y tumor pr ognosti c featur e that i ndependentl y
pr edi cted sur vi val i n pati ents wi th nodal metastases. As such,
pati ents wi th an ul cerated pr i mar y l esi on ar e upstaged wi thi n the N
categor y (as wel l as the T categor y) compar ed wi th pati ents wi th

si mi l ar nodal tumor bur den wi th a nonul cerated pr i mar y l esi on
(Tabl e 3.3).
The pr esence of cl i ni cal l y or mi cr oscopi cal l y detectabl e satel l i te
metastases ar ound a pr i mar y mel anoma or i n-transi t metastases
between the pr i mar y tumor and r egi onal l ymph nodes (see the
Management of In-transi t Metastases secti on l ater i n thi s chapter )
por tends a poor pr ognosi s. In r ecogni ti on of thi s i mpor tant concept
and i n vi ew of the si mi l ar sur vi val rates among pati ents wi th
satel l i te and i n-transi t metastases, the AJCC Mel anoma Task For ce
omi tted satel l i tosi s fr om the T categor y, i n whi ch i t was for mer l y
i ncl uded, and i n-transi t metastasi s or satel l i te(s) ar e now assi gned
a separate cl assi fi cati on, N2c. F ur ther mor e, because pati ents who
have both satel l i tes or i n-transi t metastases and concomi tant l ymph
node metastases have a wor se outcome than pati ents wi th ei ther
di sease featur e al one, pati ents wi th both mi cr osatel l i tes or i ntransi t metastases and l ymph node metastases ar e cl assi fi ed as N3,
r egar dl ess of the number of synchr onous metastati c l ymph nodes.
M Classification
Al l pr i mar y mel anomas associ ated wi th di stant metastati c di sease
ar e cl assi fi ed as stage IV. Wi thi n the M cl assi fi cati on ther e i s
onl y one gr oup, M1, but ther e ar e thr ee subcategor i es. The
subcategor i es r efl ect the fact that ther e ar e sur vi val di ffer ences
among pati ents wi th metastati c di sease, dependi ng on the
anatomi cal si tes of metastasi s. Di stant metastases to the ski n,
subcutaneous ti ssue, or di stant l ymph nodes ar e desi gnated M1a;
they ar e associ ated wi th a better pr ognosi s than metastases at any
other anatomi cal si te. Metastases to the l ung ar e associ ated wi th an
i nter medi ate pr ognosi s and ar e desi gnated M1b. Vi sceral metastases
ar e associ ated wi th the wor st pr ognosi s and ar e desi gnated M1c. In
general , the 1-year sur vi val rates of pati ents who have M1a, M1b,
and M1c di sease ar e 59% , 57% , and 41% , r especti vel y.
Table 3.3. Affect of ulceration on American

Joint Committee on cancer (AJCC) T
classification and 5-year survival
Ser um l actate dehydr ogenase (LDH) l evel i s i ncl uded i n the M
categor y because i n the anal ysi s on whi ch the new AJCC stagi ng
system i s based, ser um LDH l evel was one of the most i mpor tant
pr edi ctor s of poor pr ognosi s i n pati ents wi th metastati c di sease,
even after accounti ng for si te and number of metastases. Pati ents
wi th di stant metastases who have an el evated ser um LDH l evel at
the ti me of stagi ng ar e assi gned to categor y M1c, r egar dl ess of the
si te of thei r di stant metastases.
Metastatic Melanoma of Unknown Primary

Site
One ar ea of cl ear i nter est to the sur gi cal oncol ogi st i s metastati c
mel anoma of unknown pr i mar y si te. Appr oxi matel y 5% of pati ents
wi th mel anoma pr esent wi th metastati c di sease of the l ymph nodes
fr om an unknown pr i mar y tumor. Several studi es
have compar ed these pati ents wi th si mi l ar cohor ts of pati ents who
have equi val ent nodal status and a known pr i mar y si te i n ter ms of
r ecur r ence and sur vi val . Al though pati ents wi th unknown pr i mar y
tumor s wer e hi stor i cal l y bel i eved to have a wor se pr ognosi s, several
r ecent l ar ge studi es have contradi cted these ear l y fi ndi ngs. Pati ents
wi th metastati c mel anoma and an unknown pr i mar y tumor must be
exami ned car eful l y fr om scal p to toes for a potenti al pr i mar y tumor
si te. For the pur pose of studyi ng thi s subgr oup of pati ents, str i ct
cr i ter i a have been establ i shed i n the cour se of r etr ospecti ve
anal ysi s to excl ude pati ents wi th potenti al si tes of an occul t pr i mar y
tumor that may have been mi ssed Tabl e 3.4. In an i mpor tant study
fr om Memor i al Sl oan-Ketter i ng Cancer Center, publ i shed by Chang
and Knapper i n 1982, 166 pati ents wi th metastati c mel anoma of
unknown pr i mar y si te wer e r evi ewed r etr ospecti vel y. Thi s gr oup
compr i sed 4.4% of al l the mel anoma cases fol l owed dur i ng the
r evi ew per i od. These pati ents wer e compar ed on several parameter s
wi th a contr ol gr oup of pati ents who had known pr i mar y tumor s. Al l
pati ents had cl i ni cal stage II di sease accor di ng to the ol der stagi ng
cr i ter i a i n whi ch pati ents wi th suggesti ve pal pabl e l ymph nodes
wer e defi ned as havi ng cl i ni cal stage II di sease. The di str i buti on of
metastases i n pati ents wi th unknown pr i mar y tumor s was si mi l ar to
that i n pati ents wi th known pr i mar y tumor s. Most tumor s wer e
found i n the axi l l ar y l ymph nodes, and many wer e found i n the
gr oi n and cer vi cal r egi ons. Pati ents wi th cl i ni cal stage II di sease
had a 46% 5-year sur vi val rate and a 41% 10-year sur vi val rate, a
fi ndi ng si mi l ar for men and women. Pati ents who had r esi dual
di sease i n the l ymphadenectomy speci men, i ndi cati ng the pr esence
of mor e extensi ve l ymph node i nvol vement, had l ower sur vi val
rates. F i nal l y, pati ents who had pr ompt l ymphadenectomy had a
substanti al l y better pr ognosi s than those who had a del ay i n
tr eatment, wi th a thr eefol d i mpr ovement i n the 5- and 10-year
sur vi val rates. A second l ar ge ser i es fr om the John Wayne Cancer
Center r evi ewed 188 pati ents wi th l ymph node metastases fr om
unknown pr i mar y mel anoma and compar ed these wi th a gr oup of
pati ents wi th a known pr i mar y tumor. Several var i abl essuch as
age, gender, anatomi cal si te, and tr eatment wi th adjuvant
i mmunotherapywer e si mi l ar i n the two gr oups. In thi s gr oup of
pati ents wi th cl i ni cal stage II mel anoma, those wi th l ymph node
metastases fr om an
unknown pr i mar y mel anoma had no si gni fi cant i mpr ovement i n 5and 10-year sur vi val rates than pati ents wi th a known pr i mar y
mel anoma. Recentl y, a r etr ospecti ve anal ysi s fr om the Uni ver si ty of
Pennsyl vani a of 40 pati ents wi th mel anoma of unknown pr i mar y si te
r eveal ed that overal l 4-year sur vi val rate for these pati ents was
si gni fi cantl y hi gher than that for pati ents wi th equi val ent nodal
di sease and a known concur r ent pr i mar y mel anoma (57% vs. 19% ).
Si mi l ar l y, pati ents wi th mel anoma of unknown pr i mar y si te wi th
vi sceral metastases had l onger medi an sur vi val than those wi th
known pr i mar y tumor s.
Table 3.4. Metastatic melanoma of unknown

primary: Stringent definition of patient
population
Exclude patients with any of the following:
History of having had a mole, birthmark,
freckle, chronic paronychia, or skin blemish
previously excised, electrodesiccated, or
cauterized
Metastatic melanoma in one of the nodebearing areas and presentation with a scar
indicating previous local treatment in the
skin area drained by this lymphatic basin
No recorded physical examination of anus
and genitalia
Previous orbital enucleation or exenteration
Mor e r ecentl y, Cor mi er et al , fr om the Uni ver si ty of Texas M. D.

Ander son Cancer Center conducted a r etr ospecti ve anal ysi s of
consecuti ve pati ents wi th mel anoma (fr om 1990 to 2001) metastati c
to r egi onal l ymph nodes. Among these pati ents, 71 pati ents wi th
MUP and 466 contr ol l ed pati ents who had r egi onal l ymph node
metastases of a si mi l ar stage wi th a known pr i mar y si te wer e
i denti fi ed. The author s found that after they under went l ymph node
di ssecti on, pati ents wi th MUP wer e cl assi fi ed wi th Ni b di seases
(47% ), N2b di sease (14% ), or N3 di sease (39% ). Wi th a medi an
fol l ow-up of 7.7 year s, the 5-year and 10-year overal l sur vi val rate
wer e 55% and 44% , r especti vel y, for pati ents wi th MUP, compar ed
to 42% and 32% , r especti vel y, for the contr ol gr oup (P=0.04). By
mul ti var i ate anal yses, age 50 year s or ol der, mal e gender and N2b
or N3 di sease status wer e i denti fi ed as adver se pr ognosti cs factor s,
and MUP was i denti fi ed as a favorabl e pr ognosti c factor (haz ar d
rati o 0.61; 95% confi dence i nter val , 0.420.86; P=.006) for overal l
sur vi val . The author s concl uded that the r el ati vel y favorabl e l ongter m sur vi val of pati ents wi th MUP i n thi s study have a natural
hi stor y that i s si mi l ar to (i f not better than) the sur vi val of many
pati ents wi th Stage III di sease. Ther efor e, pati ents wi th MUP shoul d
be tr eated wi th an aggr essi ve sur gi cal appr oach wi th curati ve i ntent
and shoul d be consi der ed for stage III adjuvant therapy pr otocol s.
Management of Local Disease

Local contr ol of a pr i mar y mel anoma r equi r es wi de exci si on of the
tumor or bi opsy si tedown to but not i ncl udi ng the deep fasci a, and
wi th a mar gi n of nor mal -appear i ng ski n. The r i sk of l ocal r ecur r ence
cor r el ates mor e wi th tumor thi ckness than wi th mar gi ns of sur gi cal
exci si on. Thus, i t i s rati onal to var y sur gi cal mar gi ns accor di ng to
tumor thi ckness.
Margin Width
Hi stor i cal l y, even thi n mel anomas wer e exci sed wi th wi de mar gi ns
(35 cm). Studi es have demonstrated, however, that nar r ower
mar gi ns ar e associ ated wi th the same r ecur r ence rates as wi der
mar gi ns.
The fi r st randomi zed study i nvol vi ng sur gi cal mar gi ns for
mel anomas l ess than 2 mm thi ck was r epor ted by the WHO
Mel anoma G r oup. In an update of the study i ncl udi ng 612 pati ents
randoml y assi gned to a 1-cm or 3-cm mar gi n of exci si on, ther e wer e
no l ocal r ecur r ences among pati ents wi th pr i mar y mel anomas
thi nner than 1 mm. Ther e wer e four l ocal r ecur r ences
among the 100 pati ents wi th mel anomas 1 to 2 mm thi ck, and al l
four occur r ed i n pati ents wi th 1-cm mar gi ns. Ther e was no
si gni fi cant di ffer ence i n sur vi val between the 1- and 3-cm sur gi cal
mar gi n gr oups. These r esul ts demonstrate that a nar r ow exci si on
mar gi n (i .e., 1 cm) i s safe for thi n (<1 mm) mel anomas.
A mul ti -i nsti tuti onal pr ospecti ve randomi zed tr i al fr om F rance
compar ed 5- and 2-cm mar gi ns i n 319 pati ents wi th mel anomas at
l east 2 mm thi ck. Ther e wer e no di ffer ences i n l ocal r ecur r ence rate
or sur vi val between the two gr oups. A randomi zed cl i ni cal tr i al fr om

the Uni ted Ki ngdom compar ed 1- and 3-cm mar gi ns i n 900 pati ents
wi th mel anomas at l east 2 mm thi ck. Wi th a medi an fol l ow-up ti me
of 60 months, a 1-cm mar gi n was associ ated wi th a si gni fi cantl y
i ncr eased r i sk of l ocor egi onal r ecur r ence; however, overal l sur vi val
was si mi l ar i n the two gr oups. A randomi zed pr ospecti ve study
conducted by the Inter gr oup Mel anoma Commi ttee compar ed 2- and
4-cm radi al mar gi ns of exci si on for i nter medi ate-thi ckness
mel anomas (14 mm). Ther e was no di ffer ence i n l ocal r ecur r ence
rate between the two gr oups. For ty-si x per cent of pati ents i n the 4cm gr oup r equi r ed ski n grafts, wher eas onl y 11% of pati ents i n the
2-cm gr oup di d (p <0.001). Taken together, these data str ongl y
suppor t the use of a 2-cm mar gi n for i nter medi ate-thi ckness
l esi ons.
The opti mal mar gi n wi dth for thi ck mel anomas (>4 mm) i s sti l l
unknown. A r etr ospecti ve r evi ew of 278 pati ents wi th thi ck pr i mar y
mel anomas demonstrated that the wi dth of the exci si on mar gi n (2
cm vs. >2 cm) di d not si gni fi cantl y affect l ocal r ecur r ence, di seasefr ee sur vi val , or overal l sur vi val rates after a medi an fol l ow-up of
27 months.
Based i n l ar ge par t on the data fr om randomi zed, pr ospecti ve tr i al s,
several r ecommendati ons can be made for mar gi ns of exci si on
(Tabl e 3.5). Pati ents wi th i nvasi ve mel anoma l ess than 1 mm thi ck
can be tr eated wi th a 1-cm mar gi n of exci si on, wher eas pati ents
wi th mel anoma 2 to 4 mm thi ck can be tr eated wi th a 2-cm mar gi n.
For pati ents wi th mel anoma 1 to 2 mm thi ck, a si mpl e
r ecommendati on i s di ffi cul t because thi s pati ent popul ati on has
been studi ed i n several tr i al s eval uati ng a range of exci si on
mar gi ns. In general , a 2-cm mar gi n i s pr efer r ed i f anatomi cal l y
feasi bl e, and i n r egi ons of anatomi cal constrai nt (e.g., the face), a
1-cm mar gi n i s suffi ci ent. Thi s r ecommendati on i s based on the fact
that overal l sur vi val was si mi l ar for pati ents wi th 1- and 3-cm
mar gi ns i n the WHO tr i al . In pati ents wi th mel anoma thi cker than 4
mm, a 2-cm mar gi n i s pr obabl y safe, al though
no pr ospecti ve randomi zed tr i al s have speci fi cal l y addr essed thi s
thi ckness gr oup.
Table 3.5. Summary of recommendations for

excision margins
Tumor Thickness
Excision Margin
1 mm
1 cm
12 mm
12 cm
24 mm
2 cm
>4 mm
2 cma
a No
randomized prospective trials have

specifically addressed this cohort.
Wound Closure
If ther e i s any questi on about the abi l i ty to achi eve sui tabl e wound
cl osur e, a pl asti c or r econstr ucti ve sur geon shoul d be consul ted.
Opti ons for cl osur e i ncl ude pr i mar y cl osur e, ski n grafti ng, and l ocal
and di stant fl aps.
Pr i mar y cl osur e i s the method of choi ce for most l esi ons, but i t
shoul d be avoi ded when i t wi l l di stor t the appearance of a mobi l e
faci al featur e or i nter fer e wi th functi on. Many defects can be cl osed
usi ng an advancement fl ap, under mi ni ng the ski n and subcutaneous
ti ssues to per mi t pr i mar y cl osur e. Pr i mar y cl osur e usual l y r equi r es
that the l ongi tudi nal axi s of an el l i pti cal i nci si on be at l east thr ee
ti mes the l ength of the shor t axi s. Cl osur e of the wound edges i s
usual l y per for med i n two l ayer sa der mal l ayer of 3-0 or 4-0
undyed absor babl e sutur es and ei ther i nter r upted ski n cl osur e usi ng
3-0 or 4-0 nonabsor babl e sutur es or a r unni ng subcuti cul ar ski n
cl osur e usi ng 4-0 monofi l ament absor babl e sutur es. Thr ee l ayer s
ar e someti mes used.
Appl i cati on of a ski n graft i s one of the si mpl est r econstr ucti ve
methods used for wound cl osur e. Spl i t-thi ckness ski n grafts ar e
used most commonl y. For l ower-extr emi ty pr i mar y l esi ons, spl i tthi ckness grafts shoul d be har vested fr om the extr emi ty opposi te
the mel anoma. In general , ski n grafts shoul d be har vested fr om an

ar ea r emote fr om the pr i mar y mel anoma and outsi de the zone of
potenti al i n-transi t metastasi s. A ful l -thi ckness ski n graft can
pr ovi de a r esul t that i s both mor e durabl e and of hi gher aestheti c
qual i ty than a spl i t-thi ckness graft. F ul l -thi ckness grafts have most
commonl y been used on the face, wher e aestheti c consi derati ons
ar e most si gni fi cant. Donor si tes for ful l -thi ckness ski n graft to the
face shoul d be chosen fr om l ocati ons that ar e l i kel y to match the
col or of the face, such as the postaur i cul ar or pr eaur i cul ar ski n or
the supracl avi cul ar por ti on of the neck.
Local fl aps offer numer ous advantages for r epai r of defects that
cannot be cl osed pr i mar i l y, especi al l y on the di stal extr emi ti es and
on the head and neck. Col or match i s excel l ent, durabi l i ty of the
ski n i s essenti al l y nor mal , and nor mal sensati on i s usual l y
pr eser ved. Transposi ti on fl aps and r otati on fl aps of many var i eti es
have been used successful l y.
Di stant fl aps shoul d be used when suffi ci ent ti ssue for a l ocal fl ap i s
not avai l abl e and when a ski n graft woul d not pr ovi de adequate
wound coverage. Myocutaneous fl aps and fr ee fl aps can be used.
Di scussi on of such compl ex methods i s beyond the scope of thi s
chapter, but these techni ques ar e fami l i ar to pl asti c and
r econstr ucti ve sur geons and ar e di scussed i n gr eater detai l i n
Chapter 24.
Special Anatomical Sites

Fingers and Toes
Mor e than thr ee-four ths of subungual mel anomas i nvol ve ei ther the
gr eat toe or the thumb. A mel anoma l ocated on the ski n of a di gi t
or beneath the nai l shoul d be r emoved by a di gi tal
amputati on, wi th as much of the di gi t saved as possi bl e. In general ,
amputati ons ar e per for med at the mi ddl e i nter phal angeal joi nt of
the fi nger s or pr oxi mal to the di stal joi nt of the thumb. Mor e
pr oxi mal amputati ons ar e not associ ated wi th i mpr oved sur vi val . For
a mel anoma l ocated on a toe, an amputati on of the enti r e di gi t at
the metatar sal -phal angeal joi nt i s i ndi cated; for mel anomas of the
gr eat toe, the amputati on can be per for med pr oxi mal to the
i nter phal angeal joi nt. Lesi ons ar i si ng between two toes may r equi r e
amputati on of both toes.
Sole of the Foot

Exci si on of a mel anoma on the pl antar sur face of the foot often
pr oduces a si z abl e defect i n a wei ght-bear i ng ar ea. If possi bl e, a
por ti on of the heel or bal l of the pl antar sur face shoul d be r etai ned
to bear the gr eatest bur den of pr essur e. Wher e possi bl e, deep fasci a
over the extensor tendons shoul d be pr eser ved as a base for ski n
coverage. A pl antar fl ap, whi ch can be rai sed ei ther l ateral l y or
medi al l y, can pr ovi de wel l -vascul ar i zed l ocal ti ssue for wei ghtbear i ng ar eas, whi l e al so pr ovi di ng some sensati on. Mor e r ecentl y,
staged cl osur e of some pl antar mel anomas, par ti cul ar l y of the heel ,
have been per for med wi th i ni ti al use of a vacuum-assi sted cl osur e
devi ce to sti mul ate granul ati on ti ssue fol l owed by staged ski n graft
appl i cati on. Such an appr oach may obvi ate compl ex r econstr ucti on.
Face
Faci al l esi ons usual l y cannot be exci sed wi th mor e than a 1-cm
mar gi n because of adjacent vi tal str uctur es. The tumor di ameter,
the tumor thi ckness, and the tumor 's exact l ocati on on the face
must al l be consi der ed when mar gi n wi dth i s pl anned.
Breast
Wi de l ocal exci si on wi th pr i mar y cl osur e i s the tr eatment of choi ce
for mel anoma on the ski n of the br east; mastectomy i s not
general l y r ecommended. As wi th any tr unk l esi on,
l ymphosci nti graphy shoul d be done befor e sel ecti ve
l ymphadenectomy (see the Management of Regi onal Lymph Nodes
secti on l ater i n thi s chapter ) i f sel ecti ve l ymphadenectomy i s
i ndi cated on the basi s of pr i mar y tumor factor s.
Special Clinical Situations

Giant Congenital Nevi
A gi ant congeni tal nevus has been defi ned as a nevus that measur es
at l east 15 cm i n di ameter or at l east twi ce the si ze of the affected
per son's pal m. Pati ents wi th gi ant congeni tal nevi have an
esti mated 6% l i feti me r i sk of devel opi ng a mel anoma. Hal f of the
mel anomas that devel op i n gi ant congeni tal nevi devel op wi thi n the
fi r st 5 year s of l i fe. Deci si ons about the management of gi ant
congeni tal nevi ar e di ffi cul t because such l esi ons ar e often so
extensi ve that pr ophyl acti c sur gi cal exci si on i s i mpossi bl e. When
the l ocati on and si ze of a l esi on per mi t pr ophyl acti c exci si on,

exci si on shoul d be consi der ed befor e the age of 2 year s.
Mucosal Melanoma
Pati ents wi th tr ue mucosal mel anomai ncl udi ng mel anoma of the
mucosa of the head and neck, vagi na, and anal canal have a
general l y poor pr ognosi s, r egar dl ess of sur gi cal therapy. We usual l y
do not r ecommend an aggr essi ve sur gi cal appr oach to pati ents wi th
cl i ni cal l y l ocal i zed di sease. We r eser ve extended r esecti on for bul ky
or r ecur r ent tumor s and favor therapeuti c l ymphadenectomy over
el ecti ve l ymph node di ssecti on (see the Management of Regi onal
Lymph Nodes secti on l ater i n thi s chapter ). In par ti cul ar, we
r ecommend l ocal exci si on of anal mel anomas over abdomi noper i neal
r esecti on. Abdomi noper i neal r esecti on i s associ ated wi th much
gr eater mor bi di ty, l eaves the pati ent wi th a per manent col ostomy,
offer s no sur vi val advantage, and does not tr eat at-r i sk i ngui nal
nodes unl ess the pr ocedur e i s combi ned wi th gr oi n di ssecti on.
Adjuvant radi ati on therapy may be admi ni ster ed to pati ents wi th
mucosal mel anoma i n an attempt to decr ease the r i sk of
l ocor egi onal r ecur r ence.
Desmoplastic Melanoma
Desmopl asti c mel anoma i s an uncommon hi stol ogi c var i ant of
mel anoma that i s character i zed by unusual spi ndl e-cel l mor phol ogy
and the pr esence of fusi for m mel anocytes di sper sed i n a pr omi nent
col l agenous str oma. Cl assi cal l y pr esenti ng as a thi ck pr i mar y tumor,
desmopl asti c mel anoma i s associ ated wi th a hi gher i nci dence of
l ocal r ecur r ence than nondesmopl asti c mel anoma. Hi stol ogi cal l y,
desmopl asti c mel anoma may di spl ay mor phol ogi c heter ogenei ty.
Speci fi cal l y, some desmopl asti c mel anomas ar e character i zed by a
uni for m desmopl asi a that i s pr omi nent thr oughout the enti r e tumor
(pur e desmopl asti c mel anoma), wher eas other desmopl asti c
mel anomas appear to ar i se i n associ ati on wi th other hi stol ogi c
subtypes (mi xed desmopl asti c mel anoma). Di sti ngui shi ng the
phenotypi c heter ogenei ty of desmopl asti c mel anomas has been
r epor ted to be i mpor tant for strati fyi ng pati ents wi th r egar d to rate
of l ymph node metastasi s and pr ognosi s. Recent data i ndi cate that
pati ents wi th pur e desmopl asti c mel anoma have a l ower i nci dence of
posi ti ve senti nel l ymph nodes than do pati ents wi th mi xed
desmopl asti c mel anoma or nondesmopl asti c mel anoma. Al though
some author s have r epor ted a wor se pr ognosi s for pati ents wi th
desmopl asti c mel anoma, the major i ty of studi es have descr i bed a
better pr ognosi s for pati ents wi th desmopl asti c mel anoma compar ed
wi th pati ents who have nondesmopl asti c mel anoma of si mi l ar stage.
In a few studi es i n whi ch pur e desmopl asti c mel anoma was
di ffer enti ated fr om mi xed desmopl asti c mel anoma, pati ents wi th
mi xed desmopl asti c mel anoma had a gr eater r i sk of death or
metastati c di sease than pati ents wi th the pur e for m.
Pregnancy
The pr eci se i nfl uence of pr egnancy or hor monal mani pul ati on on the
cl i ni cal cour se of mal i gnant mel anoma has not been defi ned.
Because hi stor i cal case r epor ts suggested a poor outcome for
pr egnant women wi th mel anoma, some i nvesti gator s suggested
that mel anoma may be hor monal l y sti mul ated and ther efor e mor e
aggr essi ve i n pr egnant women. Mor e r ecentl y, mul ti pl e studi es have
documented overal l good outcomes for women wi th mel anoma
dur i ng pr egnancy.
A WHO study r epor ted that women who wer e di agnosed dur i ng
pr egnancy had a wor se pr ognosi s compar ed wi th women di agnosed
and tr eated befor e pr egnancy. The two gr oups of women i n thi s
study wer e not si mi l ar ; mean tumor thi ckness was 2.38 mm i n the
pr egnant women and 1.49 mm i n the nonpr egnant women. After
adjusti ng for thi s di ffer ence, ther e was no di ffer ence i n sur vi val .
Other studi es have si mi l ar l y shown that tumor s tend to be thi cker i n
pr egnant women than i n nonpr egnant women and that pr egnancy at
the ti me of di agnosi s i s not a si gni fi cant pr ognosti c factor i n
mul ti var i ate anal yses. In a r ecent l ar ge popul ati on-based study of
pr egnant women conducted over a 9-year per i od i n Cal i for ni a, ther e
was no evi dence of a mor e advanced stage, thi cker tumor s,
i ncr eased r i sk of metastasi s to l ymph nodes, or wor se sur vi val i n
pr egnant women. F ur ther mor e, mater nal and neonatal outcomes
wer e equi val ent to those of pr egnant women and thei r newbor ns
wi thout mel anoma.
In aggr egate, these data suppor t the concept that mal i gnant
mel anoma i s not mor e common, mor e aggr essi ve, or mor e l ethal
dur i ng pr egnancy. Sur ger y i s the tr eatment of choi ce i n pr egnant
pati ents wi th ear l y-stage mel anoma. Ther e i s no pr oof that abor ti on
pr otects the mother fr om subsequent devel opment of metastases.
Al though opi ni ons di ffer on pl anni ng pr egnancy after a di agnosi s of
mel anoma, the wei ght of evi dence does not demonstrate an
i ncr eased r i sk of devel opi ng metastati c di sease wi th pr egnancy.

F ur ther mor e, several studi es have found no associ ati on between
oral contracepti ve use and sur vi val i n mel anoma.
Management of Local Recurrence

Tr ue l ocal r ecur r ence i s defi ned as r ecur r ence at the si te of the
pr i mar y tumor, wi thi n or conti nuous wi th the scar, and i s most l i kel y
the r esul t of i ncompl ete exci si on of the pr i mar y tumor ; i t r epr esents
a r el ati vel y rar e patter n of r ecur r ence. In many cases, such l ocal
r ecur r ences may mor e appr opr i atel y be consi der ed per si stence of
the pr i mar y tumor. The pr ognosi s after a tr ue l ocal r ecur r ence i s
si gni fi cantl y better than that associ ated wi th i n-transi t di sease (see
the next secti on), and ther efor e the cor r ect cl assi fi cati on of l ocal
r ecur r ence ver sus i n-transi t di sease i s i mpor tant i n tr eatment
pl anni ng. A l ocal r ecur r ence consi sti ng of a si ngl e l esi on i n a
pati ent whose pr i mar y mel anoma had favorabl e pr ognosti c featur es
may be appr opr i atel y tr eated wi th exci si on al one. Pati ents wi th l ocal
r ecur r ences consi sti ng of mul ti pl e, smal l and super fi ci al l esi ons may
be tr eated i n a fashi on si mi l ar to that used to tr eat pati ents wi th i ntransi t di sease (see the next secti on).
Management of In-Transit Disease

Tradi ti onal l y, i n-transi t di sease has been descr i bed as r ecur r ent
l ocor egi onal di sease found i n the der mi s or subcutaneous ti ssue
between the pr i mar y mel anoma and the r egi onal l ymph node basi n.
Thi s patter n of r ecur r ence i s uni que to mel anoma and i s
r epor ted to occur i n 5% to 10% of mel anoma cases. Al though the
mol ecul ar deter mi nants and pathophysi ol ogy of i n-transi t di sease
ar e poor l y under stood, i n-transi t r ecur r ences ar e most l i kel y an
i ntral ymphati c mani festati on of mel anoma metastases. Independent
pr edi ctor s of i n-transi t r ecur r ence i ncl ude age gr eater than 50
year s, a l ower-extr emi ty pr i mar y tumor, i ncr easi ng Br esl ow depth,
ul cerati on, and posi ti ve senti nel l ymph node (SLN) status. Regi onal
nodal metastases occur i n about two-thi r ds of pati ents wi th i ntransi t di sease and, i f pr esent, ar e associ ated wi th l ower sur vi val
rates. Pr edi ctor s of di stant r ecur r ence among pati ents wi th i ntransi t r ecur r ence i ncl ude posi ti ve SLN status, i n-transi t tumor si ze
of at l east 2 cm, and di sease-fr ee i nter val befor e i n-transi t
r ecur r ence of l ess than 12 months. Inter esti ngl y, r ecent data
suggest that pati ents who pr esent wi th synchr onous di stant and i ntransi t di sease have a wor se di sease-speci fi c sur vi val compar ed wi th
pati ents who pr esent wi th onl y i n-transi t or di stant di sease.

Some have suggested that di ssecti on of the r egi onal nodal basi nby
ei ther SLNB or compl ete l ymphadenectomyi ncr eases the r i sk of i ntransi t metastases. These author s hypothesi ze that di ssecti on
di stur bs l ymph fl ow, l eadi ng to deposi ti on of metastati c cel l s i n the
i nter veni ng l ymphati c vessel s. A cr i ti cal anal ysi s of the data,
however, pr ovi des compel l i ng evi dence that nei ther SLNB nor
compl eti on l ymph node di ssecti on i n SLN-posi ti ve pati ents i ncr eases
the i nci dence of i n-transi t metastases. In a r ecent r evi ew of 2,018
pati ents wi th pr i mar y mel anomas at l east 1 mm thi ck tr eated over a
10-year per i od at the Sydney Mel anoma Uni t, ther e was no
si gni fi cant di ffer ence i n the rate of i n-transi t metastases between
pati ents tr eated wi th wi de l ocal exci si on al one (4.9% ) and those
tr eated wi th wi de l ocal exci si on and SLNB (3.6% ). Because the two
gr oups wer e si mi l ar i n ter ms of medi an tumor depth, rate of
ul cerati on, and Cl ar k l evel , these data str ongl y suppor t the concept
that ear l y nodal i nter venti on has l i ttl e i mpact on the natural hi stor y
of i n-transi t metastases. In a separate study of 1,395 pati ents fr om
The Uni ver si ty of Texas M. D. Ander son Cancer Center, pati ents wi th
a posi ti ve SLN had a si gni fi cantl y hi gher rate of i n-transi t
metastases (12% ) than pati ents wi th a negati ve SLN (3.5% ). Taken
together, these data i ndi cate that bi ol ogynot sur gi cal techni que
establ i shes the r i sk of i n-transi t metastases.
For pati ents wi th i n-transi t metastases confi ned to a l i mb that ar e
not amenabl e to standar d sur gi cal measur es (e.g., pati ents wi th
r ecur r ent and/or mul ti pl e i n-transi t metastases and pati ents wi th
l ar ge-bur den i n-transi t di sease), r egi onal chemotherapy techni ques
such as i sol ated l i mb per fusi on or, mor e r ecentl y, i sol ated l i mb
i nfusi on, may be consi der ed. Amputati on i s rar el y i ndi cated.
Hyperthermic Isolated Limb Perfusion

Hyper ther mi c i sol ated l i mb per fusi on wi th mel phal an has been used
to tr eat i n-transi t metastases of the extr emi ti es si nce the mi d1950s. Mel phal an i s cur r entl y the most acti ve si ngl e agent for use
i n hyper ther mi c i sol ated l i mb per fusi on. Overal l r esponse rates of
7% to 80% (compl ete r esponse rate, 46% ; par ti al r esponse rate,
34% ) can be achi eved, and the medi an r esponse
durati on i n pati ents wi th a compl ete r esponse ranges fr om 9 to 19
months. Nonrandomi zed studi es of hyper ther mi c l i mb per fusi on by
Li enar d et al . r epor ted a hi gh compl ete r esponse rate (90% ) wi th a
combi nati on of mel phal an, tumor necr osi s factor- (TNF -), and
i nter fer on- (IF N-) and a somewhat l ower r esponse rate wi th
mel phal an al one (52% ). The durabi l i ty of these r esponses has not
yet been r epor ted. F raker et al . r epor ted a 100% r esponse rate i n
pati ents tr eated wi th mel phal an al one and a 90% r esponse rate i n
pati ents tr eated wi th mel phal an, IF N-, and TNF -, al though the
l atter combi nati on r esul ted i n a hi gher compl ete r esponse rate
(80% vs. 61% ). A mul ti center randomi zed tr i al sponsor ed by the
Amer i can Col l ege of Sur geons Oncol ogy G r oup compar i ng mel phal an
al one wi th a combi nati on of mel phal an and TNF - for pati ents who
have i n-transi t metastases was r ecentl y cl osed to accr ual because
the i nter i m anal ysi s fai l ed to r eveal a benefi t for TNF -. As a r esul t,
TNF - i s not cur r entl y bei ng used i n the Uni ted States i n i sol ated
l i mb per fusi on pr ocedur es.
The r outi ne use of hyper ther mi c i sol ated l i mb per fusi on i n the
adjuvant setti ng has mar gi nal , i f any, benefi t. Al though a
randomi zed mul ti center phase III tr i al showed i ncr eased di seasefr ee i nter val i n pati ents wi th i n-transi t metastases and r egi onal
l ymph node metastasi s, thi s effect was transi ent and pr edomi nantl y
occur r ed i n pati ents wi th a mor e favorabl e pr ognosi s (tumor
thi ckness of 1.5 to 2.99 mm). Thi s study showed no benefi t of
i sol ated l i mb per fusi on wi th r espect to ti me to di stant metastasi s or
sur vi val durati on.
Al though hyper ther mi c i sol ated l i mb per fusi on may be effecti ve as
pr i mar y tr eatment for i n-transi t metastases, the i sol ated l i mb
per fusi on techni que i nvol ves a compl ex and i nvasi ve operati ve
pr ocedur e entai l i ng expensi ve equi pment, l ong operati ng ti mes, and
consi derabl e anci l l ar y staff. In an attempt to achi eve si mi l ar r esul ts
usi ng l ess compl ex techni ques, a new r egi onal chemotherapy
techni que, i sol ated l i mb i nfusi on, has r ecentl y been devel oped for
the management of i n-transi t metastases.
Isolated Limb Infusion

Isol ated l i mb i nfusi on i s essenti al l y a l ow-fl ow i sol ated l i mb
per fusi on per for med vi a per cutaneousl y i nser ted catheter s, but
wi thout oxygenati on of the ci r cui t (F i g. 3-1). In general , usi ng
standar d radi ol ogi c techni ques, catheter s ar e i nser ted
per cutaneousl y i nto the mai n ar ter y and vei n of the unaffected l i mb
and del i ver ed i ntravascul ar l y to the contral ateral tumor-bear i ng
extr emi ty. Under general anesthesi a, after a pneumati c tour ni quet
i s i nfl ated pr oxi mal l y, cytotoxi c agents (general l y mel phal an and
acti nomyci n-D) ar e i nfused thr ough the ar ter i al catheter and hand-
ci r cul ated wi th a syr i nge techni que for 20 to 30 mi nutes.

Pr ogr essi ve hypoxi a occur s because, i n contrast to i sol ated l i mb
per fusi on, no oxygenator i s used. The hypoxi a and aci dosi s
associ ated wi th i sol ated l i mb i nfusi on ar e therapeuti cal l y attracti ve
because numer ous cytotoxi c agents, i ncl udi ng mel phal an, appear to
damage tumor cel l s mor e effecti vel y under hypoxi c condi ti ons. In
fact, hypoxi a and aci dosi s have been r epor ted to i ncr ease the
cytotoxi c effects of mel phal an i n exper i mental model s by a factor of
thr ee. The Sydney Mel anoma Uni t has al so shown
that i sol ated l i mb i nfusi on wi th fotemusti ne after dacar baz i ne
chemosensi ti z ati on can be successful when gr oss l i mb di sease has
not been contr ol l ed by one or mor e i sol ated l i mb i nfusi ons wi th
mel phal an.
F i gur e 3.1. Schemati c drawi ng depi cti ng an i sol ated l i mb

i nfusi on. The catheter s ar e typi cal l y pl aced per cutaneousl y by an
i nter venti onal radi ol ogi st vi a the contral ateral extr emi ty, wi th
the catheter ti ps posi ti oned i n the tumor-bear i ng extr emi ty just
bel ow the i ngui nal l i gament i n the super fi ci al femoral ar ter y and
vei n. After i nfl ati on of the tour ni quet, chemotherapy i s manual l y
i nfused for 20 to 30 mi nutes, after whi ch the l i mb i s washed out
wi th 1 l i ter of nor mal sal i ne. (Repr i nted fr om Li ndner P,
Doubr ovsky A, Kam PC, et al . Pr ognosti c factor s after i sol ated
l i mb i nfusi on wi th cytotoxi c agents for mel anoma. Ann Sur g
Oncol 2002;9:127136, wi th per mi ssi on.)
At the compl eti on of the dr ug exposur e, the l i mb vascul atur e i s

fl ushed wi th a cr ystal l oi d sol uti on vi a the ar ter i al catheter, and the
effl uent i s di scar ded. Al though the l i mb ti ssues ar e exposed to the
cytotoxi c agent for onl y a shor t per i od (up to 30 mi nutes), ther e
appear s to be adequate cel l ul ar uptake for tumor cel l ki l l i ng.
Isol ated l i mb i nfusi on has been shown to yi el d r esponse rates
si mi l ar to those obser ved after conventi onal hyper ther mi c i sol ated
l i mb per fusi on; overal l r esponse rates of 85% (compl ete r esponse
rate, 41% ; par ti al r esponse rate, 44% ) have been achi eved i n at
l east one study. Because of the si mpl i ci ty of the i sol ated i nfusi on
techni que, i t may be a mor e attracti ve opti on for pati ents wi th
comor bi di ti es or the el der l y.
Toxicity and Morbidity

Hyper ther mi c i sol ated l i mb per fusi on and i sol ated l i mb i nfusi on can
be associ ated wi th potenti al l y si gni fi cant r egi onal adver se effects,
i ncl udi ng myonecr osi s, ner ve i njur y, compar tment syndr ome, and
ar ter i al thr ombosi s, someti mes necessi tati ng fasci otomy or even
major amputati on. Fol l owi ng i sol ated l i mb i nfusi on, r egi onal adver se
effects appear to be si mi l ar to those r epor ted after conventi onal
hyper ther mi c i sol ated l i mb per fusi on, wi th 41% of pati ents
exper i enci ng grade II toxi c effects and 53% exper i enci ng grade III
toxi c effects. Systemi c toxi c effects, i ncl udi ng hypotensi on and adul t
r espi rator y di str ess syndr ome, have someti mes been seen wi th the
addi ti on of TNF - to the per fusi on or i nfusi on r egi men. Because l i mb
per fusi on or i nfusi on r equi r es a hi gh degr ee of techni cal exper ti se
and i s associ ated wi th a si gni fi cant r i sk of compl i cati ons, the
pr ocedur e shoul d be per for med onl y i n center s that have exper i ence
wi th the techni que. At pr esent, ther e i s l i ttl e evi dence to justi fy the
use of pr ophyl acti c per fusi on or i nfusi on, except as par t of a cl i ni cal
tr i al .
Management of Regional Lymph Nodes

Regi onal l ymph nodes ar e the most common si te of mel anoma
metastasi s. Effecti ve pal l i ati on and someti mes cur e can be achi eved
i n pati ents wi th r egi onal metastases. F i ne-needl e aspi rati on or cor e
bi opsy can usual l y yi el d a di agnosi s i n pati ents who devel op
cl i ni cal l y enl ar ged r egi onal nodes. Open bi opsy i s rar el y war ranted.
The management of cl i ni cal l y negati ve r egi onal l ymph nodes has

been the focus of a l ong and someti mes contenti ous debate.
Hi stor i cal l y, some sur geons pr efer r ed to per for m l ymphadenectomy
onl y for cl i ni cal l y demonstrabl e nodal metastases. Thi s type of
exci si on has been ter med delayed or ther apeutic lymph node
dissection (TLND). Other sur geons have chosen to exci se the nodes
even when they appear ed nor mal i n pati ents who ar e at i ncr eased
r i sk of devel opi ng nodal metastases. Thi s exci si on has been ter med
immediate, pr ophylactic, or elective lymph node dissection (ELND).
Mor e r ecentl y, many sur geons have adopted a sel ecti ve appr oach to
r egi onal l ymph node di ssecti onthe techni que of i ntraoperati ve
l ymphati c mappi ng and SLN i denti fi cati on or i gi nal l y devel oped by
Mor ton et al .
Therapeutic Lymph Node Dissection

Wi th TLND, onl y pati ents wi th known metastases under go a major
l ymphadenectomy; thi s r educes the number of potenti al l y
unnecessar y l ymphadenectomi es and may not r educe the chance for
cur e. The di sadvantage of TLND i s that del ayi ng tr eatment unti l
l ymph node metastases ar e cl i ni cal l y evi dent may r esul t i n many
pati ents havi ng di stant mi cr ometastases at the ti me of
l ymphadenectomy. Chances for cur e may ther efor e be di mi ni shed.
Elective Lymph Node Dissection

ELND has the theor eti cal advantage of tr eati ng mel anoma nodal
metastases at a r el ati vel y ear l y stage i n the natural hi stor y of the
di sease. The di sadvantage of ELND i s that many pati ents under go
sur ger y when they do not have nodal metastasi s. Advocates of ELND
ar gue that pati ents wi th cl i ni cal l y negati ve, hi stol ogi cal l y posi ti ve
l ymph nodes at ELND have a better chance for sur vi val (50% 60% )
than do pati ents i n whom the r egi onal l ymph nodes ar e not
di ssected, and cl i ni cal l y appar ent metastases devel op i n the
r egi onal l ymph nodes dur i ng fol l ow-up (15% 35% ). None of four
randomi zed, pr ospecti ve studi es assessi ng ELND have demonstrated
an overal l sur vi val advantage for thi s techni que. Two tr i al s, one
fr om the WHO and another fr om the Mayo Cl i ni c, wer e ul ti matel y
cr i ti ci zed because the study popul ati ons wer e at l ow r i sk for occul t
nodal di sease, and pati ents wer e ther efor e unl i kel y to benefi t fr om
the pr oposed sur gi cal tr eatment.
Al though ELND does not offer a sur vi val benefi t to al l pati ents, two
r ecentl y compl eted pr ospecti ve randomi zed tr i al s that tar geted

hi gher-r i sk, cl i ni cal l y node-negati ve pati ents suggest that ELND may
have some sur vi val benefi t i n cer tai n pati ent subgr oups. In the
WHO ELND Tr i al , pati ents wi th tr uncal mel anoma at l east 1.5 mm
thi ck wer e randomi zed to wi de l ocal exci si on and ELND ver sus wi de
l ocal exci si on and obser vati on. Updated r esul ts fr om thi s tr i al
demonstrated that pati ents i n the ELND tr eatment ar m who wer e
found to have mi cr oscopi c nodal di sease at ELND had better overal l
sur vi val than di d pati ents i n whom pal pabl e adenopathy devel oped
after wi de exci si on al one. The l ong-ter m r esul ts of the Inter gr oup
Mel anoma Tr i al ar e si mi l ar. In thi s tr i al , pati ents wi th i nter medi atethi ckness mel anomas (1.04.0 mm) who under went wi de exci si on
and ELND wer e compar ed wi th a si mi l ar gr oup of pati ents who
under went wi de exci si on al one fol l owed by obser vati on of the
r egi onal nodal basi n. Al though thi s tr i al di d not demonstrate a
di ffer ence i n overal l 10-year sur vi val rates, four pr ospecti vel y
sel ected subgr oups wer e found to have si gni fi cantl y better 10-year
sur vi val wi th ELND than wi th nodal obser vati on: pati ents whose
pr i mar y tumor s wer e wi thout ul cerati on (84% vs. 77% ; p = 0.03);
pati ents wi th pr i mar y tumor thi ckness between 1.0 and 2.0 mm (vs.
thi cker ) (86% vs. 80% ; p = 0.03); pati ents wi th extr emi ty (vs.
tr uncal ) mel anoma (84% vs. 78% ; p = 0.05); and pati ents younger
than 60 year s (81% vs. 74% ; p = 0.03). The r esul ts of a r ecentl y
publ i shed mul ti center tr i al fr om G er many al so demonstrated an
absol ute sur vi val advantage, of at l east 13% , for pati ents wi th
posi ti ve nodes detected on SLNB compar ed wi th pati ents wi th
posi ti ve nodes detected dur i ng obser vati on of the nodal basi n.
Al though thi s anal ysi s was r etr ospecti ve, the r esul ts wer e
consi stent wi th the fi ndi ngs of the WHO study.
Taken together, these data cal l i nto questi on r ecommendati ons to
del ay l ymphadenectomy unti l pal pabl e nodal di sease devel ops; the
data al so suppor t the use of al ter nati ve appr oaches to per mi t ear l i er
i denti fi cati on of occul t nodal di sease. A mor e rati onal , sel ecti ve
appr oach, l ymphati c mappi ng and SLNB, has now been
wi del y adopted. Thi s techni que sati sfi es many pr oponents of both
ELND and TLND.
Intraoperative Lymphatic Mapping and

Sentinel Lymph Node Biopsy
Several i nvesti gator s have pr oposed i ntraoperati ve l ymphati c
mappi ng and SLNB as a mi ni mal l y i nvasi ve pr ocedur e for i denti fyi ng
the appr oxi matel y 20% of pati ents who har bor occul t mi cr oscopi c
di sease. Thi s appr oach i s someti mes ter med selective
lymphadenectomy.
Several studi es have demonstrated that the SLNs ar e the fi r st nodes
to contai n metastases, i f metastases ar e pr esent, and thus the
pathol ogi cal status of the SLNs r efl ects that of the enti r e r egi onal
nodal basi n. If the SLN l acks metastasi s, the r emai nder of the
r egi onal l ymph nodes i s unl i kel y to contai n di sease, and a
compl eti on l ymphadenectomy need not be per for med. Mul ti pl e
studi es have demonstrated that the fal se-negati ve rate for SLNB i s
l ess than 4% , wi th the pr edi cti ve val ue of a negati ve SLN
appr oachi ng 99% . Other studi es have confi r med the val i di ty of the
SLN concept and the accuracy of SLNB as a stagi ng pr ocedur e. It i s
i mperati ve, however, that the sur geon empl oyi ng SLNB have
adequate pathol ogy and nucl ear medi ci ne suppor t.
Technique
Lymphati c mappi ng and SLNB i s per for med at the ti me of wi de
exci si on of the pr i mar y tumor or bi opsy si te. Si nce the i ntr oducti on
of l ymphati c mappi ng and SLNB, the techni que has under gone
several r efi nements that have r esul ted i n i mpr oved detecti on of
SLNs.
Use of a vi tal bl ue dye (i sosul fan bl ue 1% ) to hel p i denti fy SLNs has
been par t of the l ymphati c mappi ng and SLNB pr ocedur e si nce i ts
i ntr oducti on. The bl ue dye i s i njected i nto the pati ent i ntrader mal l y
ar ound the i ntact tumor or bi opsy si te. The bl ue dye i s taken up by
the l ymphati c system and car r i ed vi a affer ent l ymphati cs to the
SLN. The drai ni ng nodal basi n i s expl or ed, and the affer ent
l ymphati c channel s and fi r st drai ni ng l ymph nodes (the SLNs) ar e
i denti fi ed by the uptake of the bl ue dye. Wi th the use of bl ue dye
al one, a SLN i s i denti fi ed i n appr oxi matel y 85% of cases. Al though
thi s i ni ti al appr oach was pr omi si ng, i t l eft 15% of pati ents unabl e to
benefi t fr om SLNB because no SLN was i denti fi ed.
Subsequentl y, two addi ti onal techni ques have been i ncor porated
that have si gni fi cantl y i mpr oved SLN l ocal i z ati on: (a) pr eoperati ve
l ymphosci nti graphy and (b) i ntraoperati ve i njecti on of techneti um99 (9 9 Tc)-l abel ed sul fur col l oi d accompani ed by i ntraoperati ve use of
a handhel d gamma pr obe. Pr eoperati ve l ymphosci nti graphy usi ng
9 9 Tc-l abel ed sul fur col l oi d per mi ts the i denti fi cati on of pati ents wi th
mul ti pl e drai ni ng nodal basi ns and pati ents wi th l ymphati c drai nage
to SLNs l ocated outsi de standar d nodal basi ns, i ncl udi ng
epi tr ochl ear, popl i teal , and ectopi c si tes (F i g. 3-2). In pati ents wi th
mel anomas that drai n to mul ti pl e r egi onal nodal basi ns, the
hi stol ogi c status of one drai ni ng basi n does not pr edi ct the status of
other basi ns. In one study, among
54 pati ents who under went an SLNB of an unusual nodal si te, 7

(13% ) had l ymph node metastases i n that l ocati on. In four of the
seven pati ents, the onl y posi ti ve SLN was fr om the unusual si te.
Ther efor e, i t i s par ti cul ar l y i mpor tant to i denti fy and assess al l atr i sk r egi onal nodal basi ns to pr oper l y stage the di sease.
F i gur e 3.2. Pr eoperati ve l ymphosci nti graphy. After i njecti on of

9 9 Tc-l abel ed sul fur col l oi d at the pr i mar y cutaneous mel anoma
si te (upper mi dl i ne back), pr eoperati ve l ymphosci nti graphy
r eveal ed (A ) drai nage to mul ti pl e nodal basi ns (bi l ateral neck
and l eft axi l l a), (B) i n-transi t/ectopi c senti nel l ymph nodes
(SLNs) i n the r i ght fl ank r egi on and r i ght axi l l a fr om a pr i mar y
tumor of the r i ght l ateral back, and (C) SLNs i n a r i ght l owerextr emi ty popl i teal fossa l ymph node basi n and a r i ght i ngui nal
l ymph node basi n fr om a pr i mar y tumor of the heel . (Photos
cour tesy of Jeffr ey E. G er shenwal d, MD.)
Pr obabl y the most i mpor tant devel opment i n the SLNB techni que
has been the i ntr oducti on of i ntraoperati ve l ymphati c mappi ng usi ng
a handhel d gamma pr obe. In thi s appr oach, 0.5 to 1.0 mCi of 9 9 Tcl abel ed sul fur col l oi d i s i njected i ntrader mal l y 1 to 4 hour s befor e
sur ger y. Dur i ng sur ger y, a handhel d gamma pr obe i s used to
transcutaneousl y i denti fy SLNs that wi l l be r emoved. The use of
both bl ue dye and radi ocol l oi d i ncr eases the sur geon's abi l i ty to
i denti fy the SLN (gr eater than 96% to 99% accuracy) compar ed
wi th the use of bl ue dye al one (84% accuracy). Al though most
cl i ni ci ans use thi s combi ned modal i ty appr oach, some favor the
si ngl e-agent strategy of 9 9 Tc-l abel ed sul fur col l oi d al one, and they
have r epor ted si mi l ar l y excel l ent r esul ts.
Side Effects
SLNB i s associ ated wi th substanti al l y fewer postoperati ve
compl i cati ons compar ed wi th ELND, whi ch i s character i zed by
compl ete r egi onal node exti r pati on. SLNB i s associ ated wi th l ess
extensi ve sur ger y and thus a l ower rate of si de effects. Mor eover,
the SLNB techni que i tsel f i s associ ated wi th substanti al l y fewer
postoperati ve compl i cati ons than ELND, i ncl udi ng l ower rates of
l ymphedema, pai n, numbness, and l oss of acti ve range of moti on. In
addi ti on, r ecent data have shown that the SLNB techni que does not
i ncr ease the i nci dence of i n-transi t r ecur r ence compar ed wi th wi de
l ocal exci si on al one.
Incidence and Predictors of Positive Sentinel

Lymph Nodes
Knowl edge of the factor s pr edi cti ve of a posi ti ve SLN i s useful for
counsel i ng pati ents r egar di ng tr eatment opti ons. In most studi es,
the i nci dence of posi ti ve SLNs i n pati ents under goi ng SLNB ranges
fr om 15% to 20% . However, mul ti var i ate anal yses have r eveal ed
several factor s that i ncr ease the r i sk of posi ti ve SLNs: i ncr eased
tumor thi ckness, ul cerati on, hi gh mi toti c i ndex, age younger than
50 year s, and axi al tumor l ocati on. In one r epor t, the i nci dence of a
posi ti ve SLN was 4% among pati ents wi th mel anomas 1.0 mm or
thi nner and 44% among pati ents wi th mel anomas thi cker than 4.00
mm (Tabl e 3.6). In the same r epor t, pati ents wi th ul cerated pr i mar y
tumor s had a hi gher i nci dence of SLN metastases compar ed wi th
those wi th nonul cerated l esi ons (35% vs. 12% , r especti vel y). The
i nci dence of SLN metastases by
AJCC stage i s shown i n F i gur e 3.3. The i nci dences of posi ti ve SLNs
for stages IA, IB, IIA, IIB, and IIC wer e 2% , 9% , 24% , 34% , and
53% , r especti vel y.
Table 3.6. Effect of ulceration on SLN metasta

tumor thickness (n = 1,375)
Positive SLN
Tumor
Total
Thickness Patients All
(mm)
(%)
(%)
Not
Ulcerated
Ulcera
AJCC
AJ
(%)
(%)
Stage b
St
1.00
28
IA
16
IB
1.01
2.00
38
12
11
IB
22
II
2.01
4.00
23
28
25
IIA
34
II
>4.00
11
44
33
IIB
53
II
All
Patients
100
17
12
35
SLN, sentinel lymph node; AJCC, American Joint Co

Cancer.
a Fisher exact test for each tumor thickness group.
b Stage groupings calculated using tumor thickness
data only.
Reprinted from Rousseau DL, Jr, Ross MI, Johnson
Revised American Joint Committee on Cancer stagin
accurately predict sentinel lymph node positivity in
negative melanoma patients. Ann Surg Oncol 2003;
with permission.
F i gur e 3.3. Inci dence of posi ti ve senti nel l ymph nodes (SLNs) by
Amer i can Joi nt Commi ttee on Cancer di sease stage (n = 1,375).
The di ffer ence between each stage i s stati sti cal l y si gni fi cant. The
inset shows the per centage of pati ents wi th a posi ti ve SLN wi thi n
each categor y. (Repr i nted fr om Rousseau DL, Jr, Ross MI,
Johnson MM, et al . Revi sed Amer i can Joi nt Commi ttee on Cancer
stagi ng cr i ter i a accuratel y pr edi ct senti nel l ymph node posi ti vi ty
i n cl i ni cal l y node-negati ve mel anoma pati ents. Ann Sur g Oncol
2003;10:569574, wi th per mi ssi on.)
Prognostic Value of Sentinel Lymph Node
Status
The pr ognosti c si gni fi cance of the pathol ogi cal status of the SLNs
has been convi nci ngl y demonstrated. Data fr om M. D. Ander son
Cancer Center demonstrated that SLN status was the most
si gni fi cant cl i ni copathol ogi cal pr ognosti c factor wi th r espect to
sur vi val i n pati ents wi th mel anoma. In an updated anal ysi s of 1,487
pati ents who under went SLNB (medi an tumor thi ckness, 1.5 mm),
the 5-year sur vi val rate for pati ents wi th posi ti ve SLNs was 73.3% ,
compar ed wi th 96.8% for pati ents wi th negati ve SLNs (F i g. 3-4) (J.
G er shenwal d, unpubl i shed data, 2005). Several other mul ti var i ate
r egr essi on anal yses have shown that r egi onal l ymph node status i s
the most power ful pr edi ctor of r ecur r ence (both r egi onal and
di stant) and sur vi val , even among pati ents wi th thi ck mel anomas.
Accor di ng to a r ecent anal ysi s of the AJCC database, 5-year sur vi val
rates for pati ents wi th stage III di sease range fr om 69% for
pati ents wi th onl y one mi cr oscopi cal l y posi ti ve l ymph node and a
nonul cerated pr i mar y mel anoma to 13% for pati ents wi th cl i ni cal l y
evi dent nodal di sease wi th mor e than thr ee pathol ogi cal l y i nvol ved
nodes and an ul cerated pr i mar y tumor.
F i gur e 3.4. Di sease-speci fi c sur vi val by senti nel l ymph node

(SLN) status i n 1,487 pati ents. SLN status was the most
si gni fi cant cl i ni copathol ogi al pr ognosti c factor wi th r espect to
sur vi val . The 5-year di sease-speci fi c sur vi val rate was 73.3% for
pati ents wi th posi ti ve SLNs, compar ed wi th 96.8% for pati ents
wi th negati ve SLNs.
The pr ognosti c i mpor tance of di sti ngui shi ng between mi cr oscopi cal l y
and macr oscopi cal l y posi ti ve l ymph nodes has been emphasi zed by
i ncor porati on of thi s cr i ter i on i nto the newl y
r evi sed mel anoma stagi ng system. The concept of tumor bur den wi l l
l i kel y be i mpor tant i n the era of SLNB as accurate mi cr oscopi c
stagi ng of SLNs becomes even mor e wi despr ead and pati ents ar e
better strati fi ed on the basi s of mi cr oscopi c tumor bur den i nto
si mi l ar r i sk subgr oups. In fact, several studi es have shown that the
di ameter of the l ar gest l ymph node tumor nodul e and the total
l ymph node tumor vol ume ar e si gni fi cant pr edi ctor s of r ecur r ence
and sur vi val . In one study, a tumor deposi t di ameter of 3 mm was
i denti fi ed as a si gni fi cant cut-off poi nt: The 3-year sur vi val
pr obabi l i ty was 86% for pati ents wi th a l ar gest tumor deposi t
di ameter of 3 mm or l ess and 27% for pati ents wi th a l ar gest
deposi t di ameter gr eater than 3 mm. In the futur e, as our
under standi ng of the si gni fi cance of mi cr oscopi c nodal tumor bur den
i s r efi ned, cl i ni cal deci si ons r egar di ng the need for and extent of
fur ther sur ger y or adjuvant therapy may al so be based on the
extent of mi cr oscopi c nodal tumor bur den.
The r ecentl y compl eted Mul ti center Sel ecti ve Lymphadenectomy
Tr i al -I was desi gned to assess whether a sel ecti ve appr oach to
r egi onal l ymphadenectomyl i mi ti ng compl ete nodal di ssecti on to
pati ents wi th mi cr oscopi c di sease i n SLNsconfer s a sur vi val benefi t
compar ed wi th wi de l ocal exci si on of the pr i mar y mel anoma and
obser vati on of the r egi onal nodal basi n. Pati ents wi th pr i mar y
cutaneous mel anomas at l east 1 mm thi ck or wi th Cl ar k l evel IV or
V tumor s wi th any Br esl ow thi ckness wer e el i gi bl e for the tr i al .
Pati ents wer e randoml y assi gned to wi de
exci si on al one pl us obser vati on or wi de exci si on pl us l ymphati c
mappi ng and SLNB, wi th subsequent compl eti on l ymphadenectomy i f
SLNs wer e posi ti ve. Al though thi s tr i al has r eached tar get accr ual ,
fi nal r esul ts ar e not yet avai l abl e. Resul ts fr om thi s i mpor tant study
shoul d hel p defi ne whether sel ecti ve l ymphadenectomy i s associ ated
wi th a sur vi val benefi t. Another tr i al , the Mul ti center Sel ecti ve
Lymphadenectomy Tr i al -II, wi l l expl or e the i mpact of compl eti on
l ymphadenectomy i n pati ents wi th a posi ti ve SLN.
Pathological Evaluation of Sentinel Lymph

Nodes
Pathol ogi sts have tradi ti onal l y exami ned the mul ti tude of l ymph
nodes obtai ned fr om a l ymphadenectomy by exami ni ng one
hematoxyl i n-eosi nstai ned secti on fr om each paraffi n bl ock. Thi s
conventi onal appr oach, however, can mi ss di sease i n SLNs, pr i mar i l y
because of sampl i ng er r or. In one study, 8 of 10 pati ents who
under went SLNB and subsequentl y devel oped r egi onal nodal fai l ur e
i n nodal basi ns that wer e negati ve for di sease accor di ng to
conventi onal hi stol ogi c exami nati on of SLNs had mi cr oscopi c di sease
detected when the SLNs wer e r eassessed usi ng speci al i zed
pathol ogi cal techni ques. Data fr om thi s and other studi es suggest
that fai l ur e to use speci al i zed techni ques, rather than fai l ur e to
cor r ectl y i denti fy SLNs, accounts for many cases of fal se-negati ve
fi ndi ngs on SLNB.
Wi th the SLNB techni que, fewer l ymph nodes ar e submi tted for
anal ysi s than ar e submi tted wi th compl ete l ymphadenectomy, and
the pathol ogi st can ther efor e focus on onl y those nodesthe SLNs
that ar e at the hi ghest r i sk. Cur r entl y, the combi nati on of
hematoxyl i n-eosi n assessment of several l evel s and
i mmunohi stochemi cal anal ysi s i s general l y consi der ed a standar d
practi ce i n assessi ng SLNs. Several anti bodi es di r ected agai nst
mel anoma-associ ated anti gens (S-100, HMB-45, tyr osi nase, MAG E3,
and MART-1) ar e r outi nel y used for i mmunohi stochemi cal
eval uati on. Because cer tai n anti bodi es have l ow speci fi ci ty (S-100)
and other s have l ow sensi ti vi ty (HMB-45, MAG E3, and tyr osi nase), a
panel of anti bodi es i s commonl y used. At our i nsti tuti on, thi s panel
i ncl udes HMB-45 and MART-1.
Because even the combi nati on of hi stol ogi c and
i mmunohi stochemi cal exami nati on of SLNs may fai l to i denti fy
i sol ated mel anoma cel l s or ol i gocel l ul ar deposi ts, some have
suggested a mol ecul ar-based appr oach to exami nati on of SLNs. Wi th
use of the r ever se transcr i ptase-pol ymerase chai n r eacti on (RTPCR), i t i s esti mated that one mel anoma cel l i n a backgr ound of 1
10 6 to 1 107 nor mal cel l s can be i denti fi ed. Some i nvesti gator s
have pr oposed, however, that thi s l evel of di agnosti c sensi ti vi ty may
actual l y over esti mate cl i ni cal l y r el evant di sease. Posi ti vi ty rates i n
studi es usi ng RT-PCR to eval uate SLNs for mi cr ometastati c
mel anoma range fr om 55% to 73% , compar ed wi th a rate of 30% ,
whi ch woul d be expected on the basi s of known cl i ni copathol ogi cal
r i sk factor s and patter ns of r ecur r ence. Some studi es show that the
pr ognosi s of pati ents wi th an SLN that i s posi ti ve by RT-PCR but
negati ve by hi stol ogi c or i mmunohi stochemi cal anal ysi s i s wor se
than that of pati ents who have SLNs negati ve by both techni ques.
Al though pr el i mi nar y r esul ts have been i ntr i gui ng, the tr ue cl i ni cal
si gni fi cance of posi ti ve RT-PCR fi ndi ngs i n a hi stol ogi cal l y negati ve
SLN i s sti l l unknown, i n par t because most studi es that have
addr essed thi s questi on to date had shor t fol l ow-up ti mes and di d
not compar e RT-PCR wi th cur r ent standar d hi stol ogi c techni ques. It
ther efor e r emai ns di ffi cul t to draw fi nal concl usi ons about the
pr ognosti c si gni fi cance of SLNs that ar e posi ti ve by RT-PCR but
negati ve by cur r ent conventi onal hi stol ogi c anal ysi s. Impor tantl y, at
l east one r ecent study suggests that pati ents wi th submi cr oscopi c
di sease detected by tyr osi nase RT-PCR do not have a hi gher
r ecur r ence r i sk than pati ents wi th RT-PCRnegati ve SLNs. The
r el ati ve cl i ni cal i mpor tance of conventi onal hi stol ogi c exami nati on,
ser i al secti oni ng, i mmunohi stochemi cal anal ysi s, and mol ecul ar
stagi ng i n pati ents under goi ng l ymphati c mappi ng and SLNB i s bei ng
eval uated i n a l ar ge, mul ti center, randomi zed, pr ospecti ve tr i al
known as the Sunbel t Mel anoma Tr i al .
Prediction of Metastatic Melanoma in

Nonsentinel Nodes
Cur r entl y, pati ents who have a mel anoma-posi ti ve SLN i denti fi ed on
SLNB subsequentl y under go compl eti on l ymphadenectomy. When the
non-SLNs ar e exci sed and eval uated by hematoxyl i n-eosi n stai ni ng
and i mmunohi stochemi str y, l ess than one-thi r d of compl eti on
l ymphadenectomy speci mens contai n addi ti onal nodes wi th
metastati c di sease. Because mor e than two-thi r ds of pati ents have
metastati c di sease i denti fi ed onl y i n SLNs, ther e has been i nter est
i n i denti fyi ng pati ents who, despi te havi ng a posi ti ve SLN, have a
l ow pr obabi l i ty of metastati c di sease i n non-SLNs.
In an anal ysi s of pr i mar y tumor and SLN character i sti cs, the
r el ati ve ar ea of tumor i n the SLN and the Br esl ow thi ckness of the
pr i mar y tumor most accuratel y pr edi cted the pr esence of tumor i n
non-SLNs. The densi ty of dendr i ti c l eukocytes i n the paracor tex al so
pr edi cted the pr esence of tumor i n non-SLNs. These thr ee featur es
al one and i n combi nati on wer e abl e to pr edi ct the pr esence of tumor
i n non-SLNs wi th hi gh accuracy. Al though these r esul ts ar e
i ntr i gui ng and war rant fur ther study, deci si ons r egar di ng compl eti on
l ymphadenectomy cannot yet be made str i ctl y on the basi s of
pr i mar y tumor or SLN character i sti cs. Compl eti on l ymphadenectomy
fol l owi ng i denti fi cati on of a posi ti ve SLN r emai ns the cur r ent
standar d of car e.
Current Practice Guidelines

In general , pati ents wi th cutaneous mel anoma ar e offer ed SLNB i f
the pr i mar y tumor i s at l east 1.0 mm thi ck, or i f the pr i mar y tumor
i s l ess than 1.0 mm thi ck, i f i t i s at l east Cl ar k l evel IV, i s
ul cerated, or demonstrates evi dence of r egr essi on and i f the pati ent
has no evi dence of metastati c mel anoma i n r egi onal l ymph nodes
and di stant si tes on physi cal exami nati on and stagi ng eval uati on.
Evi dence of ver ti cal gr owth phase, a pathol ogi cal featur e that has
been associ ated wi th an i ncr eased r i sk of l ymphati c metastases, has
al so been adopted as an i ndi cati on for SLNB. Recentl y, several
gr oups have offer ed SLNB to pati ents whose pr i mar y tumor s have a
hi gh mi toti c rate because thi s factor has al so been r epor ted to be a
str ong pr edi ctor of SLN posi ti vi ty.
When the SLNs ar e negati ve, no fur ther sur ger y i s per for med, and
the r emai ni ng r egi onal l ymph nodes ar e l eft i ntact. When the SLNs
show evi dence of metastati c di sease, compl eti on l ymphadenectomy
of the affected nodal basi n i s the cur r ent standar d of car e.
Pathol ogi cal eval uati on of compl eti on l ymphadenectomy speci mens
often r eveal s no addi ti onal di sease. However, i t i s i mpor tant to
r emember that compl eti on l ymphadenectomy speci mens ar e
r outi nel y assessed wi th standar d hi stol ogi c techni ques rather than
the mor e r i gor ous exami nati on r eser ved for SLNB speci mens. As a
r esul t, ther e may actual l y be addi ti onal di sease i n the compl eti on
nodal speci men that goes undetected. Thi s di sease woul d r epr esent
a potenti al sour ce of subsequent r ecur r ence i f i t wer e not r emoved.
Because such r ecur r ences ar e di ffi cul t to tr eat sur gi cal l y and may
contr i bute to si gni fi cant mor bi di ty, compl eti on l ymphadenectomy
per for med for mi cr oscopi c di sease pr ovi des the potenti al for
i mpr oved r egi onal contr ol . In addi ti on, i denti fyi ng pati ents wi th
mi ni mal di sease bur den by usi ng the SLN appr oach may hel p
i denti fy the gr oup of pati ents who may der i ve an i mpr oved sur vi val
benefi t fr om ear l y TLND. F ur ther mor e, knowl edge of the
pathol ogi cal status of the SLNs al l ows pr oper stagi ng and thus
faci l i tates deci si on maki ng r egar di ng adjuvant tr eatment.
Technical Considerations
Axillary Dissection
General
Axi l l ar y di ssecti on must be compl ete and i ncl ude the l evel III l ymph
nodes (F i g. 3-5). The ar m, shoul der, and chest ar e pr epar ed and
i ncl uded i n the sur gi cal fi el d.
Incision
We use a hor i zontal , sl i ghtl y S-shaped i nci si on begi nni ng anter i or l y
al ong the super i or por ti on of the pectoral i s major muscl e, traver si ng
the axi l l a over the four th r i b, and extendi ng i nfer i or l y al ong the
anter i or bor der of the l ati ssi mus dor si muscl e.
Skin Flaps
Ski n fl aps ar e rai sed anter i or l y to the mi dcl avi cul ar l i ne, i nfer i or l y
to the si xth r i b, poster i or l y to the anter i or bor der of the l ati ssi mus
dor si muscl e, and super i or l y to just bel ow the pectoral i s major
i nser ti on. The medi al si de of the l ati ssi mus dor si muscl e i s di ssected
fr ee fr om the speci men, exposi ng the thoracodor sal vessel s and
ner ve. The l ateral edge of the di ssecti on then pr oceeds cephal ad
beneath the axi l l ar y vei n. These maneuver s al l ow the r emai nder of
the di ssecti on to pr oceed fr om medi al to l ateral . The fatty and
l ymphati c ti ssue over the pectoral i s major muscl e i s di ssected fr ee
ar ound to i ts under sur face, wher e the pectoral i s mi nor muscl e i s
encounter ed. The i nter pectoral gr oove i s exposed.
Lymph Node Dissection

The medi al pectoral ner ve i s pr eser ved. The i nter pectoral nodes ar e
di ssected fr ee. The upper axi l l a i s exposed by br i ngi ng the pati ent's
ar m over the chest by adducti on and i nter nal r otati on. If nodes ar e
bul ky, the pectoral i s mi nor muscl e may be di vi ded to faci l i tate
exposur e. Di ssecti on pr oceeds fr om the apex of the axi l l a
i nfer ol ateral l y. Di ssecti on of the upper axi l l ar y l ymph nodes shoul d
be suffi ci entl y compl ete that the thoraci c outl et beneath the
cl avi cl e, Hal sted's l i gament, and subcl avi us muscl e ar e seen (F i g. 36). Fatty and l ymphati c
ti ssues ar e di ssected downwar d over the axi l l ar y vei n. The apex of
the di ssected speci men i s tagged. Di ssecti on then conti nues unti l
the thoracodor sal vessel s and the l ong thoraci c and thoracodor sal
ner ves ar e i denti fi ed. The fatty ti ssue between the two ner ves i s
separated fr om the subscapul ar i s muscl e. The speci men i s r emoved
fr om the l ateral chest wal l . Inter costobrachi al ner ves traver si ng the
speci men ar e sacr i fi ced. The speci men i s swept off the l ati ssi mus
dor si and ser ratus anter i or muscl es.
F i gur e 3.5. Lymphati c anatomy of the axi l l a showi ng the thr ee

gr oups of axi l l ar y l ymph nodes defi ned by thei r r el ati onshi p to
the pectoral i s mi nor muscl e. The hi ghest axi l l ar y nodes (l evel
III) medi al to the pectoral i s mi nor muscl e shoul d be i ncl uded i n
an axi l l ar y l ymph node di ssecti on for mel anoma. (F r om Bal ch
CM, Mi l ton G W, Shaw HM, et al ., eds. Cutaneous Melanoma.
Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th per mi ssi on.)
Wound Closure
One 15F cl osed-sucti on catheter i s pl aced per cutaneousl y thr ough
the i nfer i or fl ap i nto the axi l l a. An addi ti onal catheter may be
i nser ted thr ough the i nfer i or fl ap and pl aced over the pectoral i s
major muscl e. The ski n i s cl osed wi th i nter r upted 3-0 undyed
absor babl e sutur es and r unni ng 4-0 subcuti cul ar undyed absor babl e
sutur es.
Postoperative Management
Sucti on drai nage i s conti nued unti l output i s l ess than 30 mL per
day. By appr oxi matel y 3 weeks, the sucti on catheter s ar e r emoved,
r egar dl ess of the amount of drai nage, to avoi d i nfecti on. Any
subsequent col l ecti ons of ser um ar e r emoved by needl e aspi rati on.
Mobi l i z ati on of the ar m i s di scouraged dur i ng the fi r st 7 to 10 days
after sur ger y. Over the
ensui ng 4 weeks, gradual mobi l i z ati on of the ar m i s encouraged.
The compl i cati on rate for axi l l ar y l ymph node di ssecti on i s l ow. The
most fr equent compl i cati on i s wound ser oma (see the Compl i cati ons
secti on).
F i gur e 3.6. Access to the upper axi l l a. The ar m i s draped so that

i t can be br ought over the chest wal l dur i ng the operati on. Thi s
faci l i tates r etracti on of the pectoral i s muscl es upwar d to r eveal
the l evel III axi l l ar y l ymph nodes. (F r om Bal ch CM, Mi l ton G W,
Shaw HM, et al ., eds. Cutaneous Melanoma. Phi l adel phi a, Pa:
Li ppi ncott; 1985, wi th per mi ssi on.)
Groin Dissection
For gr oi n di ssecti on, the pati ent i s pl aced i n a sl i ght fr og-l eg
posi ti on.
Incision
A r ever se l az y-S i nci si on i s made fr om super omedi al to the anter i or
super i or i l i ac spi ne, ver ti cal l y down to the i ngui nal cr ease, obl i quel y
acr oss the cr ease, and then ver ti cal l y down to the apex of the
femoral tr i angl e.
F i gur e 3.7. Techni que of i ngui nal l ymph node di ssecti on. (F r om
Bal ch CM, Mi l ton G W, Shaw HM, et al ., eds. Cutaneous
Melanoma. Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th per mi ssi on.)
Skin Flaps
The l i mi ts of the ski n fl aps ar e medi al l y to the pubi c tuber cl e and
the mi dbody of the adductor magnus muscl e, l ateral l y to the l ateral
edge of the sar tor i us muscl e, super i or l y to above the i ngui nal
l i gament, and i nfer i or l y to the apex of the femoral tr i angl e. We
someti mes i ncor porate an el l i pse of ski n wi th the speci men.
Lymph Node Dissection

Di ssecti on i s car r i ed down to the muscul ar fasci a super i or l y (F i g. 3-
7). Al l fatty, node-bear i ng ti ssue i s swept down to the i ngui nal

l i gament and off the exter nal obl i que fasci a. Medi al l y, the sper mati c
cor d or r ound l i gament i s exposed, and nodal ti ssue i s swept
l ateral l y. Nodal ti ssue i s swept off the adductor fasci a to the femoral
vei n. At the apex of the femoral tr i angl e, the saphenous vei n i s
di vi ded. Lateral l y, nodal ti ssue i s di ssected off the sar tor i us muscl e
and the femoral ner ve. Wi th di ssecti on i n the pl ane of the femoral
vessel s, the nodal ti ssue i s el evated up to the l evel of the fossa
oval i s, wher e the saphenous vei n i s sutur e-l i gated at the
saphenofemoral juncti on. The speci men i s di ssected to beneath the
i ngui nal l i gament, wher e i t i s di vi ded. Cl oquet's node (the l owest
i l i ac node) i s sent as a separate speci men for fr ozen-secti on
exami nati on (F i g. 3-8).
Sartorius Muscle Transposition

The sar tor i us muscl e i s di vi ded at i ts or i gi n on the anter i or super i or
i l i ac spi ne (F i g. 3-9). The l ateral femoral cutaneous ner ve i s
pr eser ved. The pr oxi mal
two or thr ee neur ovascul ar bundl es goi ng to the sar tor i us muscl e
ar e di vi ded to faci l i tate transposi ti on. The muscl e i s pl aced over the
femoral vessel s and tacked to the i ngui nal l i gament, fasci a of the
adductor, and vastus muscl e gr oups. Dependi ng on the bul k of
di sease and pati ent anatomy, the saphenous vei n and sar tor i us
muscl es may be pr eser ved.
F i gur e 3.8. A : Lymphati c anatomy of the i ngui nal ar ea

demonstrati ng the super fi ci al and deep l ymphati c chai ns.
Cl oquet's node l i es at the transi ti on between the super fi ci al and
deep i ngui nal nodes. It i s l ocated beneath the i ngui nal l i gament
i n the femoral canal . B: The i l i ac nodes i ncl ude those on the
common and super fi ci al i l i ac vessel s and the obturator nodes.
Obturator nodes shoul d be exci sed as par t of an i l i ac nodal
di ssecti on. (F r om Bal ch CM, Mi l ton G W, Shaw HM, et al ., eds.
Cutaneous Melanoma. Phi l adel phi a, Pa: Li ppi ncott; 1985, wi th
per mi ssi on.)
Wound Closure
The ski n edges ar e exami ned for vi abi l i ty and tr i mmed back to
heal thy ski n, i f necessar y. Intravenous admi ni strati on of fl uor escei n
and a Wood's l amp may be used to i denti fy poor l y per fused ski n
edges. Two cl osed-sucti on drai ns ar e pl aced thr ough separate smal l
i nci si ons i nfer i or l y. One i s l ai d medi al l y
and the other i s l ai d l ateral l y wi thi n the operati ve wound. The
wound i s cl osed wi th i nter r upted 3-0 undyed absor babl e sutur es i n

the der mi s and fol l owed by ski n stapl es.
F i gur e 3.9. Transecti on of the sar tor i us muscl e at i ts or i gi n on

the anter i or super i or i l i ac spi ne i n pr eparati on for transposi ti on
over the femoral vessel s and ner ves. (F r om Bal ch CM, Mi l ton
G W, Shaw HM, et al ., eds. Cutaneous Melanoma. Phi l adel phi a,
Pa: Li ppi ncott, 1985; wi th per mi ssi on.)
Postoperative Management
The pati ent begi ns ambul ati ng the day fol l owi ng sur ger y; a customfi t el asti c stocki ng may be used dur i ng the day for 6 months. After
thi s per i od, the stocki ng may be di sconti nued i f no l eg swel l i ng
occur s.
Dissection of the Iliac and Obturator Nodes

We general l y per for m deep di ssecti ondi ssecti on of the i l i ac and
obturator nodesfor the fol l owi ng i ndi cati ons: (a) known
i nvol vement of the nodes r eveal ed by pr eoperati ve i magi ng studi es,
(b) mor e than thr ee gr ossl y posi ti ve nodes i n the super fi ci al l ymph
node di ssecti on speci men, or (c) metastati c di sease i n Cl oquet's
node by fr ozen-secti on exami nati on. To gai n access to the deep
nodes, we extend the ski n i nci si on super i or l y. The exter nal obl i que
muscl e i s spl i t fr om a poi nt super omedi al to the anter i or super i or

i l i ac spi ne to the l ateral bor der of the r ectus sheath. The i nter nal
obl i que and transver sus abdomi ni s muscl es ar e di vi ded, and the
per i toneum i s r etracted super i or l y. An al ter nati ve appr oach i s to
spl i t the i ngui nal l i gament ver ti cal l y, medi al to the femoral vei n.
The ur eter i s exposed as i t cour ses over the i l i ac ar ter y. Di ssecti on
conti nues i n fr ont of the exter nal i l i ac ar ter y to separate the
exter nal i l i ac nodes. The i nfer i or epi gastr i c ar ter y and vei n ar e
di vi ded, i f necessar y. Di ssecti on of the l ymph nodes conti nues
to the common i l i ac ar ter y. Nodes i n fr ont of the exter nal i l i ac vei n
ar e di ssected to the poi nt at whi ch the i nter nal i l i ac vei n pr oceeds
under the i nter nal i l i ac ar ter y. The pl ane of the per i toneum i s
traced al ong the wal l of the bl adder, and the fatty ti ssues and l ymph
nodes ar e di ssected off the per i vesi cal fat star ti ng at the i nter nal
i l i ac ar ter y. Di ssecti on i s compl eted on the medi al wal l of the
exter nal i l i ac vei n, and the nodal chai n i s fur ther separated fr om
the pel vi c fasci a unti l the obturator ner ve i s seen. Obturator nodes
ar e l ocated i n the space between the exter nal i l i ac vei n and the
obturator ner ve (i n an anter oposter i or di r ecti on) and between the
i nter nal i l i ac ar ter y and the obturator foramen (i n a cephal adcaudad di r ecti on). The obturator ar ter y and vei n usual l y need not
be di stur bed. The transver sus abdomi ni s, i nter nal obl i que, and
exter nal obl i que muscl es may be cl osed wi th r unni ng sutur es. The
i ngui nal l i gament, i f pr evi ousl y di vi ded, i s appr oxi mated wi th
i nter r upted nonabsor babl e sutur es to Cooper 's l i gament medi al l y
and to the i l i ac fasci a l ateral to the femoral vessel s.
Neck Dissection
Lymph node metastases fr om mel anomas i n the head and neck wer e
pr evi ousl y bel i eved to fol l ow a pr edi ctabl e patter n. However, i t i s
now known that l ymphati c drai nage fr om mel anomas of the head
and neck can be mul ti di r ecti onal and unpr edi ctabl e. ELND or SLNB
may be mi sdi r ected i n as many as 59% of pati ents i f the operati on
i s based on cl assi c anatomi cal studi es wi thout pr eoperati ve
l ymphosci nti graphy. These fi ndi ngs str ongl y suppor t the use of
l ymphosci nti graphy i n pati ents wi th mel anomas i n the head and
neck.
At M. D. Ander son, the tr eatment of choi ce for pati ents wi th
mel anoma i n the head and neck r egi on and cl i ni cal l y i nvol ved nodes
i s wi de l ocal exci si on of the pr i mar y l esi on wi th ei ther modi fi ed
radi cal neck di ssecti on or sel ecti ve neck di ssecti on, fol l owed by
adjuncti ve radi ati on therapy. In pati ents wi th l esi ons at l east 1.5
mm thi ck who have under gone sel ecti ve neck di ssecti on and i n
pati ents wi th nodal r el apse, adjuncti ve radi ati on therapy gi ves a
l ocor egi onal contr ol rate of 88% .
Mel anomas ar i si ng on the scal p or face anter i or to the pi nna of the
ear and super i or to the commi ssur e of the l i p can metastasi ze to
i ntrapar oti d l ymph nodes because these nodes ar e conti guous wi th
the cer vi cal nodes. When i ntrapar oti d nodes ar e cl i ni cal l y i nvol ved,
i t i s advi sabl e to combi ne neck di ssecti on wi th par oti d l ymph node
di ssecti on and then admi ni ster radi ati on therapy.
Complications
The most common acute postoperati ve compl i cati on of sel ecti ve
l ymphadenectomy i s wound i nfecti on. Rates range fr om 5% to 19% .
In an anal ysi s of data fr om the Sunbel t Mel anoma Tr i al , the
compl i cati ons associ ated wi th SLNB for mel anoma wer e eval uated i n
2,120 pati ents. Overal l , 96 (4.6% ) of the pati ents devel oped major
or mi nor compl i cati ons associ ated wi th SLNB, wher eas 103 (23.3% )
of 444 pati ents exper i enced compl i cati ons associ ated wi th SLNB pl us
compl eti on l ymph node di ssecti on. The author s concl uded that the
SLNB al one i s associ ated wi th si gni fi cantl y l ess mor bi di ty compar ed
wi th SLNB pl us compl eti on l ymph node di ssecti on.
Fol l owi ng for mal l ymphadenectomy, the rate of l ymphocel e or
ser oma for mati on i s 3% to 23% . Leavi ng sucti on catheter s i n pl ace
unti l the drai nage decr eases to 30 to 40 mL per day may r educe the
i nci dence of ser oma. However, pr ol onged use of catheter s i s
associ ated wi th a hi gher rate of i nfecti on. Lymphedema i s the most
ser i ous l ong-ter m compl i cati on of for mal l ymphadenectomy. Thr ee
ser i es have shown that the i nci dence of l eg edema after gr oi n
di ssecti on can be decr eased by pr eventi ve measur es, i ncl udi ng
per i operati ve anti bi oti cs, el asti c stocki ngs, l eg el evati on exer ci ses,
and di ur eti cs. Pr ophyl acti c measur es ar e i mpor tant because
r ever si ng the pr ogr essi on of edema i s di ffi cul t. Ski n fl ap pr obl ems
can occur wi th some fr equency. Expectant management of i schemi c
edges often r esul ts i n ful l -thi ckness necr osi s and pr ol onged
hospi tal i z ati on. Ther efor e, i f ski n fl ap edges ar e of questi onabl e
vi abi l i ty, we r etur n the pati ent to the operati ng r oom ear l y for fl ap
r evi si on. Cl i ni cal l y detectabl e deep vei n thr ombosi s i s uncommon.
Adjuvant Therapy
Interferon Alfa-2b
Hi gh-dose IF N al fa-2b i s appr oved by the U.S. Food and Dr ug
Admi ni strati on as adjuvant tr eatment for pati ents wi th mel anoma
who have a hi gh r i sk of r ecur r ence. Cur r entl y, pati ents wi th l ocal l y
r ecur r ent, nodal , i n-transi t, or satel l i te di sease shoul d be
consi der ed candi dates for adjuvant hi gh-dose IF N al fa-2b.
Appr oval of IF N al fa-2b was based on the r esul ts of the Easter n
Cooperati ve Oncol ogy G r oup (ECOG ) E1684 pr ospecti ve randomi zed
tr i al , whi ch assi gned pati ents to hi gh-dose IF N al fa-2b or
obser vati on after wi de l ocal exci si on. The IF N al fa-2b dosage was 20
mi l l i on uni ts/m2 /day i ntravenousl y for 4 weeks fol l owed by 10
mi l l i on uni ts per m2 thr ee ti mes a week subcutaneousl y for the next
48 weeks. Both node-posi ti ve and hi gh-r i sk node-negati ve (T4pN0)
pati ents wer e i ncl uded; the major i ty of pati ents had exper i enced
r ecur r ence of di sease i n the r egi onal nodes after pr i or wi de l ocal
exci si on. Al l pati ents under went ei ther ELND or TLND. Of the 287
pati ents enr ol l ed, 89% wer e node posi ti ve. IF N al fa-2b i mpr oved
medi an overal l sur vi val fr om 2.8 to 3.8 year s and i mpr oved 5-year
r el apse-fr ee sur vi val rates fr om 26% to 37% at a medi an fol l ow-up
of 7 year s. The benefi ci al effect of IF N al fa-2b was most pr onounced
i n the node-posi ti ve pati ents. Of note, the rate of toxi c effects was
hi gh: Two pati ents di ed, 67% of pati ents exper i enced grade 3 toxi c
effects, and 50% of pati ents ei ther stopped tr eatment ear l y or
r equi r ed dose r educti on.
A r ecent updated anal ysi s of E1684, at a medi an fol l ow-up of 12.6
year s, showed a per si stent gai n i n medi an overal l sur vi val (45.8
months for the IF N al fa-2b ar m vs. 32 months for obser vati on). The
sur vi val di ffer ence, however, was no l onger stati sti cal l y si gni fi cant,
possi bl y because deaths fr om i nter cur r ent i l l ness on both ar ms
over shadowed mel anoma-speci fi c mor tal i ty. The updated r esul ts di d
conti nue to show a hi ghl y si gni fi cant i mpr ovement i n r el apse-fr ee
sur vi val .
The E1690 tr i al , another ECOG tr i al , was i ni ti ated befor e a
si gni fi cant i mpact on sur vi val had been noted i n E1684. In E1690,
desi gned as a confi r mati on and extensi on of E1684, 642 pati ents
wi th hi gh-r i sk (stage IIb or III) mel anoma wer e randomi zed i n a
thr ee-ar m study to r ecei ve the E1684 hi gh-dose r egi men, l ow-dose
IF N al fa-2b (3 mi l l i on uni ts per m2 thr ee ti mes a week for 2 year s),
or obser vati on onl y. Seventy-fi ve per cent of the pati ents had nodal
metastases (50% had r ecur r ent di sease i n the r egi onal nodes).
Unl i ke E1684, E1690 al l owed entr y of pati ents wi th T4 pr i mar y

tumor s, r egar dl ess of whether l ymph node di ssecti on was
per for med, and 25% of the pati ents i n the tr i al had deep pr i mar y
tumor s (compar ed wi th 11% i n E1684).
In E1690, at a medi an fol l ow-up of 52 months, hi gh-dose IF N al fa2b demonstrated a r el apse-fr ee sur vi val benefi t exceedi ng that of
l ow-dose IF N al fa-2b or obser vati on. The 5-year esti mated r el apsefr ee sur vi val rates for hi gh-dose IF N al fa-2b, l ow-dose IF N al fa-2b,
and obser vati on wer e 44% , 40% , and 35% , r especti vel y (p = 0.03).
The r el apse-fr ee sur vi val benefi t was equi val ent for node-negati ve
and node-posi ti ve pati ents. As of thi s wr i ti ng, nei ther hi gh-dose nor
l ow-dose IF N al fa-2b has demonstrated an overal l sur vi val benefi t
compar ed wi th obser vati on.
An anal ysi s of sal vage therapy for pati ents whose di sease r el apsed
on E1690 demonstrated that a si gni fi cantl y l ar ger pr opor ti on of
pati ents i n the obser vati on ar m than i n the hi gh-dose IF N ar m
r ecei ved IF N al fa-contai ni ng sal vage therapy, whi ch may have
confounded i nter pr etati on of the sur vi val benefi t of assi gned
tr eatments. Some of the di scr epancy between the fi ndi ngs of E1684
and E1690 may be attr i butabl e to di ffer ences i n pati ent
demographi c pr ofi l es. E1690 i ncl uded pati ents wi th mor e favorabl e
di sease character i sti cs: Onl y 75% of pati ents wer e node posi ti ve,
and of these, 51% had nodal r ecur r ence. In E1690, 25% of pati ents
enr ol l ed wer e cl i ni cal stage II; i n E1684, 11% wer e pathol ogi cal
stage II. Pr esumabl y, some of the cl i ni cal stage II pati ents i n E1690
woul d have been pathol ogi cal stage III had l ymphadenectomy been
r equi r ed. An updated anal ysi s of E1690 wi th a medi an fol l ow-up of
7.2 year s has confi r med the study's or i gi nal concl usi ons.
ECOG tr i al E1694 was i ni ti ated to compar e the effi cacy and safety
of a gangl i osi de vacci ne wi th the effi cacy and safety of hi gh-dose
IF N al fa-2b i n pati ents wi th stage IIb or stage III mel anoma. The
gangl i osi de G M2 i s a ser ol ogi cal l y wel l -defi ned mel anoma anti gen
and the most i mmunogeni c gangl i osi de expr essed on mel anoma
cel l s. Pr el i mi nar y studi es had suggested that the anti body r esponse
to G M2 was cor r el ated wi th r el apse-fr ee and overal l sur vi val . In
E1694, 774 el i gi bl e pati ents wi th hi gh-r i sk mel anoma (tumor
thi ckness >4.0 mm or r egi onal l ymph node metastasi s) wer e
randomi zed to r ecei ve hi gh-dose IF N al fa-2b or G M2 vacci ne. The
study was cl osed ear l y by the data safety moni tor i ng boar d because
of the cl ear super i or i ty of IF N al fa-2b i n ter ms of both di sease-fr ee
and overal l sur vi val . The esti mated 2-year r el apse-fr ee sur vi val
rates wer e 62% i n the hi gh-dose IF N al fa-2b ar m and 49% i n the
G M2 vacci ne ar m. F ur ther mor e, anal ysi s of the haz ar d of r el apse

and death i n subgr oups based on the number of l ymph nodes
demonstrated the super i or i ty of IF N al fa-2b over G M2 i n al l nodal
subsets. E1694 al so showed a stati sti cal l y si gni fi cant benefi t for IF N
al fa-2b i n node-negati ve hi gh-r i sk pati ents.
A r ecent pool ed meta-anal ysi s of pr i mar y data fr om the
ECOG /Inter gr oup tr i al s of hi gh-dose IF N (n = 1,916) r eveal ed a
cl ear benefi t of hi gh-dose IF N al fa-2b i n ter ms of r el apse-fr ee
sur vi val and a mor e modest benefi t i n ter ms of overal l sur vi val
(odds rati o = 0.9, p = 0.05). Data fr om an updated anal ysi s of the
ECOG database demonstrated that (a) the sur vi val i mpact of IF N
al fa-2b was confi ned to r egi mens that i ncor porated both hi gh-dose
i nducti on and hi gh-dose subcutaneous mai ntenance; (b) r educti on
of haz ar d was obser ved ear l y; and (c) the r el apse-fr ee sur vi val
advantage was sustai ned off tr eatment, i n contrast to the mor e
l i mi ted r el apse-fr ee sur vi val advantage r epor ted by the l ow-dose
tr i al s.
Resul ts of tr i al s i nvesti gati ng l ow-dose IF N al fa-2b have been
di sappoi nti ng. The pr evi ousl y menti oned E1690 tr i al , a thr ee-ar m
tr i al that i ncl uded l ow-dose IF N al fa-2b as one of the tr eatments,
demonstrated a nonsi gni fi cant i mpr ovement i n r el apse-fr ee sur vi val
i n pati ents wi th hi gh-r i sk stage II or stage III mel anoma who
r ecei ved l ow-dose IF N al fa-2b for 2 year s. The modest i mpr ovement
i n the l ow-dose IF N al fa-2b ar m compar ed wi th the contr ol ar m
di sappear ed wi thi n 2 year s after therapy was stopped. The Eur opean
Or gani z ati on for Resear ch and Tr eatment of Cancer 18871 tr i al al so
demonstrated that a r egi men of ver y l ow-dose IF N al fa-2b (1 mi l l i on
uni ts per m2 ) i njected subcutaneousl y on al ter nate days for 1 year
di d not affect overal l sur vi val for pati ents wi th hi gh-r i sk mel anoma.
Because of the l ack of a demonstrabl e durabl e cl i ni cal benefi t, l owdose IF N al fa-2b has not been appr oved as adjuvant therapy for
mel anoma i n the Uni ted States.
Radiation Therapy
Al though sur ger y r emai ns the pr i mar y tr eatment for pati ents wi th
l ocal i zed mel anoma, avai l abl e data i ndi cate a need for i mpr oved
l ocor egi onal contr ol i n cases i n whi ch compl ete sur gi cal r esecti on i s
di ffi cul t or hi gh-r i sk featur es ar e noted pathol ogi cal l y. Factor s
associ ated wi th a hi gh r i sk of subsequent r egi onal basi n r ecur r ence
i ncl ude l ymph nodes at l east 3 cm i n si ze, four or mor e posi ti ve
l ymph nodes, the pr esence of extracapsul ar extensi on, and

r ecur r ent di sease after i ni ti al sur gi cal r esecti on. Retr ospecti ve and
phase II pr ospecti ve studi es have r eveal ed that adjuvant radi ati on
therapy can si gni fi cantl y i mpr ove the l ocor egi onal contr ol rate i n
these cl i ni cal setti ngs. In one study i n pati ents wi th l ymph node
metastases fr om mel anoma wi th hi gh-r i sk featur es, adjuvant
radi ati on therapy del i ver ed usi ng a hypofracti onated r egi men
r esul ted i n an 87% 5-year r egi onal nodal basi n contr ol rate,
super i or to the 50% to 70% l ocal contr ol rate achi eved wi th sur ger y
al one. The hypofracti onated r egi men was wel l tol erated and i s
conveni ent for such pati ents, i n whom sur vi val expectati ons may be
l ow. The i mpact of adjuvant radi ati on therapy on the i nci dence of
di stant metastasi s and overal l sur vi val has yet to be deter mi ned.
Si gni fi cant i mpr ovements i n outcome wi l l r equi r e commensurate
i mpr ovements i n systemi c di sease contr ol . The i mpor tance of l ocal
contr ol i n r educi ng mor bi di ty, however, shoul d not be
under esti mated, and futur e r esear ch goal s shoul d i ncl ude
randomi zed cl i ni cal tr i al s to fur ther defi ne the r ol e of adjuvant
radi ati on therapy al one or i n combi nati on wi th systemi c
therapy. In general , pati ents wi th mul ti pl e i nvol ved or matted
r egi onal nodes or wi th extracapsul ar extensi on of r egi onal
l ymphati c metastases shoul d be consi der ed for adjuvant radi ati on
therapy.
Chemotherapy
No confi r med studi es have demonstrated a benefi t of adjuvant
chemotherapy i n pati ents wi th mel anoma who ar e at hi gh r i sk for
r el apse. On the contrar y, a randomi zed tr i al of adjuvant dacar baz i ne
ver sus no adjuvant tr eatment showed a stati sti cal l y si gni fi cant
decr ease i n sur vi val i n the adjuvant tr eatment ar m. Adjuvant
chemotherapy shoul d be consi der ed onl y i n the context of a cl i ni cal
tr i al .
Management of Distant Metastatic Disease

Common si tes of di stant metastasi s i n mel anoma pati ents ar e, i n
or der of decr easi ng fr equency, ski n and subcutaneous ti ssues, l ung,
l i ver, and brai n. Pati ents wi th systemi c metastases have a poor
pr ognosi s. G eneral gui del i nes for choosi ng tr eatment modal i ti es
fol l ow, but no tr eatment for metastati c mel anoma has been pr oven
to pr ol ong sur vi val . Exper i mental tr eatments ar e an opti on for most
pati ents i n whom di stant metastases ar e di agnosed.
Surgery
Sur ger y i s a ver y effecti ve pal l i ati ve tr eatment for i sol ated
accessi bl e di stant metastases. Exampl es of accessi bl e l esi ons
i ncl ude i sol ated vi sceral metastases, i sol ated brai n metastases, and
occasi onal l y i sol ated l ung metastases.
Lesions Causing Gastrointestinal Tract

Obstruction
G astr oi ntesti nal tract obstr ucti on fr om metastati c mel anoma i s
usual l y due to l ar ge pol ypoi d l esi ons that mechani cal l y obstr uct the
bowel or act as a l ead poi nt for i ntussuscepti on. These submucosal
l esi ons ar e general l y r emoved by bowel r esecti on.
Pulmonary Metastases
The val ue of r esecti ng pul monar y metastases fr om mal i gnant
mel anoma i s contr over si al . In a study exami ni ng 65 pul monar y
r esecti ons per for med for hi stol ogi cal l y pr oven pul monar y
metastases di scover ed after tr eatment of the pr i mar y mel anoma,
the postthoracotomy actuar i al sur vi val rate was 25% at 5 year s
(medi an i nter val fr om pul monar y r esecti on to death, 18 months).
Sur vi val was not affected by the l ocati on, hi stol ogi c subtype,
Br esl ow thi ckness, or Cl ar k l evel of the pr i mar y tumor, or by the
type of r esecti on. Pati ents wi thout r egi onal nodal metastases befor e
thoracotomy had a medi an sur vi val of 30 months, compar ed wi th 16
months for al l other pati ents. The author s concl uded that pati ents
wi th i sol ated pul monar y metastases fr om mel anoma may benefi t
fr om r esecti on of metastases.
Liver Metastases
F i fteen to 20% of pati ents wi th metastati c mel anoma have l i ver
metastases. Hi stor i cal l y, the medi an sur vi val of pati ents wi th l i ver
metastases has ranged fr om 2 to 7 months. Chemotherapy i s of
l i mi ted effi cacy agai nst l i ver metastases, so sur gi cal r esecti on
may r epr esent the onl y potenti al l y curati ve opti on for pati ents wi th
mel anoma metastati c to the l i ver.
Some i nvesti gator s have suggested that r esecti on of hepati c
metastasi s i s not war ranted because of the associ ated di smal
pr ognosi s. Other i nvesti gator s have suggested that r esecti on may be
appr opr i ate onl y i n pati ents wi th an ocul ar pr i mar y tumor because
thei r cl i ni cal cour se i s better than that of pati ents wi th l i ver
metastases fr om cutaneous pr i mar y tumor s. In a r ecent ser i es of 40
pati ents who under went r esecti on of l i ver metastases fr om
mel anoma, 75% of the pati ents devel oped a subsequent r ecur r ence.
Pati ents wi th cutaneous mel anoma wer e si gni fi cantl y mor e l i kel y to
have a subsequent r ecur r ence outsi de the l i ver, suggesti ng that the
di sease i s systemi c at the ti me of hepati c r esecti on. No pati ent wi th
cutaneous mel anoma metastati c to the l i ver was al i ve at 5 year s.
Thus, sel ecti on of pati ents for r esecti on of hepati c metastases must
be i ndi vi dual i zed and i ncl ude an extensi ve eval uati on of the extent
of the di sease. We cur r entl y r ecommend that pati ents wi th l i mi ted
hepati c metastases who can be r ender ed sur gi cal l y fr ee of di sease
be consi der ed for hepati c r esecti on. However, because r ecur r ence
after r esecti on i s common, r esecti on shoul d be per for med as par t of
a mul ti di sci pl i nar y appr oach i n conjuncti on wi th systemi c therapy.
Brain Metastases
Mel anoma ranks behi nd onl y smal l -cel l car ci noma of the l ung as the
most common tumor that metastasi zes to the brai n. An unusual
featur e of brai n metastases i s thei r pr opensi ty for hemor r hage,
whi ch occur s much mor e fr equentl y wi th mel anoma brai n
metastases than wi th brai n metastases fr om other pr i mar y tumor s.
Hemor r hage occur s i n 33% to 50% of pati ents wi th brai n
metastases fr om mel anoma.
Sur gi cal exci si on (fol l owed i n sel ected cases by crani al i r radi ati on)
i s the tr eatment of choi ce i n the case of a sol i tar y, sur gi cal l y
accessi bl e brai n metastasi s. Tumor exci si on i s r el ati vel y safe,
al l evi ates symptoms i n most pati ents, and pr events fur ther
neur ol ogi c damage. Al though l ong-ter m di sease-fr ee sur vi val i s
uncommon, a rar e pati ent may l i ve mor e than 5 year s after sur ger y.
Radi ati on therapy i s pr efer r ed when the l esi ons ar e numer ous or ar e
l ocated i n ar eas that pr ecl ude a safe operati on. G amma kni fe
radi osur ger y i s al so an opti on for pati ents wi th smal l to medi um
brai n metastases who have a r easonabl e l i fe expectancy and no
si gns of i ncr eased i ntracrani al pr essur e.
Recurrent Distant Metastases

Unfor tunatel y, many pati ents under goi ng compl ete sur gi cal
r esecti on of di stant metastati c mel anoma (stage IV) devel op
r ecur r ent di sease. A r ecent study exami ned whether a second
metastasectomy coul d pr ol ong the sur vi val of pati ents wi th

r ecur r ent stage IV mel anoma. In thi s study, the r ecur r ent di sease
affected soft ti ssue, pul monar y, gastr oi ntesti nal , cer ebral , skel etal ,
and gynecol ogi c si tes. Medi an sur vi val fol l owi ng tr eatment for
r ecur r ent stage IV mel anoma was 18.2 months after compl ete
metastasectomy, compar ed wi th 12.5 months after a pal l i ati ve
sur gi cal pr ocedur e and 5.9 months after nonsur gi cal management.
The 5-year sur vi val rate was 20% for pati ents i n the compl ete
metastasectomy gr oup, compar ed wi th 7% for those i n the pal l i ati ve
sur ger y gr oup and 2% for those i n the nonsur gi cal gr oup. By
mul ti var i ate anal ysi s, the two most i mpor tant pr ognosti c factor s for
sur vi val fol l owi ng di agnosi s of r ecur r ent stage IV mel anoma wer e a
pr ol onged di sease-fr ee i nter val befor e r ecur r ence and compl ete
sur gi cal r emoval of the r ecur r ent di sease. These fi ndi ngs i ndi cate
that metastasectomy can pr ol ong the sur vi val of pati ents wi th
r ecur r ent stage IV mel anoma and shoul d be consi der ed i f al l
cl i ni cal l y evi dent tumor s can be r esected.
Radiation Therapy
In the tr eatment of cutaneous and l ymph node metastases wi th
radi ati on, most author s have obser ved i mpr oved r esponse rates wi th
hi gher fracti onal doses of radi ati on. The appr opr i ate dose
fracti onati on shoul d be based on nor mal ti ssue tol erance. Mul ti pl e
or r ecur r ent ski n or subcutaneous l esi ons may be tr eated
successful l y wi th hypofracti onated radi ati on therapy. Pr edi ctor s of a
r esponse to radi ati on therapy i ncl ude pr i mar y tumor l ocati on i n the
head and neck r egi on and total radi ati on dose above 40 G y; age,
gender, and hi stol ogi c subtype have no i mpact. Exter nal -beam
radi ati on therapy can pr ovi de l ong-ter m l ocal contr ol and effecti ve
pal l i ati on. Symptomati c bony metastases fr om mel anoma al so
fr equentl y r espond to exter nal -beam radi ati on therapy.
Chemotherapy
Si ngl e-agent chemotherapy r emai ns the standar d of car e for
systemi c chemotherapy i n pati ents wi th metastati c mel anoma.
Dacar baz i ne i s the dr ug of choi ce, wi th a r esponse rate of 16% .
Other dr ugs, i ncl udi ng ci spl ati n, pacl i taxel , docetaxel , and the
dacar baz i ne anal og, temozol omi de, have al so shown acti vi ty i n thi s
di sease. In a phase II tr i al of 56 pati ents tr eated wi th
temozol omi de, a compl ete r esponse was documented i n thr ee
pati ents (al l wi th l ung metastases) and a par ti al r esponse i n ni ne
pati ents (21% overal l r esponse rate).

Based on obser ved si ngl e-agent acti vi ty, several combi nati on
r egi mens have been i nvesti gated, and pr el i mi nar y r esul ts appear
pr omi si ng. The Dar tmouth r egi men (dacar baz i ne, ci spl ati n,
car musti ne, and tamoxi fen) was i ni ti al l y r epor ted to have an overal l
r esponse rate of 55% and compl ete r esponse rate of 20% . However,
subsequent mul ti center tr i al s have fai l ed to cor r oborate these
favorabl e r esul ts. In fact, i n randomi zed phase III tr i al s, the two
most acti ve combi nati on chemotherapy r egi mens, the Dar tmouth
r egi men and ci spl ati n, vi nbl asti ne, and dacar baz i ne, have not
pr oven to be super i or to si ngl e-agent dacar baz i ne i n ter ms of
overal l sur vi val . Other combi nati ons, such as temozol omi de and
ci spl ati n, have not been shown to have cl ear benefi ts i n ter ms of
r esponse rates but may be associ ated wi th a hi gher i nci dence of
grade 3 or grade 4 emesi s.
If no objecti ve r esponse i s obser ved after two or thr ee cour ses of a
par ti cul ar chemotherapy r egi men, i t i s usual l y pr udent to
di sconti nue that r egi men and consi der other appr oaches. In general ,
even when metastati c mel anoma r esponds to systemi c
chemotherapy, the durati on of the r esponse i s usual l y shor t, i n the
range of 3 to 6 months.
Vaccine and Biological Therapies

Mor ton et al . demonstrated that i ntral esi onal i njecti on of vi abl e
baci l l us Cal mette-G ur i n (BCG ) or gani sms coul d l ead to the
r egr essi on of i ntrader mal mel anoma metastasi s. Even mor e
si gni fi cantl y, uni njected l esi ons occasi onal l y r egr essed fol l owi ng
BCG therapy. Thi s fi ndi ng demonstrated the abi l i ty of the body's
i mmune system to destr oy mel anoma when pr oper l y sti mul ated,
l eadi ng to i nvesti gati ons of BCG as a potenti al therapy for
mel anoma. Al though several nonrandomi zed tr i al s usi ng hi stor i cal
contr ol s and two smal l randomi zed tr i al s of i ntral esi onal or
i ntral ymphati c BCG showed a stati sti cal l y si gni fi cant overal l sur vi val
benefi t i n favor of BCG , mul ti pl e other randomi zed tr i al s fai l ed to
substanti ate these fi ndi ngs. Nonethel ess, i nter est i n modul ati ng the
i mmune system to tr eat mel anoma has per si sted.
Monoclonal Antibodies
Monocl onal anti body therapy i s general l y wel l tol erated and has
shown acti vi ty i n phase I tr i al s i n pati ents wi th metastati c
mel anoma. Monocl onal anti bodi es have been used to tar get
radi ati on and potent pl ant toxi ns to tumor s, and anti -i di otype
anti bodi es have been used to sti mul ate i mmune r esponses.
Tumor Vaccines
Tumor vacci nes have been used i n the tr eatment of advanced
mel anoma and as adjuvant therapy for pati ents wi th hi gh-r i sk
mel anoma. These vacci nes may contai n (a) i r radi ated tumor cel l s,
usual l y obtai ned fr om the pati ent; (b) par ti al l y or compl etel y
pur i fi ed mel anoma anti gens; or (c) tumor cel l membranes fr om
mel anoma cel l s i nfected wi th vi r us (vi ral oncol ysates). Syntheti c
vacci nes contai ni ng genes that encode for tumor anti gens and the
pepti de anti gens themsel ves ar e al so bei ng eval uated, as ar e
vacci nes contai ni ng genes encodi ng for i mmune costi mul ator y si gnal
pr otei ns.
Al l ogenei c tumor cel l vacci nes, general l y pr epar ed fr om cul tur ed
cel l l i nes or l ysates ther eof, offer several potenti al i mpor tant
advantages over autol ogous tumor cel l vacci nes: Al l ogenei c vacci nes
ar e r eadi l y avai l abl e and can be standar di zed, pr eser ved, and
di str i buted i n a manner aki n to any other therapeuti c agent. To
date, the major i ty of studi es i nvol vi ng al l ogenei c tumor vacci nes
have been smal l , si ngl e-i nsti tuti on studi es. None of these have
demonstrated an unequi vocal benefi t for i mmunotherapy wi th
al l ogenei c tumor cel l s admi ni ster ed i n conjuncti on wi th BCG
compar ed wi th no tr eatment or tr eatment wi th BCG al one. Two
randomi zed studi es have been conducted i n whi ch al l ogenei c
mel anoma vacci nes wer e admi ni ster ed wi th or wi thout
cycl ophosphami de gi ven for 3 days pr i or to vacci nati on. The r esul ts
of these studi es have been confl i cti ng, wi th one suggesti ng a
decr ease i n suppr essor cel l acti vi ty and one suggesti ng an i ncr ease
i n suppr essor cel l acti vi ty and augmented anti body r esponse.
Novel vacci ne strategi es under i nvesti gati on i ncl ude admi ni strati on
of syntheti c pepti des based on known mel anoma T-cel l
anti gens, geneti c vacci nes, and combi nati ons of vacci nes wi th
cytoki nes or costi mul ator y mol ecul es. Mor ton et al . conducted
nonrandomi zed studi es of a pol yval ent mel anoma vacci ne
(Canvaxi n) i n pati ents wi th stage III or stage IV di sease. Matchedpai r anal yses of data fr om extensi ve phase 2 tr i al s demonstrated a
consi stent overal l sur vi val benefi t for Canvaxi n therapy i n stage III
mel anoma (5-year overal l sur vi val rate: 49% for Canvaxi n vs. 37%
for no vacci ne; p = 0.0001) and stage IV mel anoma (5-year overal l
sur vi val rate: 39% for Canvaxi n vs. 20% for no vacci ne; p =
0.0009). Vacci ne-i nduced i mmune r esponses have cor r el ated wi th
i mpr oved sur vi val after r esecti on of l ocal , r egi onal , and di stant
di sease. Two seperate phase 3 cl i ni cal tr i al s of Canvaxi n i n pati ents
wi th stage III or IV mel anoma wer e di sconti nued i n 2005 based on
the r ecommendati on of the data safety moni tor i ng boar d after an
i nter i m anal ysi s of the study data. The moni tor i ng boar d found that
the data wer e unl i kel y to pr ovi de si gni fi cant evi dence of a sur vi val
benefi t for Canvaxi n ver sus pl acebo i n pati ents wi th stage III or
stage IV mel anoma.
In 2002, the Southwest Oncol ogy G r oup publ i shed the r esul ts of a
l ar ge, randomi zed tr i al (S9035) compar i ng co-admi ni strati on of an
al l ogenei c mel anoma cel l l ysate (Mel aci ne) and detoxi fi ed
endotoxi n/mycobacter i al cel l wal l skel eton (DETOX) ver sus no
tr eatment i n pati ents wi th i nter medi ate thi ckness, node-negati ve
mel anoma. The pr i mar y ai m of thi s tr i al was to deter mi ne the effect
of the vacci ne on r el apse-fr ee sur vi val . A major secondar y ai m was
to deter mi ne i f the effecti veness of the vacci ne was based on
pati ents HLA cl ass I al l el e expr essi on. At a medi an fol l ow-up of 4.1
year s, ther e was no di ffer ence i n overal l r el apse-fr ee sur vi val
between the two gr oups. The pati ents i n the vacci ne ar m expr essi ng
at l east 2 M5 al l el es, however, had better di sease-fr ee sur vi val than
the cor r espondi ng pati ents i n the obser vati on ar m. F ur ther mor e,
vacci ne-ar m pati ents expr essi ng at l east 2 M5 al l el es had better
di sease-fr ee sur vi val than vacci ne-ar m pati ents expr essi ng fewer
than 2 M5 al l el es.
Cellular Therapies
Cel l ul ar therapi es al so exhi bi t some pr omi se. Rosenber g et al . at
the U.S. Nati onal Cancer Insti tute and other s have r epor ted thei r
exper i ences wi th adopti ve i mmunotherapy usi ng tumor-i nfi l trati ng
l ymphocytes and, mor e r ecentl y, dendr i ti c cel l s. An overal l r esponse
rate of 37% was seen i n pati ents wi th stage IV di sease. Newer
for ms of cel l ul ar-based therapy ar e bei ng devel oped, i ncl udi ng
effector cel l s fr om tumor vacci ne-pr i med l ymph nodes. Tr i al s usi ng
i n vi tr o pul sed dendr i ti c cel l i nfusi on ar e ongoi ng. In addi ti on, new
wor k i s exami ni ng whether pr efer enti al i nducti on of apoptosi s by
sequenti al 5-Az a-2 deoxycyti di ne-depsi pepti de (F R901228)
tr eatment i n mel anoma cel l s to i mpr ove r ecogni ti on of speci fi c
tar gets by cytol yti c T l ymphocytes may ser ve as a useful adjunct to
i mmunotherapy.
Immunotherapy
Immunotherapy wi th ei ther i nter l euki n (IL)-2 or IF N has
demonstrated r esponse rates of 10% to 15% i n appr opr i atel y
sel ected
pati ents. In pati ents who have a compl ete r esponse, r esponses can
be of gr eater durabi l i ty than those wi th chemotherapy. IL-2
pr omotes the pr ol i ferati on, di ffer enti ati on, and r ecr ui tment of T, B,
and NK cel l s and i ni ti ates cytol yti c acti vi ty i n a subset of
l ymphocytes. In pati ents who had a compl ete r esponse to IL-2, the
major i ty (86% ) r emai ned i n ongoi ng compl ete r emi ssi on fr om 39 to
mor e than 148 months. In pati ents wi th a par ti al r esponse, medi an
r esponse durati on has been 36 to 45 months. Al though the overal l
r esponse rate i s l ow (10% 15% ), the durabi l i ty of the r esponses l ed
the U.S. Food and Dr ug Admi ni strati on to appr ove hi gh-dose IL-2 for
metastati c mel anoma. However, IL-2 and IF N admi ni strati on ar e
associ ated wi th mul ti pl e si de effects; ther efor e, these agents shoul d
be admi ni ster ed onl y by physi ci ans exper i enced i n the management
of such therapi es. One major systemi c toxi c effect wi th hi gh-dose
IL-2 admi ni strati on i s capi l l ar y l eak syndr ome. Thi s toxi c effect i s,
for tunatel y, uncommon, but i t can be l i fe thr eateni ng.
Biochemotherapy
Mul ti pl e tr i al s have been conducted to i nvesti gate the benefi t of
combi ni ng bi ol ogi cal therapy wi th chemotherapy (so-cal l ed
bi ochemotherapy). These tr i al s i ndi cate that bi ochemotherapy i s
associ ated wi th hi gher r esponse rates and l onger medi an sur vi val s
than chemotherapy al one. Speci fi cal l y, phase I and II studi es have
eval uated combi nati ons of IL-2, IF N, and chemotherapy (ci spl ati n,
dacar baz i ne, or cycl ophosphami de). Pr el i mi nar y r esul ts fr om a
ser i es of smal l studi es usi ng combi nati ons of IL-2, IF N al fa, and
ci spl ati n have i ndi cated overal l r esponse rates of 40% . Recentl y, a
phase III tr i al was compl eted at M. D. Ander son that compar ed
i npati ent sequenti al bi ochemotherapy wi th tradi ti onal outpati ent
chemotherapy wi th r espect to r esponse, ti me to pr ogr essi on, overal l
sur vi val rate, and toxi ci ty. Al l pati ents had ei ther stage IV or
i noperabl e stage III di sease, an ECOG per for mance status of 0 to 3,
no symptomati c brai n metastases, no pr i or chemotherapy, and
adequate car di ac, hematol ogi c, and r enal r eser ves. The r esponse
rate was 48% wi th bi ochemotherapy and 25% wi th standar d
chemotherapy (p = 0.0001). The ti me to pr ogr essi on was 4.6
months wi th bi ochemotherapy and 2.4 months wi th standar d

chemotherapy (p = 0.0007). The medi an sur vi val was 11.8 months
wi th bi ochemotherapy and 9.5 months wi th standar d chemotherapy
(p = 0.055). Bi ochemotherapy di d i nduce sever e consti tuti onal toxi c
effectsmyel osuppr essi on, i nfecti ons, and hypotensi onbut al l of
these wer e found to be manageabl e on the general war d. In a mor e
r ecent phase II tr i al by the same gr oup, the addi ti on of IF N al fa-2a
to IL-2 was exami ned. Al though the r esponse rate for thi s r egi men
was l ow, durabl e r esponses wi th medi an sur vi val durati ons of 30+
months wer e seen i n sel ected pati ents. However, several phase III
tr i al s have not consi stentl y demonstrated an i mpr ovement i n ei ther
r esponse rates or overal l sur vi val .
Adopti ve i mmunotherapy combi ni ng nonmyel oabl ati ve chemotherapy
wi th hi gh-dose IL-2 i s another potenti al l y pr omi si ng therapeuti c
strategy cur r entl y under i nvesti gati on.
Follow-Up
Mel anoma has a mor e var i abl e and unpr edi ctabl e cl i ni cal cour se
than al most any other human cancer. At M. D. Ander son, the
schedul e of fol l ow-up eval uati ons for pati ents wi th mel anoma var i es
accor di ng to the r i sk of r ecur r ence. In general , pati ents wi th ear l ystage mel anoma (i n si tu or <1.0-mm thi ck, nonul cerated, l ymphnode negati ve) have fol l ow-up vi si ts ever y 6 months for 2 year s and
then annual l y. Pati ents wi th thi cker or ul cerated mel anomas and
those wi th posi ti ve l ymph nodes general l y r etur n for fol l ow-up vi si ts
mor e fr equentl yever y 3 to 4 months up to 3 year s, ever y 6
months dur i ng year s 3 and 4, and annual l y ther eafter. At each vi si t,
the pati ent under goes a physi cal exami nati on, ski n sur vey, chest
radi ography, and measur ement of LDH. Excepti ons to thi s r outi ne
cl i ni c vi si t ar e made for pati ents wi th mel anoma i n si tu, i n whom
chest radi ography and measur ement of LDH l evel s ar e not r outi nel y
per for med, and pati ents wi th thi n mel anomas, i n whom chest
radi ography and measur ement of LDH l evel s ar e general l y done
annual l y. Abnor mal fi ndi ngs may pr ompt fur ther wor kup. Par ti cul ar
attenti on shoul d be pai d to si gns or symptoms of central ner vous
system i nvol vement. Extensi ve radi ographi c eval uati on of
asymptomati c pati ents wi th AJCC stage I, stage II, or stage III
mel anoma who ar e cl i ni cal l y fr ee of di sease rar el y r eveal s
metastases and thus i s not r outi nel y per for med.
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M.
Edition
> Ta ble o f C o nt e nt s > 4 - No nm e la no m a Sk in C a nc e r
4
Nonmelanoma Skin Cancer
Kelly Herne
Sharon R. Hymes
Jeffrey E. Gershenw ald
Epidemiology and Etiology

Most nonmel anoma ski n cancer s (NMSCs) ar e ei ther basal cel l
car ci noma (BCC) or squamous cel l car ci noma (SCC). Together, these
cancer s account for appr oxi matel y 90% of al l mal i gnanci es of the
ski n. BCC exceeds SCC i n fr equency by a factor of 4 or 5 to 1 i n the
Uni ted States, Austral i a, and the Uni ted Ki ngdom. However, i n ar eas
of decr easi ng l ati tude such as Afr i ca, Japan, and Indonesi a, SCC i s
mor e common. The mal e-to-femal e rati o of NMSC i s 3:1, r efl ecti ng a
gr eater tendency among men to expose ski n to the sun. In addi ti on,
men ar e mor e l i kel y than women to have these cancer s on the l i ps,
ear s, and scal p, agai n r efl ecti ng patter ns of sol ar exposur e.
Many factor s contr i bute to the devel opment of NMSC, most notabl y
ul travi ol et (UV) radi ati on i n the for m of sunl i ght. UV radi ati on i s
accepted as the domi nant r i sk factor for the devel opment of both
SCC and BCC, al though the r el ati onshi p between UV radi ati on and
the devel opment of BCC i s l ess cl ear. Indeed, mutati ons of the p53
tumor suppr essor gene i nduced by UV l i ght ar e found i n mor e than
90% of SCCs but onl y 50% of BCCs. Another i mpor tant r i sk factor
for both types of cancer i s i mmunosuppr essi on, especi al l y i n
pati ents who have under gone or gan transpl antati on. These pati ents
tend to devel op NMSC, especi al l y SCC, mor e rapi dl y and wi th hi gher
fr equency than those i n the general popul ati on, and i t tends to
fol l ow a mor e aggr essi ve cour se. Pati ents wi th AIDS al so have an
i ncr eased i nci dence of NMSC, al though factor s such as human
papi l l oma vi r us (HPV) i nfecti on may act syner gi sti cal l y wi th UV
exposur e. HPV i nfecti on, especi al l y HPV16 and 18, has al so been
i mpl i cated i n the devel opment of anogeni tal SCC. Ar seni c exposur e
i n wel l dr i nki ng water and hydr ocar bon (tar ) exposur e have been
l i nked to both SCC and BCC.
Differential Diagnosis
Several other epi der mal tumor s common to the ski n can be ei ther
cl i ni cal l y confused wi th NMSC or ar e pr ecur sor s to NMSC.
Recogni ti on of these tumor s i s i mpor tant for both tumor
sur vei l l ance and cancer pr eventi on.
Sebor r heic ker atoses ar e beni gn pr ol i ferati ons of epi der mi s that
appear on any par t of the ski n, except mucous membranes, and
usual l y appear after age 30. They ar e not r el ated to sun exposur e
but ar e common on the face, neck, and tr unk, often i n l ar ge
number s. They i ni ti al l y appear as fl at br own macul es, eventual l y
becomi ng l ar ger, stuck on br own pl aques wi th dul l , cr umbl y
sur faces (F i g. 4.1A). Sebor r hei c keratoses can someti mes be
confused wi th mel anoma. Bi opsy of these l esi ons i s pr udent i f
sudden change i n si ze or col or occur s.
F i gur e 4.1. A : Sebor r hei c keratosi s. B: Acti ni c keratosi s. C:

Cutaneous hor n.
Actinic ker atoses (AKs) ar e pr emal i gnant l esi ons wi th the potenti al
to devel op i nto SCC. They ar e found mai nl y on l i ght-ski nned
i ndi vi dual s on sun-exposed ar eas. These l esi ons pr esent as ski ncol or ed, er ythematous, or br own i l l -defi ned patches wi th adher ent
scal es (F i g. 4.1B). The mean si ze i s appr oxi matel y 3 to 4 mm. These
l esi ons ar e extr emel y common on the face, scal p, ear s, and l i ps and
can often be better appr eci ated by pal pati on than by i nspecti on wi th
the naked eye.
Ker atoacanthoma i s a tumor that often occur s on ol der, sundamaged ski n, especi al l y on the neck and face. They may rapi dl y
gr ow as a r ed- or ski n-col or ed dome-shaped nodul es wi th a central
crater. Maxi mum si ze may be attai ned by 6 to 8 weeks, wi th sl ow
r egr essi on over a per i od of 2 to 12 months. Because these tumor s
can be confused both cl i ni cal l y and hi stol ogi cal l y wi th SCC,

conser vati ve exci si on i s r ecommended.
Cutaneous hor n i s a cl i ni cal descr i pti on for a gr owth that appear s as
a dense cone of epi thel i um r esembl i ng a hor n (F i g. 4.1C). They
range i n si ze fr om several mi l l i meter s to over a centi meter, ar e
general l y whi te or yel l owi sh i n col or, and appear on sun-exposed
ski n i n ol der i ndi vi dual s. Hi stol ogi cal l y, cutaneous hor ns can
devel op fr om beni gn l esi ons such as war ts or sebor r hei c keratoses
and fr om pr emal i gnant or mal i gnant l esi ons such as AK or SCC.
Bi opsy of these tumor s i s ther efor e al ways i ndi cated to r ul e out the
l atter.
Nevus sebaceus i s a beni gn tumor of the scal p that appear s at or
soon after bi r th as a yel l owi sh-orange, wel l -demar cated pl aque.
Ini ti al l y, the sur face has a smooth or waxy appearance that
gradual l y becomes mor e war ty or ver r ucous dur i ng puber ty. In
adul thood, appr oxi matel y 10% of these l esi ons devel op i nto BCC. It
i s ther efor e r ecommended that these l esi ons be exci sed or cl osel y
moni tor ed for the l i fe of the pati ent.
Basal Cell Carcinoma

BCC i s the most common cancer i n humans and the most common
type of ski n cancer. The i nci dence of BCC conti nues to r i se, wi th an
annual esti mated i nci dence of 200 per 100,000 i n the Uni ted
States. It i s bel i eved to ar i se fr om cel l s of the hai r fol l i cl e and i s
ther efor e found al most excl usi vel y on hai r-bear i ng ski n. Most
l esi ons ar e found on sun-exposed ar eas such as the head and neck,
but nonsun-exposed ar eas ar e al so at r i sk. These tumor s tend to
gr ow sl owl y, wi th eventual i nvasi on i nto l ocal str uctur es, i ncl udi ng
muscl e, car ti l age, and bone. Al though the bi ol ogi cal behavi or of BCC
i s character i zed by l ocal and someti mes di sfi gur i ng i nvasi veness,
metastasi s i s rar e, occur r i ng i n l ess than 0.05% of cases.
In general , the hi stol ogi c type of BCC i s pr edi cti ve of i ts behavi or.
Nodul ar BCC i s the cl assi c l esi on of thi s type of NMSC. It appear s as
a pi nk transl ucent nodul e, often descr i bed as pear l y. Over l yi ng
tel angi ectasi as and ul cerati on ar e al so common (F i g. 4-2). In dar kski nned i ndi vi dual s, these tumor s ar e often pi gmented and can
r esembl e mel anoma.
Super fi ci al BCC i s a var i ant that i s mor e common on the l i mbs and
tr unk, as wel l as on ar eas wi th l i ttl e or no sun exposur e. It pr esents
as a sl ow-gr owi ng, scal y pi nk pl aque and can easi l y be confused
wi th super fi ci al SCC or squamous cel l car ci noma i n si tu (Bowen's
di sease).
The scl er osi ng or mor pheafor m type r epr esents the rar est for m of
BCC and often the most di ffi cul t to r ecogni ze. It pr esents as a
poor l y defi ned i ndurated or scl er oti c pl aque, often mi staken for a
scar. In addi ti on, thi s type of BCC fr equentl y i s found to be l ar ger
hi stopathal ogi cal l y than cl i ni cal l y evi dent. Ther efor e, both di agnosi s
and tr eatment r emai n a chal l enge.
F i gur e 4.2. Nodul ar basal cel l car ci noma.
Squamous Cell Carcinoma

SCC i s the second most common type of cutaneous cancer. In the
Uni ted States, i t occur s at a fr equency one-fi fth that of BCC. The
devel opment of SCC i s pr i nci pal l y r el ated to two factor s: sol ar
damage and l i ghter ski n types. SCC devel ops fr om the kerati nocytes
of the epi der mi s. SCC i s al so found i n associ ati on wi th scar s or
ar eas of chr oni c i nfl ammati on such as non-heal i ng ul cer s. In
addi ti on, ther e ar e ver r ucous for ms of SCC found on the mucous
membranes of the oral cavi ty and geni tal s.
SCC has many cl i ni cal var i ants. As stated pr evi ousl y, i t can ar i se
fr om a pr ecur sor l esi on such as an AK or can devel op at the base of
a cutaneous hor n. Uncommonl y, i t pr esents de novo as a si ngl e
l esi on on other wi se nor mal -appear i ng ski n. The most common l esi on
i s found on a backgr ound of sun-damaged ski n, especi al l y on the
head, neck, or ar ms. The l esi ons ar e usual l y r ed, poor l y defi ned
pl aques or nodul es wi th an ul cerated, fr i abl e sur face (F i g. 4-3).
Bowen's di sease, or SCC i n si tu, i s character i zed by a wel l demar cated pi nk pl aque wi th a rai sed bor der and uni for m scal i ng
thr oughout.
SCC has a hi gher metastati c potenti al than does BCC, wi th an
overal l i nci dence of 2% to 3% . However, many factor s affect the
metastati c potenti al of any gi ven tumor, such as hi stol ogi c subtype
based on nucl ear pl eomor phi sm and cytol ogi c atypi a (Br oder
cl assi fi cati on IIV); SCC types II and hi gher ar e mor e l i kel y to
metastasi ze. In addi ti on, tumor si ze mor e than 2 cm and depth
mor e than 4 mm (si mi l ar to Br esl ow thi ckness for mel anoma) ar e
r i sk factor s for metastasi s. Anatomi c si te al so pl ays a r ol e i n the
tendency of SCC to metastasi ze. SCC of the l i p has a metastati c rate
up to 20% , and SCC of the ear, 11% . SCC ar i si ng i n scar s and other
ar eas of chr oni c i nfl ammati on ar e al so mor e l i kel y to metastasi ze,
wi th rates of 18% to 31% r epor ted. Regi onal l ymph nodes ar e the
most common metastati c si te, wi th di stant si tes such as bone, brai n,
and l ungs occasi onal l y r epor ted. For tumor s of the head and neck,
the par oti d gl and i s a common si te for metastases.
F i gur e 4.3. Squamous cel l car ci noma.
Syndromes Associated with Nonmelanoma

Skin Cancers
Xer oder ma pi gmentosum i s an autosomal r ecessi ve di sease that

occur s i n appr oxi matel y 1 i n 250,000 i ndi vi dual s and i s
character i zed by photophobi a, sever e sun sensi ti vi ty, and advanced
sun damage. Affected i ndi vi dual s have defecti ve DNA exci si on r epai r
on exposur e to UV radi ati on and devel op mal i gnanci es of the ski n
and eyes, i ncl udi ng mel anoma, SCC, and BCC, at a rate 1,000 ti mes
that of the general popul ati on. Aggr essi ve sun pr otecti on i n the
for m of ful l -body sun sui ts and r egul ar ski n exams i s i mpor tant.
Ideal l y, these pati ents shoul d onl y go outsi de at ni ght.
Nevoi d basal cel l syndr ome i s an autosomal domi nant di sor der
character i zed by the devel opment of mul ti pl e BCCs. These pati ents
ar e al so exqui si tel y sensi ti ve to radi ati on and shoul d not under go
radi ati on therapy or excessi ve sun exposur e. Often, these tumor s
ar e qui te smal l , number i ng i n the hundr eds on any gi ven ski n
sur face, and ar e thus di ffi cul t to moni tor and tr eat. Agai n, r egul ar
fol l ow-up and aggr essi ve sun avoi dance ar e i mpor tant.
Al bi ni sm i s an autosomal r ecessi ve di sor der character i zed by
decr eased or absent mel ani n i n the ski n and eyes. Pati ents may
devel op mul ti pl e SCCs, BCCs, and mel anomas.
Biopsy Techniques
Any cutaneous l esi on suspi ci ous for mal i gnancy shoul d be bi opsi ed
to assess pathol ogy. Changes noted by pati ents may be qui te subtl e
and i ncl ude i tchi ng, tender ness, bl eedi ng, or change i n si ze, col or,
or textur e. In addi ti on, l esi ons that pati ents do not r outi nel y
obser ve themsel ves, such as those on the back, poster i or l egs, and
buttocks, shoul d be car eful l y exami ned.
Bi opsy of pi gmented l esi ons shoul d be l i mi ted to punch or exci si onal
bi opsy techni ques i n whi ch the ful l thi ckness of the der mi s can be
eval uated i n the pathol ogi cal speci men. A punch bi opsy usual l y
ranges i n si ze fr om 2 to 8 mm and i nvol ves r emovi ng a r ound
cyl i nder of ti ssue, i deal l y to the l evel of the subcutaneous fat. Thi s
si te i s then sutur ed or l eft to granul ate. Often, enti r e l esi ons can be
r emoved for pathol ogi cal exami nati on; i f not, the most suspi ci ous
aspect of the tumor may be sampl ed.
Shave bi opsy i s an excel l ent techni que for super fi ci al l esi ons or
nonpi gmented l esi ons suspi ci ous for BCC or SCC. It i s al so a good
bi opsy techni que for cutaneous hor ns or keratoacanthomas,
pr ovi ded the base of the tumor i s i ncl uded i n the speci men. A shave
bi opsy i nvol ves i njecti ng l ocal anesthesi a i nto the epi der mi s and
upper der mi s to for m a pl umped up wheal bel ow the l esi on i n

questi on. A tangenti al sampl e i s per for med at the base of the wheal
wi th ei ther a ster i l e fl exi bl e razor bl ade or a no. 15 bl ade so that
mi d der mi s i s i ncl uded i n the bi opsy speci men. If per for med too
super fi ci al l y, i nvasi on i nto the der mi s cannot be eval uated, and
r ebi opsy may be i ndi cated.
Exci si on i nvol ves r emoval of the enti r e l esi on wi th a mar gi n of
cl i ni cal l y cl ear ti ssue and i s general l y used for cl assi c l esi ons such
as nodul ar or super fi ci al BCC or super fi ci al SCC. Mar gi ns can be
eval uated i n the speci men, and fur ther tr eatment i s often not
necessar y.
Treatment
The tr eatment of NMSC r equi r es car eful eval uati on of tumor si ze,
pathol ogi cal character i sti cs, anatomi cal l ocati on, age and overal l
heal th of the pati ent, cost to the pati ent, and cosmesi s. Tr eatment
modal i ti es can be di vi ded i nto sur gi cal and nonsur gi cal therapi es.
Sur gi cal exci si on i s the mai nstay of tr eatment of NMSC and i s
effecti ve for al l hi stol ogi c types of tumor s. Pr i mar y sur gi cal exci si on
wi th a mar gi n of cl i ni cal l y nor mal ti ssue al l ows subsequent
eval uati on of the enti r e speci men for cl ear sur gi cal mar gi ns.
Excisions with pr edeter mined mar gins ar e i deal l y per for med al ong
Langer 's l i nes of cl eavage to ensur e a good cosmeti c r esul t.
El l i pti cal exci si ons ar e usual l y per for med on the scal p, for ehead,
cheeks, chi n, tr unk, and extr emi ti es. When deal i ng wi th l esi ons on
the eyel i ds, al ar r i m of the nose, l i ps, and ear s, however, wedgeshaped exci si ons may mi ni mi ze di stor ti on.
Mohs mi cr ographi c sur ger y i s a useful modal i ty for l esi ons of the
head and neck, r ecur r ent or l ar ge (i .e., >2 cm) l esi ons, or l esi ons of
aggr essi ve hi stol ogi c type (e.g., scl er osi ng BCC or hi gh-grade SCC).
For NMSCs wi th metastati c potenti al , cl i ni cal eval uati on of r egi onal
l ymph nodes may be i ndi cated.
Mohs mi cr ographi c sur ger y i nvol ves r emoval of the cl i ni cal mar gi n
of the tumor under l ocal anesthesi a, wi th i mmedi ate
eval uati on of the mar gi ns i n fr ozen secti ons. Smal l i ncr emental
secti ons ar e r emoved unti l the mar gi ns ar e cl ear. Thi s techni que
pr eser ves nor mal ti ssue, thus al l owi ng for the best cosmeti c r esul t.
It al so ensur es that l ar ger l esi ons wi th subcl i ni cal extensi on ar e
enti r el y r emoved. Mohs mi cr ographi c sur ger y of pr i mar y NMSC of
the head and neck has a cur e rate (i .e., negati ve hi stol ogi c mar gi n)
of 99% . The r econstr ucti ve choi ces after Mohs sur ger y ar e si mi l ar
to those avai l abl e after tradi ti onal exci si on. Al though Mohs
mi cr ographi c sur ger y i s ti me-consumi ng, the benefi ts of super i or
cosmesi s and excel l ent cur e rates make i t a tr eatment of choi ce for
many pati ents.
Destr ucti ve techni ques for super fi ci al BCC and SCC i ncl ude
cur ettage, cr yotherapy, and l aser abl ati on. Cur ettage i nvol ves
debul ki ng the tumor under l ocal anesthesi a wi th a shar p cur ette
unti l fi r m under l yi ng der mi s i s r eached. The base i s hyphr ecated
and the pr ocess i s r epeated two or thr ee ti mes. Thi s techni que i s
r eser ved for smal l or super fi ci al tumor s.
Cr yotherapy i s a destr ucti ve method pr i mar i l y r eser ved for the
tr eatment of pr ecancer ous l esi ons such as AKs and occasi onal l y for
smal l super fi ci al BCCs or SCCs. Li qui d ni tr ogen i s ei ther sprayed
wi th a cr yogun or di r ectl y appl i ed to the l esi on wi th cotton-ti pped
appl i cator s for a per i od of ti me such that the vi si bl e thawi ng of the
l esi ons takes at l east 15 seconds (30 seconds for super fi ci al SCC or
BCC).
Laser abl ati on wi th a car bon di oxi de l aser may be consi der ed for
pr e-cancer ous l esi ons. However, fol l i cul ar i nvol vement may be
di ffi cul t to tr eat and l ead to r ecur r ence.
Nonsur gi cal therapi es for the tr eatment of NMSC i ncl ude radi ati on
and several topi cal therapi es. Radi ati on therapy i s often r eser ved
for pati ents unabl e or unwi l l i ng to under go sur gi cal tr eatment of
pr i mar y l esi ons and for the adjuvant tr eatment of r ecur r ent or
hi stol ogi cal l y aggr essi ve tumor s (e.g., those exhi bi ti ng per i neural
i nvasi on). In such pati ents, radi ati on therapy can be qui te useful for
tumor s of the face, especi al l y of the nose, l i ps, eyel i ds, and canthi .
However, the number of tr eatment sessi ons depends on the si ze and
l ocati on of the tumor. Al though pai nl ess, radi ati on therapy may be
associ ated wi th acute or chr oni c radi ati on-i nduced changes. For
hi gh-grade SCC wi th per i neural i nvol vement or i nvasi on i nto bone,
radi ati on therapy i s general l y r ecommended i n conjuncti on wi th
sur gi cal exci si on or Mohs mi cr ographi c sur ger y.
Topi cal therapi es for super fi ci al NMSC and AKs i ncl ude 5%
fl uor ouraci l (5-F U) and i mi qui mod cr eams. Tr eatment r egi mens for
AKs var y wi del y; i n general , 5-F U i s appl i ed to the enti r e affected
ar ea once or twi ce dai l y for a per i od rangi ng fr om 2 to 6 weeks.
Si gni fi cant er ythema, sti ngi ng, ooz i ng and cr usti ng ar e often
r epor ted, especi al l y wi th mor e aggr essi ve tr eatment r egi mens. 5-F U
can be appl i ed to an enti r e r egi on, such as the face, chest, ar ms, or
hands. Retr eatment several months l ater, ei ther wi th cr yotherapy or

other modal i ti es may be necessar y.
For the tr eatment of super fi ci al BCC, 5-F U can be appl i ed dai l y to
the tumor and to several mi l l i meter s of sur r oundi ng ski n for a
per i od of at l east 4 weeks. After a several -week r espi te, the ar ea i s
then eval uated cl i ni cal l y for r esi dual tumor. Bi opsy i s often
i ndi cated to ensur e adequate therapy.
Imi qui mod therapy for AKs and super fi ci al BCC has r ecentl y become
popul ar. For AKs, the cr eam i s appl i ed 2 non-consecuti ve days a
week for 16 weeks. In general , l ess i r r i tati on i s r epor ted wi th
i mi qui mod, except on mucosal ar eas such as the l i ps. Imi qui mod i s
al so appr oved for the tr eatment of super fi ci al BCC, al though not for
SCC. The cr eam shoul d be appl i ed 5 to 7 ni ghts a week for at l east
8 weeks. After a 2- to 3-month r espi te, the l esi on i s eval uated
ei ther cl i ni cal l y or hi stol ogi cal l y (r ebi opsy) to confi r m adequate
therapy. Thi s tr eatment r egi men i s often wel l tol erated and i s
par ti cul ar l y useful for mul ti pl e super fi ci al BCCs i n one ar ea, such as
the back or chest.
Photodynami c therapy i s cur r entl y under i nvesti gati on for the
tr eatment of AKs and super fi ci al BCC. A photosensi ti zermost
commonl y, ami nol evul i ni c aci di s appl i ed to the ski n and acti vated
wi th a l i ght sour ce. The tumor cel l s r etai n the photosensi ti zer for
l onger per i ods of ti me than nor mal cel l s, r esul ti ng i n pr efer enti al
ki l l i ng. Cur e rates for AKs ar e r epor ted to be as hi gh as 90% , but
no l ong-ter m data ar e avai l abl e for rates for super fi ci al BCC.
Chemopr eventi on wi th l ow-dose oral r eti noi ds for chr oni cal l y
i mmunosuppr essed pati ents who have under gone or gan
transpl antati on has shown some pr omi se i n the pr eventi on of SCC.
Ten year s after or gan transpl antati on, these pati ents have an 18fol d i ncr eased r i sk for the devel opment of SCC. However, l ong ter m
therapy i s needed as benefi ci al effects ar e often l ost when these
dr ugs ar e di sconti nued.
Screening and Prevention

Aggr essi ve scr eeni ng of pati ents at r i sk for ski n cancer i s essenti al
to mi ni mi ze the mor bi di ty and mor tal i ty of NMSC. Pati ents at r i sk
i ncl ude those wi th l i ght ski n types, i mmunosuppr essi on, and a
fami l y or per sonal hi stor y of ski n cancer. Ear l y exposur e to UV
shoul d be l i mi ted i n chi l dr en, wi th r egul ar use of sunscr een fr om an
ear l y age. Appr opr i ate SPF l evel and appl i cati on techni ques shoul d
be emphasi zed for al l pati ents, especi al l y appl i cati ons to the face
and neck.
Regul ar exami nati on of the ski n by a der matol ogi st i s r ecommended
for al l pati ents at r i sk for ski n cancer, on at l east a year l y basi s. For
pati ents wi th a hi stor y of AKs or NMSC, r egul ar fol l ow-up wi th a
der matol ogi st i s r ecommended. A compl ete ski n exam i ncl udes
exami nati on of the enti r e ski n sur face, i ncl udi ng the scal p, wi th
par ti cul ar attenti on to pr evi ous ar eas of ski n cancer. In addi ti on,
pati ents wi th a hi stor y of SCC shoul d under go a thor ough
exami nati on of al l r egi onal l ymph node basi ns to eval uate for
metastases.
Recommended Reading
Bol ogni a JL, Jor i z zo JL, Rapi ni RP. Der matology. Phi l adel phi a, Pa:
El sevi er Li mi ted; 2003.
Br odl and AG , Zi tel l i JA. Sur gi cal mar gi ns for exci si on of
cutaneous SCC. J Am Acad Der matol 1992;27(2pt):241248.
Chakrabar ty A, G ei sse JK. Medi cal therapi es for non-mel anoma
ski n cancer. Clin Der matol 2004;22(3):183188.
G upta AK, Cher man AM, Tyr i ng SK. Vi ral and nonvi ral uses of
i mi qui mod: a r evi ew. J Cutan Med Sur g 2005; May 5. 8(5):338
352.
Har wood CA, Leedham-G r een M, Lei gh IM, Pr oby CM. Low-dose
r eti noi ds i n the pr eventi on of cutaneous squamous cel l
car ci nomas i n or gan transpl ant r eci pi ents: a 16-year
r etr ospecti ve study. Ar ch Der matol 2005;141(4):456464.
Mi l l er SJ, Mor esi JM. Acti ni c keratosi s, basal cel l car ci noma and
squamous cel l car ci nomas. Der matology. Phi l adel phi a, PA:
Pi er son DM, Bandel C, Ehr i g T, Cocker el l CJ. Beni gn epi thel i al
tumor s and pr ol i ferati ons. Der matology. Phi l adel phi a, PA:
Ponten F, Lundeber g J. Pr i nci pl es of tumor bi ol ogy and

pathogenesi s of BCCs and SCCs. Der matology. Phi l adel phi a, PA:
Smeets NW, Kr ekel s G A, Oster tag JU, et al . Sur gi cal exci si on vs
Mohs mi cr ographi c sur ger y for basal -cel l car ci noma of the face:
randomi sed contr ol l ed tr i al . Lancet 2004;364(9447):17661772.
Wol f DJ, Zi tel l i JA. Sur gi cal mar gi ns for basal cel l car ci noma.
Ar ch Der matol 1987;123(3):340344.

M.
Edition
> Ta ble o f C o nt e nt s > 5 - So ft- t is s ue a nd Bo ne Sa rc o m a
5
Soft-tissue and Bone Sarcoma
Keith A . Delman
Janice N. Cormier
Epidemiology
In 2005, an esti mated 9,400 new cases of soft-ti ssue sar coma wer e
di agnosed i n the Uni ted States, wi th 3,400 pati ents expected to di e
of the di sease. These rar e tumor s account for l ess than 1% of al l
newl y di agnosed adul t cancer s and 7% of al l newl y di agnosed
cancer s i n chi l dr en. Several di sti nct gr oups of sar comas have been
r ecogni zed: soft-ti ssue sar comas, bone sar comas
(osteosar comas/chondr osar comas), Ewi ng sar comas, and per i pheral
pr i mi ti ve neur oectoder mal tumor s.
Encompassi ng mor e than 50 hi stol ogi c types, soft-ti ssue sar comas
can occur anywher e i n the body. The major i ty of pr i mar y l esi ons
or i gi nate i n an extr emi ty (59% ), wi th the next most fr equent
anatomi cal si te of or i gi n bei ng the tr unk (19% ), fol l owed by the
r etr oper i toneum (13% ) and the head/neck r egi on (9% ). The most
common hi stol ogi c types of soft-ti ssue sar coma i n adul ts (excl udi ng
Kaposi sar coma) ar e mal i gnant fi br ous hi sti ocytoma (24% ),
l ei omyosar coma (21% ), l i posar coma (19% ), synovi al sar coma
(12% ), and mal i gnant per i pheral ner ve sheath tumor s (6% ).
Rhabdomyosar coma i s the most common soft-ti ssue sar coma of
chi l dhood and accounts for appr oxi matel y 250 cases annual l y.
Dur i ng the past 25 year s, a mul ti modal i ty tr eatment appr oach has
been successful l y appl i ed to pati ents wi th extr emi ty sar comas, and
thi s has l ed to i mpr ovements i n both sur vi val and qual i ty of l i fe.
However, pati ents wi th abdomi nal sar comas conti nue to have hi gh
rates of r ecur r ence and poor overal l sur vi val . The overal l 5-year
sur vi val rate for pati ents wi th al l stages of soft-ti ssue sar coma i s
50% to 60% . Of the pati ents who di e of sar coma, most wi l l succumb
to metastati c di sease, whi ch 80% of the ti me occur s wi thi n 2 to 3
year s of the i ni ti al di agnosi s.
Etiology
Numer ous factor s have been associ ated wi th an i ncr eased r i sk of
soft-ti ssue sar coma. These factor s ar e di scussed i n the fol l owi ng
secti ons.
Trauma
Al though pati ents wi th sar coma fr equentl y r epor t a hi stor y of
trauma i n the tumor ar ea, a causal r el ati onshi p has not been
establ i shed. Mor e often, a mi nor i njur y cal l s attenti on to a pr eexi sti ng tumor that may be accentuated by edema or a hematoma.
Occupational Chemicals
Exposur e to some her bi ci des such as phenoxyaceti c aci ds and wood
pr eser vati ves contai ni ng chl or ophenol s has been l i nked to an
i ncr eased r i sk for soft-ti ssue sar coma. Several chemi cal
car ci nogens, i ncl udi ng Thor otrast (thor i um oxi de), vi nyl chl or i de,
and ar seni c, have been associ ated wi th hepati c angi osar coma.
Exposur e to asbestos has been associ ated wi th mesothel i oma.
Previous Radiation Exposure

Exter nal radi ati on therapy i s a rar e but wel l -establ i shed cause of
soft-ti ssue sar coma. An 8- to 50-fol d i ncr ease i n the i nci dence of
sar comas has been noted for pati ents tr eated for cancer s of the
br east, cer vi x, ovar y, testes, and l ymphati c system. In addi ti on, the
r i sk for sar comas after radi ati on therapy i ncr eases wi th hi gher
dosage. The i nter val between i r radi ati on and the devel opment of
sar coma i s usual l y at l east 10 year s. In a r evi ew of 160 pati ents
wi th posti r radi ati on sar comas, the most common hi stol ogi c types
wer e osteogeni c sar coma, mal i gnant fi br ous hi sti ocytoma,
angi osar coma, and l ymphangi osar coma. Posti r radi ati on sar comas ar e
often di agnosed at a mor e advanced stage and ar e ther efor e
associ ated wi th a poor er pr ognosi s compar ed wi th other sar comas.
Chronic Lymphedema
In 1948, Stewar t and Tr eves wer e the fi r st to descr i be the
associ ati on of chr oni c l ymphedema fol l owi ng axi l l ar y di ssecti on wi th

subsequent l ymphangi osar coma. Lymphangi osar coma has al so been
obser ved i n pati ents fol l owi ng fi l ar i al i nfecti ons and i n the l ower
extr emi ti es of pati ents wi th congeni tal pr i mar y l ymphedema.
Genetic Predisposition
Speci fi c i nher i ted geneti c al terati ons have been associ ated wi th an
i ncr eased r i sk of bone and soft-ti ssue sar comas. For exampl e,
pati ents wi th G ar dner syndr ome (fami l i al pol yposi s) have a hi gher
than nor mal i nci dence of desmoi ds, pati ents wi th ger m-l i ne
mutati ons i n the tumor suppr essor gene p53 (Li -F raumeni
syndr ome) have a hi gh i nci dence of sar comas, and pati ents wi th von
Reckl i nghausen di sease who have abnor mal i ti es i n the
neur ofi br omatosi s type 1 gene have an i ncr eased r i sk of
neur ofi br osar comas. Soft-ti ssue sar comas can al so occur i n pati ents
wi th her edi tar y r eti nobl astoma as a second pr i mar y mal i gnancy.
Oncogene Activation
Oncogenes ar e genes that ar e capabl e of i nduci ng mal i gnant
transfor mati on and tend to dr i ve cel l s towar d pr ol i ferati on. Several
oncogenes have been i denti fi ed i n associ ati on wi th soft-ti ssue
sar comas, i ncl udi ng MDM2, N-myc, c-er B2, and member s of the r as
fami l y. Ampl i fi cati on of these genes has been shown to cor r el ate
wi th an adver se outcome i n pati ents wi th var i ous soft-ti ssue
sar comas.
Cytogeneti c anal ysi s of soft-ti ssue tumor s has l ed to the
i denti fi cati on of di sti nct chr omosomal transl ocati ons i n oncogenes
that ar e associ ated wi th cer tai n hi stol ogi c subtypes. These i ncl ude
the TLS-CHOP fusi on, whi ch i s obser ved i n myxoi d l i posar coma, and
the EWS-ATF 1 fusi on, whi ch i s obser ved i n cl ear-cel l sar coma,
among other s. The gene r ear rangements best character i zed to date
ar e those found i n Ewi ng sar coma, cl ear cel l sar coma, myxoi d
l i posar coma, al veol ar r habdomyosar coma, desmopl asti c smal l r ound
cel l tumor s, and synovi al sar coma.
Tumor Suppressor Genes

Tumor suppr essor genes pl ay a cr i ti cal r ol e i n suppr essi ng tumor
cel l gr owth. However, these genes can be i nacti vated as a r esul t of
her edi tar y or sporadi c mechani sms. Two genes that have shown the
gr eatest r el evance to soft-ti ssue tumor s ar e the r eti nobl astoma (Rb)
tumor suppr essor gene and the p53 tumor suppr essor gene.
Mutati ons or del eti ons i n Rb can l ead to the devel opment of
r eti nobl astoma, as wel l as sar comas of soft ti ssue and bone.
Mutati ons i n the p53 tumor suppr essor gene ar e the most common
mutati ons i n human sol i d tumor s and have been obser ved i n 30% to
60% of cases of soft-ti ssue sar comas.
Pathology
Sar comas ar e a heter ogeneous gr oup of tumor s that not onl y ar i se
pr edomi nantl y fr om the embr yoni c mesoder m, but can al so ar i se
fr om the ectoder m (e.g., per i pheral ner vous sheath tumor s).
Mesoder mal cel l s gi ve r i se to the connecti ve ti ssues di str i buted
thr oughout the body, i ncl udi ng per i car di um, pl eura, bl ood vessel
endothel i um, smooth and str i ated muscl e, bone, car ti l age, and
synovi um. These ar e the cel l s fr om whi ch near l y al l sar comas
or i gi nate. Consequentl y, sar comas devel op i n a wi de var i ety of
anatomi cal si tes.
Despi te the var i ous hi stol ogi c subtypes, sar comas have many
common cl i ni cal and pathol ogi cal featur es. The overal l cl i ni cal
behavi or of most types of sar coma i s si mi l ar and deter mi ned by
anatomi cal l ocati on (depth, speci fi cal l y r el ated to fasci al
boundar i es), grade, and si ze. The domi nant r oute of metastasi s i s
hematogenous. Tumor grade has been fi r ml y establ i shed to have
pr ognosti c si gni fi cance and has ther efor e been i ncor porated i nto the
stagi ng of soft-ti ssue sar comas. However, some exper ts have
suggested that the pathol ogi cal cl assi fi cati on i s far mor e i mpor tant
than grade when other pr etr eatment var i abl es ar e taken i nto
account. Tabl e 5.1 shows a br eakdown of the hi stol ogi c types of
tumor s by thei r aggr essi veness. Tumor s wi th l i ttl e or no metastati c
potenti al i ncl ude desmoi ds, atypi cal l i pomatous tumor s (al so cal l ed
wel l -di ffer enti ated l i posar coma), der matofi br osar coma pr otuberans,
and hemangi oper i cytomas. Those subtypes wi th an i nter medi ate r i sk
of metastati c spr ead i ncl ude myxoi d l i posar coma, myxoi d mal i gnant
fi br ous hi sti ocytoma, and extraskel etal chondr osar coma. Hi ghl y
aggr essi ve tumor s that have a substanti al metastati c potenti al
i ncl ude angi osar coma, cl ear cel l sar coma, pl eomor phi c and
dedi ffer enti ated l i posar coma, l ei omyosar coma, r habdomyosar coma,
and synovi al sar coma. Appr oxi matel y 15% of al l soft-ti ssue
sar comas occur i n the r etr oper i toneum. Appr oxi matel y 80% ar e
mal i gnant, wi th l i posar coma, fi br osar coma, l ei omyosar coma, and
mal i gnant fi br ous hi sti ocytoma accounti ng for the vast major i ty of
the hi stol ogi c types.
In as many as 25% to 40% of cases, exper t sar coma pathol ogi sts
may di sagr ee about speci fi c hi stol ogi c di agnoses or cr i ter i a for
defi ni ng tumor grade. Thi s l ow concor dance rate may stem fr om the
fact that few pathol ogi sts have the oppor tuni ty to study many of
these rar e tumor s dur i ng thei r car eer s. It al so emphasi zes the need
for mor e objecti ve mol ecul ar and bi ochemi cal mar ker s to i mpr ove
the accuracy of conventi onal hi stol ogi c assessment.
Table 5.1. Breakdown of sarcoma histologic

type by tumor aggressiveness
Low metastatic potential
Desmoid tumor
Atypical lipomatous tumor
Dermatofibrosarcoma protuberans
Hemangiopericytoma
Intermediate metastatic potential
Myxoid liposarcoma
Myxoid malignant fibrous histiocytoma
Extraskeletal chondrosarcoma
High metastatic potential
Alveolar soft part sarcoma
Angiosarcoma
Clear cell sarcoma (melanoma of soft parts)
Epithelioid sarcoma
Extraskeletal Ewing sarcoma
Extraskeletal osteosarcoma
Malignant fibrous histiocytoma
Liposarcoma (pleomorphic and
dedifferentiated)
Leiomyosarcoma
Neurogenic sarcoma (malignant schwannoma)
Rhabdomyosarcoma
Synovial sarcoma
Staging
The stagi ng cr i ter i a for soft-ti ssue sar comas i n the cur r ent ver si on
of the Amer i can Joi nt Commi ttee on Cancer (AJCC) stagi ng
gui del i nes consi st of the hi stopathol ogi cal grade (G ), tumor si ze and
depth (T), and the pr esence of metastases (di stant [M] or nodal [N])
(Tabl e 5.2). Thi s system does not appl y to vi sceral sar comas, Kaposi
sar coma, der matofi br osar coma, or desmoi d tumor s.
Histopathological Grade
Hi stopathol ogi cal grade r emai ns the most i mpor tant pr ognosti c
factor for deter mi ni ng di sease-fr ee and overal l sur vi val rate. In the
2002 AJCC stagi ng system, grades 1 and 2 (wel l and moderatel y
di ffer enti ated), N0, M0 l esi ons ar e cl assi fi ed as stage I l esi ons,
r egar dl ess of tumor si ze and depth. To accuratel y deter mi ne tumor
grade, an adequate ti ssue sampl e must be wel l fi xed, wel l stai ned,
and r evi ewed by an exper i enced sar coma pathol ogi st. The
pathol ogi cal featur es that defi ne grade i ncl ude cel l ul ar i ty,
di ffer enti ati on, pl eomor phi sm, necr osi s, and the number of mi toses.
Table 5.2. American Joint Committee on

cancer staging criteria for soft-tissue
sarcomas
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
Tumor 5 cm in greatest dimension

T1
T1a
Tumor above superficial fascia
T1b Tumor invading or deep to

superficial fascia
Tumor >5 cm in greatest dimension
T2
T2a
Tumor above superficial fascia
T2b Tumor invading or deep to

superficial fascia
NX
Regional lymph nodes cannot be

assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis

MX
Distant metastasis cannot be assessed
M0
M1
Distant metastasis
Histopathological grade (G)

GX
Grade cannot be assessed
G1
Well differentiated
G2
Moderately differentiated
G3
Poorly differentiated
G4
Undifferentiated
Stage grouping
Stage I
A
G12, T1a
1b, N0, M0
(low grade, small,

superficial, and deep)
G12, T2a,
N0, M0
(low grade, large, and

superficial)
Stage II
A
G12, T2b,
N0, M0
(low grade, large, and

deep)
G34, T1a
1b, N0, M0
(high grade, small,

superficial, and deep)
G34, T2a,
(high grade, large, and
Stage
III
Stage
IV
N0, M0
superficial)
G34, T2b,
N0, M0
(high grade, large, and

deep)
Any G, any
T, N1, M0
(any metastasis)
Any G, any
T, N0, M1
Adapted from Greene FL, Page DL, Fleming ID,

et al., eds. Cancer Staging Manual. 6th ed.
Philadelphia, Pa: Lippincott-Raven; 2002, with
permission.
Tumor Size
Tumor si ze at pr esentati on i s al so an i mpor tant deter mi nant of
outcome. Sar comas have cl assi cal l y been strati fi ed i nto two gr oups
based on si ze: T1 l esi ons (5 cm) and T2 l esi ons (>5 cm). The 2002
AJCC stagi ng system conti nues to use depth (i .e., super fi ci al or
deep) to defi ne pr ognosi s. Extr emi ty soft-ti ssue sar comas that ar e
super fi ci al to the i nvesti ng muscul ar fasci a ar e desi gnated a l esi ons
i n the T scor e (Ta), wher eas tumor s deep to the fasci a and al l
r etr oper i toneal and vi sceral l esi ons ar e desi gnated b (Tb).
Nodal Metastases
Lymph node metastases ar e rar e, wi th l ess than 5% of soft-ti ssue
sar comas metastasi z i ng to the nodes. Nodal metastases ar e
associ ated wi th a poor pr ognosi s and conti nue to be cl assi fi ed as
stage IV di sease. A few hi stol ogi c subtypes, such as epi thel i oi d
sar coma, r habdomyosar coma, cl ear cel l sar coma, angi osar coma, and
mal i gnant fi br ous hi sti ocytoma, have been found to be associ ated
wi th a hi gher i nci dence of nodal i nvol vement (10% 20% ).
Distant Metastasis
Di stant metastases occur most fr equentl y i n the l ung. Resecti on of
the pul monar y l esi ons i n sel ected pati ents wi th i sol ated l ung
metastases may offer up to a 30% 5-year sur vi val rate. Other
potenti al si tes of metastasi s i ncl ude bone, brai n, and l i ver. Vi sceral
and r etr oper i toneal sar comas have a pr opensi ty to metastasi ze to
the l i ver and per i toneum.
Extremity Soft-Tissue Sarcomas

Mor e than 50% of soft-ti ssue sar comas or i gi nate i n an extr emi ty.
The most common hi stol ogi c subtypes that occur i n the extr emi ty
i ncl ude mal i gnant fi br ous hi sti ocytoma, l i posar coma, synovi al
sar coma, and fi br osar coma, al though var i ous other hi stol ogi c types
ar e al so seen i n the extr emi ti es.
Most extr emi ty soft-ti ssue sar comas pr esent as an asymptomati c
mass, but the si ze at pr esentati on usual l y depends on the
anatomi cal si te of the tumor. For exampl e, al though a 2- to 3-cm
tumor may become r eadi l y appar ent on the back of the hand, a
tumor i n the thi gh may gr ow to 10 to 15 cm i n di ameter befor e i t
becomes appar ent. F r equentl y, trauma to the affected ar ea wi l l cal l
attenti on to the pr e-exi sti ng l esi on. Smal l l esi ons that on the basi s
of the cl i ni cal hi stor y r emai n unchanged for several year s may be
cl osel y obser ved wi thout bi opsy. However, al l other tumor s shoul d
be bi opsi ed.
Biopsy
Accurate pr eoperati ve hi stol ogi c di agnosi s i s a cr i ti cal step i n
deter mi ni ng the pr i mar y tr eatment of a soft-ti ssue sar coma. The
bi opsy shoul d yi el d enough ti ssue so that a pathol ogi cal di agnosi s
can be made wi thout i ncr easi ng the r i sk of compl i cati ons.
Cor e-needl e bi opsy and fi ne-needl e aspi rati on have been
demonstrated to be r el i abl e means of obtai ni ng enough mater i al
for an accurate pathol ogi cal di agnosi s to be made, par ti cul ar l y when
the pathol ogi cal fi ndi ngs cor r el ate cl osel y wi th cl i ni cal and i magi ng
fi ndi ngs. Bi opsy per for med under ul trasound or computed
tomography (CT) gui dance can i mpr ove the posi ti ve yi el d rate by
hel pi ng pathol ogi sts mor e accuratel y l ocate the needl e i n the tumor,
par ti cul ar l y i n pati ents wi th deep extr emi ty or r etr oper i toneal
tumor s.
Evaluation
The goal s of pr etr eatment radi ol ogi c i magi ng ar e to accuratel y
defi ne the l ocal extent of a tumor and to l ook for metastati c
di sease. Magneti c r esonance i magi ng (MRI) has suppl anted CT as
the i magi ng techni que of choi ce i n the eval uati on of soft-ti ssue
sar comas of the extr emi ty, except i n pati ents who do not have
access to MRI or who have a contrai ndi cati on to MRI, i n whom CT
r emai ns the pr eferabl e techni que. MRI accuratel y del i neates muscl e
gr oups and di sti ngui shes between bone, vascul ar str uctur es, and
tumor. In addi ti on, sagi ttal and cor onal vi ews al l ow thr eedi mensi onal eval uati on of anatomi cal compar tments.
CT r emai ns the i magi ng techni que of choi ce for eval uati ng
r etr oper i toneal sar comas. The cur r ent generati on of CT scanner s
can rapi dl y pr ovi de a detai l ed sur vey of the abdomen and pel vi s and
del i neate adjacent or gans and vascul ar str uctur es. A CT scan of the
abdomen and pel vi s shoul d be obtai ned when the hi stol ogi c
assessment of an extr emi ty sar coma r eveal s myxoi d l i posar coma,
because thi s hi stol ogi c subtype i s known to metastasi ze to the
abdomen. Chest CT i s used most often i n pati ents wi th hi gh-grade
l esi ons. Sear ches for bone and brai n metastases ar e rar el y
i ndi cated, unl ess a pati ent has symptoms of metastases to these
si tes.
Management of Local Disease

The success of l ocal tumor contr ol depends on several tumor- and
tr eatment-r el ated pr ognosti c factor s. In mul ti var i ate anal yses, hi gh
hi stol ogi c grade, l ar ge tumor si ze (>5 cm), posi ti ve sur gi cal
mar gi ns, and i ntraoperati ve vi ol ati on of the tumor capsul e have
been associ ated wi th a hi gh rate of l ocal r ecur r ence. Hi stol ogi c
grade and tumor si ze ar e the most si gni fi cant r i sk factor s for di stant
metastasi s and tumor-r el ated mor tal i ty.
Surgery
The type of sur gi cal r esecti on per for med i n pati ents wi th extr emi ty
soft-ti ssue sar comas i s deter mi ned by a number of factor s, i ncl udi ng
tumor l ocati on, tumor si ze, the depth of i nvasi on, the i nvol vement
of near by str uctur es, the need for ski n grafti ng or autogenous
ti ssue r econstr ucti on, and the pati ent's per for mance status. In the
1970s, 50% of pati ents wi th extr emi ty sar comas wer e tr eated wi th
amputati on for l ocal contr ol of thei r tumor s. However, despi te a
l ocal r ecur r ence rate of l ess than 10% fol l owi ng radi cal sur ger y,
l ar ge number s of pati ents conti nued to di e fr om metastati c di sease.
Thi s r eal i z ati on l ed to the devel opment and adopti on of other
methods of l ocal therapy that combi ned conser vati ve sur gi cal
exci si on wi th postoperati ve radi ati on therapy, wi th r esul tant l ocal
contr ol rates of 78% to 91% .
Wi de l ocal exci si on i s the pr i mar y tr eatment for pati ents wi th
extr emi ty sar comas. It i s i mpor tant, when pl anni ng sur ger y and
radi otherapy, to r emember that ther e i s general l y a zone of
compr essed r eacti ve ti ssue that for ms a pseudocapsul e ar ound the
tumor s and that tumor s may extend beyond thi s pseudocapsul e. The
i nexper i enced sur geon may mi stakenl y use thi s to gui de r esecti on.
The goal of l ocal therapy i s to r esect the tumor wi th a 2-cm mar gi n
of sur r oundi ng nor mal soft ti ssue. In some anatomi cal ar eas,
however, these mar gi ns ar e not attai nabl e because of the pr oxi mi ty
of vi tal str uctur es. When possi bl e, the bi opsy si te or tract shoul d
al so be i ncl uded en bl oc wi th the r esected speci men.
El ecti ve r egi onal l ymphadenectomy i s rar el y i ndi cated i n pati ents
wi th soft-ti ssue sar comas. However, i n pati ents wi th
r habdomyosar coma or epi thel i oi d sar coma wi th suspi ci ous cl i ni cal or
radi ol ogi c fi ndi ngs, fi ne-needl e aspi rati on of the l ymph nodes shoul d
be per for med pr eoperati vel y. In these rar e cases, a l ymph node
di ssecti on may be i ndi cated for r egi onal contr ol of the di sease. A
pr ospecti ve tr i al i s cur r entl y under way to eval uate the r ol e of
l ymphati c mappi ng and senti nel l ymph node bi opsy i n pedi atr i c
pati ents wi th extr emi ty r habdomyosar comas.
Ther e have been several studi es that have shown favorabl e l ocal
contr ol rates for pati ents wi th extr emi ty tumor s tr eated wi th
conser vati ve r esecti on combi ned wi th radi ati on therapy. For
exampl e, i n a smal l study fr om the Nati onal Cancer Insti tute, ther e
was no di ffer ence i n sur vi val among pati ents tr eated wi th
conser vati ve sur ger y pl us radi ati on therapy compar ed wi th pati ents
tr eated wi th amputati on. In 1985, on the basi s of the l i mi ted data
avai l abl e, the Nati onal Insti tutes of Heal th devel oped a consensus
statement r ecommendi ng l i mb-spar i ng sur ger y for the major i ty of
pati ents wi th hi gh-grade extr emi ty sar comas. However, amputati on
r emai ns the tr eatment of choi ce for pati ents whose tumor cannot be
gr ossl y r esected wi th a l i mb-spar i ng pr ocedur e that pr eser ves
functi on (<5% of cases).
Radiation Therapy
The pr i mar y goal of radi ati on therapy i s to opti mi ze l ocal tumor
contr ol . The evi dence for adjuncti ve radi ati on therapy i n pati ents
el i gi bl e for conser vati ve sur gi cal r esecti on comes fr om two
randomi zed tr i al s and a number of l ar ge si ngl e-i nsti tuti on r epor ts.
In one of these randomi zed tr i al s, conducted by the Nati onal Cancer
Insti tute, 91 pati ents wi th hi gh-grade extr emi ty tumor s wer e
tr eated wi th l i mb-spar i ng sur ger y fol l owed by chemotherapy al one
or radi ati on therapy pl us adjuvant chemotherapy. A second gr oup of
50 pati ents wi th l ow-grade tumor s wer e tr eated wi th r esecti on al one
ver sus r esecti on wi th radi ati on therapy. The 10-year l ocal contr ol
rate for al l pati ents r ecei vi ng radi ati on therapy was 98% compar ed
wi th 70% for those not r ecei vi ng radi ati on therapy.
In the second randomi zed tr i al , whi ch was per for med at Memor i al
Sl oan-Ketter i ng Cancer Center, 164 pati ents wer e randomi zed to
obser vati on or brachytherapy fol l owi ng conser vati ve sur ger y. The 5year l ocal contr ol rate for pati ents wi th hi gh-grade tumor s was 66%
i n the obser vati on gr oup and 89% i n the gr oup tr eated wi th
brachytherapy. Ther e was no si gni fi cant di ffer ence between the
gr oups of pati ents wi th l ow-grade tumor s.
Unti l r ecentl y, the pol i cy at the M. D. Ander son Cancer Center was
to admi ni ster radi ati on therapy as an adjunct to sur ger y for al l
pati ents wi th i nter medi ate- and hi gh-grade tumor s of any si ze.
However, because T1 tumor s ar e l ess fr equentl y associ ated wi th
l ocal r ecur r ences, radi ati on therapy for these pati ents i s cur r entl y
consi der ed on an i ndi vi dual basi s because i t may not confer a
si gni fi cant cl i ni cal benefi t. In fact, two r ecent studi es have fai l ed to
demonstrate an i mpr ovement i n the 5-year r ecur r ence or sur vi val
rates i n pati ents wi th smal l sar comas who r ecei ved postoperati ve
radi ati on therapy.
Preoperative Versus Postoperative Externalbeam Radiation Therapy

The opti mal ti mi ng of exter nal -beam radi ati on therapy for sar comas
l ocated ei ther i n an extr emi ty or i n the r etr oper i toneum r emai ns a
focus of acti ve i nvesti gati on. Cur r entl y, the onl y randomi zed tr i al
compar i ng pr eoperati ve and postoperati ve radi ati on therapy i s a
mul ti center tr i al per for med i n Canada. In thi s tr i al , fr om October

1994 to December 1997, pati ents wer e randomi zed to r ecei ve ei ther
50 G y of exter nal -beam radi ati on therapy pr eoperati vel y or 66 G y
of exter nal -beam radi ati on therapy postoperati vel y. One hundr ed
and ni nety pati ents wer e enter ed i nto the study. Wi th a medi an
fol l ow-up of 3.3 year s, the r ecur r ence and pr ogr essi onfr ee sur vi val
rates wer e si mi l ar between the gr oups, wi th the onl y stati sti cal l y
si gni fi cant di ffer ence bei ng i n the rates of wound compl i cati ons.
That i s, the i nci dence of wound compl i cati ons was 35% i n the
pati ents who r ecei ved pr eoperati ve therapy, but onl y 17% i n the
pati ents who r ecei ved postoperati ve radi ati on therapy.
At M. D. Ander son, despi te the potenti al for i ncr eased wound
pr obl ems, radi ati on therapy i s pr efer enti al l y gi ven pr eoperati vel y
for several r easons. F i r st, thi s enabl es mul ti di sci pl i nar y pl anni ng
wi th the radi ati on oncol ogi st, medi cal oncol ogi st, and sur geon to
occur ear l y i n the cour se of therapy whi l e the tumor i s i n pl ace.
Al so, pr eoperati ve radi ati on therapy al l ows l ower doses of radi ati on
to be del i ver ed to an undi stur bed ti ssue bed that i s potenti al l y
better oxygenated. In addi ti on, the si ze of the pr eoperati ve
radi ati on fi el ds and the number of joi nts i ncl uded i n the fi el ds i s
si gni fi cantl y smal l er than those of postoperati ve radi ati on fi el ds,
whi ch may r esul t i n an i mpr oved functi onal outcome.
Cr i ti cs of pr eoperati ve radi ati on therapy ci te the di ffi cul ty wi th the
pathol ogi cal assessment of mar gi ns and the i ncr eased i nci dence of
wound compl i cati ons as deter r ents to pr eoperati ve radi ati on
therapy. However, pl asti c sur ger y techni ques that i ncl ude advanced
ti ssue transfer pr ocedur es ar e bei ng used mor e fr equentl y i n
pati ents wi th such hi gh-r i sk wounds. The outcomes i n pati ents
tr eated i n thi s fashi on have been encouragi ng, wi th a hi gh success
rate (>90% ) of heal ed wounds fr om a si ngl e-stage operati on.
Brachytherapy
Brachytherapy, whi ch i nvol ves the pl acement of mul ti pl e catheter s
i n the tumor r esecti on bed, has been r epor ted to achi eve l ocal
contr ol rates comparabl e to those achi eved wi th exter nal -beam
radi ati on therapy. G ui del i nes have been establ i shed that
r ecommend pl aci ng the after l oadi ng catheter s at 1-cm i nter val s wi th
a 2-cm mar gi n ar ound the sur gi cal bed. Usual l y, after the fi fth
postoperati ve day, the catheter s ar e then l oaded wi th radi oacti ve
wi r es (i r i di um 192) that del i ver 42 to 45 G y to the tumor bed over
4 to 6 days. The fr equency of wound compl i cati ons associ ated wi th

brachytherapy i s si mi l ar to that seen for postoperati ve radi ati on
therapy (appr oxi matel y 10% ).
The pr i mar y benefi t of brachytherapy i s the shor ter overal l
tr eatment ti me of 4 to 6 days, compar ed wi th the 4 to 6 weeks
general l y consumed by pr eoperati ve or postoperati ve r egi mens.
Brachytherapy al so pr oduces l ess radi ati on scatter i n cr i ti cal
anatomi cal r egi ons (e.g., gonads, joi nts), wi th i mpr oved functi on a
potenti al cl i ni cal benefi t. Cost-anal ysi s compar i sons of
brachytherapy ver sus exter nal -beam radi ati on therapy have fur ther
shown that the char ges for adjuvant i r radi ati on wi th brachytherapy
ar e l ower than those for exter nal -beam radi ati on therapy.
Systemic Chemotherapy
Despi te i mpr ovements i n the l ocal contr ol rate, metastasi s and
death r emai n si gni fi cant pr obl ems for pati ents wi th hi gh-r i sk softti ssue sar comas. Thi s i ncl udes pati ents pr esenti ng wi th metastati c
di sease and l ocal i zed sar comas that ar e i n nonextr emi ty si tes, show
an i nter medi ate- or hi gh-grade hi stol ogy, or ar e l ar ge (T2). The
tr eatment r egi men for pati ents wi th hi gh-r i sk l ocal i zed di sease,
metastati c di sease, or both, often i ncl udes chemotherapy.
As a gr oup, sar comas i ncl ude hi stol ogi c subtypes that ar e ver y
r esponsi ve to cytotoxi c chemotherapy as wel l as subtypes that ar e
uni ver sal l y r esi stant to cur r ent agents. Onl y thr ee dr ugs,
doxor ubi ci n, dacar baz i ne, and i fosfami de, have consi stentl y
achi eved r esponse rates of 20% as si ngl e-agent tr eatments i n
pati ents wi th advanced soft-ti ssue sar comas. The major i ty of acti ve
chemotherapeuti c tr i al s have i ncl uded doxor ubi ci n as par t of the
tr eatment r egi men. The r esponse rate to i fosfami de has been found
to var y fr om 20% to 60% i n si ngl e-i nsti tuti on ser i es i n whi ch
hi gher-dose r egi mens have been used or i n whi ch i t has been gi ven
i n combi nati on wi th doxor ubi ci n.
Adjuvant (Postoperative) Chemotherapy

Indi vi dual randomi zed tr i al s of adjuvant chemotherapy have fai l ed
to demonstrate an i mpr ovement i n di sease-fr ee and overal l sur vi val
i n pati ents wi th soft-ti ssue sar comas. However, ther e ar e several
cr i ti ci sms of these i ndi vi dual tr i al s that may expl ai n why they fai l ed
to demonstrate i mpr ovement i n sur vi val . F i r st, the chemotherapy
r egi mens used wer e subopti mal , i n that si ngl e-agent dr ugs (most
commonl y doxor ubi ci n) wer e studi ed and dosi ng schedul es wer e l ess
i ntensi ve. Second, the sampl e si zes i n these tr i al s wer e not l ar ge

enough to al l ow the detecti on of cl i ni cal l y si gni fi cant di ffer ences i n
sur vi val . Thi r d, the major i ty of pati ents who di d not r espond to the
i ni ti al tr eatment r egi men wer e star ted on other chemotherapeuti c
r egi mens that potenti al l y affected di sease-fr ee and overal l sur vi val .
F i nal l y, most studi es i ncl uded pati ents at l ow r i sk for metastasi s and
death, that i s, those wi th smal l (<5 cm) and l ow-grade tumor s.
Hence, adjuvant chemotherapy for pati ents wi th soft-ti ssue
sar comas r emai ns contr over si al . To hel p settl e thi s i ssue, a for mal
meta-anal ysi s cal l ed the Sar coma Meta-Anal ysi s Col l aborati on was
conducted i n 1997. Thi s gr oup anal yzed the data on 1,568 pati ents
fr om 14 tr i al s of doxor ubi ci n-based adjuvant chemotherapy to
deter mi ne the effect of adjuvant chemotherapy on l ocal i zed,
r esectabl e soft-ti ssue sar comas. Wi th a medi an fol l ow-up of 9.4
year s, doxor ubi ci n-based chemotherapy was found to have
si gni fi cantl y l engthened the ti me to l ocal and di stant r ecur r ence and
the overal l r ecur r ence-fr ee sur vi val . However, the absol ute
i mpr ovement i n the overal l sur vi val rate for the enti r e gr oup was
onl y by 4% , whi ch was not stati sti cal l y si gni fi cant. When subsets of
pati ents wer e exami ned, ther e was a 7% i ncr ease i n the sur vi val
rate i n those pati ents wi th extr emi ty tumor s.
Neoadjuvant (Preoperative) Chemotherapy

The rati onal e for neoadjuvant/pr eoperati ve chemotherapy for softti ssue sar comas i s that, gi ven that onl y 30% to 50% of pati ents wi l l
r espond to standar d chemotherapeuti c r egi mens, i t enabl es the
oncol ogi st to i denti fy those sel ect pati ents i n whom speci fi c
r egi mens ar e effecti ve, as shown by measur i ng the pr i mar y tumor i n
si tu. Pati ents whose tumor s shr i nk after two or four cour ses
subsequentl y under go l ocal tr eatment wi th sur ger y and/or radi ati on
therapy, fol l owed by postoperati ve chemotherapy wi th the same
agents that wer e admi ni ster ed pr eoperati vel y. At the same ti me,
pati ents who do not r espond to shor t cour ses of pr eoperati ve
chemotherapy ar e spar ed the toxi c effects of pr ol onged
postoperati ve chemotherapy wi th agents to whi ch they ar e
i nsensi ti ve.
In an effor t to better assess the r ol e of chemotherapy, a cohor t
anal ysi s of the combi ned databases fr om both M. D. Ander son and
Memor i al Sl oan-Ketter i ng was r ecentl y per for med. The data on 674
pati ents wi th stage III extr emi ty sar coma who r ecei ved ei ther
pr eoperati ve or postoperati ve doxor ubi ci n-based chemotherapy wer e

r evi ewed to deter mi ne thei r outcomes (5-year di sease-speci fi c
sur vi val , as wel l as 5-year l ocal and di stant r ecur r ence rates) fr om
systemi c therapy. The 5-year di sease-speci fi c sur vi val rate was
61% , and the pr obabi l i ty of l ocal and di stant r ecur r ences at 5 year s
was 83% and 56% , r especti vel y. An i mpor tant concl usi on fr om thi s
study was that the cl i ni cal benefi ts of doxor ubi ci n-based
chemotherapy i n pati ents wi th hi gh-r i sk extr emi ty sar comas wer e
not sustai ned beyond 1 year after therapy. The i nvesti gator s then
went on to compar e thei r study wi th the Sar coma Meta-Anal ysi s
Col l aborati on and made the fol l owi ng obser vati ons. F i r st, the
pati ent popul ati on of the Sar coma Meta-Anal ysi s Col l aborati on was
mor e heter ogeneous than that of the cohor t study, i n that i t
i ncl uded pati ents wi th both pr i mar y and r ecur r ent extr emi ty and
nonextr emi ty sar comas. Second, ther e wer e al so fewer uncontr ol l ed
var i abl es i n the cohor t study. On the basi s of these fi ndi ngs, the
author s ur ged cauti on when r evi ewi ng studi es of chemotherapeuti c
r egi mens wi th a shor t-ter m fol l ow-up and concl uded that ther e
r emai ns no consensus r egar di ng the r ol e of chemotherapy i n
pati ents wi th l ocal i zed hi gh-r i sk soft-ti ssue sar comas.
Regional Chemotherapy/Isolated Limb

Perfusion
Isol ated l i mb per fusi on (ILP) i s an i nvesti gati onal appr oach for
tr eati ng extr emi ty sar comas i n the appr oxi matel y 10% of pati ents
wi th extr emi ty sar comas for whom amputati on i s the onl y opti on for
l ocal tr eatment. It has been used mai nl y as a l i mb-spar i ng
al ter nati ve i n these pati ents and consi sts of the r egi onal
admi ni strati on of hi gh-dose chemotherapy vi a ILP.
The techni que of ILP i nvol ves i sol ati on of the mai n ar ter y and vei n
of the per fused l i mb fr om the systemi c ci r cul ati on. The speci fi c
tumor si te deter mi nes the choi ce of the speci fi c anatomi cal
appr oach. Exter nal i l i ac vessel s ar e used for thi gh tumor s, femoral
or popl i teal vessel s for cal f tumor s, and axi l l ar y vessel s for upperextr emi ty tumor s. The vessel s ar e di ssected, and al l col l ateral
vessel s ar e l i gated. The vessel s ar e then cannul ated and connected
to a pump oxygenator si mi l ar to that used i n car di opul monar y
bypass. A tour ni quet or Esmar ch bandage i s appl i ed to the l i mb to
achi eve compl ete vascul ar i sol ati on. The chemotherapeuti c agents
ar e then added to the per fusi on ci r cui t and r eci r cul ated for 90
mi nutes. The temperatur e of the per fused l i mb i s mai ntai ned dur i ng
the enti r e pr ocedur e by both exter nal heati ng and war mi ng of the
per fusates. At the end of the pr ocedur e, the dr ugs ar e washed out
of the l i mb, the cannul as ar e r emoved, and the bl ood vessel s
r epai r ed.
Ther e ar e several pr obl ems wi th tr yi ng to i nter pr et the data fr om
studi es of ILP per for med to date. These pr obl ems i ncl ude the
heter ogeneous natur e of the pati ents tr eated and the wi de var i ety
of chemotherapeuti c agents used. Despi te these pr obl ems, favorabl e
r esponse rates of 18% to 80% wi th overal l 5-year sur vi val rates of
50% to 70% have been r epor ted.
Recentl y, i nter est has devel oped i n a l ess i nvasi ve techni que ter med
isolated limb infusion. Thi s techni que has al so been ter med
minimally invasive isolated limb per fusion. Regar dl ess of the
nomencl atur e, the pr ocedur e i nvol ves the pl acement of i nfusi on
catheter s by i nter venti onal radi ol ogi sts, after whi ch the pati ent i s
transfer r ed to the operati ng r oom wi th the catheter s i n pl ace. Under
i schemi c condi ti ons, chemotherapy i s admi ni ster ed vi a a
nonoxygenated bypass ci r cui t. The i schemi c condi ti ons ar e vi tal to
thi s techni que because thi s i s bel i eved to enhance the effi cacy of
the chemotherapeuti c agents. Cur r entl y, i sol ated l i mb i nfusi on i s
onl y avai l abl e as an exper i mental pr otocol at cer tai n center s.
Management of Local Recurrence

Di sease can r ecur i n up to 20% of pati ents wi th extr emi ty sar coma,
but pati ents wi th mi cr oscopi cal l y posi ti ve sur gi cal mar gi ns ar e the
ones i n whom the r i sk of l ocal r ecur r ence i s gr eatest. It r emai ns a
matter of contr over sy, however, as to what the i mpact of l ocal
fai l ur es i s on sur vi val and di stant di sease-fr ee sur vi val . Many
bel i eve r ecur r ence r epr esents a har bi nger of di stant metastati c
di sease. Regar dl ess, the adequacy of the sur gi cal r esecti on cl ear l y
pl ays a r ol e i n deter mi ni ng whether di sease r ecur s l ocal l y.
An i sol ated l ocal r ecur r ence shoul d be tr eated aggr essi vel y wi th
mar gi n-negati ve r e-r esecti on (possi bl y amputati on) pl us radi ati on
therapy. Pati ents pr evi ousl y tr eated wi th exter nal -beam
radi ati on therapy may be consi der ed for brachytherapy or
i ntraoperati ve radi ati on therapy. Several smal l studi es have shown
that pati ents wi th i sol ated l ocal r ecur r ences may be successful l y
r etr eated, wi th l ocal r ecur r ence-fr ee sur vi val rates appr oachi ng
72% .
Management of Distant Disease

Di stant metastases occur i n 40% to 50% of pati ents wi th
i nter medi ate- and hi gh-grade extr emi ty sar comas, compar ed wi th
onl y 5% of pati ents wi th l ow-grade sar comas. Most metastases to
di stant si tes occur wi thi n 2 year s of the i ni ti al di agnosi s. The
pr edomi nant si te of di stant metastases fr om pr i mar y extr emi ty
sar comas i s the l ung (73% of cases).
Lung metastases shoul d be r esected i f ther e ar e no extrapul monar y
metastases, the pati ent i s medi cal l y fi t enough to wi thstand a
thoracotomy, and the l esi ons ar e amenabl e to r esecti on. Lar ge
ser i es have r eveal ed 3-year sur vi val rates of 40% to 50% i n
pati ents wi th compl etel y r esected pul monar y metastases. A di seasefr ee i nter val of mor e than 12 months, the abi l i ty to r esect al l
metastati c di sease, age younger than 50 year s, and absence of
pr ecedi ng l ocal r ecur r ence wer e found to be i ndependent pr ognosti c
factor s i n a mul ti var i ate anal ysi s of pati ents who under went
r esecti on of pul monar y metastases.
General Recommendations
G eneral r ecommendati ons for the management of extr emi ty softti ssue sar comas ar e as fol l ows:
1. Soft-ti ssue tumor s that ar e enl ar gi ng or gr eater than 3 cm i n
di ameter shoul d be eval uated wi th radi ol ogi c i magi ng
(ul trasonography or CT), and a ti ssue di agnosi s made on the
basi s of fi ne-needl e aspi rati on or cor e-needl e bi opsy fi ndi ngs.
2. Eval uate for metastati c di sease once a sar coma di agnosi s i s
establ i shed: chest radi ography for l ow- or i nter medi ate-grade
l esi ons and T1 tumor s, and chest CT for hi gh-grade or T2
tumor s.
3. A wi de l ocal exci si on wi th 2-cm mar gi ns i s adequate therapy for
l ow-grade l esi ons and T1 tumor s.
4. Radi ati on therapy pl ays a cr i ti cal r ol e i n the management of T2
tumor s.
5. Pati ents wi th r ecur r ent hi gh-grade sar comas or di stant
metastati c di sease shoul d be consi der ed for pr eoperati ve
(neoadjuvant) or postoperati ve (adjuvant) chemotherapy.
6. An aggr essi ve sur gi cal appr oach shoul d be taken i n the
tr eatment of pati ents wi th an i sol ated l ocal r ecur r ence or

r esectabl e di stant metastases.
Retroperitoneal Sarcomas
F i fteen per cent of soft-ti ssue sar comas i n adul ts occur i n the
r etr oper i toneum. Most r etr oper i toneal tumor s ar e mal i gnant, and
appr oxi matel y one-thi r d ar e soft-ti ssue sar comas. The di ffer enti al
di agnosi s i n a pati ent pr esenti ng wi th a r etr oper i toneal tumor
i ncl udes l ymphoma, ger m cel l tumor s, and undi ffer enti ated
car ci nomas. The most common sar comas occur r i ng i n the
r etr oper i toneum ar e l i posar comas, mal i gnant fi br ous hi sti ocytomas,
and l ei omyosar comas.
Al though si gni fi cant advances i n our under standi ng of extr emi ty
soft-ti ssue sar comas have r esul ted i n i mpr oved tr eatments and
outcomes, si mi l ar pr ogr ess has not been achi eved i n our
under standi ng and tr eatment of r etr oper i toneal soft-ti ssue
sar comas. For several r easons, pati ents wi th r etr oper i toneal softti ssue sar comas general l y have a wor se pr ognosi s than those wi th
extr emi ty sar comas. One r eason i s that r etr oper i toneal soft-ti ssue
sar comas commonl y gr ow to l ar ge si zes befor e they become
cl i ni cal l y appar ent, by whi ch ti me they often i nvol ve i mpor tant vi tal
str uctur es, whi ch pr ecl udes sur gi cal r esecti on. A second r eason i s
that the sur gi cal mar gi ns that can be obtai ned ar ound these
sar comas ar e often i nadequate because of anatomi cal constrai nts.
Retr oper i toneal sar comas general l y pr esent as l ar ge masses; near l y
50% ar e l ar ger than 20 cm at the ti me of di agnosi s. They typi cal l y
do not pr oduce symptoms unti l they gr ow l ar ge enough to compr ess
or i nvade conti guous str uctur es. On occasi on, pati ents may pr esent
wi th neur ol ogi c symptoms, r esul ti ng fr om the compr essi on of l umbar
or pel vi c ner ves, or obstr ucti ve gastr oi ntesti nal symptoms, r esul ti ng
fr om the di spl acement or di r ect tumor i nvol vement of an i ntesti nal
or gan.
Evaluation
The wor kup i n a pati ent wi th a r etr oper i toneal mass begi ns wi th an
accurate hi stor y that shoul d excl ude si gns and symptoms of
l ymphoma (e.g., fever, ni ght sweats). A compl ete physi cal
exami nati on wi th par ti cul ar attenti on to al l nodal basi ns and a

testi cul ar exami nati on i n mal es ar e cr i ti cal l y i mpor tant. Laborator y
assessment can be hel pful ; an i ncr eased l actate dehydr ogenase
concentrati on can be suggesti ve of l ymphoma, wher eas an i ncr eased
-human chor i oni c gonadotr opi n l evel , al pha-fetopr otei n l evel , or
both can i ndi cate a ger m cel l tumor.
The radi ol ogi c assessment shoul d i ncl ude a CT scan of the abdomen
and pel vi s to defi ne the extent of the tumor and i ts r el ati onshi p to
sur r oundi ng str uctur es, par ti cul ar l y vascul ar str uctur es. Imagi ng
shoul d i ncl ude the l i ver i n a sear ch for metastases and
di sconti nuous abdomi nal di sease. The ki dneys shoul d al so be
eval uated to assess bi l ateral r enal functi on. Thoraci c CT i s i ndi cated
to l ook for l ung metastases. A CT-gui ded cor e-needl e bi opsy i s
appr opr i ate for obtai ni ng a ti ssue di agnosi s i n pati ents pr esenti ng
wi th an equi vocal hi stor y, an unusual -appear i ng mass, an
unr esectabl e tumor, or di stant metastasi s and i n pati ents who ar e
potenti al l y el i gi bl e for a neoadjuvant pr otocol .
Management
Compl ete sur gi cal r esecti on i s the most effecti ve tr eatment for
pr i mar y or r ecur r ent r etr oper i toneal sar comas, but i t i s fr equentl y
not possi bl e. For exampl e, i n several r etr ospecti ve assessments of
pati ents wi th r etr oper i toneal sar coma, compl ete sur gi cal exci si on
was achi eved i n onl y 40% to 60% of pati ents. The effects of an
i ncompl ete sur gi cal r esecti on on outcome ar e qui te demonstrabl e. In
an anal ysi s of 500 pati ents wi th r etr oper i toneal soft-ti ssue
sar comas tr eated at Memor i al Sl oan-Ketter i ng Cancer Center, the
medi an sur vi val durati on of pati ents who under went
compl ete r esecti on was 103 months ver sus 18 months for pati ents
who under went i ncompl ete r esecti on, whi ch was no di ffer ent than
the sur vi val seen i n pati ents tr eated wi th obser vati on wi thout
r esecti on.
Sur gi cal r esecti on shoul d not be offer ed to pati ents unl ess
radi ographi c evi dence i ndi cates the potenti al for compl ete r esecti on,
al though pal l i ati ve sur gi cal pr ocedur es may be per for med to r educe
the symptoms of i ntesti nal obstr ucti on or bl eedi ng. In par ti cul ar,
pati ents wi th atypi cal l i pomatous tumor s, al so ter med welldiffer entiated liposar comas, may benefi t symptomati cal l y fr om
r epeated tumor debul ki ng.
Adjuvant Therapy
Chemotherapy has not been shown to be an effecti ve tr eatment for
r etr oper i toneal sar comas. Several center s have ongoi ng pr otocol s to
deter mi ne the r ol e of pr eoperati ve chemotherapy and radi ati on
therapy for these tumor s, but the fi ndi ngs fr om these studi es have
not yet been r el eased. A tr i al sponser ed by the Amer i can Col l ege of
Sur geon's Oncol ogy G r oup eval uati ng the benefi t of pr eoperati ve
radi ati on i n pati ents wi th r etr o per i toneal sar comas r ecentl y cl osed
for fai l ur e to meet accr ual tar gets.
Management of Recurrent Disease

Retr oper i toneal sar comas r ecur i n two-thi r ds of pati ents. In addi ti on
to r ecur r i ng l ocal l y i n the tumor bed and metastasi z i ng to the l ungs,
r etr oper i toneal l ei omyosar comas fr equentl y spr ead to the l i ver.
Retr oper i toneal sar comas can al so r ecur di ffusel y thr oughout the
per i toneal cavi ty (sar comatosi s). The appr oach to r esectabl e
r ecur r ent di sease after the tr eatment of a r etr oper i toneal sar coma
i s si mi l ar to the appr oach taken after the r ecur r ence of an
extr emi ty sar coma. However, the abi l i ty to r esect a r ecur r ent
r etr oper i toneal sar coma decl i nes pr eci pi tousl y wi th each r ecur r ence.
In a l ar ge ser i es of pati ents tr eated at Memor i al Sl oan-Ketter i ng
Cancer Center, the author s wer e abl e to r esect r ecur r ent tumor s i n
57% of pati ents wi th a fi r st r ecur r ence, but i n onl y 20% of pati ents
after a second r ecur r ence and 10% after a thi r d r ecur r ence.
Isol ated l i ver metastases, i f stabl e over several months, may be
amenabl e to r esecti on, radi ofr equency abl ati on, or
chemoembol i z ati on.
In as many as 25% of pati ents, wel l -di ffer enti ated l i posar coma may
r ecur i n a poor l y di ffer enti ated for m or devel op ar eas of
dedi ffer enti ati on. Dedi ffer enti ated r etr oper i toneal l i posar coma i s
mor e aggr essi ve wi th a gr eater pr opensi ty for di stant metastasi s
than i ts wel l -di ffer enti ated pr ecur sor.
Follow-up
The rati onal e behi nd fol l ow-up strategi es to detect the r ecur r ence of
any type of cancer i s that the ear l y r ecogni ti on and tr eatment of
r ecur r ent, l ocal , or di stant di sease can pr ol ong sur vi val . The i deal
fol l ow-up strategy shoul d ther efor e be easy to i mpl ement, accurate,
and cost-effecti ve.
The devel opment of metastases i s the pr i mar y deter mi nant of
sur vi val i n pati ents wi th soft-ti ssue sar coma. The si te of r ecur r ence
i s r el ated to the anatomi cal si te of the pr i mar y tumor. Extr emi ty
sar comas general l y r ecur i n the for m of di stant
pul monar y metastases, wher eas r etr oper i toneal or i ntra-abdomi nal
sar comas tend to r ecur as fr equentl y l ocal l y as they do i n the l ungs.
Whether the ear l y detecti on of r ecur r ence can i mpr ove overal l
sur vi val depends on the avai l abi l i ty of effecti ve therapeuti c
i nter venti ons. A few r epor ts i nvol vi ng smal l number s of pati ents
have shown that i t i s possi bl e to sal vage pati ents wi th r ecur r ent
l ocal di sease wi th radi cal r e-exci si on wi th or wi thout radi ati on
therapy. Si mi l ar l y, several gr oups have r epor ted on pati ents who
have exper i enced pr ol onged sur vi val fol l owi ng the r esecti on of
pul monar y metastases. These l i mi ted data for m the i mpetus for the
aggr essi ve sur vei l l ance strategi es taken i n pati ents wi th soft-ti ssue
sar comas.
The major i ty of soft-ti ssue sar comas that r ecur do so wi thi n the
fi r st 2 year s after the compl eti on of therapy. Pati ents shoul d
ther efor e be eval uated wi th a compl ete hi stor y and physi cal
exami nati on ever y 3 months wi th a chest radi ograph and tumor si te
i magi ng dur i ng thi s hi gh-r i sk per i od. If the chest radi ograph r eveal s
a suspi ci ous nodul e, a CT scan of the chest shoul d be obtai ned for
fur ther assessment. Most exper ts r ecommend that the tumor si te be
eval uated wi th ei ther MRI for an extr emi ty tumor or CT for i ntraabdomi nal or r etr oper i toneal tumor s. In some ci r cumstances,
ul trasonography can be used to l ook for the r ecur r ence of an
extr emi ty tumor ei ther l ocal l y or at a di stant si te. Fol l ow-up
i nter val s may be l engthened to ever y 6 months, wi th annual
i magi ng dur i ng year s 2 thr ough 5 after the compl eti on of therapy.
After 5 year s, pati ents shoul d be assessed annual l y and a chest
radi ograph shoul d be obtai ned.
Gastrointestinal Stromal Tumors

G astr oi ntesti nal str omal tumor s (G ISTs) consti tute the major i ty of
mesenchymal tumor s i nvol vi ng the gastr oi ntesti nal tract. It i s
esti mated that ther e ar e 2,500 to 6,000 cases per year i n the
Uni ted States. Al though the cl i ni cal pr esentati on of these tumor s
var i es dependi ng on the tumor si ze and anatomi cal l ocati on, most
tumor s ar e found i nci dental l y at the ti me of endoscopy or radi ol ogi c
i magi ng. G ISTs ar i se most fr equentl y i n the stomach (60% 70% ),
fol l owed by the smal l i ntesti ne (20% 25% ), col on and r ectum (5% ),
and esophagus (<5% ). Most G ISTs ar e sporadi c and, i n 95% of

cases, sol i tar y. Most pati ents wi th G ISTs pr esent i n the fi fth to the
seventh decades of l i fe, and these tumor s ar e equal l y di str i buted
between the gender s. Symptoms of these l esi ons i ncl ude pai n and
gastr oi ntesti nal bl eedi ng, wi th abdomi nal mass a fr equent fi ndi ng.
Si nce the l ate-1990s, i t has been r ecogni zed that G ISTs have
di sti ncti ve i mmunohi stochemi cal and geneti c featur es. G ISTs
or i gi nate fr om the i ntesti nal pacemaker cel l s (the i nter sti ti al cel l s
of Cajal ), whi ch expr ess CD117, a transmembrane tyr osi ne ki nase
r eceptor that i s the pr oduct of the c-KIT pr oto-oncogene. The
expr essi on of CD117 has emer ged as an i mpor tant defi ni ng featur e
of G ISTs, bei ng found i n near l y 95% of cases. The pathogenesi s of
these tumor s i s r el ated to mutati ons i n the c-KIT gene. Expl oi tati on
of thi s geneti c character i sti c has l ed to si gni fi cant i nr oads i nto the
devel opment of successful exper i mental therapy for these tumor s.
Treatment
Sur gi cal r esecti on r emai ns the tr eatment of choi ce for G ISTs.
However, despi te compl ete sur gi cal r esecti on, the major i ty of
pati ents (76% i n one study fr om Memor i al Sl oan-Ketter i ng Cancer
Center ) wi l l suffer l ocal r ecur r ence. Sal vage sur ger y for these
r ecur r ences i s associ ated wi th a 15-month medi an sur vi val .
Pr omi si ng pr ecl i ni cal r esul ts have been the dr i vi ng for ce for the
rapi d cl i ni cal devel opment of i mati ni b mesyl ate (G l eevec, for mer l y
known as STI571; Novar ti s), a sel ecti ve tyr osi ne ki nase i nhi bi tor of
c-KIT. Thi s agent r epr esents a novel i nter venti on and has
demonstrated the mer i ts of speci fi cal l y tar geted mol ecul ar therapi es
i n the management of oncol ogi c di seases. In Febr uar y 2002,
i mati ni b mesyl ate was appr oved by the U.S. Food and Dr ug
Admi ni strati on for use i n the tr eatment of G ISTs on the basi s of the
r esul ts of tr i al s conducted i n pati ents wi th metastati c and l ocal l y
advanced di sease (Tabl e 5.3). Ini ti al r esul ts have shown that near l y
54% of pati ents wi th G ISTs r espond to i mati ni b and that ther e i s no
benefi t to doses over 400 mg per day. Li ttl e i s cur r entl y known
about the opti mal l ength of tr eatment, the durati on of benefi t, or
the l ong-ter m toxi ci ty of thi s dr ug. At M. D. Ander son, ther e ar e
thr ee ongoi ng cl i ni cal pr otocol s i nvol vi ng the use of i mati ni b i n
di ffer ent setti ngs. The fi r st pr otocol i s par t of the Amer i can Col l ege
of Sur geons Oncol ogy G r oup Z9001 phase III pr ospecti ve
randomi zed tr i al ; i n i t, adjuvant i mati ni b tr eatment pl us sur ger y i s
bei ng compar ed wi th sur ger y al one i n pati ents wi th G ISTs who have
under gone R0 or R1 r esecti on. The second pr otocol (Z9000) i s a
phase II pr ospecti ve randomi zed study i n whi ch combi ned
pr eoperati ve and postoperati ve i mati ni b i s bei ng used for pati ents
wi th pr i mar y, r ecur r ent, or metastati c r esectabl e G IST. The thi r d
pr otocol i s a phase II tr i al that i s i nvesti gati ng whether
pr eoperati ve and postoperati ve i mati ni b wi l l r educe the r ecur r ence
rate i n pati ents wi th pr i mar y and r ecur r ent operabl e G IST.
Other Soft-Tissue Lesions

Sarcoma of the Breast
Sar comas of the br east ar e rar e tumor s, accounti ng for l ess than
1% of al l br east mal i gnanci es and l ess than 5% of al l soft-ti ssue
sar comas. Var i ous hi stol ogi c subtypes have been r epor ted to occur
wi thi n the br east, i ncl udi ng angi osar coma, str omal sar coma,
fi br osar coma, and mal i gnant fi br ous hi sti ocytoma. Cystosar coma
phyl l odes i s general l y consi der ed to be a separate enti ty fr om other
soft-ti ssue sar comas because these tumor s ar e bel i eved to or i gi nate
fr om hor monal l y r esponsi ve str omal cel l s of the br east and the
major i ty ar e beni gn.
As wi th sar comas at other anatomi cal si tes, the hi stopathol ogi cal
grade and si ze of the tumor ar e i mpor tant pr ognosti c factor s.
Li kewi se, the l i kel i hood of l ocal r ecur r ences i ncr eases as the tumor
si ze i ncr eases; tumor s smal l er than 5 cm ar e associ ated wi th better
overal l sur vi val . Local and di stant r ecur r ence ar e mor e common i n
pati ents wi th hi gh-grade l esi ons. Compl ete exci si on wi th negati ve
mar gi ns i s the pr i mar y therapy. Si mpl e mastectomy car r i es no
addi ti onal benefi t i f compl ete exci si on can be accompl i shed by
segmental mastectomy. Because of l ow rates
of r egi onal l ymphati c spr ead, axi l l ar y di ssecti on i s not r outi nel y
i ndi cated. Neoadjuvant chemotherapy or radi ati on therapy may be
consi der ed for pati ents wi th l ar ge, hi gh-r i sk tumor s.
Table 5.3. Summary of clinical trials of imatin

with advanced gastrointestinal st
Study,
Year
Phase
No. of
Overall
CR
Patients Response
PR
Van
Oosterom,
2001
36
53%
0%
53
Demetri,
2002
II
147
54%
0%
54
Verwiej,
2003
II
27
71%
4%
67
Rankin,
2004
III
746
400 mg daily
48%
3%
45
800 mg daily
48%
3%
45
400 mg daily
50%
5%
45
800 mg daily
54%
6%
48
Verwij,
2004
III
946
CR, complete response; PR, partial response.
Desmoids
Desmoi d tumor s do not metastasi ze and ar e consi der ed l ow-grade

sar comas. Appr oxi matel y hal f of these tumor s ar i se i n the
extr emi ty, wi th the r emai ni ng l esi ons l ocated on the tr unk or i n the
r etr oper i toneum. Abdomi nal wal l desmoi ds ar e associ ated wi th
pr egnancy and ar e bel i eved to ar i se as the r esul t of hor monal
i nfl uences. Pati ents wi th G ar dner syndr ome may have
r etr oper i toneal desmoi ds as an extracol oni c mani festati on of the
di sease. Sur gi cal r esecti on wi th wi de l ocal exci si on shoul d be the
pr i mar y therapy for desmoi d tumor s. Local r ecur r ence may occur i n
up to one-thi r d of pati ents. Adjuvant radi ati on therapy has been
associ ated wi th a r educed i nci dence of l ocal r ecur r ence.
Dermatofibrosarcoma Protuberans
Der matofi br osar coma pr otuberans i s a neopl asm ar i si ng i n the
der mi s that may occur anywher e i n the body. Appr oxi matel y 40%
ar i se on the tr unk, wi th most of the r emai ni ng tumor s di str i buted
between the head and neck and extr emi ti es. The l esi on pr esents as
a nodul ar, cutaneous mass that shows sl ow and per si stent gr owth.
Satel l i te l esi ons may be found i n pati ents wi th l ar ger tumor s. Wi de
l ocal exci si on i s r ecommended, al though r ecur r ence rates can be as
hi gh as 30% to 50% .
Bone Sarcomas
Epidemiology
Mal i gnant tumor s of the muscul oskel etal system consti tute 10% of
newl y di agnosed cancer s i n the popul ati on younger than 30 year s of
age, wi th 1,000 cases di agnosed annual l y i n the Uni ted States.
However, mal i gnant tumor s ar i si ng fr om the skel etal systems
r epr esent onl y 0.2% of al l pr i mar y cancer s. Osteosar coma and
Ewi ng sar coma ar e the two most common mal i gnant condi ti ons of
bone. Osteosar coma has a peak fr equency dur i ng adol escent gr owth,
wher eas Ewi ng sar coma occur s most fr equentl y i n the second decade
of l i fe.
The most common pr esentati on of bone sar comas (Ewi ng sar coma or
osteosar coma) i s pai n or swel l i ng i n a bone or joi nt. As wi th softti ssue sar comas i n adul ts, often a traumati c event draws attenti on
to the swel l i ng and can thr ow off the cor r ect di agnosi s.
Osteosar coma most commonl y i nvol ves the metaphysi s of l ong
bones, especi al l y the di stal femur, pr oxi mal ti bi a, or humer us.

Ewi ng sar coma may i nvol ve fl at bones or the di aphysi s of tubul ar
bones such as the femur, pel vi s, ti bi a, and fi bul a. Ewi ng sar coma
may al so occur i n soft ti ssues. Chondr osar coma occur s most
commonl y i n the pel vi s, pr oxi mal femur, and shoul der gi r dl e.
Up to 25% of pati ents pr esenti ng wi th osteosar coma or Ewi ng
sar coma have metastati c di sease at pr esentati on. The most fr equent
metastati c si tes for osteosar coma i ncl ude the l ung (90% of cases)
and the bone (10% ), wher eas Ewi ng sar coma metastases occur i n
the l ung (50% ), bone (25% ), and bone mar r ow (25% ).
Staging
As wi th soft-ti ssue sar comas, hi stopathol ogi cal grade i s a cr uci al
component of the stagi ng of bone sar comas. The sur gi cal stagi ng
system for muscul oskel etal sar coma i s based on the system by
Enneki ng and i ncl udes pr ognosti c var i abl es such as hi stopathol ogi cal
grade (G ), the l ocati on of the tumor (T), and the pr esence or
absence of metastases (M). The thr ee stages ar e stage I, l ow grade
(G 1); stage II, hi gh grade (G 2); and stage III, G 1 or G 2 wi th the
pr esence of metastases (M1). Each stage i s then desi gnated a i f the
l esi on i s anatomi cal l y confi ned wi thi n wel l -del i neated sur gi cal
compar tments (T1) and b i f the l esi on i s l ocated beyond such
compar tments i n i l l -defi ned fasci al pl anes and spaces (T2).
Diagnosis
The eval uati on of pati ents wi th a suspected bone tumor shoul d
i ncl ude a thor ough hi stor y and physi cal exami nati on, pl ai n
radi ographs, and MRI of the enti r e affected bone. Bone scanni ng
and CT of the chest ar e al so necessar y.
On pl ai n radi ographs, mal i gnant bone tumor s show i r r egul ar
bor der s, and ther e i s often evi dence of bone destr ucti on and a
per i osteal r eacti on. Soft-ti ssue extensi on i s al so fr equentl y seen.
Biopsy
A cor e-needl e bi opsy i s the di agnosti c pr ocedur e of choi ce i n a
pati ent suspected of har bor i ng an osteosar coma. A cor e-needl e
bi opsy per for med under radi ographi c gui dance shoul d yi el d
di agnosti c fi ndi ngs i n al most al l cases of osteosar coma.
Treatment
Effecti ve mul ti modal i ty therapy for chi l dhood muscul oskel etal
tumor s has dramati cal l y i mpr oved the 5-year sur vi val rates fr om
10% to 20% i n 1970 to the cur r ent 60% to 70% . Li mb sal vage i s
the standar d tr eatment for most pati ents wi th osteosar coma.
Surgery
Whenever feasi bl e, l i mb sal vage i s the standar d sur gi cal appr oach
to bone sar comas. Successful l i mb-spar i ng sur ger y consi sts of thr ee
phases: tumor r esecti on, bone r econstr ucti on, and soft-ti ssue
coverage. Compl ete sur gi cal exti r pati on of the pr i mar y tumor and
any metastases i s essenti al i n pati ents wi th osteosar coma because
thi s tumor i s r el ati vel y r esi stant to radi ati on therapy.
It i s al so desi rabl e to r esect a Ewi ng sar coma, i f thi s can be done. If
sur gi cal r emoval wi th a wi de sur gi cal mar gi n can be achi eved, the
pr ognosi s i s favorabl e (12-year r el apsefr ee sur vi val of 60% ).
However, Ewi ng sar coma most typi cal l y i nvol ves the pel vi s wi th an
extensi ve soft-ti ssue mass that i nvades the pel vi c cavi ty, whi ch
makes i t di ffi cul t to car r y out radi cal sur ger y.
Sur gi cal r esecti on i s usual l y the onl y tr eatment i ndi cated for the
management of chondr osar comas because thi s type of tumor i s
unr esponsi ve to exi sti ng systemi c therapi es.
Chemotherapy
Chemotherapy has r evol uti oni zed the tr eatment of most bone
sar comas and i s consi der ed standar d car e for osteosar coma and
Ewi ng sar coma. The bl eak 15% to 20% sur vi val rate achi eved wi th
sur ger y al one dur i ng the 1960s has i mpr oved to 55% to 80%
thr ough the addi ti on of chemotherapy to sur gi cal r esecti on. The
ti mi ng of chemotherapy, the mode of del i ver y, and the dr ug
combi nati ons conti nue to be studi ed i n mul ti -i nsti tuti onal tr i al s, so
fur ther i mpr ovements i n the cl i ni cal outcome ar e anti ci pated.
Effecti ve agents i ncl ude doxor ubi ci n, ci spl ati n, methotr exate,
i fosfami de, and cycl ophosphami de. Randomi zed cl i ni cal tr i al s of
pati ents wi th osteosar coma have shown that the use of combi nati on
chemotherapy i n addi ti on to sur ger y r esul ts i n cur e rates of 58% to
76% . Pr eoperati ve chemotherapy i s an attracti ve opti on because i t
can l ead to the downstagi ng of tumor s, whi ch then enabl es the
maxi mal appl i cati on of l i mb-spar i ng sur ger y. In addi ti on, tumor
necr osi s fol l owi ng pr eoperati ve chemotherapy has been shown to be

the most i mpor tant pr ognosti c var i abl e deter mi ni ng sur vi val .
Mul ti agent chemotherapy has al so been demonstrated to be
essenti al i n the tr eatment of Ewi ng sar coma. Tr i al s spanni ng mor e
than 20 year s per for med by the Inter gr oup Study of Ewi ng's
Sar coma have establ i shed the effi cacy of mul ti dr ug r egi mens (i .e.,
r egi mens that i nvol ve combi nati ons of vi ncr i sti ne, doxor ubi ci n,
cycl ophosphami de, i fosfami de, and etoposi de) i n i ncr easi ng the 5year r el apsefr ee sur vi val rates to up to 70% i n pati ents wi th
nonmetastati c di sease. Agents cur r entl y bei ng i nvesti gated as
tr eatments for osteosar coma i ncl ude trastuz umab, i nhal ed
granul ocyte-macr ophage col ony-sti mul ati ng factor, and i mati ni b
mesyl ate, among other s.
Radiation Therapy
Because osteosar comas ar e general l y radi ati on r esi stant, radi ati on
therapy i s pr edomi nantl y used for the pal l i ati on of l ar ge,
unr esectabl e tumor s. In contrast, radi ati on therapy i s the pr i mar y
mode of tr eatment for most l ocal i zed Ewi ng sar comas. Pr eoperati ve
i r radi ati on may al so be consi der ed to r educe tumor vol ume befor e
sur gi cal r esecti on i s attempted.
Recurrent Disease
Bone tumor s di ssemi nate thr ough the bl oodstr eam and commonl y
metastasi ze to the l ungs and bony skel eton. In the past, onl y 10%
to 30% of pati ents pr esenti ng wi th detectabl e metastati c
osteosar coma became l ong-ter m di sease-fr ee sur vi vor s. Mor e r ecent
studi es have shown that combi ned modal i ty appr oaches consi sti ng of
sur gi cal r esecti on of the pr i mar y tumor and metastati c deposi ts i n
conjuncti on wi th mul ti agent chemotherapy can i mpr ove 5-year
di sease-fr ee sur vi val rates to up to 47% .
Ewi ng sar coma may r ecur i n the for m of di stant di sease as l ong as
15 year s after the i ni ti al di agnosi s. In a r etr ospecti ve anal ysi s of
241 pati ents wi th Ewi ng sar coma of the pel vi s, tumor vol ume,
r esponsi veness to chemotherapy, and adequate sur gi cal mar gi ns
wer e found to be the major factor s that i nfl uenced pr ognosi s.
Pati ents wi th suspected tumor r ecur r ence shoul d under go a
compl ete eval uati on to deter mi ne the extent of the di sease. The
r esecti on of pul monar y metastases has become the mai nstay of
tr eatment for pati ents wi th osteosar coma. Pr ognosi s can general l y
be deter mi ned by the r esponse to pr evi ous therapy, durati on

of r emi ssi on, and extent of metastases. Mul ti modal i ty therapy,
i ncl udi ng chemotherapeuti c agents not pr evi ousl y used, i s the
general r ecommendati on for tr eatment.
Sacrococcygeal Chordoma
The notochor dal r emnant i s the si te of or i gi n of thi s rar e tumor.
Chor domas ar e l ocal l y aggr essi ve tumor s that have a hi gh
pr opensi ty to r ecur. Because symptoms can be vague, di agnosi s can
be del ayed. Sur gi cal r esecti on shoul d i nvol ve a mul ti di sci pl i nar y
team that i ncl udes the sur gi cal oncol ogi st, neur osur geon, and
r econstr ucti ve pl asti c sur geon. A two-stage pr ocedur e i s used at M.
D. Ander son. At the fi r st stage, the bl ood suppl y to the tumor
ar i si ng fr om the i l i ac vessel s i s contr ol l ed thr ough an anter i or
appr oach. Several days l ater, the tumor i s r esected vi a a poster i or
appr oach. Radi ati on therapy shoul d be consi der ed because of hi gh
rates of l ocal r ecur r ence.
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M.
Edition
> Ta ble o f C o nt e nt s > 6 - C a nc e rs o f t he He a d a nd Ne c k
6
Cancers of the Head and Neck
Kenneth A . New kirk
F. Christopher Holsinger
Epidemiology and Pathogenesis

Cancer s of the head and neck r epr esent a r el ati vel y smal l , al bei t
si gni fi cant, gr oup of cancer s. The tr eatment of these mal i gnanci es i s
associ ated wi th si gni fi cant functi onal and aestheti c mor bi di ti es that
have a dramati c i mpact on pati ents qual i ty of l i fe. Al though the
major i ty of cancer s of the head and neck ar i se i n the upper
aer odi gesti ve tract and sal i var y gl ands, cancer s of the ski n, thyr oi d
gl and, and parathyr oi d gl ands deser ve speci al consi derati on and ar e
addr essed i n Chapter s 3, 4, and 16.
Cancer s of the head and neck r epr esent appr oxi matel y 3% of al l
cancer s i n the Uni ted States (and appr oxi matel y 6% wor l dwi de i n
2002), wi th appr oxi matel y 45,000 head and neck cancer s di agnosed
i n 2004. The major i ty of head and neck cancer s ar e di agnosed i n
the si xth to ei ghth decades, wi th mal es havi ng a 4:1 rati o. Tobacco
exposur e r epr esents the most si gni fi cant r i sk factor for cancer s of
the head and neck, wi th al cohol consumpti on bei ng both a
syner gi sti c and an i ndependent r i sk factor. The r i sk of tobaccor el ated head and neck cancer s i ncr eases pr opor ti onatel y wi th the
degr ee of exposur e. In addi ti on, for some pati ents, geneti c
i nstabi l i ty (e.g., hypophar yngeal cancer s associ ated wi th Pl ummerVi nson syndr ome), vi ral i nfecti ons (e.g., Ebstei n-Bar r vi r us [EBV]
associ ated wi th nasophar yngeal cancer, human papi l l oma vi r us
associ ated wi th tonsi l l ar cancer s), and occupati onal (e.g., saw dust
exposur es and si nonasal adenocar ci nomas) and envi r onmental
exposur es (e.g., ul travi ol et [UV] exposur e and l ower l i p cancer s,
betel nut use and buccal cancer s, r ever se ci gar ette smoki ng and
pal atal cancer s) have been i mpl i cated i n some head and neck
cancer s. A smal l gr oup of pati ents (par ti cul ar l y young pati ents wi th
oral tongue cancer s) have no i denti fi abl e r i sk factor s and have a
par ti cul ar l y aggr essi ve cour se. Some studi es suggest that the
di sease cour se may be mor e aggr essi ve i n Afr i can Amer i cans than i n
whi tes, wi th death rates for Afr i can Amer i can mal es bei ng twi ce that
for whi te mal es wi th the same di sease (l ar ynx and oral cavi ty
cancer s).
Pathology
Squamous cel l car ci noma (SCC) r epr esents the most common
hi stol ogi c type, accounti ng for mor e than 90% of tumor s. Tumor s
may have ei ther an ul cerati ve or an exophyti c gr owth patter n.
Hi stol ogi cal l y, the tumor s may be i n si tu or i nvasi ve. Hi stol ogi c
di ffer enti ati on (wel l , moderate, and poor l y di ffer enti ated) has been
r epor ted to have pr ognosti c i mpl i cati ons, but thi s has not been
uni ver sal l y confi r med. Basal oi d, spi ndl e-shaped SCCs and ver r ucous
car ci noma ar e bel i eved to be var i ants of SCC, and di sti ngui shi ng
among the var i ants may have pr ognosti c i mpl i cati ons.
Pr emal i gnant l esi ons, such as l eukopl aki a and er ythr opl aki a, ar e
associ ated wi th a hi gh r i sk of cancer devel opment.
Clinical Presentation, Evaluation, and

Prognosis
The cl i ni cal si gns and symptoms of cancer of the upper
aer odi gesti ve tract i s si te speci fi c. The most common pr esenti ng
symptom for head and neck cancer s i s pai n. Other symptoms that
ar e suggesti ve of cancer of the upper aer odi gesti ve tract ar e the
pr esence of a nonheal i ng ul cer, bl eedi ng, hoar seness, dysphagi a,
odynophagi a, otal gi a (r efer r ed pai n), faci al pai n, neck mass, or new
l esi on i ntraoral l y. Symptoms can occur secondar y to l ocal
destr ucti on or i nvol vement of adjacent str uctur es (neural , softti ssue, or bony i nvol vement). The cl i ni ci an shoul d be al er ted to the
fact that an adul t, wi th any of these si gns and symptoms that do not
r esol ve wi thi n 2 weeks, shoul d be r efer r ed to an exper i enced
cl i ni ci an for eval uati on.
Cl i ni cal exami nati on of the head and neck i ncl udes vi sual i nspecti on
and pal pati on (bi manual eval uati on) of the scal p, exter nal ear s, ear
canal s, mucous membranes of the eyes, nasal passages, oral cavi ty,
nasophar ynx, or ophar ynx, hypophar ynx, and l ar ynx. Exami nati on of
the l ar ynx and phar yngeal r egi ons ar e per for med by ei ther mi r r or
exami nati on or fl exi bl e endoscopy. Car e must be taken to exami ne
the major sal i var y gl ands vi sual l y and manual l y. A detai l ed crani al
ner ve exami nati on i s i mpor tant for documenti ng pr etr eatment
functi on because l ocal l y aggr essi ve cancer s may cause functi onal
defi ci ts pr etr eatment and because var i ous tr eatment modal i ti es may
be associ ated wi th posttr eatment dysfuncti on. Exami nati on of the
neck for spr ead to cer vi cal l ymph nodes of the upper jugul odi gastr i c
chai n i s i mpor tant pr ognosti cal l y. The gr oupi ng of cer vi cal nodes of
the jugul odi gastr i c chai n (F i g. 6-1) pr ovi des a uni for m system for
communi cati ng between cl i ni ci ans. Metastasi s to speci fi c nodal
gr oups or echel ons can be pr edi cti ve of the l ocati on of the pr i mar y
si te when pati ents pr esent wi th a cer vi cal metastasi s fr om an
unknown pr i mar y.
Bi opsi es of suspi ci ous l esi ons can be per for med i n ei ther the cl i ni c
or the operati ng r oom. Bi opsi es ar e per for med wi th ei ther a scal pel
or punch bi opsy for ceps of the pr i mar y l esi on or fi ne-needl e
aspi rati on (F NA) of suspi ci ous l ymph nodes. F NA of neck masses i s
as accurate as open bi opsy i n exper i enced cytopathol ogi sts hands
and i s pr efer r ed over open bi opsy to r educe the r i sk of tumor
spi l l age and seedi ng of the neck. Intraoperati ve panendoscopy
(di r ect l ar yngoscopy, esophagoscopy, nasal endoscopy, and
br onchoscopy) i s per for med to pr ovi de adequate ti ssue for di agnosi s
fr om ar eas i naccessi bl e i n the cl i ni c, to al l ow for better hemostasi s,
and to detai l the extent of the di sease for tr eatment pl anni ng.
Impr ovements i n fi ber-opti c technol ogy (e.g., transnasal
esophagoscopy) ar e expandi ng the scope of what can be eval uated
and successful l y bi opsi ed i n the cl i ni cal setti ng.
Radi ographi c i magi ng i ncl udes pl ai n x-rays, computed tomography
(CT) scans, magneti c r esonance i magi ng (MRI) scans, ul trasound,
and posi tr on emi ssi on tomography (PET) scanni ng. Chest x-rays hel p
deter mi ne the pr esence of di stant metastasi s
(appr oxi matel y 15% of pati ents) or second pr i mar i es (5% 10% ).
Panor ex fi l ms hel p deter mi ne whether mandi bl e i nvol vement i s
pr esent. CT scans fr om the skul l base to the cl avi cl es pr ovi de
detai l ed i nfor mati on on the extent of l ocal soft-ti ssue and bony
i nvol vement of upper aer odi gesti ve tract tumor s, and the pr esence
of r egi onal l y metastati c di sease to the upper cer vi cal jugul odi gastr i c
chai n.
F i gur e 6.1. Lymph node gr oups. Level IA, submental , and l evel
1B, submandi bul ar l ymph node gr oups; l evel s IIA and IIB, upper
jugul ar gr oup; l evel III, mi ddl e jugul ar gr oups; l evel IV, l ower
jugul ar gr oup; l evel s VA and VB, poster i or tr i angl e gr oup; l evel
VI, anter i or compar tment gr oup.
In general , pr ognosi s for upper aer odi gesti ve tract cancer s i s

deter mi ned by the si ze of the pr i mar y, as wel l as the pr esence of
r egi onal (cer vi cal ) nodal metastasi s and di stant metastasi s, wi th
bul ki er di sease bei ng associ ated wi th a wor se pr ognosi s. The
pr esence of nodal metastasi s decr eases sur vi val by 50% and i s
associ ated wi th an i ncr eased r i sk of di stant metastasi s. Stagi ng for
head and neck cancer i s based on the Amer i can Joi nt Commi ttee on
Cancer cl assi fi cati on and i s outl i ned i n Tabl e 6.1. The T stage
defi nes the si ze and extent of the pr i mar y; the N stage defi nes the
si ze, number, and l ocati on of nodal spr ead; and the M stage r efer s
to the pr esence or absence of di stant metastasi s. Appr oxi matel y
15% of head and neck cancer pati ents wi l l devel op di stant
metastasi s.
Cancer staging system for head and neck

cancers
Stage grouping
Stage
I
T1, N0, M0
Stage
II
T2, N0, M0
Stage
III
T3, N0, M0
T13, N1, M0
T4, N0 or N1, M0
Stage
IV
Any T, N2 or N3, M0
Any T, any N, M1
Primary tumor (T) dependent on anatomic

location
N0
N2a
Metastasis in single ipsilateral lymph

node >3 cm but <6 cm
N2b
Metastasis in multiple ipsilateral lymph

nodes, none >6 cm
N2c
Metastasis in bilateral or contralateral

lymph nodes, none >6 cm
N3
Metastasis in a lymph node >6 cm
Metastatic disease
M0
No evidence of distant metastasis
M1
Evidence of distant metastasis

et al., eds. AJCC Cancer Staging Manual. 6th
ed. New York, NY: Springer-Verlag; 2002, with
permission.
In addi ti on to the tradi ti onal pr ognosti c mar ker s, depth of i nvasi on,
per i neural i nvasi on and per i vascul ar i nvasi on at the pr i mar y tumor
si te, and l ymph node extracapsul ar spr ead ar e associ ated wi th
wor se pr ognosi s. Sur vi val for ear l y-stage di sease (stages I and II)
acr oss si tes fal l s i n the 80% to 90% range, but dr ops to 3% to 40%
for stage III and IV di sease. Much r esear ch i s cur r entl y bei ng done
to i denti fy mor e sel ecti ve bi ol ogi cal and mol ecul ar pr edi cti ve and
pr ognosti c mar ker s, such as the expr essi on of mutated p53, and
epi der mal gr owth factor r eceptor expr essi on.
The mai nstay for tr eatment of ear l y-stage head and neck cancer i s
si ngl e modal i ty therapy, ei ther sur ger y or radi ati on therapy. Mor e
advanced di sease i s mor e appr opr i atel y tr eated wi th mul ti modal i ty
therapy. Chemotherapy has pl ayed an i ncr easi ng r ol e i n the pr i mar y
tr eatment of advanced head and neck cancer, i n addi ti on to
mai ntai ni ng i ts tradi ti onal r ol e i n tr eati ng r ecur r ent or unr esectabl e
di sease.
For most si tes (oral cavi ty, si nonasal , sal i var y gl ands), sur ger y i s
the tr eatment of choi ce for ear l y-stage di sease and pr ovi des the
best chance for cur e i f an adequate mar gi n of r esecti on i s obtai ned.
Li mi ti ng factor s may be the potenti al functi onal defi ci t
or cosmeti c defor mi ty to an or gan system, or the accessi bi l i ty of the
tumor to compl ete sur gi cal exti r pati on. Advances i n sur gi cal
r econstr ucti ve techni ques and pr ostheti cs have expanded the
envel ope of what i s appr opr i ate sur gi cal r emoval .
For ear l y-stage di sease at some si tes (l ar ynx, phar ynx), radi ati on
therapy i s as effecti ve a tr eatment modal i ty as sur ger y, wi th the
benefi t of pr eser vi ng anatomi cal str uctur es. For mor e advanced
di sease, radi ati on i s an i mpor tant adjunct pr eoperati vel y and
postoperati vel y i n contr ol l i ng l ocal and r egi onal di sease and i n
ster i l i z i ng mi cr oscopi c di sease. Indi cati ons for postoperati ve
radi ati on therapy ar e posi ti ve sur gi cal r esecti on mar gi ns, per i neural
or per i vascul ar i nvasi on, extracapsul ar spr ead, l ocal l y aggr essi ve
poor l y di ffer enti ated tumor s, tumor spi l l age dur i ng r esecti on, and
advanced-stage di sease. Al though i t pr ovi des the benefi t of
potenti al or gan pr eser vati on, radi ati on i s not wi thout si gni fi cant
functi onal defi ci ts. Mucosi ti s may be sever e wi th an acute onset. It
may al so be ver y pai nful , l eadi ng to dysphagi a. Xer ostomi a (dr y
mouth) and dysphagi a ar e often underappr eci ated but debi l i tati ng
l ong-ter m sequel ae. In addi ti on to sal i var y gl and dysfuncti on,
thyr oi d dysfuncti on and fi br osi s and scar r i ng of soft ti ssues ar e
potenti al l ong-ter m sequel ae of radi ati on therapy. Mul ti modal i ty
therapy i s the mai nstay of therapy for advanced (stage II and IV)
di sease.
An i mpor tant par t of tr eatment i s pr eser vati on of functi on
posttr eatment. Or gan-speci fi c system r ehabi l i tati on i s par ti cul ar l y
i mpor tant i n mai ntai ni ng adequate voi ce and swal l owi ng functi on.
Fol l ow-up for cancer s of the head and neck i s i mpor tant because
most r ecur r ences wi l l occur wi thi n 2 year s of tr eatment. At The
Uni ver si ty of Texas M. D. Ander son Cancer Center, fol l ow-up of
pati ents occur s ever y 3 months for the fi r st 2 year s postoperati vel y,
ever y 6 months for the next 3 year s, and year l y ther eafter unti l 5
year s. A chest x-ray and l i ver functi on studi es ar e per for med year l y.
Neck Dissection
Nodal metastases ar e associ ated wi th a 50% decr ease i n sur vi val .
Di sease of the neck can be tr eated effecti vel y wi th sur ger y and/or
radi ati on. Li mi ted di sease (si ngl e node) wi th no extracapsul ar

spr ead may be tr eated wi th si ngl e modal i ty therapy, whi l e mor e
advanced di sease may r equi r e combi nati on therapy.
Tradi ti onal l y, sur ger y of the neck consi sts of one of the fol l owi ng
types of neck di ssecti ons: r adical neck dissection (RND), modified
r adical neck dissection (MRND), and selective neck dissection. The
RND consi sts of r emoval of al l cer vi cal l ymph nodes i n l evel s I to V,
the ster nocl ei domastoi d muscl e, the i nter nal jugul ar vei n, and the
spi nal accessor y ner ve. The l i mi ts of the di ssecti on ar e the i nfer i or
bor der of the mandi bl e super i or l y, the cl avi cl e i nfer i or l y, the
trapez i us poster i or l y, the l ateral bor der of the ster nohyoi d muscl e
anter i or l y, and the deep cer vi cal fasci a over l yi ng the l evator
scapul ae and the scal ene muscl es deepl y. In an attempt to decr ease
postoperati ve mor bi di ty, the MRND was desi gned. It i s si mi l ar to the
RND but i nvol ves pr eser vati on of the spi nal accessor y ner ve,
i nter nal jugul ar vei n, and/or the ster nocl ei domastoi d muscl e.
A sel ecti ve neck di ssecti on i nvol ves r emoval of l i mi ted cer vi cal
l ymph node gr oups (l evel s IIII [a supr aomohyoid neck dissection],
l evel s IIIV [a later al neck dissection], l evel s IIV, VII, and
postocci pi tal and r etr oaur i cul ar nodes [a poster olater al neck
dissection]), al ong wi th pr eser vati on of the spi nal accessor y ner ve,
i nter nal jugul ar vei n, and ster nocl ei domastoi d muscl e. The type of
sel ecti ve neck di ssecti on per for med depends on the si te and
hi stol ogy of the pr i mar y tumor and the most common r outes of
l ymphati c spr ead. A supraomohyoi d neck di ssecti on i s per for med for
cl i ni cal l y l i mi ted (nonpal pabl e) spr ead fr om oral cavi ty cancer s, a
l ateral neck di ssecti on for cl i ni cal l y l i mi ted (nonpal pabl e) spr ead
fr om l ar ynx cancer s, and a poster ol ateral neck di ssecti on for ski n
cancer s (e.g., mel anoma, SCC) of the scal p. Of note, a l evel VI or
anter ior compar tment neck dissection i s used i n the management of
thyr oi d cancer, al ong wi th a l ateral neck di ssecti on. Mor e extensi ve
di sease encounter ed at sur ger y may war rant a mor e i nvol ved neck
di ssecti on. Al l pati ents under goi ng di ssecti on of the spi nal accessor y
ner ve wi l l have some for m of neur opraxi a and shoul d under go
postsur gi cal physi cal therapy r ehabi l i tati on.
In pati ents tr eated wi th sur ger y of the pr i mar y and neck di ssecti on
pr eradi ati on at M. D. Ander son, a sel ecti ve neck di ssecti on (e.g.,
supraomohyoi d neck di ssecti on for oral cavi ty cancer s, l ateral neck
di ssecti on for l ar yngeal cancer s) i s the pr ocedur e most commonl y
used for cl i ni cal l y occul t di sease. Cl i ni cal nodal di sease i s tr eated by
a MRND. For postradi ati on pati ents, a sel ecti ve neck di ssecti on
(l evel s II and III) i s the pr ocedur e of choi ce for per si stent

adenopathy, and i s associ ated wi th good l ocal -r egi onal contr ol and
functi onal outcomes.
Carcinoma of the Oral Cavity

The oral cavi ty i s the por ti on of the aer odi gesti ve tract fr om the
ver mi l l i on bor der of the l i ps to the juncti on of the har d and soft
pal ate and the ci r cumval l ate papi l l ae of the tongue. Thi s r egi on
anatomi cal l y i ncl udes the l i ps, buccal mucosa, gi ngi va, fl oor of
mouth, anter i or fl oor of mouth, anter i or two-thi r ds of the tongue,
har d pal ate, and r etr omol ar tr i gone r egi on. Oral cavi ty cancer
accounts for appr oxi matel y 3% of cancer s i n the Uni ted States, i s
the si xth most common cancer wor l dwi de, and compr i ses 30% of al l
head and neck cancer s. In 2005, i n the Uni ted States al one, an
esti mated 20,000 cancer s occur r ed i n the oral cavi ty, and
appr oxi matel y 5,000 deaths wer e attr i butabl e to oral cavi ty cancer s.
Men ar e mor e commonl y affected than women (34:1), and the
mean age of occur r ence i s i n the si xth to seventh decades.
Stagi ng of the pr i mar y i s based on the TNM stage, wi th si ze of the
pr i mar y tumor deter mi ni ng the T stage. T1 l esi ons measur e l ess
than 2 cm, T2 measur e fr om 2 to 4 cm, T3 measur e 4 cm, and T4
measur e gr eater than 4 cm or i nvol ve extensi on to l ocal ti ssues
(Tabl e 6.2).
Sur gi cal exci si on i s the mai nstay of therapy for oral cavi ty cancer s.
An adequate mar gi n of nor mal ti ssue (at l east 11.5 cm) i s taken to
ensur e pr oper r esecti on. Sur gi cal defects can be l eft to heal by
secondar y i ntenti on or ar e r epai r ed by pr i mar y cl osur e, spl i tthi ckness ski n grafti ng, l ocal r otati onal or advancement fl ap
r econstr ucti on, or fr ee fl ap r econstr ucti on for l ar ge defects. Neck
di ssecti ons ar e done for cl i ni cal l y evi dent nodal di sease and
el ecti vel y for l ar ge pr i mar y tumor s or tumor s wi th a depth of
i nvasi on gr eater than 4 mm or other poor pr ognosti c factor s as
l i sted pr evi ousl y. The tradi ti onal neck di ssecti on for oral cavi ty
l esi ons i s a supraomohyoi d neck di ssecti on (l evel s IIII), al though
some data exi st for i ncl udi ng l evel IV l ymph nodes due to the
possi bi l i ty of ski p metastasi s. Pr i mar y tumor s cl ose to the mi dl i ne
may r equi r e bi l ateral neck di ssecti ons because the r i sk of spr ead to
the contral ateral neck may be gr eater than 20% .
Table 6.2. Staging system for oral cavity

tumors
Tis
Carcinoma in situ
T1
Tumor 2 cm at greatest dimension
T2
Tumor >2 cm but not 4 cm at greatest

dimension
T3
Tumor >4 cm at greatest dimension
T4
Tumor invades adjacent structures (e.g.,

cortical bone, deep extrinsic muscle of
tongue, maxillary sinus, or skin)

permission.
Radi ati on therapy i s gi ven i n the for m of exter nal -beam therapy or
brachytherapy i mpl ants (pr i mar y i nter sti ti al brachytherapy i mpl ants
ar e used for smal l l esi ons of the anter i or commi sur e of the l i p, oral
tongue, and fl oor of mouth [T1 l esi ons]). Radi ati on therapy i s onl y
rar el y used as the pr i mar y therapy and i s r eser ved for postoperati ve
tr eatment of pati ents at hi gh r i sk for l ocal -r egi onal r ecur r ence (i .e.,
l ar ge pr i mar y tumor s [T3 or T4], pr i mar y tumor s wi th cl ose or
posi ti ve mar gi ns, evi dence of per i neural or l ymphovascul ar
i nvasi on, tumor s wi th a depth of i nvasi on gr eater than 4 mm, nodal
metastasi s wi th evi dence of extracapsul ar spr ead, or mul ti pl e
posi ti ve nodes).
The pr ognosi s for ear l y l esi ons (T1 and T2) of the oral cavi ty i s
good, wi th a 5-year sur vi val of 80% to 90% . Sur vi val for advanced
l esi ons (T3 and T4) can range fr om 30% to 60% , dependi ng on the
factor s that affect pr ognosi s as outl i ned pr evi ousl y.
LIP
Cancer of the l i p accounts for appr oxi matel y 25% to 30% of oral
cavi ty cancer s, wi th gr eater than 90% bei ng SCC and gr eater than
90% occur r i ng on the l ower l i p. Smoki ng and sun exposur e ar e
major r i sk factor s. Sur ger y i s the tr eatment of choi ce for smal l
l esi ons, wi th the excepti on of commi ssur e l esi ons, whi ch may be
better tr eated wi th radi ati on. Cur e rates appr oachi ng 90% ar e
achi evabl e for ear l y l esi ons, wi th mor e advanced l esi ons havi ng a 5year sur vi val of l ess than 50% . Nodal metastases ar e associ ated
wi th l ar ge pr i mar y tumor s; tumor s of the upper l i p and commi ssur e,
as wel l as per i neural spr ead al ong the mental ner ve, por tends a
poor er pr ognosi s.
Buccal Mucosa
Buccal mucosa cancer s r epr esent 5% of oral cavi ty cancer s. Tobacco
smoki ng, al cohol use, smokel ess tobacco use, and betel nut use
have been associ ated wi th buccal cancer s. The r egi on near
the l ower thi r d mol ar i s a common si te for buccal cancer s, and
pati ents may pr esent wi th tr i smus due to i nvol vement of the
pter ygoi d muscl es. Cer vi cal metastases may be common (50% ) and
ar e associ ated wi th a poor pr ognosi s. Wi de l ocal exci si on i s the
tr eatment of choi ce, and a possi bl e mar gi nal mandi bul ectomy may
be necessar y to obtai n cl ear mar gi ns. Ear l y-stage di sease may be
associ ated wi th cur e rates i n the 60% to 70% range, whi l e
advanced tumor s have sur vi val of appr oxi matel y 40% . Local r egi onal r ecur r ence i s a si gni fi cant pr obl em. Sur vi val may be
i mpr oved wi th postoperati ve radi ati on. The sur gi cal defect may be
r econstr ucted wi th l ocal advancement fl aps (e.g., tongue) or may
r equi r e fr ee fl ap r econstr ucti on.
Floor of Mouth
Appr oxi matel y 10% to 15% of oral cavi ty cancer s occur i n the fl oor
of the mouth. Appr oxi matel y 50% of pati ents wi l l pr esent wi th
cer vi cal metastasi s, whi ch, as wi th other oral cavi ty si tes, i s a
pr edi ctor of poor pr ognosi s. Deep tongue muscl e and mandi bl e
i nvol vement i s fr equentl y seen, r equi r i ng par ti al gl ossectomy and
mar gi nal or segmental mandi bul ectomy wi th fr ee fl ap r econstr ucti on

to obtai n cl ean mar gi ns. Bi l ateral cer vi cal metastasi s i s not
uncommon. Overal l 5-year sur vi val rates range fr om 30% to 70% ,
wi th stages I and II appr oachi ng 70% to 80% and stage IV di sease
bei ng l ess than 50% .
Oral Tongue
Oral tongue (anter i or two-thi r ds of the tongue) car ci noma accounts
for appr oxi matel y 37% of esti mated new oral cavi ty cancer s i n
2005. Par ti al gl ossectomy wi th heal i ng by secondar y i ntenti on,
pr i mar y cl osur e, ski n grafti ng, or fr ee fl ap r econstr ucti on i s the
accepted tr eatment. In addi ti on to the si ze of the pr i mar y and
hi stol ogi c grade, tumor thi ckness al so has pr ognosti c si gni fi cance
for l ocal -r egi onal r ecur r ence, wi th l esi ons gr eater than 4 mm
havi ng a 40% to 50% i nci dence of nodal metastasi s. For tumor s of 4
mm or gr eater thi ckness, an i psi l ateral supraomohyoi d neck
di ssecti on (l evel s IIII) i s r ecommended for management of the
neck. Ther e ar e some data that suggest that a l evel IV di ssecti on
may be war ranted due to the pr esence of ski p metastasi s; however,
thi s i s usual l y done for pati ents metastasi s i n l evel s I to III. Ear l ystage tumor s have a good pr ognosi s (70% 80% 3-year sur vi val for
stages I and II and 40% 50% for stage III and IV di sease), whi l e
advanced l esi ons r equi r e combi ned modal i ty tr eatment. A smal l
subset of oral tongue cancer s occur s i n pati ents younger than 40
year s of age wi th no known r i sk factor s; these cancer s appear to be
mor e aggr essi ve and ther efor e war rant mor e aggr essi ve therapy.
Speech and swal l owi ng r ehabi l i tati on ar e essenti al for good
postoperati ve functi on. SCC of the base of the tongue behaves
di ffer entl y and i s r evi ewed i n the Cancer of the Or ophar ynx,
Nasophar ynx, and Hypophar ynx secti on l ater i n thi s chapter.
Hard Palate
Har d pal ate SCCs r epr esent appr oxi matel y 0.5% of al l oral cavi ty
cancer s i n the Uni ted States. Cancer s of the har d pal ate and gi ngi va
ar e tr eated wi th wi de l ocal exci si on. Tumor s wi thi n cl ose
pr oxi mi ty to or i nvol vi ng bone and l ar ge tumor s may r equi r e par ti al
pal atectomy or maxi l l ectomy to obtai n cl ear mar gi ns. Bony defects
ar e best r econstr ucted wi th a pal atal pr osthesi s or obturator. F i veyear cur e rates appr oach 40% to 70% i n pati ents wi thout nodal
di sease.
Cancer of the Larynx

In the Uni ted States, l ar ynx cancer s wi l l have an esti mated
i nci dence of 10,000 new cases i n 2005. Cancer s occur i n the si xth
to ei ghth decades wi th a mal e-to-femal e rati o of 4:1. Tobacco and
al cohol abuse ar e the most common r i sk factor s associ ated wi th
devel opment of l ar yngeal cancer. The l ar ynx i s di vi ded i nto thr ee
subsi testhe supr aglottis, glottis, and subglottisthat have
i mpl i cati ons for behavi or, tr eatment, and pr ognosi s.
The supr aglottis i s the por ti on of the l ar ynx above the l ar yngeal
ventr i cl e and bel ow the l ar yngeal sur face of the epi gl otti s. The
supragl otti s contai ns the epi gl otti s, ar ytenoi ds, ar yepi gl otti c fol ds,
fal se cor ds, and ventr i cl es. The l ymphati c drai nage i s i nto the upper
and mi d-jugul odi gastr i c chai n vi a the pyr i for m si nuses and i s
bi l ateral , whi ch makes addr essi ng both si des of the neck for a
supragl otti c cancer a necessi ty. Sensati on i s vi a the i nter nal branch
of the super i or l ar yngeal ner ve. Cancer s of the supragl otti s account
for 35% of l ar yngeal cancer s. The glottis i s the por ti on of the l ar ynx
that compr i ses the tr ue vocal fol ds. The l ymphati c drai nage i s
mi ni mal due to the cl ose adher ence of the mucosa to the under l yi ng
vocal l i gament. Sensati on i s vi a the super i or l ar yngeal ner ve.
G l otti c cancer s compr i se 65% of l ar yngeal cancer s. The subglottis
extends fr om the i nfer i or por ti on of the tr ue vocal fol ds to the
i nfer i or bor der of the cr i coi d car ti l age. Lymphati c drai nage i s vi a
effer ents that enter i nto the deep cer vi cal jugul odi gastr i c nodes and
the paratracheal and pr etracheal l ymph nodes bi l ateral l y. Subgl otti c
cancer s compr i se l ess than 5% of l ar yngeal cancer s. Subsi te
di vi si on i s i mpor tant for di agnosi s and tr eatment of ear l y tumor s;
however, i n advanced stages, l ar yngeal cancer s may have extensi ve
par aglottic (submucosal spr ead ar ound the l ar yngeal framewor k) and
tr ansglottic (extensi on acr oss subsi tes) spr ead. Stagi ng for
l ar yngeal cancer s var i es and i s l i sted i n Tabl e 6.3.
Pr esenti ng symptoms for l ar yngeal cancer s i ncl ude hoar seness,
pai n, dysphagi a, and r espi rator y di str ess. Eval uati on of the l ar ynx i s
essenti al for stagi ng of l ar yngeal cancer s. Impai r ed vocal fol d
mobi l i ty and subsi te extensi on por tend a mor e advanced cancer and
poor er pr ognosi s. Cancer s that affect the tr ue vocal fol d usual l y
pr esent ear l y due to the i mpai r ment i n functi on (voi ce and
r espi rati on). Supragl otti c cancer s usual l y pr esent l ate, wi th
submucosal and l ocal spr ead, and symptoms ar e due to i nvasi on of
l ocal ti ssues causi ng hoar seness, dysphagi a, odynophagi a, otal gi a
(r efer r ed pai n), and r espi rator y di str ess. Imagi ng of the l ar ynx (CT
scanni ng) i s i mpor tant i n deter mi ni ng l ocal extensi on of the pr i mar y

di sease, l ar yngeal car ti l age destr ucti on, and the pr esence of
cl i ni cal l y occul t di sease.
Treatment
Because gl otti c cancer s ar e the most common l ar yngeal cancer s
seen, these ar e di scussed i n detai l . The goal of tr eatment of
l ar yngeal cancer i s eradi cati on of the di sease, as wel l as
pr eser vati on of functi on and anatomy when possi bl e. Both sur ger y
and radi ati on pr ovi de excel l ent contr ol rates for T1 and T2 gl otti c
l esi ons. Esti mated 5-year sur vi val for al l cancer s of the l ar ynx i s
65% . Local contr ol rates i n the l i teratur e for both tr eatment
modal i ti es range fr om 70% to 100% , whi ch i mpr oves wi th sal vage
l ar yngectomy. T3 and T4 tumor s have contr ol rates i n the 80% to
85% and 60% to 70% range, r especti vel y. F i ve-year sur vi val for T1
and T2 l esi ons i s 80% to 90% , and for T3 and T4 di sease, 50% to
60% . Mor e advanced l ar yngeal cancer s r equi r e combi ned modal i ty
therapy wi th total l ar yngectomy (or a modi fi cati on ther eof ) and
postoperati ve radi ati on therapy.
Table 6.3. Staging system for cancers of the

larynx
Supraglottis
T1
Tumor confined to site of origin
T2
Tumor involving adjacent supraglottic

sites, without glottic fixation
T3
Tumor limited to the larynx, with fixation

and/or extension to the postericoid
medial wall of the pyriform sinus or preepiglottic space
T4
Massive tumor extending beyond the

larynx to involve the oropharynx, soft
tissues of the neck, or destruction of
thyroid cartilage
Glottis
T1
Tumor confined to vocal folds, with

normal vocal cord mobility
T1a
Limited to one vocal fold
T1b
Involves both vocal folds
T2
Tumor extension to supraglottis and/or

subglottis with normal or impaired vocal
cord mobility
T3
Tumor confined to larynx, with fixation of

the vocal cords
T4
Massive tumor, with thyroid cartilage

destruction and/or extension beyond the
confines of the larynx

permission.
Surgery
Ear l y-stage gl otti c di sease may be tr eated effecti vel y wi th sur ger y
or radi ati on therapy. Sur gi cal opti ons for ear l y gl otti c di sease
i ncl ude vocal cor d str i ppi ng, transoral l aser mi cr osur ger y,
hemi l ar yngectomy, subtotal l ar yngectomy (supracr i coi d par ti al
l ar yngectomy [SCPL]), and total l ar yngectomy. The advantages of
sur ger y ar e compl ete exti r pati on of the di sease and r eser vati on of
other tr eatments (e.g., radi ati on) for futur e r ecur r ences. Both vocal
cor d str i ppi ng and l aser mi cr osur ger y may l eave the cor d wi th
scar r i ng that can make i t di ffi cul t to eval uate for r ecur r ence. A
ver tical par tial lar yngectomy ( VPL or hemilar yngectomy) i nvol ves
r emoval of hal f of the l ar ynx ver ti cal l y, as wel l as
pr eser vati on of hal f of the l ar ynx ver ti cal l y, to mai ntai n voi ce and
functi on. Pati ents wi th smal l vol ume di sease after radi ati on ar e
good candi dates for thi s pr ocedur e. For ear l y-stage supragl otti c
cancer s (T1 and T2), a supr aglottic or hor iz ontal lar yngectomy may
be per for med. The cr i coi d and at l east one ar ytenoi d i s pr eser ved
and sutur ed onto the base of the tongue, agai n i n an attempt to
pr eser ve adequate r espi rati on, voi ce, and swal l owi ng functi on.
Candi dates for thi s pr ocedur e r equi r e adequate pul monar y r eser ve
and car di ac functi on to pr event aspi rati on pneumoni a.
The SCPL i s an extended hor i zontal par ti al l ar yngectomy techni que
that pr eser ves the pati ent's nati ve voi ce and per mi ts near-total
l ar yngectomy wi thout per manent tracheostoma. SCPL can i ncl ude
r emoval of the fal se and tr ue vocal cor ds, the enti r e thyr oi d
car ti l age i ncl udi ng the enti r e paragl otti c spaces, and a por ti on or al l
of the supragl otti s and pr e-epi gl otti c space. In sel ected cases, one
ar ytenoi d may be r esected. Phonator y functi on and degl uti ti on i s
mai ntai ned by the movement of the spar ed ar ytenoi d(s) agai nst the
tongue base. It r epr esents a dramati c advance because i t uses the
pati ent's l ar yngeal framewor k to pr eser ve the pati ent's nati ve voi ce,
whi l e pr ovi di ng a tr ue en bl oc tumor r esecti on.
Total l ar yngectomy i s r eser ved for mor e advanced di sease (T3 and
T4) or pati ents who have fai l ed pr evi ous therapy and who ar e l i kel y
to have poor functi onal outcomes (voi ce and swal l owi ng) wi th voi cespar i ng sur gi cal pr ocedur es. A bi l ateral l ateral neck di ssecti on can
be per for med at the same ti me for mor e extensi ve di sease (a wi defi el d l ar yngectomy), and hemi - or total thyr oi dectomy i s per for med
for di sease that destr oys car ti l age or i nvol ves the pyr i for m si nuses,
subgl otti s, or paratracheal nodes. In cases wi th si gni fi cant
hypophar yngeal or cer vi cal esophageal extensi on, a

l ar yngophar yngectomy can be per for med and r epai r ed wi th a fr ee
ti ssue transfer mi cr ovascul ar r econstr ucti on. Postoperati ve radi ati on
i s typi cal l y gi ven i n advanced di sease. Speech pathol ogy
consul tati on i s essenti al pr eoperati vel y for adequate voi ce and
swal l owi ng r ehabi l i tati on postoperati vel y. Voi ce r ehabi l i tati on wi th
an el ectr ol ar ynx, tracheoesophageal punctur e, or esophageal speech
can l ead to good voi ce qual i ty. In addi ti on to bei ng moni tor ed for
r ecur r ence, pati ents al so need to be fol l owed for potenti al
hypothyr oi di sm (ei ther fr om sur ger y or radi ati on).
Radiation Therapy
G i ven the good rates of l ocal -r egi onal contr ol , radi ati on therapy has
been advocated as the tr eatment of choi ce for ear l y-stage di sease.
The advantages of radi ati on ar e spar i ng of the anatomy wi th
pr eser vati on of voi ce. The di sadvantages ar e postradi ati on sequel ae
(e.g., xer ostomi a, potenti al radi onecr osi s of the l ar yngeal
framewor k) and the i nabi l i ty to use radi ati on agai n i n the event of a
r ecur r ence. Postoperati ve radi ati on therapy i s typi cal l y gi ven to
pati ents wi th extensi ve pr i mar y di sease (submucosal spr ead, subsi te
extensi on [i .e., supra- or subgl otti c, extral ar yngeal extensi on]),
di sease wi th posi ti ve mar gi ns, mul ti pl e posi ti ve l ymph nodes, or
l ymph nodes wi th extracapsul ar spr ead, and pati ents r equi r i ng
pr el ar yngectomy tracheotomy (who have a hi gher r i sk of stomal
r ecur r ence).
Typi cal doses of pr i mar y radi ati on for ear l y l ar yngeal di sease ar e i n
the 65 to 70 G y range. For gl otti c cancer s, the radi ati on can be
focused on the pr i mar y si te due to the l ow i nci dence of nodal
metastasi s. For supragl otti c cancer s wi th a hi gher pr opensi ty of
cer vi cal metastasi s at the ti me of di agnosi s, fi el ds shoul d encompass
the pr i mar y nodal drai nage basi ns (l evel s IIV), wi th doses i n the
50 to 60 G y ranges.
Cancer of the Oropharynx, Nasopharynx, and

Hypopharynx
The phar ynx i s a tubul ar str uctur e that contai ns the l ar ynx. The
phar ynx can be di vi ded i nto thr ee anatomi cal subsi tes: the
nasophar ynx, the or ophar ynx, and the hypophar ynx. The anatomi cal
boundar i es of the or ophar ynx ar e the anter i or tonsi l l ar pi l l ar, uvul a
and base of tongue, and the val l ecul ar sur face of the epi gl otti s
i nfer i or l y. Incl uded i n thi s subsi te ar e the phar yngeal tonsi l s and
the base of tongue. The nasophar ynx i s separated fr om the
or ophar ynx by the soft pal ate. The boundar i es of the hypophar ynx
ar e the l ar yngeal sur face of the epi gl otti s, the pyr i for m si nuses, the
poster i or phar yngeal wal l , and the postcr i coi d ar ea above the
cr i cophar yngeus muscl e. Lymphati c drai nage for the nasophar ynx i s
the r etr ophar yngeal l ymph node basi n, the paraphar yngeal l ymph
nodes, and the upper and poster i or jugul odi gastr i c nodes.
Lymphati cs for the or ophar ynx ar e i n the deep, upper
jugul odi gastr i c chai n, whi l e the hypophar ynx drai ns i nto the mi dand l ower deep jugul odi gastr i c chai n. Bi l ateral cer vi cal metastases
ar e not uncommon. The paraphar yngeal space i s a potenti al space
l ocated outsi de the phar ynx pr oper. It i s pyrami dal shape and
extends fr om the skul l base to the hyoi d bone. Most tumor s of thi s
r egi on ar e beni gn; the most common tumor s ar i se fr om the deep
l obe of the par oti d gl and and i ncl ude unusual hi stol ogi c var i ants
such as pl eomor phi c adenomas, paragangl i omas, and neur ogeni c
tumor s (schwannomas and neur ofi br omas), rather than the common
squamous tumor s of the upper aer odi gesti ve tract.
The most common pr esenti ng symptoms ar e pai n, dysphagi a,
r efer r ed otal gi a, and a neck mass. In an attempt to cur e di sease
wi th decr eased mor bi di ty and to pr eser ve functi on (swal l owi ng),
exter nal -beam radi ati on (tonsi l , hypophar ynx, base of tongue) has
become the tr eatment of choi ce for or ophar yngeal and
hypophar yngeal cancer s. Sur vi val rates have been i n the 70% to
80% range for stage I and II di sease and 50% for stage II di sease.
Sur ger y i s r eser ved for smal l l esi ons and r ecur r ent di sease, due to
the i ncr eased mor bi di ty associ ated wi th sur ger y. Brachytherapy i s
al so used i n some center s for base of tongue tumor s.
Nasophar yngeal cancer s ar e mal i gnanci es that ar i se fr om or near
the fossa of Rosenml l er i n the nasophar ynx. These cancer s ar e
most commonl y seen i n r egi ons of Chi na and Afr i ca, wher e ther e i s
a str ong associ ati on wi th EBV. Indeed, EBV vi ral capsi d IgA anti gen
(VC) and ear l y anti gen IgA (EA) ti ter s ser ve as a tumor mar ker for
r ecur r ence. The average age at pr esentati on i s i n the fi fth and si xth
decades. Most pati ents pr esent wi th a pai nl ess neck mass, nasal
obstr ucti on, uni l ateral ser ous oti ti s medi a, or epi staxi s. Crani al
neur opathy (par ti cul ar l y i nvol vi ng crani al ner ves II, IV, V, and VI)
may occur as a r esul t of skul l base
i nvasi on, whi ch may be seen i n as many as 25% of pati ents. An
i r r egul ar mass i s seen on nasophar yngoscopy. Tumor s ar e cl assi fi ed
accor di ng to the Wor l d Heal th Or gani z ati on cl assi fi cati on (type I

bei ng wel l -di ffer enti ated kerati ni z i ng SCC, type II bei ng
nonkerati ni z i ng car ci noma, and type III bei ng poor l y di ffer enti ated
[undi ffer enti ated] car ci noma, whi ch i ncl udes l ymphoepi thel i omas
and anapl asti c car ci nomas).
The mai nstay of therapy i s ci spl ati n-based chemotherapy and
radi ati on therapy to the nasophar yngeal bed and pr i mar y drai ni ng
l ymph node echel ons. Tumor s ar e staged based on extent of di sease
wi th stage I tumor s l i mi ted to the nasophar ynx; stage II di sease
i nvol vi ng extensi on i nto the or ophar ynx, nasal fossa, and
paraphar yngeal space; stage III di sease i nvol vi ng extensi on i nto the
skul l base fossa and paranasal si nuses; and stage IV di sease
i nvol vi ng the i nfratemporal fossa, or bi t, and hypophar ynx, or wi th
i ntracrani al extensi on and/or cer vi cal adenopathy. F i ve-year
sur vi val for nasophar yngeal car ci noma i s l ess than 20% for type I
tumor s and appr oaches 50% for type II and III tumor s. Sur ger y may
be used for l i mi ted, ear l y-stage di sease, but i s associ ated wi th
si gni fi cant mor bi di ty. Neck di ssecti ons ar e per for med for r esi dual
di sease post chemoradi otherapy.
Cancer s of the hypophar ynx usual l y pr esent at advanced stages
(gr eater than 60% ar e stage III and IV) and ar e associ ated wi th
poor l ocal contr ol and sur vi val . The major i ty of cancer s occur i n the
pyr i for m si nus (70% 80% ), and nodal di sease at the ti me of
pr esentati on i s common (70% 80% ). Chemoradi ati on i s the
mai nstay of therapy, al though total l ar yngectomy or
l ar yngophar yngectomy may be sui tabl e for some pati ents. F i ve-year
sur vi val for hypophar yngeal cancer s i s di smal , rangi ng fr om 20% to
40% .
Cancer of the Nasal Cavity and Paranasal

Sinuses
The nasal cavi ty extends fr om the exter nal nasal dor sum and
pyr i for m aper tur e to the choana and the nasophar ynx, and fr om the
nasal fl oor (whi ch i s compr i sed of the maxi l l a anter i or l y and the
pal ati ne bone poster i or l y) to the nasal r oof (whi ch houses the
ol factor y bul bs and crani al ner ve I). The nasal septum, whi ch i s
composed of car ti l age anter i or l y and the vomer and per pendi cul ar
pl ate of the ethmoi d bones poster i or l y, separates the nose i nto
hal ves. The l ateral nasal wal l s house the osti a for the paranasal
si nuses; the nasofr ontal duct; and the i nfer i or, mi ddl e, and super i or
tur bi nates. The nasal cavi ty and paranasal si nuses ar e l i ned by
r espi rator y epi thel i um (pseudostrati fi ed ci l i ated col umnar

epi thel i um), except at the nasal vesti bul e, whi ch i s l i ned by
kerati ni z i ng squamous epi thel i um. The sensor y i nner vati on to the
nasal and paranasal mucosa i s fr om branches of the tr i gemi nal
ner ve (V1 and V2). The bl ood suppl y i s fr om the exter nal car oti d
(super i or l abi al , angul ar, and i nter nal maxi l l ar y ar ter i es) and
i nter nal car oti d (anter i or and poster i or ethmoi dal ar ter i es) ar ter i es.
Ther e ar e four pai r ed paranasal si nuses: the maxi l l ar y, fr ontal ,
ethmoi d, and sphenoi d si nuses. The si nuses communi cate wi th the
nasal cavi ty thr ough thei r osti a. The osti um of the maxi l l ar y si nus
drai ns under neath the mi ddl e tur bi nate at the osteomeatal compl ex,
as do the osti a of the anter i or and mi ddl e ethmoi d
si nuses. The fr ontal si nus drai ns thr ough the nasofr ontal duct
l ocated at the anter i or aspect of the nose. The osti a of the sphenoi d
si nuses ar e l ocated above and medi al to the super i or tur bi nate on
the face of the si nus. Lymphati c drai nage of the paranasal si nuses
occur s vi a the r etr ophar yngeal , paraphar yngeal , and deep upper
jugul odi gastr i c l ymph nodes.
The most common pr esenti ng symptoms for si nonasal tumor s ar e
uni l ateral nasal obstr ucti on, faci al pai n, faci al numbness, and
epi staxi s. Pati ents may al so pr esent wi th uni l ateral ser ous oti ti s
medi a (due to obstr ucti on of the eustachi an tube or i fi ce), epi phora,
or excessi ve tear i ng (due to obstr ucti on of the nasol acr i mal duct,
whi ch drai ns under neath the i nfer i or tur bi nate). Nodal metastases
ar e uncommon i n si nonasal mal i gnanci es. Occupati onal exposur es
ar e associ ated wi th cer tai n si nonasal mal i gnanci es (e.g., wood dust
wi th adenocar ci nomas, smoki ng ni ckel and heavy metal exposur es
wi th SCCs).
Eval uati on of the nose and paranasal si nuses i ncl udes exter nal and
endoscopi c i nspecti on. Bi opsi es of nasal and paranasal tumor s
shoul d be done cauti ousl y because of the r i sk of bl eedi ng and
cer ebr ospi nal fl ui d l eak due to i ntracrani al extensi on, and may
war rant i magi ng pr i or to bi opsy. Imagi ng (both CT scan and MRI
scan) i s i mpor tant i n deter mi ni ng the extent of the di sease (i .e.,
extensi on beyond the nose and paranasal si nuses i nto the brai n,
or bi t, skul l base, and i nfratemporal fossa). Contrast CT scan i s used
to deter mi ne the pr esence of bony destr ucti on and the vascul ar i ty
of the l esi on. MRI scanni ng i s hel pful i n del i neati ng the extent of
soft-ti ssue destr ucti on (i ntracrani al and i ntraor bi tal i nvol vement)
and di sti ngui shi ng tumor fr om i nspi ssated fl ui d on T2-wei ghted
i mages.
Beni gn tumor s of the nasal cavi ty i ncl ude nasal papi l l omas and
angi ofi br omas. Nasal papi l l omas ar e di vi ded i nto squamous and
Schnei der i an papi l l omas (the most common). Schnei der i an
papi l l omas usual l y pr esent wi th uni l ateral nasal obstr ucti on,
epi staxi s, and r hi nor r hea. Ther e ar e thr ee subtypes of Schnei der i an
papi l l omas: cyl i ndr i cal , septal , and i nver ti ng, the l atter two bei ng
the most common. Septal papi l l omas account for 50% of
Schnei der i an papi l l omas. They ar i se fr om the nasal septum, ar e
exophyti c i n natur e, and occur most commonl y i n mal es i n the thi r d
to si xth decades of l i fe. Inver ti ng papi l l omas most commonl y ar i se
fr om the l ateral nasal wal l , ar e pol ypoi d i n natur e, occur most
commonl y i n mal es (fi fth to ei ghth decades), and, as the name
i mpl i es, push the str oma i nwar d (hence, the ter m i nver ti ng
papi l l oma). Up to 15% of tumor s may har bor SCC, and ther e i s a
r i sk (10% ) of squamous degenerati on. Sur gi cal exci si on i s the
tr eatment of choi ce; thi s i nvol ves a medi al maxi l l ectomy, or an open
or endoscopi c r esecti on of the l ateral nasal wal l .
Angi ofi br omas ar e beni gn l ocal l y destr ucti ve vascul ar tumor s. They
ar e seen most commonl y i n young mal es (second to four th decades)
who pr esent wi th a hi stor y of uni l ateral nasal obstr ucti on and
r ecur r ent, r efractor y epi staxi s. It i s a smooth l obul ated mass ar i si ng
i n the poster i or l ateral nose near the sphenopal ati ne foramen
(der i ves i ts bl ood suppl y fr om the sphenopal ati ne ar ter y). Contrast
CT scan or MRI i s di agnosti c (anter i or bowi ng of the poster i or
maxi l l ar y si nus wal l [Hol man-Mi l l er si gn]). Offi ce bi opsy shoul d not
be per for med due to the r i sk of bl eedi ng.
Sur ger y fol l owi ng embol i z ati on (wi thi n 48 hour s) i s the tr eatment
of choi ce.
Si nonasal mal i gnanci es ar e rar e, accounti ng for l ess than 5% of
head and neck mal i gnanci es. The di ffer enti al for si nonasal
mal i gnanci es i ncl ude mucosal mel anomas, sar comas, SCCs,
si nonasal undi ffer enti ated car ci nomas (SNUCs), l ymphomas
(angi ocentr i c T-cel l l ymphoma), esthesi oneur obl astomas (al so cal l ed
ol factor y neur obl astomas), extramedul l ar y pl asmacytomas,
adenocar ci nomas, and adenoi d cysti c car ci nomas. Hematoxyl i n and
eosi n stai ni ng may onl y r eveal smal l bl ue cel l s, maki ng the
di agnosi s di ffi cul t. Immunohi stochemi cal anal ysi s i s i mpor tant i n
establ i shi ng the di agnosi s.
The most common type of si nonasal tumor i s SCC, occur r i ng
pr edomi nantl y i n mal es i n the si xth to ei ghth decades.
Hi stol ogi cal l y, they ar e si mi l ar to SCCs el sewher e i n the head and

neck. Mucosal mel anomas ar e rar e (1% 2% of al l mel anomas), wi th
a fai r l y equal mal e-to-femal e rati o. Up to one-thi r d may be
amel anoti c, and i mmunohi stochemi cal stai ni ng i s i mpor tant i n
establ i shi ng the di agnosi s. Sur vi val i s poor, wi th l ess than 30% of
pati ents al i ve at 5 year s. Esthesi oneur obl astoma i s a rar e tumor
ar i si ng fr om the ol factor y neur oepi thel i um wi th i ntranasal
extensi on. Epi staxi s, anosmi a, pai n, and nasal obstr ucti on ar e
common pr esenti ng symptoms. Combi ned nasal and i ntracrani al
sur ger y (crani ofaci al r esecti on) fol l owed by radi ati on i s the
pr efer r ed tr eatment. F i ve-year sur vi val appr oaches 70% for
r esectabl e di sease, al though ther e i s a hi gh i nci dence of l ocal
r ecur r ence. Angi ocentr i c T-cel l l ymphoma i s a non-Hodgki n
l ymphoma that may pr esent wi th nasal obstr ucti on, epi staxi s, and
l ocal ti ssue destr ucti on of the mi dl i ne mi dface (septum). The ti ssues
ar e fr i abl e and necr oti c on endoscopy. Mul ti pl e bi opsi es may be
needed to confi r m the di agnosi s. Radi ati on i s the tr eatment of
choi ce. Si nonasal sar comas ar e rar e and associ ated wi th a poor
pr ognosi s. Tr eatment usual l y i nvol ves some combi nati on of sur ger y
and radi ati on. Chemotherapy may be used, based on the hi stol ogi c
subtype. SNUC i s al so rar e and associ ated wi th a poor pr ognosi s.
Local extensi on i s common (i ntracrani al and i ntraor bi tal ).
Crani ofaci al r esecti on wi th postoperati ve radi ati on i s the tr eatment
of choi ce. Extramedul l ar y pl asmacytoma i s the most common type of
l ocal i zed pl asma cel l neopl asm i n the head and neck; yet, i t
accounts for l ess than 1% of al l head and neck neopl asms. Mal es
ar e mor e commonl y affected than femal es (3:1), and up to 70%
occur i n the head and neck. Nasal obstr ucti on and epi staxi s ar e
common. CT and MRI ar e nondi agnosti c, and bi opsy i s i mpor tant i n
establ i shi ng the di agnosi s. Stai ni ng for l ambda and kappa l i ght
chai ns confi r ms the di agnosi s. Systemi c wor kup for mul ti pl e
myel oma i s i mpor tant because these tumor s may pr ogr ess to
mul ti pl e myel oma i n up to 30% of cases. Radi ati on i s the tr eatment
of choi ce wi th l ocal contr ol rates of 70% to 80% and 5-year sur vi val
of 60% to 70% . Adenocar ci nomas and adenoi d cysti c car ci nomas ar e
commonl y seen i n si nus mal i gnanci es, and ar e associ ated wi th l ocal
extensi on and per i neural spr ead.
Sur ger y fol l owed by radi ati on has been the accepted tr eatment for
these di sor der s. Smal l tumor s ar e amenabl e to sur gi cal exti r pati on
vi a open or endoscopi c appr oaches. Smal l squamous cel l tumor s of
the nasal vesti bul e r espond wel l to brachytherapy.
However, due to the l ate pr esentati on of many si nonasal tumor s and
l ocal extensi on to the skul l base and or bi t, sur ger y may be

associ ated wi th hi gh mor bi di ty (e.g., neur ol ogi c sequel ae and
sacr i fi ce of the or bi t). Sur ger y may entai l a par ti al or total
r hi nectomy, par ti al or total maxi l l ectomy and adjacent si nuses
(ethmoi d and fr ontal ), or bi tal exenterati on, and combi ned
appr oaches wi th neur osur ger y for i ntracrani al extensi on
(crani ofaci al r esecti on). Neck di ssecti on i s r eser ved for cl i ni cal l y
gr oss di sease. Ther e ar e some data that suggest that pr eoperati ve
chemotherapy may be benefi ci al i n mi ni mi z i ng the extent of
sur ger y, but thi s r emai ns i nvesti gati onal . Pr ognosi s for si nonasal
mal i gnanci es i s poor, wi th overal l 5-year sur vi val rates of 20% to
30% . Sur vi val for ear l y-stage di sease (60% 70% for T1) i s better
than for l atter stages (10% 20% for T4).
Unknown Primary with Cervical Metastasis

Appr oxi matel y 2% to 9% of pati ents who pr esent wi th SCC
metastati c to the neck wi l l have an undi agnosed or unknown
pr i mar y at the ti me of pr esentati on. However, after car eful
eval uati on and wor kup, appr oxi matel y 90% of these pati ents wi l l
have a pr i mar y di agnosi s. Thus, onl y appr oxi matel y 10% of pati ents
have an unknown pr i mar y tumor. Al though per si stent adenopathy
can be associ ated wi th numer ous i nfl ammator y or i nfecti ous
condi ti ons (e.g., cat scratch di sease, atypi cal mycobacter i um),
mal i gnant cer vi cal adenopathy shoul d be suspected i n pati ents wi th
adenopathy that per si sts for mor e than 2 weeks after appr opr i ate
medi cal (anti bi oti c) therapy. The most common pathol ogy seen i s
ACC, al though l ymphoma, mel anoma metastasi s fr om the ski n, and
metastati c thyr oi d, l ung, and br east cancer may rar el y pr esent wi th
per si stent adenopathy i n the head and neck.
A thor ough hi stor y and physi cal , whi ch shoul d i ncl ude endoscopy to
r ul e out the pr i mar y, shoul d be per for med on al l pati ents. Random
bi opsi es of potenti al si tes ar e not r ecommended. However, goal di r ected bi opsi es of suspi ci ous ar eas and bi l ateral tonsi l l ectomy ar e
i ndi cated, dependi ng on the si te of the nodal metastasi s, because as
many as 25% of tonsi l s may har bor an occul t pr i mar y. The si te of
nodal metastasi s may i ndi cate the si te of the pr i mar y. For exampl e,
cysti c or l evel II adenopathy may suggest an or ophar yngeal pr i mar y
(base of tongue or tonsi l ), whi l e l evel V adenopathy may be
suggesti ve of a nasophar yngeal or thyr oi d pr i mar y and a
supracl avi cul ar node may suggest a l ung or gastr oi ntesti nal pr i mar y.
Common occul t upper aer odi gesti ve tract si tes for pr i mar y di sease
ar e the tonsi l , base of tongue, pyr i for m si nus, and nasophar ynx. If
F NA suggests a pr i mar y other than SCC, then an appr opr i ate,

systemi c metastati c wor kup needs to be per for med. Di r ected
di agnosti c i magi ng of the head and neck, such as CT or MRI
scanni ng, i s i mpor tant. The r ol e of PET scans has not been
establ i shed i n head and neck cancer s, but data ar e pr omi si ng i n the
setti ng of known and unknown pr i mar y di sease, dependi ng on the
vol ume of di sease pr esent.
Tr eatment for tr ue unknown cer vi cal pr i mar i es i s sur ger y (neck
di ssecti on), radi ati on, or sur ger y fol l owed by postoperati ve
radi ati on, ei ther to the nodal basi n al one or wi th el ecti ve i r radi ati on
of the most common mucosal si tes (i .e., the nasophar ynx,
or ophar ynx, hypophar ynx, and supragl otti s). Data suggest that
ther e may be a decr ease i n the occur r ence of an occul t pr i mar y wi th
the l atter appr oach. Some author s vi ew thi s as contr over si al and
r ecommend r eser vi ng radi ati on to the el ecti ve si tes unti l a pr i mar y
devel ops to r educe the mor bi di ty associ ated wi th radi ati on.
Sur ger y for squamous cel l pr i mar i es usual l y entai l s a sel ecti ve or
MRND. If ther e i s si ngl e nodal di sease wi th no poor pr ognosti c
cr i ter i a (e.g., extracapsul ar spr ead, mul ti pl e nodes, l ess than 3 cm),
then sur ger y al one or radi ati on al one may r esul t i n a good outcome.
For bul ki er, mor e aggr essi ve di sease, sur ger y (e.g., MRND, RND)
and radi ati on (usual l y postoperati ve, but someti mes pr eoperati ve) i s
the tr eatment of choi ce. Sur ger y i s al so i ndi cated for the di agnosi s
of metastati c wel l -di ffer enti ated thyr oi d cancer, whi ch woul d entai l
a total thyr oi dectomy and neck di ssecti on (l ateral and anter i or
compar tment).
Sur ger y for tumor s of i nfracl avi cul ar or i gi n (e.g., br east or
gastr oi ntesti nal ) must be car eful l y consi der ed i n l i ght of the hi gh
r i sk of systemi c metastasi s el sewher e i n the body. If the tumor i s
l i mi ted to the neck wi th no other di stant metastasi s, then sur ger y
and postoperati ve radi ati on may i mpr ove l ocal contr ol . For poor l y
di ffer enti ated tumor s suggesti ve of nasophar yngeal or i gi n, the
pr efer r ed tr eatment i s radi ati on.
F i ve-year sur vi val for tr eatment of unknown squamous cer vi cal
metastases appr oaches 40% to 60% i n many studi es, whether usi ng
sur ger y al one or sur ger y and radi ati on. Cl ose fol l ow-up i s i mpor tant
because the pr i mar y wi l l decl ar e i tsel f i n as many as 20% of
pati ents. Pr ognosi s for metastati c di sease fr om an i nfracl avi cul ar
pr i mar y i s poor, bei ng l ess than 10% i n most studi es.
Cancers of the Ear and Temporal Bones

The ear i s composed of the exter nal ear (pi nna, aur i cl e, and
exter nal canal ), the mi ddl e ear, and the i nner ear. The epi thel i um
over the exter nal ear i s squamous wi th adjacent adnexal and
gl andul ar (sebaceous) str uctur es, whi l e ci l i ated epi thel i um and
gl ands l i ne the mi ddl e ear. The framewor k of the aur i cl e and outer
thi r d of the exter nal canal i s compr i sed of el asti c car ti l age, whi l e
the i nner thi r d of the exter nal canal and mi ddl e ear i s made up of
the temporal bone.
Cancer s of the ear and temporal bones ar e rar e and account for l ess
than 1% of al l head and neck cancer s. Al though cutaneous
mal i gnanci es of the pi nna and aur i cl e ar e common, cancer s of the
temporal bone ar e rar e. The major i ty of tumor s of the ear i nvol ve
the aur i cl e (>80% ), fol l owed by the ear canal and mi ddl e ear and
mastoi d. Mal es ar e mor e commonl y affected, and sun exposur e i s a
major r i sk factor. SCC i s the most common hi stol ogi c cancer of the
outer ear, fol l owed by basal cel l car ci nomas. Rhabdomysar comas and
adenocar ci nomas can occur i n the mi ddl e ear. Pai n, aural ful l ness,
conducti ve hear i ng l oss, ul cerati on, and chr oni c otor r hea ar e
common pr esenti ng symptoms. Extensi on towar d the mi ddl e ear may
be associ ated wi th crani al neur opathi es such as faci al paral ysi s and
sensor i neural hear i ng l oss i n up to one-thi r d of pati ents.
Sur ger y i s often the pr efer r ed therapy for SCC and basal cel l
car ci nomas, al though radi ati on therapy may pl ay a r ol e i n hi ghl y
sel ected cases. Smal l l esi ons of the outer ear ar e tr eated
effecti vel y by par ti al or total aur i cul ectomy. Ear l y exter nal canal
l esi ons can be effecti vel y tr eated by sl eeve r esecti on. Lateral
temporal bone r esecti on i s r eser ved for l ar ge tumor s wi th medi al
extensi on, whi ch may i ncl ude par oti dectomy for par oti d nodal
metastasi s.
Sur vi val for cancer s of the outer ear appr oaches 90% for cancer s
confi ned to the aur i cl e, wi th decr easi ng pr ognosi s for those wi th
medi al extensi on and mi ddl e ear extensi on to l ess than 30% .
Temporal bone mal i gnanci es have a sur vi val rate of 20% to 30% at
5 year s.
Neoplasms of the Salivary Gland

Sal i var y gl and ti ssue i n the upper aer odi gesti ve tract consi sts of
thr ee pai r s of major sal i var y gl andspar oti d gl ands, submandi bul ar
or submaxi l l ar y gl ands, and subl i ngual gl andsand thousands of

mi nor sal i var y gl ands that exi st i n the mucosa of the l i ps, buccal
mucosa, har d and soft pal ate, and or ophar ynx. The par oti d gl ands
l i e l ateral and poster i or to the mandi bl e, and can be di vi ded i nto a
super fi ci al and a deep l obe by the cour se of the faci al ner ve. The
deep l obe of the par oti d gl and abuts the pr estyl oi d, paraphar yngeal
space, and deep l obe par oti d tumor s (e.g., pl eomor phi c adenomas)
ar e the most common tumor s i n thi s r egi on. The duct of the par oti d
gl and (Stenson duct) drai ns i ntraoral l y near the second maxi l l ar y
mol ar. Lymph nodes ar e pr esent i n the substance of the gl and, and
the nodal basi n for the par oti d gl and i s the pr eaur i cul ar and upper
jugul odi gastr i c nodes. Of note, the par oti d gl and and associ ated
l ymph nodes ar e a pr i mar y nodal drai nage basi n for scal p and
aur i cul ar mal i gnanci es, and a par oti dectomy shoul d be i ncl uded i n
any compr ehensi ve tr eatment of these mal i gnanci es. The
submandi bul ar gl ands ar e l ocated beneath the mandi bl e and thei r
ducts (Whar ton ducts), and drai n near the fr enul um of the tongue i n
the fl oor of the mouth. The mar gi nal mandi bul ar branch of the faci al
ner ve over l i es the gl and super fi ci al l y, the faci al vessel s (and
associ ated l ymph nodes) ar e i nti matel y associ ated wi th gl and, and
the l i ngual and hypogl ossal ner ves ar e cl osel y associ ated wi th the
deep sur face of the gl and. The subl i ngual gl ands ar e l ocated deep to
the mucosa of the fl oor of the mouth on top of the myl ohyoi d
muscl e.
Tumor s of the sal i var y gl ands can occur i n both major and mi nor
sal i var y gl ands, wi th the major i ty occur r i ng i n the major sal i var y
gl ands. The major i ty of tumor s occur i n the par oti d gl ands (90% ),
and the major i ty of these ar e beni gn (80% ). As the si ze of the
gl and decr eases, the r i sk of mal i gnancy i ncr eases, wi th 50% of
submandi bul ar gl and tumor s bei ng mal i gnant and 80% of subl i ngual
gl and tumor s bei ng mal i gnant. Some tumor s ar e associ ated wi th
pr evi ous radi ati on exposur e or smoki ng (e.g., War thi n tumor s).
However, the major i ty of sal i var y gl and tumor s have no i denti fi abl e
r i sk factor s.
Most sal i var y gl and tumor s pr esent as a pai nl ess mass, al though
rapi d gr owth and pai n may be seen but ar e not al ways suggesti ve of
mor e omi nous or aggr essi ve di sease because i nfl ammator y or
i nfecti ous di seases can pr esent wi th si mi l ar symptoms (e.g.,
par oti ti s or col l agen vascul ar di seases such as Sjgr en syndr ome or
Wegner granul omatosi s). Faci al paral ysi s, nodal metastasi s, and
l ocal ti ssue i nvasi on may be i ndi cati ve of a mor e
aggr essi ve di sease. Of note, Bel l pal sy (i di opathi c faci al ner ve

paral ysi s) i s a di agnosi s of excl usi on, and the pati ent wi th a sudden
faci al ner ve paral ysi s shoul d have a par oti d mal i gnancy (ei ther
pr i mar y or metastati c fr om a ski n pr i mar y) r ul ed out.
F NA i s hel pful i n establ i shi ng the di agnosi s but i s hi ghl y dependent
on the ski l l of the cytopathol ogi st (accuracy ranges fr om 60%
90% ). If an F NA cannot establ i sh the di agnosi s, then an open,
exci si onal bi opsy shoul d be per for med. In the case of the par oti d
gl and, an exci si onal bi opsy woul d entai l per for mi ng a super ficial
par otidectomy to i denti fy and pr eser ve the faci al ner ve. Inci si onal
bi opsy shoul d be avoi ded to pr event tumor vi ol ati on, tumor spi l l age,
and, i n the case of the par oti d gl and, faci al ner ve i njur y. CT and
MRI scans ar e hel pful i n detai l i ng the extent of di sease (e.g.,
paraphar yngeal space extensi on of deep l obe par oti d tumor s or skul l
base i nvol vement).
The major i ty of tumor s i n the sal i var y gl ands ar e beni gn, wi th
pl eomor phi c adenomas bei ng the most common. Other beni gn
tumor s i ncl ude War thi n tumor s (whi ch ar e associ ated wi th smoki ng
and ar e bi l ateral i n 10% of cases), monomor phi c adenomas, and
oncocytomas. Mal i gnant tumor s i ncl ude mucoepi der moi d car ci nomas,
adenoi d cysti c car ci nomas, adenocar ci nomas, and SCCs.
Treatment
Sur ger y i s the mai nstay of therapy for al l par oti d tumor s. For
beni gn tumor s, super fi ci al par oti dectomy and submandi bul ar gl and
exci si on ar e both di agnosti c and curati ve. Because of the i nti mate
r el ati onshi p of the par oti d gl and and submandi bul ar gl ands to the
faci al ner ve and i ts branches, as wel l as the mor bi di ty associ ated
wi th faci al ner ve paral ysi s, onl y gr oss i nvol vement of the ner ve by
tumor i s an i ndi cati on for sacr i fi ce. Pl eomor phi c adenomas ar e the
most common beni gn tumor s of the sal i var y gl ands. Car e must be
taken to r emove a r i m of nor mal ti ssue ar ound the tumor, as wel l as
to avoi d r uptur e of the pseudocapsul e and tumor spi l l age, to r educe
the r i sk of r ecur r ence.
Mal i gnant tumor s of the sal i var y gl ands typi cal l y r equi r e sur ger y
and radi ati on. The excepti ons ar e l ow-grade neopl asms (e.g., l owgrade mucoepi der moi d car ci nomas and pol ymor phous l ow-grade
adenocar ci nomas), whi ch may be tr eated wi th sur ger y al one.
Super fi ci al par oti dectomy i s i ndi cated for smal l l esi ons. For par oti d
tumor s wi th deep l obe extensi on, total par oti dectomy wi th faci al
ner ve pr eser vati on i s the tr eatment of choi ce. G r oss i nvol vement of
the faci al ner ve by tumor i s an i ndi cati on for sacr i fi ce of the ner ve.
In such cases, the ner ve shoul d be traced pr oxi mal l y (as far back as
the brai nstem, i f necessar y) unti l tumor i s cl ear ed. Thi s i s
especi al l y tr ue of adenoi d cysti c car ci nomas, whi ch ar e neur otr opi c
tumor s. Sacr i fi ce of the faci al ner ve shoul d be r epai r ed i mmedi atel y
ei ther by i nter posi ti onal ner ve grafti ng (usi ng the sural ner ve fr om
the l eg or medi al antebrachi al cutaneous ner ve fr om the ar m) or a
crani al ner ve XII to VII grafti ng. Par oti d tumor s wi th l ocal extensi on
(ski n or exter nal canal i nvol vement) may r equi r e a mastoi dectomy
(to trace the ner ve pr oxi mal l y) and r emoval of the l ateral par t of
the temporal bone. Exci si on of the submandi bul ar gl and and
adjacent faci al l ymph nodes i s the tr eatment for submandi bul ar
tumor s. As wi th the
par oti d, onl y gr oss i nvol vement wi th tumor i s an i ndi cati on for
ner ve sacr i fi ce (e.g., l i ngual and hypogl ossal ner ves), and l ocal
extensi on to sur r oundi ng ti ssues (e.g., fl oor of mouth muscul atur e,
tongue) necessi tates mor e radi cal sur ger y. Neck di ssecti on
(sel ecti ve) i s r eser ved for cl i ni cal l y appar ent neck di sease.
Radi ati on i s r eser ved for pr i mar y tr eatment of mal i gnant tumor s i n
pati ents who ar e poor sur gi cal candi dates or who do not want to
under go sur ger y, as wel l as for the postoperati ve tr eatment of hi ghgrade or r ecur r ent di sease. Adenoi d cysti c car ci nomas, hi gh-grade
mucoepi der moi d car ci nomas, hi gh-grade adenocar ci nomas, SCCs,
and metastati c di sease to the neck ar e typi cal l y i r radi ated. In
addi ti on, pati ents wi th pl eomor phi c adenomas that ar e r ecur r ent or
i nvol ve gr oss tumor spi l l age may be candi dates for postoperati ve
radi ati on. Doses to the pr i mar y tumor bed ar e i n the range of 50 to
70 G y.
F i ve-year sur vi val for beni gn tumor s appr oaches 100% , wi th the
gr eatest r i sk of r ecur r ence occur r i ng i n pati ents who have had
i nadequate i ni ti al operati ons. For mal i gnant tumor s, 5-year sur vi val
i s 70% to 90% for l ow-grade tumor s and 20% to 30% for hi ghgrade mal i gnanci es. Regi onal and di stant r ecur r ences range fr om
15% to 20% and ar e common i n tumor s wi th per i neural i nvasi on
(e.g., adenoi d cysti c car ci nomas). Adenoi d cysti c car ci nomas have a
pr opensi ty to spr ead al ong ner ves and metastasi ze to the l ung;
ther efor e, sur vei l l ance shoul d entai l i magi ng (i .e., MRI scans and
chest x-rays) to excl ude r ecur r ence.
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M.
Edition
> Ta ble o f C o nt e nt s > 7 - Tho ra c ic M a ligna nc ie s
7
Thoracic Malignancies
Shanda H. Blackmon
A ra A . Vaporciyan
Primary Neoplasms of the Lung

In 2005, l ung cancer accounted for an esti mated 163,510 deaths
and 172,570 new cases of cancer i n the Uni ted States. Al though
l ess publ i ci zed than br east or pr ostate cancer, l ung cancer i s the
most common cause of cancer-r el ated death i n both men and
women. Appr oxi matel y 30% of al l cancer deaths ar e attr i butabl e to
l ung cancer. However, as seen i n F i gur e 7.1, the overal l ageadjusted death rates for l ung cancer have begun to l evel off. Thi s
l evel i ng off i s attr i butabl e to an overal l decr ease i n the number of
mal es who smoke and no fur ther i ncr ease i n the number of women
who smoke. Unfor tunatel y, thi s good news i s counter ed by a
di stur bi ng i ncr ease i n smoki ng among cer tai n mi nor i ty and
adol escent age gr oups. The overal l 5-year sur vi val rate for l ung
cancer i s onl y 15% , pr i mar i l y because the di sease i s usual l y
advanced at pr esentati on. If found at an ear l y stage, the 5-year
sur vi val rate appr oaches 60% to 70% .
Epidemiology
Smoki ng i s the pr i mar y eti ol ogy i n mor e than 80% of l ung cancer s,
and secondhand smoke i ncr eases the r i sk of l ung cancer by 30% .
Despi te the str ong associ ati on of l ung cancer wi th smoki ng, such
cancer s devel op i n onl y 15% of heavy smoker s. G i ant bul l ous
emphysema and ai r way obstr ucti ve di sease can act syner gi sti cal l y
wi th smoki ng to i nduce l ung cancer, per haps because of poor
cl earance and trappi ng of car ci nogens. Industr i al and envi r onmental
car ci nogens have been i mpl i cated, i ncl udi ng r esi denti al radon gas,
asbestos, urani um, cadmi um, ar seni c, and ter penes.
Pathology
Lung cancer can be br oadl y separated i nto two gr oups: nonsmal l cel l l ung cancer s (NSCLCs) and smal l -cel l l ung cancer s (SCLCs). Thi s
i s a popul ar di vi si on because, for the most par t, NSCLC i s often
managed wi th sur ger y when the tumor i s l ocal i zed, wher eas SCLC i s
al most al ways managed nonsur gi cal l y wi th chemotherapy and
radi ati on therapy. The thr ee major types of NSCLC ar e
adenocar ci noma, squamous cel l car ci noma, and l ar ge-cel l car ci noma
(Tabl e 7.1).
Nonsmall-cell Lung Carcinoma

Adenocar cinoma i s the most common type of NSCLC and accounts for
mor e than 40% of cases. It i s the most common l ung cancer found
i n nonsmoker s and women. The l esi ons tend to be l ocated i n the
per i pher y and devel op systemi c metastases, even i n the face of
smal l pr i mar y tumor s.
Br onchoalveolar cell car cinoma i s a subset of adenocar ci noma,
whose i nci dence appear s to be i ncr easi ng. Thi s tumor i s mor e
fr equent i n women and nonsmoker s, and can pr esent as a si ngl e
mass, mul ti pl e nodul es, or an i nfi l trate. The cl i ni cal cour se can var y
fr om i ndol ent pr ogr essi on to rapi d di ffuse di ssemi nati on.
F i gur e 7.1. Annual age-adjusted cancer death rates for sel ected
cancer types i n mal es (top) and femal es (bottom), Uni ted States,
1930 to 2001.
Table 7.1. Frequency of histologic subtypes

of primary lung cancer
Cell Type
Estimated
Frequency (%)
Non-small-cell lung cancer

Adenocarcinoma
40
Bronchoalveolar
Squamous cell carcinoma

Large-cell carcinoma
25
7
Small-cell lung cancer

Small-cell carcinoma
20
Neuroendocrine, well
differentiated
Carcinoids
Squamous cell car cinoma accounts for appr oxi matel y 25% of al l l ung
cancer s. Most (66% ) pr esent as central l esi ons. Cavi tati on i s found
i n 7% to 10% of cases. Unl i ke adenocar ci noma, the tumor often
r emai ns l ocal i zed, tendi ng to spr ead i ni ti al l y to r egi onal l ymph
nodes rather than systemi cal l y.
Lar ge-cell car cinoma accounts for appr oxi matel y 7% to 10% of al l
l ung cancer s. Cl i ni cal l y, l ar ge-cel l car ci nomas behave aggr essi vel y,
wi th ear l y metastases to the r egi onal nodes i n the medi asti num and
di stant si tes such as the brai n.
Small-cell Lung Carcinoma
Small-cell car cinoma i s associ ated wi th neur oendocr i ne car ci noma

because of ul trastr uctural and i mmunohi stochemi cal si mi l ar i ti es.
Some pathol ogi sts thi nk smal l -cel l car ci nomas r epr esent a spectr um
of di sease begi nni ng wi th the wel l -di ffer enti ated, beni gn car ci noi d
tumor (Kul chi tsky I), i ncl udi ng the l ess di ffer enti ated atypi cal
car ci noi ds (Kul chi tsky II) or neur oendocr i ne car ci nomas, and endi ng
wi th the undi ffer enti ated smal l -cel l car ci nomas (Kul chi tsky III).
Smal l -cel l car ci nomas tend to pr esent wi th metastati c and r egi onal
spr ead, and ar e usual l y tr eated wi th chemotherapy wi th or wi thout
radi ati on therapy. Sur ger y i s onl y used to r emove the occasi onal
l ocal i zed per i pheral nodul e.
Car cinoids tend to ar i se fr om major br onchi and ar e central tumor s.
Metastasi s i s rar e. Immunohi stochemi cal l y, car ci noi ds expr ess
neur on-speci fi c enol ase, chr omograni n, and synaptophysi n vi r tual l y
wi thout excepti on.
Neur oendocr ine car cinomas or atypical car cinoids occur mor e
per i pheral l y than car ci noi ds and have a mor e aggr essi ve cour se,
al though sur ger y shoul d sti l l be consi der ed accor di ng to cl i ni cal
stage. Wi thout appr opr i ate i mmunostai ni ng, they may i nadver tentl y
be cl assi fi ed as l ar ge-cel l car ci nomas.
Diagnosis
Si gns and symptoms occur i n 90% to 95% of pati ents at the ti me of
di agnosi s. Intrapar enchymal tumor s cause cough, hemoptysi s,
dyspnea, wheez i ng, and fever (often due to i nfecti on fr om pr oxi mal
br onchi al tumor obstr ucti on). Regi onal spr ead of the tumor wi thi n
the thorax can l ead to pl eural effusi ons or chest wal l pai n. Less
common symptoms ar e super i or vena cava syndr ome, Pancoast
syndr ome (shoul der and ar m pai n, Hor ner syndr ome, and weakness
and atr ophy of the hand muscl es), and i nvol vement of the r ecur r ent
l ar yngeal ner ve, the phr eni c ner ve, the vagus ner ve, or the
esophagus. Paraneopl asti c syndr omes ar e found i n 10% of pati ents
wi th l ung cancer, most commonl y those wi th SCLC. These syndr omes
ar e numer ous and can affect endocr i ne, neur ol ogi c, skel etal ,
hematol ogi c, and cutaneous systems.
A standar d chest radi ograph (CXR) i s the i ni ti al di agnosti c study for
the eval uati on of suspected l ung cancer, fol l owed r outi nel y by
computed tomography (CT). CT shoul d i ncl ude i magi ng of the l i ver
and adr enal gl ands to r ul e out two common si tes for i ntraabdomi nal metastases. CT hel ps assess l ocal extensi on to other
thoraci c str uctur es and the pr esence of medi asti nal adenopathy. At
pr esent, magneti c r esonance i magi ng (MRI) adds l i ttl e to the
i nfor mati on gai ned by CT i magi ng. Posi tr on emi ssi on tomography
(PET), especi al l y i ntegrated PET-CT, has become a fr equent method
of di sti ngui shi ng beni gn fr om mal i gnant pul monar y nodul es.
Al though the accuracy of PET scanni ng i n eval uati ng a pul monar y
nodul e can exceed 90% i n some studi es, cl i ni ci ans shoul d be awar e
that fal se-negati ve PET scans occur i n pati ents wi th neopl asms
havi ng l ow metabol i c acti vi ty (car ci noi d and br onchi oal veol ar
neopl asms). Even wi th advances i n i magi ng, hi stol ogi c confi r mati on
wi l l fr equentl y be r equi r ed to di sti ngui sh beni gn fr om mal i gnant
di sease and to deter mi ne the hi stol ogi c type of cancer. For a
sol i tar y l esi on wi th a hi gh i ndex of suspi ci on, hi stol ogi c
confi r mati on can be obtai ned at the ti me of sur ger y (thoracotomy or
vi deo-assi sted thoraci c sur ger y [VATS]) usi ng fr ozen secti oni ng of a
wedge r esecti on or a needl e bi opsy. If i mmedi ate sur ger y i s not
appr opr i ate, then ti ssue can be obtai ned by sputum cytol ogy and
br onchoscopy (central l esi ons) or by fl uor oscopi c fi ne-needl e
aspi rati on (F NA), or CT-gui ded bi opsy (per i pheral l esi ons). Pati ents
wi th beni gn l esi ons shoul d be fol l owed for i nter val gr owth over a
per i od of at l east 2 year s.
Staging
The pr i mar y goal of pr etr eatment stagi ng i s to deter mi ne the extent
of di sease so pr ognosi s and tr eatment can be deter mi ned. In SCLC,
most pati ents pr esent wi th metastati c or advanced l ocor egi onal
di sease. A si mpl e two-stage system cl assi fi es the SCLC as l i mi ted or
extensi ve di sease. Li mi ted di sease i s confi ned to one hemi thorax,
i psi l ateral or contral ateral hi l ar or medi asti nal nodes, and
i psi l ateral supracl avi cul ar l ymph nodes. Extensi ve di sease has
spr ead to the contral ateral supracl avi cul ar nodes or di stant si tes
such as the contral ateral l ung, l i ver, brai n, or bone mar r ow. Stagi ng
for SCLC r equi r es a bone scan;
bone mar r ow bi opsy; and CT scans of the abdomen, brai n, and
chest.
Stagi ng of NSCLC has most r ecentl y i nvol ved a system pr oposed i n
1985: the Inter nati onal Lung Cancer Stagi ng System or
Inter nati onal Stagi ng System (ISS). Thi s system i s based on TNM
cl assi fi cati ons as shown i n Tabl e 7.2. Sur vi val rates for pati ents
wi th NSCLC by stage of di sease ar e shown i n F i gur e 7.2. Because of
heter ogenei ty wi thi n gr oups, fur ther modi fi cati ons to the ISS have
been pr oposed that i nvol ve spl i tti ng stage I i nto IA (T1N0) and IB
(T2N0) and stage II i nto IIA (T1N0) and IIB (T2N0) and movi ng the
good-pr ognosi s T3N0 pati ents (chest wal l i nvol vement wi thout nodal
spr ead) i nto IIB. Stagi ng of NSCLC i nvol ves a thor ough hi stor y and
physi cal exami nati on, CXR, and CT scans of the chest and upper
abdomen, wi th the adjuncti ve use of PET scanni ng when avai l abl e.
Unfor tunatel y, CT cannot defi ni ti vel y pr edi ct medi asti nal nodal
i nvol vement because not al l mal i gnant l ymph nodes ar e enl ar ged,
and many enl ar ged nodes ar e si mpl y l ar ger because of pr oxi mal
i nfecti on. Lymph nodes l ar ger than 1 cm have a 30% chance of
bei ng beni gn, wher eas l ymph nodes smal l er than 1 cm sti l l have a
15% chance of contai ni ng tumor. PET-CT has a hi gher negati ve
pr edi cti ve val ue i n the eval uati on of medi asti nal N2 di sease,
al though fal se posi ti ves can occur i n pati ents wi th i nfecti ous
granul omas, i nfl ammator y pr ocesses, and r heumatoi d nodul es. Most
i nvesti gator s agr ee that ti ssue confi r mati on of PET l ocal i zed
medi asti nal di sease and metastases i s r equi r ed. Because of the l ow
yi el d i n asymptomati c ear l y-stage pati ents (T1N0), a bone scan, CT,
or MRI of the brai n shoul d onl y be obtai ned when suspected by
hi stor y.
Treatment
Pretreatment Assessment
Once a pati ent has been staged cl i ni cal l y wi th noni nvasi ve tests, a
physi ol ogi cal assessment shoul d be per for med to deter mi ne the
pati ent's abi l i ty to tol erate di ffer ent therapeuti c modal i ti es. In
addi ti on to a general eval uati on of the pati ent's overal l medi cal
status, speci fi c attenti on shoul d be pai d to the car di ovascul ar and
r espi rator y systems. Car di ovascul ar scr eeni ng shoul d i ncl ude a
hi stor y and physi cal exami nati on, as wel l as a CXR and
el ectr ocar di ography. Pati ents wi th si gns and symptoms of si gni fi cant
car di ac di sease shoul d under go fur ther noni nvasi ve testi ng,
i ncl udi ng ei ther exer ci se testi ng, echocar di ography, or nucl ear
per fusi on scans. Si gni fi cant r ever si bl e car di ac pr obl ems shoul d be
addr essed befor e therapy (i .e., chemotherapy, radi ati on therapy, or
sur ger y).
The pul monar y r eser ve of pati ents wi th l ung cancer i s commonl y
di mi ni shed as a r esul t of tobacco abuse. Si mpl e spi r ometr y i s an
excel l ent i ni ti al scr eeni ng test to quanti fy a pati ent's pul monar y
r eser ve and abi l i ty to tol erate sur gi cal r esecti on. A pr edi cted
postoperati ve for ced expi rator y vol ume i n 1 second (F EV1 ) of l ess
than 0.8 L or l ess than 35% of pr edi cted postoperati ve F EV1 i s

associ ated wi th an i ncr eased r i sk of per i operati ve compl i cati ons,
r espi rator y i nsuffi ci ency, and death. The pr edi cted postoperati ve
F EV 1 i s esti mated by subtracti ng the contr i buti on of the l ung to be
r esected fr om the pr eoperati ve F EV1 . In cer tai n
i nstances, the l ung to be r esected does not contr i bute much to the
pr eoperati ve F EV1 because of tumor, atel ectasi s, or pneumoni ti s.
Thus, mor e accurate deter mi nati on of pr edi cted postoperati ve F EV1
can be obtai ned by per for mi ng a venti l ati on-per fusi on scan and
subtracti ng the exact contr i buti on of the l ung to be r esected. In
good per for mance pati ents wi th bor der l i ne spi r ometr y cr i ter i a,
oxygen consumpti on studi es can be obtai ned that measur e both
r espi rator y and car di ac capaci ty. A maxi mum oxygen consumpti on
(VO 2 max) of gr eater than 15 mL mi n- 1 kg - 1 i ndi cates l ow r i sk,
wher eas a VO2 max of l ess than 10 mL mi n- 1 kg - 1 i s associ ated wi th
hi gh r i sk (a mor tal i ty rate of mor e than 30% i n some ser i es).
Addi ti onal r i sk factor s for l ung r esecti on i ncl ude a pr edi cted
postoperati ve di ffusi ng capaci ty (DLCO)
or maxi mum venti l ator y venti l ati on (MVV) of l ess than 40% and
hyper car bi a (>45 mm CO2 ) or hypoxemi a (<60 mm O2 ) on
pr eoperati ve ar ter i al bl ood gases. In conjuncti on wi th cl i ni cal
assessment (6-mi nute wal k and number of fl i ghts of stai r s cl i mbed),
these tests can hel p i denti fy those pati ents at hi gh r i sk for
compl i cati ons dur i ng and after sur gi cal r esecti on.
Table 7.2. TNM descriptors

Primary tumor (T)
Tx
Primary tumor cannot be assessed or

tumor proven by the presence of
malignant cells in sputum or bronchial
washings but not visualized by imaging or
bronchoscopy
T0
Tis
Carcinoma in situ
T1
Tumor 3 cm in greatest dimension,

surrounded by lung or visceral pleura,
without bronchoscopic evidence of
invasion more proximal than the lobar
bronchus a (i.e., not in the main bronchus)
T2
Tumor with any of the following features

of size or extent:
>3 cm in greatest dimension
Involving main bronchus, 2 cm distal to
the carina
Invading the visceral pleura
Associated with atelectasis or obstructive
pneumonitis that extends to the hilar
region but does not involve the entire
lung
T3
Tumor of any size that directly invades

any of the following: chest wall (including
superior sulcus tumors), diaphragm,
mediastinal pleura, parietal pericardium;
or tumor in the main bronchus <2 cm
distal to the carina but without
involvement of the carina; or associated
atelectasis or obstructive pneumonitis of
the entire lung
T4
Tumor of any size that invades any of the

followingmediastinum, heart, great
vessels, trachea, esophagus, vertebral
body, carinaor tumor with a malignant
pleural or pericardial effusion,b or with
satellite tumor nodule(s) within the
ipsilateral primary tumor lobe of the lung

Nx
Regional lymph nodes cannot be assessed
N0
N1
Metastasis to ipsilateral peribronchial

and/or ipsilateral hilar lymph nodes, and
intrapulmonary nodes involved by direct
extension of the primary tumor
N2
Metastasis to ipsilateral mediastinal

and/or subcarinal lymph nodes(s)
N3
Metastasis to contralateral mediastinal,

contralateral hilar, ipsilateral or
contralateral scalene, or supraclavicular
lymph node(s)

Presence of distant metastasis cannot be
Mx
assessed
M0
M1
Distant metastasis presentc
a The
uncommon superficial tumor of any size

with its invasive component limited to the
bronchial wall, which may extend proximally to
the main bronchus, is also classified T1.
b Most pleural effusions associated with lung
cancer are due to tumor. However, there are a
few patients in whom multiple cytopathological
examinations of pleural fluid show no tumor. In
these cases, the fluid is nonbloody and is not
an exudate. When these elements and clinical
judgment dictate that the effusion is not
related to the tumor, the effusion should be
excluded as a staging element, and the
patient's disease should be staged T1, T2, or
T3. Pericardial effusion is classified according
to the same rules.
c Separate metastatic tumor nodule(s) in the
ipsilateral nonprimary tumor lobe(s) of the lung
are also classified M1.
F i gur e 7.2. Cumul ati ve sur vi val accor di ng to cl i ni cal stage of

nonsmal l -cel l l ung cancer.
Pr eoperati ve trai ni ng wi th an i ncenti ve spi r ometer, i ni ti ati on of

br onchodi l ator s, wei ght r educti on, good nutr i ti on, and cessati on of
smoki ng for at l east 2 weeks befor e sur ger y can hel p mi ni mi ze
compl i cati ons and i mpr ove per for mance on spi r ometr y for pati ents
wi th mar gi nal pul monar y r eser ve.
Nonsmall-cell Lung Carcinoma

In ear l y-stage NSCLC, sur ger y i s a cr i ti cal par t of tr eatment.
Unfor tunatel y, mor e than 50% to 70% of NSCLC pati ents pr esent
wi th advanced di sease for whi ch sur ger y al one i s not an opti on. An
al gor i thm for tr eatment based on cl i ni cal stage i s pr esented i n
F i gur e 7.3. Physi ol ogi cal l y fi t pati ents wi th ear l y-stage l esi ons
(stage I or II) ar e tr eated wi th sur ger y. Defi ni ti ve radi ati on therapy
i s i ndi cated i f sur ger y cannot be tol erated. F i ve-year sur vi val rates
of 60% to 70% and 39% to 43% can be achi eved for pati ents wi th
stage I and II di sease, r especti vel y. Chest wal l i nvol vement wi thout
nodal spr ead (T3N0) was for mal l y consi der ed stage IIIa, but because
sur vi val rates of 33% to 60% have been achi eved wi th sur ger y,
they ar e now consi der ed as ear l y-stage l esi on (stage IIa). If these
pati ents cannot tol erate sur ger y because of poor medi cal status,
defi ni ti ve radi ati on can r esul t i n sur vi val rates of 15% to 35% .
The r emai nder of pati ents wi th stage IIIa di sease (N2 di sease or
chest wal l wi th nodal i nvol vement) cl assi cal l y has a poor r esponse
to sur ger y, wi th 5-year sur vi val rates of l ess than 15% . The
standar d tr eatment for these pati ents and those wi th stage IIIb or
IV i ncl udes chemotherapy (pl ati num-based doubl ets) and defi ni ti ve
radi ati on therapy for l ocal pal l i ati on. Impr oved sur vi val i s obtai ned
when chemotherapy i s combi ned wi th radi ati on therapy, al though
the compl i cati on rate i s i ncr eased.
A smal l subset of stage IIIb tumor s can be appr oached sur gi cal l y.
These tumor s ar e consi der ed stage IIIb because of l ocal extensi on
(T4N0) i nto adjacent str uctur es rather than systemi c spr ead (nodes,
hematogenous metastases) and may benefi t fr om aggr essi ve
sur gi cal r esecti on of the atr i um, car i na, or ver tebrae. Sur vi val rates
of up to 30% have been r epor ted. Metastati c di sease i s onl y tr eated
sur gi cal l y i n the unusual ci r cumstance of an i sol ated brai n
metastasi s wi th a node-negati ve l ung pr i mar y. Several r epor ts have
documented better l ocal contr ol (i n the brai n and l ung) wi th sur ger y
and a subset of l ong-ter m sur vi vor s. The pr esence of medi asti nal
nodes, however, contrai ndi cates sur gi cal r esecti on and mandates
radi ati on therapy for the l ung pr i mar y.
Surgery
Pneumonectomy
The r emoval of the whol e l ung was pr evi ousl y the most commonl y
per for med operati on for NSCLC; i t now accounts for onl y 20% of al l
r esecti ons. Al though a mor e
compl ete r esecti on i s accompl i shed usi ng pneumonectomy ver sus

par enchyma-conser vi ng techni ques (l obectomy), i t comes at the cost
of hi gher mor tal i ty (4% 10% ) and mor bi di ty wi thout cl ear sur vi val
benefi ts.
F i gur e 7.3. Al gor i thm for tr eatment of nonsmal l -cel l l ung

cancer.
Lobectomy
The si mi l ar sur vi val of pati ents tr eated by l obectomy ver sus
pneumonectomy, al ong wi th the l ower mor bi di ty and mor tal i ty (1%
3% ) associ ated wi th l obectomy, make l obectomy the pr efer r ed
method of r esecti on. Sl eeve l obectomi es and br onchopl asty
pr ocedur es i n whi ch por ti ons of the mai n br onchus ar e r emoved
wi thout l oss of the di stal l ung have fur ther decr eased the need for
pneumonectomi es.
Lesser Resections
Segmentectomi es and nonanatomi cal r esecti ons (wedge r esecti on
and l umpectomy) ar e associ ated wi th i ncr eased l ocal r ecur r ence
when compar ed wi th l obectomy. The general consensus r emai ns that
these pr ocedur es shoul d be per for med onl y i n hi gh-r i sk pati ents
wi th mi ni mal pul monar y r eser ve who coul d not tol erate a l obectomy.
The advent of CT scr eeni ng for l ung cancer has i denti fi ed mor e
subcenti meter cancer s. The use of l esser r esecti ons wi l l need to be
r eassessed for these types of cancer s.
Extended Operations
Recent i mpr ovements i n sur ger y and cr i ti cal car e have al l owed
cer tai n tumor s, pr evi ousl y consi der ed unr esectabl e, to be r emoved
wi th acceptabl e mor bi di ty and mor tal i ty. Car i nal sl eeve r esecti ons
and extended r esecti ons for super i or sul cus tumor s wi th
hemi ver tebr ectomy and i nstr umentati on of the spi ne can now be
per for med i n a smal l subset of pati ents whose tumor s wer e
pr evi ousl y consi der ed sur gi cal l y unr esectabl e. These pr ocedur es
shoul d onl y be per for med i n pati ents wi thout medi asti nal nodal
i nvol vement because 5-year sur vi val rates ar e l ess than 5% for
pati ents wi th extended r esecti ons i n the pr esence of nodal
i nvol vement.
Mediastinal Lymph Node Dissection

Compl ete medi asti nal l ymph node di ssecti on i mpr oves the accuracy
of l ung cancer stagi ng, i mpr oves i ndi cati ons for subsequent
adjuvant therapy, may decr ease l ocor egi onal r ecur r ence, and may
i mpr ove sur vi val . Ther e has been no i ncr ease i n mor bi di ty
associ ated wi th the addi ti on of a compl ete nodal di ssecti on i n
exper i enced hands.
Chemotherapy
Al most 50% of pati ents pr esent wi th extrathoraci c spr ead, and an
addi ti onal 15% ar e unr esectabl e because of l ocal l y advanced tumor.
In addi ti on, the l ong-ter m sur vi val for r esectabl e stage II and IIIa
tumor s r emai ns poor. Ther efor e, the use of adjuvant chemotherapy
to tr eat pati ents wi th unr esectabl e tumor s and i mpr ove the r esul ts
of sur ger y i s an ar ea of i ntense i nvesti gati on. A meta-anal ysi s of
these studi es demonstrated a sur vi val advantage usi ng pl ati numbased therapy, al though thi s di d not r each stati sti cal si gni fi cance.
These data spawned numer ous l ar ge adjuvant tr i al s i n Eur ope and
Amer i ca. The Eur opean study was the Inter nati onal Adjuvant Lung
Cancer Tr i al and enr ol l ed near l y 1,900 compl etel y r esected stage I,
II, and IIIA pati ents. The gr oup that r ecei ved ci spl ati num-based
doubl et therapy had a 4.1% i mpr ovement i n overal l sur vi val (p
<0.03). Si nce thi s publ i cati on, two addi ti onal posi ti ve tr i al s (NCIC
BR10 and CALG B 9633)
have been pr esented. Al though the i ncl usi on cr i ter i a wer e sl i ghtl y
di ffer ent, both studi es demonstrated a mor e than 30% i mpr ovement
i n sur vi val . These studi es have r equi r ed a si gni fi cant shi ft i n the
postoperati ve management of compl etel y r esected ear l y-stage l ung

cancer s. Al though the r i sk associ ated wi th adjuvant chemotherapy i s
smal l , i t must be consi der ed befor e i ni ti ati ng therapy. Ther efor e, we
now have al l pati ents wi th compl etel y r esected IB or hi gher stage
cancer s eval uated by an oncol ogi st for possi bl e adjuvant
chemotherapy.
Studi es exami ni ng the r ol e of neoadjuvant chemotherapy, common
i n the l ate 1990s, have been di ffi cul t to compl ete due to the data
r egar di ng adjuvant tr eatment. Al though mul ti modal i ty therapy has
achi eved a str ong foothol d, the opti mum ti mi ng of chemotherapy,
adjuvant ver sus neoadjuvant, r emai ns to be deter mi ned.
Small-cell Lung Carcinoma

Unl i ke NSCLC, SCLC tends to be di ssemi nated at pr esentati on and i s
ther efor e not amenabl e to cur e wi th sur ger y or thoraci c radi ati on
therapy al one. Wi thout tr eatment, the di sease i s rapi dl y fatal , wi th
few pati ents sur vi vi ng mor e than 6 months. For tunatel y, SCLC i s
ver y sensi ti ve to chemotherapy, and mor e than two-thi r ds of
pati ents achi eve a par ti al r esponse after systemi c therapy wi th
mul ti dr ug r egi mens. Tr eatment of SCLC ther efor e r evol ves ar ound
systemi c chemotherapy. An al gor i thm based on the extent of di sease
i s pr esented i n F i gur e 7.4. Compl ete r esponse i s seen i n as many as
20% to 50% of pati ents wi th l i mi ted di sease, but these r esponses
ar e not durabl e, and the 5-year sur vi val rate i s sti l l l ess than 10% .
Chemotherapeuti c r egi mens for SCLC most commonl y i ncl ude
combi nati ons of cycl ophosphami de, ci spl ati n, etoposi de, doxor ubi ci n,
and vi ncr i sti ne. Thoraci c radi ati on therapy has been shown to
i mpr ove l ocal contr ol of the pr i mar y tumor and i s often i ncl uded as
par t of the tr eatment for l i mi ted SCLC. In addi ti on, because brai n
metastases ar e noted i n 80% of pati ents wi th SCLC dur i ng the
cour se of thei r di sease, pati ents who show no evi dence of brai n
metastases on CT scans and who achi eve a good r esponse fr om
therapy ar e usual l y tr eated wi th pr ophyl acti c brai n i r radi ati on to
mi ni mi ze the chances of devel opi ng thi s mor bi d si te of tr eatment
fai l ur e.
A smal l r ol e for sur gi cal r esecti on of SCLC does exi st. Sol i tar y
per i pheral pul monar y nodul es wi th no evi dence of metastati c
di sease after eval uati on wi th bone scan, PET-CT, and CT of the
abdomen, brai n, and chest can be tr eated wi th l obectomy and
postoperati ve chemotherapy i f medi asti noscopy i s negati ve. In these
sel ect pati ents, a 5-year sur vi val rate of 50% has been achi eved for
T1N0, T2N0, and compl etel y r esected N1 di sease. Sur ger y for mor e
central l esi ons, however, has not been demonstrated to i mpr ove
sur vi val over that achi eved wi th chemotherapy and radi ati on
therapy al one.
Surveillance
The few tr eatment opti ons for tumor r ecur r ence i n NSLC have
l i mi ted the cost-effecti veness of aggr essi ve radi ol ogi c sur vei l l ance
fol l owi ng sur gi cal r esecti on. Never thel ess, ther e i s an i ncr eased
i nci dence of second pr i mar y l ung cancer s (2% per year ), and annual
or semi annual CXR may hel p detect these l esi ons. Any pati ent who
exper i ences symptoms i n the i nter i m shoul d al so be eval uated
aggr essi vel y for r ecur r ence or a new pr i mar y. The advent of l owdose hel i cal CT scanni ng may change thi s standar d, and i ts r ol e i n
the sur vei l l ance of r esected l ung cancer pati ents i s bei ng eval uated.
The l ung and l i ver ar e the most common si tes of metastases.
Pati ents wi th i sol ated l ung metastases can achi eve sur vi val rates of
25% to 40% i f compl ete sur gi cal r esecti on i s obtai ned. Because
metastases can r ecur, r esecti on i nvol ves nonanatomi cal wedge or
l aser r esecti ons to pr eser ve the l ung par enchyma.
F i gur e 7.4. Al gor i thm for tr eatment of smal l -cel l l ung cancer.
Metastatic Neoplasms to the Lung

Pathology
The bi ol ogy of the under l yi ng pr i mar y mal i gnancy deter mi nes the
behavi or of i ts metastases. Metastases may occur vi a
hematogenous, l ymphati c, di r ect, or aer ogenous r outes.
Diagnosis
Because of thei r pr edomi nantl y per i pheral l ocal i z ati on, most
pul monar y metastases r emai n asymptomati c, wi th fewer than 5%
showi ng symptoms at pr esentati on. Di agnosi s i s commonl y made
dur i ng radi ographi c fol l ow-up after tr eatment of the pr i mar y
mal i gnancy.
Routi ne CXR dur i ng sur vei l l ance after cancer tr eatment i s an
effecti ve means of scr eeni ng pati ents for pul monar y metastases.
Indeed, several studi es have demonstrated the i ncr eased sensi ti vi ty
of CT over standar d CXR. However, the cost-effecti veness of CT for
scr eeni ng r emai ns l ow, and no data as yet suggest that ear l y
detecti on wi th CT l eads to i mpr oved sur vi val . Pl anni ng of sur gi cal
i nter venti ons, however, shoul d be based on CT fi ndi ngs, even
though CT scanni ng sti l l mi sses appr oxi matel y 30% to 50% of the
nodul es found at sur ger y.
When mul ti pl e pul monar y nodul es ar e pr esent i n pati ents wi th a
known pr evi ous mal i gnancy, the l i kel i hood of metastati c di sease
appr oaches 100% . New sol i tar y l esi ons, however, can r epr esent
pr i mar y l ung cancer s because many of the r i sk factor s ar e si mi l ar.
Staging
No val i d stagi ng system exi sts for pul monar y metastases. The
Inter nati onal Regi str y of Lung Metastases has i denti fi ed thr ee
parameter s of pr ognosti c si gni fi cance: r esectabi l i ty, di sease-fr ee
i nter val , and number of metastases. The pr esent cr i ter i a for
r esectabi l i ty i ncl ude r esectabl e pul monar y nodul es, contr ol of the
pr i mar y tumor, adequate pr edi cted postoperati ve pul monar y
r eser ve, and no extrathoraci c metastases. Pati ents who meet these
cr i ter i a shoul d be offer ed metastasectomy. Favorabl e hi stol ogi es for
l ong-ter m sur vi val fol l owi ng r esecti on i ncl ude sar coma, br east,
col on, and geni tour i nar y metastases. Unfavorabl e hi stol ogi es
i ncl ude mel anomas, esophageal , pancr eati c, and gastr i c cancer s.
Treatment
Surgery
Pr eoperati ve eval uati on for r esecti on of pul monar y metastases i s
si mi l ar to that of any other pul monar y r esecti on. Because of the
i ncr eased r i sk of r ecur r ent metastases and need for futur e
thoracotomi es, par enchyma-conser vi ng pr ocedur es ar e per for med
whenever possi bl e (wedge r esecti on, l aser, or cauter y exci si on). The
var i ous sur gi cal appr oaches i ncl ude the fol l owi ng.
Median ster notomy al l ows bi l ateral expl orati on wi th one i nci si on.
Lesi ons l ocated near the hi l um can be di ffi cul t to r each, and
exposur e of the l eft l ower l obeespeci al l y i n pati ents wi th obesi ty,
car di omegal y, or an el evated l eft hemi di aphragmi s poor.
Bilater al anter othor acoster notomy (cl amshel l pr ocedur e) al l ows
excel l ent exposur e of both hemi thoraces, i ncl udi ng the l eft l ower
l obe, al though some sur geons thi nk the i nci si on i ncr eases
postoperati ve pai n.
Poster olater al thor acotomy i s a mor e common i nci si on for access to
the l ung. The l i mi tati on to one hemi thorax, however, necessi tates a
second staged operati on for r emovi ng bi l ateral metastases.
Thoracoscopi c r esecti on al l ows vi sual i z ati on of both hemi thoraces
dur i ng the same anestheti c. Pl eural -based l esi ons ar e ther efor e
easi l y vi sual i zed and exci sed. Unfor tunatel y, the abi l i ty to car eful l y
eval uate the par enchyma for deeper or smal l er nonvi sual i zed
l esi ons i s poor, and some r epor ts suggest an i ncr eased r i sk of l ocal
r ecur r ence wi th thoracoscopy.
At sur ger y, wedge r esecti ons wi th a 1-cm mar gi n ar e pr efer r ed. If
mul ti pl e nodul es wi thi n one segment, l obe, or l ung pr ecl ude
r esecti on of mul ti pl e wedges, then l aser r esecti ons can be
per for med.
Adjuvant Therapy
The r ol e of radi ati on therapy i n the tr eatment of pul monar y
metastases i s l i mi ted to the pal l i ati on of symptoms of advanced
l esi ons wi th extensi ve pl eural , bony, or neural i nvol vement. The

val ue of chemotherapy pr eoperati vel y or postoperati vel y r emai ns
contr over si al . Ther e ar e many i sol ated r epor ts of the benefi t of
chemotherapy, especi al l y when the pr i mar y tumor i s sensi ti ve (e.g.,
osteosar coma, teratoma, other ger m cel l tumor s). However,
i mpr ovements i n sur vi val ar e mor e di ffi cul t to achi eve when the
pr i mar y i s of other types.
Surveillance
The fr equency and i ntensi ty of fol l ow-up after r esecti on ar e
deter mi ned by the pr i mar y tumor but usual l y i nvol ve annual or
bi annual CT scans.
Neoplasms of the Mediastinum

The medi asti nal compar tment can har bor numer ous l esi ons of
congeni tal , i nfecti ous, devel opmental , traumati c, or neopl asti c
or i gi n. Ear l i er r ecommendati ons advocated a di r ect sur gi cal
appr oach to al l medi asti nal tumor s, wi th bi opsy or debul ki ng of
unr esectabl e l esi ons. However, r ecent advances i n i magi ng and
noni nvasi ve di agnosti c techni ques, as wel l as i mpr ovements i n
chemotherapy and radi ati on therapy, have l ed to a mor e
conser vati ve appr oach, wi th management deci si ons based on better
pr eoperati ve eval uati on.
Table 7.3. Overall incidence of mediastinal

tumors
Thymic
19 (3)a
Neurogenic
23 (39)a
Lymphoma
12
Germ cell
12
Cysts
18
Mesenchymal
Miscellaneous
a Numbers
in parentheses represent incidence

in children.
Pathology
A r ecent study combi ni ng ni ne pr evi ous ser i es was per for med to
better appr oxi mate the tr ue i nci dence of medi asti nal l esi ons (Tabl e
7.3). In adul ts, neur ogeni c and thymi c tumor s contr i bute 23% and
19% , r especti vel y, to the overal l i nci dence, wher eas i n chi l dr en
they contr i bute 39% and 3% , r especti vel y. Thi s secti on does not
attempt to descr i be the myr i ad cysti c and other rar e mi scel l aneous
l esi ons but i nstead concentrates on the mor e common di agnoses.
Neur ogenic tumor s i ncl ude schwannoma, neur ofi br oma,
gangl i oneur obl astoma, neur obl astoma, pheochr omocytoma, and
paragangl i oma. They ar e the most common tumor s ar i si ng i n the
poster i or compar tment.
Thymoma ar i ses fr om thymi c epi thel i um, al though i ts mi cr oscopi c
appearance i s a mi xtur e of l ymphocytes and epi thel i al cel l s.
Thymomas ar e cl assi fi ed as l ymphocyti c (30% of cases), epi thel i al
(16% ), mi xed (30% ), and spi ndl e cel l (24% ). Hi stol ogi c evi dence of
mal i gnancy i s di ffi cul t to obtai n because beni gn and mal i gnant
l esi ons can have si mi l ar hi stol ogi c and cytol ogi c featur es. Sur gi cal
evi dence of i nvasi on at the ti me of r esecti on i s the most r el i abl e
method of di ffer enti ati ng between mal i gnant and beni gn thymomas.
Lymphomas compr i se appr oxi matel y 50% of chi l dhood and 20% of
adul t anter i or medi asti nal mal i gnanci es. They ar e tr eated
nonsur gi cal l y but may r equi r e sur ger y to secur e a di agnosi s.
G er m cell tumor s ar e compr i sed of teratomas, semi nomas, and
nonsemi nomatous ger m cel l tumor s. Teratomas ar e the most
common and ar e mostl y beni gn. Mal i gnant teratomas ar e ver y rar e
and often wi del y metastati c at the ti me of di agnosi s. Semi nomas
pr ogr ess i n a l ocal l y aggr essi ve fashi on. Nonsemi nomatous

mal i gnant tumor s i ncl ude embr yonal car ci noma and
chor i ocar ci noma, both of whi ch car r y a poor pr ognosi s, and the
mor e favorabl e endoder mal si nus tumor.
Miscellaneous cysts and mesenchymal tumor s i ncl ude thyr oi d
goi ter s, thyr oi d mal i gnanci es, medi asti nal parathyr oi d
adenomas, br onchogeni c cysts, per i car di al cysts, dupl i cati ons,
di ver ti cul a, and aneur ysms.
Diagnosis
Medi asti nal l esi ons ar e most commonl y asymptomati c. When
symptoms do occur, they r esul t fr om compr essi on of adjacent
str uctur es or systemi c endocr i ne or autoi mmune effects of the
tumor s. Chi l dr en, wi th thei r smal l er chest cavi ti es, tend to have
symptoms at pr esentati on (two-thi r ds of chi l dr en vs. onl y one-thi r d
of adul ts) and mor e commonl y have mal i gnant l esi ons (gr eater than
50% ). Symptoms can i ncl ude cough, str i dor, and dyspnea (mor e
common i n chi l dr en), as wel l as symptoms of l ocal i nvasi on such as
chest pai n, pl eural effusi on, hoar seness, Homer syndr ome, upperextr emi ty and back pai n, parapl egi a, and di aphragmati c paral ysi s.
Chest radi ography r emai ns a mai nstay of di agnosi s. F i fty per cent of
l esi ons ar e di agnosed by CXR. The posi ti on of the tumor wi thi n the
medi asti num on l ateral pr ojecti on can hel p tai l or the di ffer enti al
di agnosi s (F i g. 7-5, Tabl e 7.4). The standar d for fur ther assessment
of the l esi on i s CT, speci fi cal l y wi th contrast enhancement. Cer tai n
tumor s and beni gn condi ti ons can be
di agnosed or str ongl y suggested by thei r appearance on CT scans.
Angi ography or MRI may be r equi r ed i f a major r esecti ve pr ocedur e
i s pl anned and vascul ar i nvol vement suspected. Nucl ear i magi ng
such as thyr oi d and parathyr oi d scanni ng, gal l i um scanni ng for
l ymphoma, and metai odobenz yl guani di ne scanni ng for
pheochr omocytomas may al so be i ndi cated.
F i gur e 7.5. Anatomi cal boundar i es of medi asti nal masses

accor di ng to one commonl y used cl assi fi cati on.
Table 7.4. Usual location of common primary

and cysts of mediastinum
Anterior
Compartment
Visceral
Compartment
Paravertebr
Thymoma
Enterogenous cyst
Neurilemoma
(schwannoma
Germ cell
tumors
Lymphoma
Neurofibroma
Lymphoma
Pleuropericardial
cyst
Malignant
schwannoma
Lymphangioma
Mediastinal
granuloma
Ganglioneuro
Hemangioma
Lymphoid
hamartoma
Ganglioneuro
Lipoma
Mesothelial cyst
Neuroblastom
Fibroma
Neuroenteric cyst
Paragangliom
Fibrosarcoma
Paraganglioma
Pheochromoc
Thymic cyst
Pheochromocytoma
Fibrosarcoma
Parathyroid
adenoma
Thoracic duct cyst
Lymphoma
Aberrant thyroid
The use of ser um mar ker s can be of some assi stance i n the
di agnosi s of some ger m cel l and neur oendocr i ne tumor s. In addi ti on,
the associ ati on of myastheni a gravi s wi th thymoma can al so assi st
i n the di agnosi s.
Because many medi asti nal tumor s ar e tr eated wi thout sur ger y, a
deter mi ned effor t shoul d be made to achi eve a ti ssue di agnosi s
noni nvasi vel y. F NA, wi th i ts r easonabl e sensi ti vi ty, i s an excel l ent
star ti ng poi nt, but the di agnosi s of l ymphoma can be di ffi cul t
because onl y a l i mi ted number of cel l s ar e r etr i eved. Br onchoscopy
and esophagoscopy can al so be useful i f symptoms or i magi ng
studi es suggest tumor i nvol vement.
If these pr ocedur es cannot faci l i tate a di agnosi s, then a
medi asti noscopy to access paratracheal l esi ons can be per for med.
Al though the r i sk of vascul ar or tracheobr onchi al i njur y i s pr esent,
the i nci dence of compl i cati ons i s ver y l ow i n exper i enced hands. If
mor e i nvasi ve pr ocedur es ar e r equi r ed to make the di agnosi s, an
anter i or or paraster nal medi asti notomy (Chamber l ai n pr ocedur e) or
thoracoscopy can be per for med. Rar el y, a ster notomy or
thoracotomy wi l l be r equi r ed to obtai n a ti ssue di agnosi s.
Staging
Stagi ng i s deter mi ned by the speci fi c hi stol ogi c character i sti cs and
i ts extent at the ti me of di agnosi s.
Treatment
Therapy, l i ke stagi ng, i s deter mi ned by the type of tumor and i ts
hi stol ogi c character i sti cs (Tabl e 7.5). The pr i mar y deter mi nati on to
be made i s whether the l esi on wi l l r equi r e r esecti on as par t of i ts
tr eatment or whether chemotherapy or radi ati on therapy i s
suffi ci ent. Thymomas shoul d al l be r esected, wi th the possi bi l i ty of
postoperati ve radi ati on therapy. Beni gn neur ogeni c tumor s ar e
someti mes obser ved i n ol der debi l i tated pati ents; however, i f the
pati ent i s other wi se heal thy or i f mal i gnant potenti al i s suspected,
then r esecti on shoul d be pur sued. G er m cel l tumor s shoul d be
tr eated on the basi s of thei r hi stol ogi c character i sti cs. In par ti cul ar,
beni gn teratomas shoul d be r esected, semi nomas shoul d be tr eated
wi th radi ati on therapy, and nonsemi nomatous tumor s shoul d be
tr eated i ni ti al l y wi th chemotherapy. In the subset of
nonsemi nomatous tumor s that have a r esi dual mass but negati ve
mar ker s, sur gi cal r esecti on shoul d be per for med to r ul e out r esi dual
tumor. Lymphomas shoul d not be r esected and shoul d be tr eated
wi th radi ati on therapy or chemotherapy on the basi s of thei r stage
and hi stol ogi c appearance (i .e., Hodgki n vs. non-Hodgki n).
Table 7.5. Frequency and treatment of

malignant chest wall tumors
Cell Type
Estimated
Frequency
Standard
Therapy
(%)
Chondrosarcoma
35
Surgical
resection
Plasmacytoma
25
Radiation +
chemotherapy
Ewing sarcoma
15
Surgery +
chemotherapy
Osteosarcoma
15
Surgery +
chemotherapy
Lymphoma
10
Chemotherapy
radiation
Surveillance
The fr equency and i ntensi ty of fol l ow-up after r esecti on ar e
deter mi ned by the pr i mar y tumor. CXR r emai ns the mai nstay of
sur vei l l ance, wi th CT scanni ng r eser ved for eval uati on subsequent
to abnor mal CXR fi ndi ngs.
Neoplasms of the Chest Wall

Pr i mar y chest wal l mal i gnanci es account for l ess than 1% of al l
tumor s, and i ncl ude a wi de var i ety of bone and soft-ti ssue l esi ons.
The absence of l ar ge ser i es makes the pr ospecti ve eval uati on of
tr eatment opti ons di ffi cul t. As mor e pati ents wi th these tumor s ar e
tr eated at l ar ge r efer ral i nsti tuti ons, the i ni ti ati on of mul ti i nsti tuti onal tr i al s wi l l hel p settl e some of the mor e contr over si al
aspects of therapy.
Pathology
Pr i mar y chest wal l tumor s i ncl ude chondr osar coma (20% ), Ewi ng
sar coma (8% 22% ), osteosar coma (10% ), pl asmacytoma

(10% 30% ), and, i nfr equentl y, soft-ti ssue sar coma.
Chondr osar comas ar i se fr om the r i bs i n 80% of cases and fr om the
ster num i n the r emai ni ng 20% . They ar e r el ated to pr i or chest wal l
trauma i n 12.5% of cases and ar e ver y r esi stant to radi ati on and
chemotherapeuti c agents. Ewi ng sar coma i s par t of a spectr um of
di sease havi ng pr i mi ti ve neur oectoder mal tumor s at one end and
Ewi ng sar coma at the other. Mul ti modal i ty therapy, i ncl udi ng both
radi ati on therapy and chemotherapy, has been shown to be
benefi ci al for thi s tumor. Osteosar comas ar e best tr eated wi th
neoadjuvant therapy, wi th pr ognosi s bei ng pr edi cted by the tumor 's
r esponse to chemotherapy. Pl asmacytoma confi ned to the chest
must be confi r med by eval uati ng the r emai ni ng skel etal system.
Sur ger y can then be used to confi r m the di agnosi s. If radi ati on
therapy i s unabl e to achi eve l ocal contr ol , then r esecti on may be
i ndi cated. Soft-ti ssue sar comas ar e rar e and ar e pr i mar i l y r esected.
Adjuvant therapy i s based on tumor hi stol ogi c fi ndi ngs.
Diagnosis
Chest wal l tumor s ar e asymptomati c i n 20% of pati ents, wher eas
the r emai ni ng 80% have an enl ar gi ng mass. F i fty per cent to 60% of
these pati ents wi l l have associ ated pai n. Radi ographi c assessment
usual l y i ncl udes CXR and CT; however, MRI i s bei ng used i nstead
wi th i ncr easi ng fr equency because of i ts abi l i ty to i mage i n mul ti pl e
pl anes wi th super i or anatomi cal di sti ncti on, whi ch can better r eveal
the extent of di sease than CT or pl ai n radi ography. Pathol ogi cal
di agnosi s i s made wi th F NA (64% accuracy) or cor e cutti ng bi opsy
(96% accuracy). Inci si onal bi opsi es shoul d be avoi ded i f possi bl e
because they may i nter fer e wi th subsequent sur gi cal tr eatment and
r econstr ucti on.
Staging
Chest wal l l esi ons ar e staged accor di ng to the pr i mar y tumor
i denti fi ed. Most pr ogr ess to pul monar y or hepati c metastases
wi thout l ymphati c i nvol vement.
Treatment
As outl i ned pr evi ousl y, the tr eatment of chest wal l l esi ons i s
deter mi ned by the di agnosi s. Most, wi th few excepti ons, r equi r e
r esecti on as par t of the tr eatment. Poster i or l esi ons r eachi ng deep
to the scapul a or that r equi r e r esecti on of l ess than two r i bs do not

r equi r e r econstr ucti on of the chest wal l . However, al l other l esi ons
r equi r e some for m of stabl e r econstr ucti ve techni que. A si mpl e
mesh cl osur e usi ng Mar l ex or Pr ol i ne mesh i s acceptabl e as l ong as
the mater i al i s secur ed i n posi ti on under tensi on. Some sur geons
bel i eve ther e i s a l oss of tensi l e str ength over ti me. A mor e r i gi d
pr osthesi s i s methyl methacr yl ate sandwi ched between two l ayer s of
Mar l ex mesh. Long-ter m ser oma for mati on pl agues al l types of
r epai r, par ti cul ar l y thi s l atter r epai r techni que.
If the chest wal l l esi on i nvol ves the over l yi ng muscl e or the ski n, a
l ar ge defect may be pr esent after r esecti on. Thi s may r equi r e a
muscl e fl ap for fi nal r econstr ucti on, especi al l y i f postoperati ve
radi ati on therapy i s consi der ed. Al though descr i pti on of the
techni ques avai l abl e i s beyond the scope of thi s manual , a
combi nati on of muscl e fl ap wi th pr i mar y ski n cl osur e, muscl e
fl ap wi th ski n grafti ng, or myocutaneous fl ap coverage can be used.
Surveillance
Once tr eated and i n r emi ssi on, chest wal l tumor s tend to r ecur
l ocal l y or wi th pul monar y or hepati c metastases. Regul ar fol l ow-up
wi th car eful exami nati on and CT scanni ng shoul d suffi ce to detect
al l si gni fi cant si tes of r ecur r ence.
Neoplasms of the Pleura

Ther e ar e two mai n types of pl eural neopl asms. The fi r st, mal i gnant
pl eural mesothel i oma, r emai ns an uncommon and hi ghl y l ethal
tumor wi th no adequate method of tr eatment. It behaves pr i mar i l y
as a l ocal l y aggr essi ve tumor wi th l ocal l y i nvasi ve fai l ur e after
therapy and onl y metastasi zes l ate i n i ts cour se. Its r el ati onshi p
wi th asbestos exposur e was suggested i n the 1940s and 1950s, and
cl ear l y establ i shed i n 1960. The second, a mor e l ocal i zed pl eural
tumor known as l ocal i zed fi br ous tumor of the pl eura, can al so
occur ; when mal i gnant, i t i s fr equentl y cl assi fi ed as a l ocal i zed
mesothel i oma.
Pathology
Local i zed mesothel i omas and mal i gnant l ocal i zed fi br ous tumor s of
the pl eura ar e ver y rar e. Ther e i s some contr over sy as to whether
these l esi ons ar e even mesothel i al at al l because no epi thel i al
component may be i denti fi abl e. Mor e commonl y, a beni gn l ocal i zed
fi br ous tumor of the pl eura i s found. However, di ffuse pl eural

mesothel i oma i s al ways a mal i gnant pr ocess. Ther e i s a 20-year
l atency for devel opment of thi s di sease after exposur e to asbestos.
A r ecent sur ge i n the i nci dence of thi s di sease r efl ects the
wi despr ead use of asbestos i n the 1940s and 1950s, and thi s sur ge
shoul d conti nue because mechani sms for l i mi ti ng occupati onal
asbestos exposur e wer e not i nsti tuted unti l the 1970s.
Mesothel i oma commonl y pr esents as an epi thel i al hi stol ogy and l ess
commonl y as a sar comatoi d or mi xed hi stol ogy. It can be har d to
di ffer enti ate thi s l esi on fr om metastati c adenocar ci noma.
Immunohi stochemi str y and el ectr on mi cr oscopy, however, have
ai ded i n establ i shi ng the di agnosi s.
Diagnosis
The pr esentati on of mesothel i oma i s often vague and nonspeci fi c,
wi th dyspnea and pai n common i n 90% of pati ents. Radi ographi c
di agnosi s i n the ear l y stage i s often di ffi cul t, wi th the fi ndi ngs
l i mi ted to a pl eural effusi on i n many cases. Even CT may fai l to
i denti fy any other abnor mal i ti es at thi s stage. The cl assi c fi ndi ng of
a thi ck, r estr i cti ve pl eural r i nd i s a l ate fi ndi ng. Thoracentesi s i s
di agnosti c i n 50% of pati ents, and pl eural bi opsy i s posi ti ve i n 33% .
If the di agnosi s r emai ns el usi ve, thoracoscopy i s di agnosti c i n 80%
of pati ents.
Staging
A stagi ng system for mesothel i oma has been pr oposed by Rusch and
the Inter nati onal Mesothel i oma Inter est G r oup (IMIG ) and i s shown
i n Tabl e 7.6.
Table 7.6. Staging of mesothelioma

T
TIa tumor limited to the ipsilateral
parietal, including mediastinal and
T1
diaphragmatic pleura
No involvement of the visceral pleura
Tib tumor involving the ipsilateral
parietal, including mediastinal and
diaphragmatic pleura
Scattered foci of tumor also involving
the visceral pleura
Tumor involving each of the ipsilateral
pleural surfaces (parietal, mediastinal,
diaphragmatic, and visceral pleura),
with at least one of the following
features:
T2
Involvement of diaphragmatic muscle

Confluent visceral pleural tumor
(including the fissures), or extension
of tumor from visceral pleura into
the underlying pulmonary
parenchyma
Describes locally advanced but
potentially resectable tumor
Tumor involving all ipsilateral pleural
surfaces (parietal, mediastinal,
diaphragmatic, and visceral pleura),
with at least one of the following
features:
T3
Involvement of the endothoracic

fascia
Extension into the mediastinal fat
Solitary, completely resectable focus

of tumor extending into the soft
tissues of the chest wall
Nontransmural involvement of the
pericardium
Describes locally advanced technically

unresectable tumor
Tumor involving all ipsilateral pleural
surfaces (parietal, mediastinal,
diaphragmatic, and visceral), with at
least one of the following features:
T4
Diffuse extension or multifocal

masses of tumor in the chest wall,
with or without associated rib
destruction
Direct transdiaphragmatic extension
of tumor to the peritoneum
Direct extension of tumor to the
contralateral pleura
Direct extension of tumor to one or
more mediastinal organs
Direct extension of tumor into the
spine
Tumor extending through to the
internal surface of the pericardium
with or without a pericardial
effusion, or tumor involving the
myocardium
Lymph nodes
NX

assessed
N0
No regional lymph node metastases
N1
Metastases in the ipsilateral

bronchopulmonary or hilar lymph nodes
N2
Metastases in the subcarinal or the

ipsilateral mediastinal lymph nodes,
including the ipsilateral internal
mammary nodes
N3
Metastases in the contralateral

mediastinal, contralateral internal
mammary, ipsilateral, or contralateral
supraclavicular lymph nodes
Metastases
MX
Presence of distant metastases cannot

be assessed
M0
M1
Distant metastasis present
Stage
Stage
I
I a T Ia N 0 M 0
I b T Ib N 0 M 0
Stage
II
T 2 N0 M 0
Stage
III
Any T3 M 0
Any N1 M 0
Any N2 M 0
Stage
IV
Any T4
Any N3
Any M1
Treatment
The tr eatment of mesothel i oma i s sti l l evol vi ng. Attempts at radi cal
r esecti ons, such as extrapl eural pneumonectomy, have l ed to some
i mpr ovements i n l ocal contr ol , but onl y l i mi ted i mpact on sur vi val at
the cost of a si gni fi cantl y i ncr eased operati ve r i sk. The addi ti on of
adjuvant radi otherapy can i ncr ease l ocal contr ol and the r emoval of
the enti r e l ung can faci l i tate i ts del i ver y. Unfor tunatel y, better l ocal
contr ol has l ed to an i ncr ease i n the number of pati ents who
succumb to systemi c di sease. The effecti veness of chemotherapy i s
l i mi ted, al though new agents may be on the hor i zon (i .e.,
Pemextr ed). By themsel ves, chemotherapy and radi ati on therapy
have had onl y l i mi ted effects, wi th l ess i mpact on pal l i ati on.
Surveillance
Mesothel i omas tend to r ecur l ocal l y. CT scans ar e r equi r ed to detect
r ecur r ences or fol l ow r esi dual di sease. Unfor tunatel y, tr eatment
opti ons ar e l i mi ted, but they do i ncl ude radi ati on therapy and
chemotherapy.
Recommended Reading
PET Scanning
Detter beck F C, Vansteenki ste JF, Mor r i s DE, Dooms CA, Khandani
AH, Soci nski MA. Seeki ng a home for a PET, par t 3: emer gi ng
appl i cati ons of posi tr on emi ssi on tomography i magi ng i n the
management of pati ents wi th l ung cancer. Chest
2004;126(5):16561666.
Erasmus JJ, Connol l y JE, McAdams HP, Roggl i VL. Sol i tar y
pul monar y nodul es: par t I. Mor phol ogi c eval uati on for
di ffer enti ati on of beni gn and mal i gnant l esi ons. Radiogr aphics
2000;20(1):4358.
Erasmus JJ, McAdams HP, Connol l y JE. Sol i tar y pul monar y
nodul es: par t II. Eval uati on of the i ndeter mi nate nodul e.
Radiogr aphics 2000;20(1):5966.
G onz al ez-Stawi nski G V, Lemai r e A, Mer chant F, et al . A
comparati ve anal ysi s of posi tr on emi ssi on tomography and
medi asti noscopy i n stagi ng non-smal l cel l l ung cancer. J Thor ac
Car diovasc Sur g 2003;126(6):19001905.
Reed CE, Har pol e DH, Posther KE, et al . Amer i can Col l ege of
Sur geons Oncol ogy G r oup Z0050 tr i al . Resul ts of the Amer i can
Col l ege of Sur geons Oncol ogy G r oup Z0050 tr i al : the uti l i ty of
posi tr on emi ssi on tomography i n stagi ng potenti al l y operabl e
non-smal l cel l l ung cancer. J Thor ac Car diovasc Sur g
2003;126(6):19431951.
Adjuvant Chemotherapy for Early-stage Lung

Cancer
The Inter nati onal Adjuvant Lung Cancer Tr i al Col l aborati ve
G r oup. Ci spl ati n-based adjuvant chemotherapy i n pati ents wi th
compl etel y r esected NSCLC. N Engl J Med 2004;350:351360.
Strauss G M, Her ndon J, Maddaus MA, et al . Randomi zed cl i ni cal
tr i al of adjuvant chemotherapy wi th pacl i taxel and car bopl ati n
fol l owi ng r esecti on i n stage IB non-smal l cel l l ung cancer
(NSCLC): r epor t of Cancer and Leukemi a G r oup B (CALG B)

Pr otocol 9633 [abstract 7019]. Pr oc Am Clin Oncol 2004;23:17b.
Wi nton TL, Li vi ngston R, Johnson D, et al . A pr ospecti ve
randomi zed tr i al of adjuvant vi nor el bi ne (VIN) and ci spl ati n (CIS)
i n compl etel y r esected stage Ib and II non-smal l cel l l ung cancer
(NSCLC) Inter gr oup JBR. 10 [abstract 7018]. Pr oc Am Clin Oncol
2004;23.
Additional References
Ander son BO, Bur t ME. Chest wal l neopl asms and thei r
management. Ann Thor ac Sur g 1994;58:1774.
Dar tevel l e PG . Extended operati ons for the tr eatment of l ung
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M.
Edition
> Ta ble o f C o nt e nt s > 8 - Es o pha ge a l C a rc ino m a
8
Esophageal Carcinoma
A lexander A . Parikh
A ra A . Vaporciyan
W ayne L. Hofstetter
Cancer of the esophagus i s uncommon, bel i eved to r epr esent
appr oxi matel y 1.5% of newl y di agnosed i nvasi ve mal i gnanci es i n
the Uni ted States; i t i s the ni nth most common mal i gnancy
wor l dwi de. It i s hi ghl y vi r ul ent, however, and causes 2% of al l
cancer-r el ated deaths. Sur gi cal r esecti on i s the mai nstay of therapy,
al though most cases ar e di agnosed at a l ate stage. Si nce the mi d1970s, the overal l 5-year sur vi val rate has i mpr oved fr om 3% to
onl y 15% . Recent tr eatment strategi es have i ncl uded mul ti modal i ty
appr oaches that combi ne sur ger y, radi ati on therapy, and
chemotherapy. These appr oaches have r esul ted i n 5-year sur vi val
rates of 40% to 75% i n the subset of pati ents who have a compl ete
hi stol ogi c r esponse after pr eoperati ve therapy.
Epidemiology
Car ci noma of the esophagus accounts for appr oxi matel y 15,000 new
cases and 13,000 deaths i n the Uni ted States each year. In the
past, squamous cel l car ci nomas (SCC) accounted for mor e than 95%
of cases, but i n r ecent year s, adenocar ci noma ar i si ng i n the
backgr ound of Bar r ett esophagus has become i ncr easi ngl y common,
and i t now accounts for mor e than 50% of the esophageal cancer s
at many major center s. Esophageal car ci noma, par ti cul ar l y SCC, has
substanti al geographi c var i ati on, fr om 1.5 to 7 cases per 100,000
peopl e i n most par ts of the wor l d, i ncl udi ng the Uni ted States, to
100 to 500 per 100,000 peopl e i n i ts endemi c ar eas such as
nor ther n Chi na, South Afr i ca, Iran, Russi a, and Indi a. Mal es have a
two to thr ee ti mes hi gher r i sk than femal es, and a seven to ten
ti mes hi gher r i sk for the devel opment of adenocar ci noma.

F ur ther mor e, i n the Uni ted States, SCC i s appr oxi matel y fi ve ti mes
mor e common among Afr i can Amer i cans than i t i s among whi tes,
wher eas adenocar ci noma occur s appr oxi matel y thr ee to four ti mes
mor e often i n whi tes, par ti cul ar l y i n men. The typi cal pati ent wi th
esophageal adenocar ci noma i s a mi ddl e-cl ass, over wei ght mal e i n
hi s si xti es or seventi es. Both major hi stol ogi c types ar e rar e i n
pati ents younger than 40 year s, but the i nci dence i ncr eases
ther eafter.
Etiology and Risk Factors

Several di ffer ent envi r onmental and geneti c r i sk factor s have been
i denti fi ed as potenti al causes of esophageal cancer s, par ti cul ar l y
SCC. In geographi c ar eas wher e esophageal cancer i s endemi c, such
as i n Chi na, di ets ar e defi ci ent i n vi tami ns A, C, r i bofl avi n, and
pr otei n, and have excessi ve ni trates and ni tr osami nes. F ungal
contami nati on of foodstuffs and the associ ated afl atoxi n pr oducti on
may be another i mpor tant r i sk factor.
The combi nati on of smoki ng and al cohol consumpti on has a
syner gi sti c effect on the devel opment of esophageal SCC,
i ncr easi ng the r i sk by as much as 44 ti mes. Other causes and r i sk
factor s i ncl ude SCC of the head and neck (pr esumabl y because of
the r i sk associ ated wi th al cohol and smoki ng), achal asi a (as hi gh as
30 ti mes i ncr eased r i sk), str i ctur es r esul ti ng fr om i ngesti on of
causti c agents such as l ye, Zenker di ver ti cul ae, esophageal webs i n
Pl ummer-Vi nson syndr ome, pr i or radi ati on, and fami l i al connecti ve
ti ssue di seases such as tyl osi s (50% have cancer by age 45 year s).
For adenocar ci noma, the pr i mar y eti ol ogi c factor i s Bar r ett
esophagus, wi th an esti mated annual i nci dence of mal i gnant
transfor mati on of 0.5% to 1% , r epr esenti ng a 125 ti mes gr eater
r i sk than that i n the general popul ati on. Si mi l ar to col on cancer s,
esophageal adenocar ci nomas ar e known to pr ogr ess thr ough a
metapl asi adyspl asi acancer sequence. G astr oesophageal r efl ux
di sease r esul ts i n the over exposur e of the esophageal mucosa to
aci d and bi l e. Speci fi cal l y, the conjugated bi l e sal ts (secondar y bi l e
aci ds) ar e bel i eved to syner gi sti cal l y damage the mucosa, l eadi ng to
i ncr eased DNA methyl ati on (as wel l as other geneti c and mol ecul ar
changes) and the for mati on of speci al i zed i ntesti nal metapl asi a
(Bar r ett mucosa) or car di ac metapl asi a. Both ar e r ecogni zed as
pr ecur sor l esi ons to esophageal /gastr oesophageal juncti on cancer s.
Obesi ty, tobacco use, and the eradi cati on of Helicobacter pylor i ar e
al so l i nked to the i ncr eased i nci dence of esophageal adenocar ci noma

i n the Uni ted States.
Pathology
Esophageal cancer i s seen i n two mai n hi stol ogi c types: SCC and
adenocar ci noma. In the Uni ted States, appr oxi matel y 20% of cases
of SCC i nvol ve the upper thi r d of the esophagus, 50% i nvol ve the
mi ddl e thi r d, and the r emai ni ng 30% extend fr om the di stal par t of
the esophagus to the gastr oesophageal juncti on. SCC rar el y i nvades
the stomach, and ther e i s usual l y a di scr ete segment of nor mal
mucosa between the cancer and the gastr i c car di a. In contrast,
near l y 97% of adenocar ci nomas devel op i n the mi ddl e and di stal
esophagus, and many extend i nto the stomach i f they ar e l ocated
near the gastr oesophageal juncti on. Cancer s ar i si ng i n Bar r ett
esophagus ar e bel i eved to compr i se upwar d of 70% of al l
adenocar ci nomas i nvol vi ng the di stal esophagus and
gastr oesophageal juncti on. They can var y i n l ength and range i n
contour fr om fl at, i nfi l trati ve l esi ons to fungati ng pol ypoi d masses.
Ul cerati on i s often pr esent and may even be deep enough to cause
per forati on. The typi cal esophageal car ci noma i s a ci r cumfer enti al ,
exophyti c, fungati ng mass that i s near l y or compl etel y transmural .
Access to the submucosal l ymphati cs al l ows tumor s to spr ead fr eel y
al ong a submucosal pl ane and pr esent wi th ver y l ong tumor s or
mul ti pl e mucosal l esi ons. Si mi l ar l y, ear l y metastases to l ymph
nodes or di stant si tes ar e common. Mi cr oscopi cal l y,
adenocar ci nomas can r esembl e cel l s i n the gastr i c car di a or col on,
and most ar e wel l or moderatel y di ffer enti ated. Si gnet r i ng
di ffer enti ati on on hi stol ogy may si gni fy a gastr i c car di a or i gi n, but
thi s i s not an absol ute r ul e.
Other l ess common pr i mar y mal i gnant neopl asms of the esophagus
i ncl ude neur oendocr i ne tumor s, gastr oi ntesti nal str omal tumor s,
var i ants of SCC or adenocar ci nomas (e.g., adenosquamous),
mel anomas, sar comas, and l ymphomas.
Clinical Features
Cl i ni cal pr esentati on i s general l y i nsi di ous, and typi cal symptoms
occur l ate i n the cour se of the di sease, usual l y pr ecl udi ng ear l y
i nter venti on. Most pati ents exper i ence symptoms for 2 to 6 months
befor e they seek medi cal attenti on. The most common symptom i s
pr ogr essi ve dysphagi a, whi ch occur s i n as many as 80% to 90% of
pati ents. Thi s i s usual l y a l ate si gn because 50% to 75% of the

esophageal l umen must be r educed befor e pati ents exper i ence thi s
symptom. Typi cal l y, mal i gnant dysphagi a wi l l begi n when the
esophageal functi onal di ameter appr oaches 12 to 13 mm, about the
si ze of a nor mal adul t endoscope. Wei ght l oss i s al so common, wi th
an esti mated mean wei ght l oss of 10 kg fr om the onset of symptoms
and wei ght l oss of gr eater than 10% of nor mal body wei ght has
been associ ated wi th decr eased l ong-ter m sur vi val i n many
publ i cati ons. Other symptoms i ncl ude var yi ng degr ees of
odynophagi a (i n appr oxi matel y 50% ), as wel l as emesi s, cough,
r egur gi tati on, anemi a, hematemesi s, and aspi rati on pneumoni a.
Hoar seness i s usual l y due to i nvasi on of the r ecur r ent l ar yngeal
ner ve, and Hor ner syndr ome i ndi cates i nvasi on of the sympatheti c
tr unk. Hematemesi s and mel ena usual l y i ndi cate fr i abi l i ty of the
tumor or i ts i nvasi on i nto major vessel s. Er osi on i nto the aor ta
r esul ti ng i n exsangui nati ng hemor r hage has been r epor ted.
Bl eedi ng fr om the tumor mass can occur i n 4% to 7% of pati ents.
Diagnostic Evaluation
Resul ts of the physi cal exami nati on depend i n l ar ge par t on the
degr ee of wei ght l oss and cachexi a. Enl ar ged cer vi cal or
supracl avi cul ar l ymph nodes can be bi opsi ed wi th fi ne-needl e
aspi rati on (F NA), and bone pai n shoul d be eval uated wi th a bone
scan to excl ude di stant metastases. Al l neur ol ogi c symptoms (e.g.,
headaches, vi sual di stur bances) shoul d al so be assessed wi th
computed tomography (CT) or magneti c r esonance i magi ng (MRI) of
the brai n.
Pl ai n poster oanter i or and l ateral chest radi ographs pr ovi de
assessment of the status of the pul monar y par enchyma (i .e.,
metastasi s, coexi sti ng br onchogeni c car ci noma, and pneumoni a). A
doubl e-contrast bar i um esophagogram pr ovi des i nfor mati on about
the l ocati on, l ength, and anatomi cal confi gurati on of the l esi on, as
wel l as an eval uati on of the stomach for evi dence of di sease or
abnor mal i ti es that woul d pr ecl ude i ts use as a condui t. The
esophagogram i s al so useful i n showi ng the degr ee of l umi nal
compr omi se or str i ctur e and the pr esence of a tumor-r el ated
tracheoesophageal fi stul a. CT scans of the chest and abdomen
shoul d al so be obtai ned to r ul e out the pr esence of l ocal i nvasi on of
medi asti nal str uctur es, adenopathy, and di stant metastasi s.
Posi tr on emi ssi on tomography (PET) i s bei ng used wi th i ncr easi ng
fr equency i n the di agnosti c stagi ng al gor i thm. When combi ned wi th
CT, i t has been shown to al ter the tr eatment cour se i n
appr oxi matel y 15% of pati ents studi ed, whi ch i n i tsel f has r ender ed
i t cost effi ci ent. Thi s modal i ty i s hel pful i n deter mi ni ng the
si gni fi cance of r egi onal adenopathy or di stant l esi ons and may car r y
pr ognosti c i nfor mati on i n ter ms of the l evel of i ni ti al nucl eoti de
uptake and mi dter m r esponse to pr eoperati ve tr eatment.
Upper endoscopy i s cur r entl y the most wi del y used techni que for the
di agnosi s of esophageal cancer. F l exi bl e endoscopy al l ows magni fi ed
vi sual obser vati on and hi stol ogi c sampl i ng of the esophagus, as wel l
as obser vati on of the stomach, pyl or us, and duodenum i n sear ch of
coexi sti ng di sease. Bi opsy and br ush cytol ogy can pr oduce
di agnosti c accuracy of near l y 100% wi th adequate sampl i ng, and
endoscopi c di l ati on of ti ght str i ctur es can be per for med to al l ow
passage of the endoscope beyond the tumor. The addi ti on of
endoscopi c ul trasound (EUS) can be used to pr edi ct the TNM stage
of the l esi on wi th r el i abl e accuracy. EUS i s most accurate i n
pr edi cti ng the depth of i nvasi on of the pr i mar y l esi on, and thi s can
l ead to ver y good i nsi ght to the potenti al of sur r oundi ng or gan
i nvol vement or l ymph node i nvol vement. Thoraci c, paraesophageal ,
paragastr i c, por tohepati c, and cel i ac l ymph nodes ar e r outi nel y
i denti fi ed and can be bi opsi ed vi a aspi rati on (F NA) for di agnosi s.
Tumor s that i nvol ve the upper or mi ddl e thi r d of the esophagus
shoul d be eval uated by fl exi bl e and/or r i gi d br onchoscopy to r ul e
out tracheobr onchi al i nvol vement.
Staging
The stagi ng system of the Amer i can Joi nt Commi ttee on Cancer uses
the TNM cl assi fi cati on and i s the most commonl y used system i n the
Uni ted States (Tabl e 8.1). Al though CT scanni ng i s pr obabl y the
most wi del y used noni nvasi ve stagi ng modal i ty, i ts accuracy i s qui te
l i mi ted. Overal l accuracy i n deter mi ni ng r esectabi l i ty and T stage
have been esti mated at 60% to 70% , wher eas accuracy i n
deter mi ni ng N stage i s general l y l ess than 60% . Accuracy i n
detecti on of metastati c di sease i s somewhat better, esti mated at
70% to 90% for l esi ons l ar ger than 1 cm. The use of combi ned
i magi ng wi th PET-CT has i mpr oved the accuracy of both tests. The
abi l i ty to combi ne anatomi cal i r r egul ar i ty to ar eas of abnor mal
F l our o-Deoxy G l ucose (F DG ) uptake on a super i mposed i mage
i ncr eases the pr edi cti ve val ue of PET al one or CT al one. Recent
studi es wi th thi s techni que have r epor ted overal l accuracy l evel s of
near l y 60% and 90% i n the abi l i ty to detect both l ocor egi onal nodal
metastases and di stant di sease, r especti vel y.
EUS i s pr obabl y the most accurate means cur r entl y avai l abl e for T
and N stagi ng. Repor ted overal l accuracy for T stagi ng i s 76% to
90% ; overal l accuracy i n pr edi cti ng r esectabi l i ty i s appr oxi matel y
90% to 100% for adenocar ci noma, but decr eases to 75% to 80% for
SCC. Studi es compar i ng EUS and CT scanni ng general l y agr ee that
EUS i s super i or i n overal l T stagi ng and assessment of r egi onal
l ymph nodes (70% 86% accuracy). The pr eci se di ffer enti ati on
between beni gn and mal i gnant nodes occasi onal l y r emai ns
pr obl emati c, however, due to mi cr ometastases that ar e undetectabl e
by EUS and enl ar ged i nfl ammator y l ymph nodes that ar e i ncor r ectl y
cl assi fi ed as metastati c. F NA can be hel pful i n maki ng thi s
di agnosi s. Mi ni mal l y i nvasi ve techni ques such as thoracoscopy and
l apar oscopy ar e i ncr easi ngl y i mpor tant i n the stagi ng of esophageal
cancer. Thoracoscopy al l ows vi sual i z ati on of the enti r e thoraci c
esophagus and the per i esophageal nodes (N1), when per for med
thr ough the r i ght hemi thorax, or the aor topul monar y and
per i esophageal nodes and the l ower esophagus, when per for med
thr ough the l eft chest. Lymph nodes can be
sampl ed for hi stol ogi c eval uati on, the pl eura can be exami ned, and
adjacent or gan i nvasi on (T4) can be confi r med. The overal l accuracy
for detecti ng l ymph node i nvol vement has been r epor ted to be as
hi gh as 81% to 95% . Lapar oscopy and l apar oscopi c ul trasonography
(LUS) ar e useful i n eval uati ng the per i toneum, l i ver, gastr ohepati c
l i gament, gastr i c wal l , di aphragm, and the per i gastr i c and cel i ac
l ymph nodes. Bi opsi es and per i toneal washi ngs can be per for med to
confi r m N1 and M1 di sease. These modal i ti es ar e especi al l y useful
i n pati ents wi th gastr oesophageal juncti on or pr oxi mal gastr i c
tumor s. In addi ti on, a feedi ng jejunostomy can be pl aced for
nutr i ti onal suppor t befor e tr eatment begi ns. Studi es have suggested
that the overal l accuracy of l apar oscopy i n stagi ng and
deter mi nati on of r esectabi l i ty i n esophageal cancer i s as hi gh as
90% to 100% , and that i nvasi ve stagi ng pr ocedur es may pr event
unnecessar y sur gi cal r esecti on i n as many as 20% of pati ents.
Pr ospecti ve compar i sons wi th CT and EUS have suggested that
l apar oscopy and LUS have super i or overal l accuracy i n stagi ng,
par ti cul ar l y for l ymph nodes and metastati c di sease.
Medi asti noscopy can al so pr ove hel pful to assess r egi onal l ymph
nodes (N1) at the r i ght and l eft paratracheal l ymph node stati ons,
al ong the mai nstem br onchi , i n the aor topul monar y wi ndow, or i n
the subcar i nal ar ea.
Table 8.1. TNM staging for esophageal

cancer
Primary tumor (T)
Tx
T0
Tis
Carcinoma in situ
T1
Tumor invades lamina propria or

submucosa
T2
Tumor invades muscularis propria
T3
Tumor invades adventitia
T4
Tumor invades adjacent structures

Nx
Regional nodes cannot be assessed
N0
No regional node metastasis
N1
Regional node metastasis
Mx
Presence of distant metastasis cannot

be assessed
M0
No distant metastases
Distant metastasis
Tumors of the lower thoracic
esophagus
M1a
nodes
M1b
Metastasis in celiac lymph
Other distant metastasis
Tumors of the midthoracic esophagus

M1
M1a
Not applicable
M1b Nonregional lymph nodes or

other distant metastasis
Tumors of the upper thoracic
esophagus
M1a
Metastasis in cervical nodes
M1b
Other distant metastasis
Stage grouping
Stage
0
Tis
N0
M0
T1
N0
M0
T2
N0
M0
T3
N0
M0
T1
N1
M0
T2
N1
M0
T3
N1
M0
T4
Any N
M0
Stage
IV
Any T
Any N
M1
Stage
IVA
Any T
Any N
M1a
Stage
IVB
Any T
Any N
M1b
Stage
I
Stage
IIA
Stage
IIB
Stage
III
Adapted from Fleming ID, Cooper JS, Henson

DE, et al., eds. AJCC Manual for Staging of
Cancer. 5th ed. Philadelphia, Pa: LippincottRaven; 1997, with permission.
Treatment
Pati ents shoul d be appr oached wi th the i ntent of per for mi ng a
sur gi cal r esecti on as i t affor ds the best chance for l ong-ter m
sur vi val (F i g. 8-1). Because accurate cl i ni cal stagi ng i s so di ffi cul t,
al l pati ents who can physi ol ogi cal l y tol erate r esecti on and have no
cl i ni cal l y evi dent di stant metastases shoul d general l y under go
expl orati on. If di stant metastases or unr esectabl e advanced
l ocor egi onal di sease i s found at expl orati on, nonoperati ve pal l i ati on
shoul d be under taken because of the hi gh per i operati ve mor tal i ty
rate (appr oxi matel y 20% ) associ ated wi th pal l i ati ve sur gi cal bypass.
Di stal esophageal tumor s l ocated at the gastr oesophageal juncti on
can be managed by subtotal esophagectomy, esophagogastr ectomy,
or segmental esophagectomy wi th bowel i nter posi ti on. The extent of
gastr i c and esophageal i nvol vement, as wel l as the stage of the
pr i mar y tumor, shoul d gui de the sur geon to an appr opr i ate
appr oach. A subtotal esophagectomy thr ough a r i ght thoracotomy
and l apar otomy (Ivor Lewi s or Tanner-Lewi s esophagectomy) al l ows
for gener ous r esecti on of the stomach because the esophageal
r econstr ucti on takes pl ace i n the chest at the l evel of the az ygous
vei n. Local l y advanced tumor s wi th i nvol vement of the di stal
esophagus and pr oxi mal stomach l end themsel ves to thi s appr oach
because a l ymphadenectomy i s easi l y per for med i n two fi el ds and
negati ve mar gi ns can be obtai ned i n the stomach wi th l ess wor r y of
gastr i c necr osi s. However, tumor s wi th extensi ve i nvol vement of the
stomach and esophagus may r equi r e an esophagogastr ectomy, wi th
i nter posi ti on of smal l or l ar ge bowel for r econstr ucti on. Ear l y di stal
tumor s or shor t segment Bar r ett esophagus wi th hi gh-grade
dyspl asi a can be tr eated wi th segmental esophagectomy and smal l
bowel i nter posi ti on (Mer endi no pr ocedur e) or vagal -spar i ng
esophagectomy wi th gastr i c or bowel i nter posi ti on.
F i gur e 8.1. Al gor i thm for tr eatment of esophageal cancer.
Pr oxi mal l y l ocated (e.g., upper and mi desophageal ) tumor s often

r equi r e a total esophagectomy because i t i s di ffi cul t to achi eve
negati ve mar gi ns wi th segmental or subtotal r esecti ons (e.g., Ivor
Lewi s esophagectomy). G i ven the pr opensi ty for esophageal cancer s
to spr ead i n the submucosal l ymphati c system, i t i s r ecommended
that a mi ni mum of a 5-cm mar gi n, and pr eferabl y a 10-cm mar gi n,
shoul d be taken on the esophagus. Thi s i s a cr i ti cal deci si on-maki ng
factor when for mul ati ng a tr eatment al gor i thm for an i ndi vi dual
pati ent. The two most popul ar methods to achi eve a total or neartotal esophagectomy di ffer accor di ng to whether thoracotomy i s
used for esophageal mobi l i z ati on. The esophagus can be mobi l i zed
usi ng a r i ght thoracotomy wi th the condui t br ought ei ther thr ough
the poster i or medi asti num (pr efer r ed) or subster nal l y to the neck
for anastomosi s (McKowen appr oach). Al ter nati vel y, a transhi atal
esophagectomy can be per for med wi th mobi l i z ati on of the
i ntrathoraci c esophagus fr om the esophageal hi atus to the thoraci c
i nl et wi thout the need for thoracotomy. The advantage of the
transhi atal techni que i s that i t avoi ds thoracotomy whi l e achi evi ng a
compl ete r emoval of the esophagus. The potenti al di sadvantages of
thi s techni que i ncl ude a l i mi ted per i esophageal and medi asti nal
l ymphadenectomy, the r i sk of causi ng tracheobr onchi al or vascul ar
i njur y dur i ng bl unt di ssecti on of the esophagus, and potenti al l y
hi gher l ocor egi onal r ecur r ence rates. In addi ti on, the use of a
cer vi cal anastomosi s i s associ ated wi th a hi gher rate of anastomoti c

l eakage than an
i ntrathoraci c anastomosi s (12% vs. 5% , r especti vel y), al though the
mor bi di ty i s much l ess wi th a cer vi cal l eak than i t i s wi th a thoraci c
l eak. Other potenti al downsi des to a cer vi cal anastomosi s i ncl ude
phar yngeal r efl ux, noctur nal aspi rati on, pr ol onged swal l owi ng
dysfuncti on after sur ger y, and an i ncr eased i nci dence of r ecur r ent
l ar yngeal ner ve pal sy. Intrathoraci c anastomoses ar e hamper ed by
r efl ux and a str i ki ng i nci dence of r ecur r ent esophageal metapl asi a,
whi ch has been r epor ted to occur i n 80% of l ong-ter m sur vi vor s.
Pati ents that pr esent wi th cer vi cal esophageal car ci nomas have
several tr eatment opti ons. Advances i n chemoradi otherapy have
r el egated r esecti on of most l ocal i zed cer vi cal l esi ons to sal vage
pr ocedur es. Pati ents that have per si stent l ocor egi onal , l i mi ted
di sease after defi ni ti ve medi cal therapy ar e candi dates for
segmental r esecti ons wi th i mmedi ate or del ayed r econstr ucti on.
Smal l bowel , neck, or muscul ocutaneous fr ee fl aps ar e wel l sui ted to
esophageal r econstr ucti ons i n the cer vi cal ar ea, wi th or wi thout
phar yngol ar yngectomy. An al ter nati ve opti on for pati ents wi th
ear l y-stage di sease i s i mmedi ate r esecti on and r econstr ucti on. At
the other end of the spectr um, l engthy l esi ons wi th i nvol vement
i nto the thoraci c esophagus may r equi r e a compl ete esophagectomy
vi a a thr ee-fi el d appr oach.
Al though i t i s general l y agr eed that sur gi cal r esecti on i s the
pr i mar y for m of therapy for l ocal and l ocor egi onal di sease, gr eat
contr over sy r emai ns over the extent of the r esecti on necessar y and
over the val ue and extent of l ymphadenectomy. Ther e i s one gr oup
of thought that l ymph node metastases ar e mar ker s for systemi c
di sease and that r emoval of i nvol ved nodes i n most cases offer s no
sur vi val benefi t. However, many wel l -r espected and exper i enced
sur geons bel i eve that some pati ents wi th affected l ymph nodes can
be successful l y cur ed wi th an aggr essi ve sur gi cal appr oach that
focuses on wi de per i tumoral exci si on and extended
l ymphadenectomy usi ng a transthoraci c/thoracoabdomi nal and
cer vi cal appr oach (en bl oc esophagectomy). Ther e i s cur r entl y no
defi ni ti ve evi dence to suppor t ei ther phi l osophy; however, many
r epor ts that have focused on speci fi c subsets of pati ents i n stages
IIb to III have shown that pati ents who have under gone compl ete
l ymphadenectomy and have l ess than 10% of thei r r esected nodes
i nvol ved wi th metastati c di sease can sti l l l ook for war d to pr ol onged
sur vi val and excel l ent l ocor egi onal contr ol . The downsi de to thi s
appr oach i s that we ar e cur r entl y unabl e to pr edi ct whi ch pati ents
wi th l ocal l y advanced di sease woul d benefi t fr om i mmedi ate
r esecti on and extensi ve l ymphadenectomy ver sus neoadjuvant
chemoradi otherapy fol l owed by r esecti on. Pr oponents of radi cal
r esecti on have r epor ted i ncr eased sur vi val rates wi th mor e
extensi ve sur gi cal pr ocedur es and excel l ent l ocor egi onal contr ol ,
but most of these compar i sons have been r etr ospecti ve.
F ur ther mor e, i t i s uncl ear whether mor e extensi ve di ssecti on
actual l y l eads to i mpr oved sur vi val or whether these super i or
r esul ts ar e a functi on of mor e accurate stagi ng (stage mi grati on
effect). Recent pr ospecti ve randomi zed studi es i n the Uni ted States
and Wester n Eur ope have fai l ed to show any si gni fi cant di ffer ence i n
mor bi di ty, mor tal i ty, or r ecur r ence rates, or i n the overal l sur vi val
rate when compar i ng transhi atal esophagectomy wi th transthoraci c
or total thoraci c esophagectomy or when compar i ng the number of
l ymph
nodes r esected. Ei ther techni que i s acceptabl e, and i t i s unl i kel y
that a pr ospecti ve randomi zed tr i al wi l l ever be per for med that
coul d concl usi vel y pr ove an advantage i n overal l sur vi val rate wi th
a par ti cul ar type of sur ger y. The choi ce among sur gi cal r esecti on
techni ques shoul d be l eft to the pr efer ence of the sur geon and
i ndi vi dual i zed to the par ti cul ar character i sti cs of the pati ent. The
sal i ent poi nts that emer ge fr om hi stor i cal compar i sons of these
pr ocedur es i s that a transhi atal r esecti on has a tendency towar d
hi gher l ocor egi onal r ecur r ence, but a l ower i nci dence of ICU car e,
and does not r equi r e thoracotomy to compl ete.
Mi ni mal l y i nvasi ve esophagectomy i s gai ni ng popul ar i ty i n some
hi gh-vol ume center s. Pati ents wi th appr opr i ate l esi ons have the
opti on of under goi ng esophageal r esecti on wi th combi ned
thoracoscopi c and l apar oscopi c r esecti on fol l owed by a smal l neck
i nci si on wi th an esophagogastr i c anastomosi s per for med i n the neck.
Compl ete l apar oscopi c (transhi atal ) r esecti ons can al so be
accompl i shed, but agai n, thi s appr oach makes extensi ve en bl oc
r esecti on of medi asti nal l ymph nodes di ffi cul t. Ear l y r esul ts on
several hundr ed pati ents r esected i n thi s manner show no di ffer ence
i n sur vi val , and a for mal phase I/II tr i al i s cur r entl y under way.
Di sadvantages of thi s modal i ty i ncl ude a fai r l y steep l ear ni ng cur ve,
especi al l y for sur geons wi th l i mi ted l apar oscopi c esophageal
exper i ence, and pr ol onged anestheti c ti mes (al though ver y
exper i enced sur geons can effecti vel y r esect the esophagus i n a
si mi l ar amount of ti me as open pr ocedur es).
Reconstruction After Resection

The stomach, col on, and jejunum have al l been successful l y used as
r epl acement condui ts after esophagectomy. The stomach i s used far
mor e fr equentl y because of the ease of mobi l i z ati on, a hear ty and
r edundant bl ood suppl y, l i mi ted per i operati ve mor bi di ty, and the
need to per for m onl y one anastomosi s.
The col on i s a commonl y used al ter nati ve r epl acement condui t.
However, some sur geons pr efer thi s condui t over the stomach i n
younger pati ents who ar e expected to have a pr ol onged sur vi val
because i t pr ovi des a bar r i er between the stomach r emnant and the
r esi dual esophagus, and thi s may pr event si gni fi cant phar yngeal
r efl ux and futur e esophageal metapl asi a or dyspl asi a wi thi n the
esophageal r emnant. Ei ther the r i ght col on or the l eft col on can be
used, but the segment of l eft and transver se col on that i s suppl i ed
by the ascendi ng branch of the l eft col i c ar ter y, ar c of Ri ol an, and
the mar gi nal ar ter y i s general l y a better si ze match to the
esophagus and has mor e r el i abl e ar ter i al ar cades. The col oni c
ar ter i al anatomy shoul d be eval uated pr eoperati vel y by
ar ter i ography i n any pati ent who i s expected to have extensi ve
l i mi ti ng ather oscl er osi s or i s suspected to have had a pr evi ous
bowel r esecti on. Other wi se, i n pati ents wi th a na ve abdomen,
eval uati on of the vascul atur e can take pl ace i n the operati ng
theater. Another al ter nati ve i s CT or MR angi ography. Col onoscopy
i s necessar y to r ul e out pathol ogi cal condi ti ons, such as
tel angi ectasi a, pol yposi s, synchr onous neopl asm, or extensi ve
di ver ti cul osi s, that woul d pr ecl ude use of the col on.
Jejunal r econstr ucti on can be per for med for l esi ons anywher e i n the
esophagus. Segmental jejunal fr ee fl aps transfer r ed to the
neck have been used successful l y after r esecti on of hypophar yngeal
or upper cer vi cal esophageal tumor s. In thi s case, the mesenter i c
vessel s ar e usual l y anastomosed to the exter nal car oti d ar ter y and
the i nter nal jugul ar vei n. Pedi cl ed grafts ar e bei ng used when
segmental di stal esophageal r esecti on i s per for med for beni gn
l esi ons r equi r i ng r esecti on or confi r med (no evi dence of cancer i n
the speci men) shor t segment Bar r ett esophagus wi th hi gh-grade
dyspl asi a. Pedi cl ed jejunal fl aps wi th pr oxi mal mi cr ovascul ar
augmentati on wi l l al l ow for total esophageal r epl acement wi th the
smal l bowel .
F i nal l y, muscul ocutaneous fl aps ar e al so fr equentl y used for
segmental cer vi cal r econstr ucti on and can be har vested fr om any of
mul ti pl e ar eas wi th mi ni mal physi ol ogi cal or aestheti c effect.

Few pr ospecti ve studi es have been per for med to eval uate the use of
di ffer ent r epl acement condui ts, but evi dence fr om several
nonrandomi zed and smal l randomi zed tr i al s suppor ts that overal l
sur vi val i s unchanged r egar dl ess of the techni que used. Revi ew
per for med by Ur schel et al . was unabl e to r each defi ni ti ve r esul ts
that woul d cause one techni que to be favor ed over another. The
basi c pr i nci pl es ar e that the stomach has the most r el i abl e bl ood
suppl y, i s a hear ty condui t, and i s associ ated wi th the l owest
i mmedi ate postoperati ve mor bi di ty. Cer vi cal l eaks fr om a col on
i nter posi ti on tend to be wel l tol erated and str i ctur e rar el y occur s. If
str i ctur es do occur, they ar e mor e easi l y di l ated than those i n
esophagogastr i c anastomoses. G raft l oss can occur wi th any condui t
i n any posi ti on. Pyl or opl asty or pyl or omyotomy i s r equi r ed to avoi d
gastr i c stasi s secondar y to the di vi si on of the vagus ner ves dur i ng
esophagectomy. No di ffer ence has been seen i n the l eak rate or i n
the devel opment of str i ctur es between stapl ed and hand-sewn
anastomoses.
Results of Surgical Therapy

Mor tal i ty rates for transhi atal or transthoraci c esophagectomi es ar e
now l ess than 5% , and r eal i sti c mor bi di ty rates range fr om 35% to
65% . Overal l sur vi val rates after sur gi cal r esecti on cor r espond to
the stage of the di sease and var y fr om 5% to 50% . The 5-year
sur vi val rates have been r epor ted to be 60% to 90% for stage I,
30% to 60% for stage II, 5% to 30% for stage III, and 0% to 20%
for stage IV (F i g. 8-2). Unfor tunatel y, the vast major i ty (70% ) of
pati ents al r eady has stage III or IV di sease at di agnosi s.
When exami ni ng the patter n of fai l ur e after sur gi cal r esecti on, one
fi nds that most pati ents exper i ence ei ther di stant metastasi s or
both l ocor egi onal and di stant r ecur r ence, and a smal l per centage
exper i ence sol el y a r ecur r ence of l ocal i zed di sease. Novel tr eatment
modal i ti es focusi ng on the patter ns of fai l ur e need to be expl or ed to
i mpr ove on the r el ati vel y poor pr ognosi s affor ded by sur ger y al one
i n most pati ents wi th esophageal car ci noma.
Adjuvant Therapy
Resul ts of several randomi zed pr ospecti ve tr i al s on the use of
adjuvant radi ati on therapy (4556 G y) after r esecti on have been
publ i shed. Some studi es have shown the potenti al benefi t of
adjuvant radi otherapy i n speci fi c subsets of pati ents. Both those
under goi ng unpl anned yet noncurati ve (pal l i ati ve) esophagectomy
and those who ar e found to have stage III or hi gher di sease may
benefi t. Most woul d gi ve consi derati on for radi ati on therapy i n
pati ents wi th posi ti ve mar gi ns or R2 r esecti on as wel l , al though
ther e i s no sci enti fi c pr oof of benefi t. Tr eatment-r el ated toxi ci ty can
be sever e. Overal l , al though r educti ons i n l ocal r ecur r ences have
been noted and speci fi c subsets may benefi t, no si gni fi cant sur vi val
advantage has been found usi ng adjuvant radi otherapy for
esophageal car ci noma.
F i gur e 8.2. Sur vi val cur ves for pati ents wi th esophageal cancer.
Accor di ng to the r esul ts of pr ospecti ve randomi zed tr i al s,

postoperati ve combi nati on chemotherapy wi th var i ous agents,
i ncl udi ng 5-fl uor ouraci l (5-F U), ci spl ati n, mi tomyci n C, vi ndesi ne,
and pacl i taxel , al so has no pr oven r ol e i n the tr eatment of
compl etel y r esected l esi ons. F ur ther mor e, adjuvant chemotherapy i s
general l y poor l y tol erated, and many pati ents fai l to compl ete thei r
tr eatment r egi men. Thi s tr eatment modal i ty, ther efor e, i s not
r ecommended outsi de cl i ni cal tr i al setti ngs.
Adjuvant chemoradi otherapy may benefi t pati ents wi th esophageal
car ci noma. Thi s modal i ty has the advantage of better pati ent
sel ecti on because the pathol ogi cal stage wi l l gui de the deci si on to
pr oceed to therapy. Pati ents wi th a hi gh r i sk of r ecur r ence (stage
IIb and above) woul d be chosen to sel ecti vel y under go tr eatment.
Thi s may i ncr ease overal l sur vi val because the r esecti on rate
r emai ns hi gh (a fr equent cr i ti ci sm for neoadjuvant therapy i s that

overal l r esecti on rates dr op secondar y to tr eatment toxi ci ty), and
pati ents that ar e found to be ear l i er stage can avoi d the potenti al
toxi ci ty. In theor y, chemoradi otherapy may i ncr ease sur vi val by
decr easi ng both di stant and l ocal di sease. To date, ther e i s some
phase II evi dence that has shown pr omi si ng r esul ts, but compl i ance
wi th tr eatment has not been i deal and for mal pr ospecti ve,
randomi zed phase III tr i al s ar e needed befor e fi nal
r ecommendati ons can be made r egar di ng i ts effi cacy.
Neoadjuvant Therapy
Lar gel y because of the di ffi cul ty admi ni ster i ng adjuvant therapy to
postesophagectomy pati ents and the di sappoi nti ng r esul ts of tr i al s
wi th adjuvant chemotherapy or radi ati on monotherapy, r esear cher s
have tur ned thei r attenti on towar d the use of pr eoperati ve or
neoadjuvant therapy. Pr eoperati ve radi ati on therapy has been
i nvesti gated i n several pr ospecti ve randomi zed tr i al s, and the
r esul ts have been subjected to meta-anal ysi s. Despi te some i ni ti al
r esponse, the r esul ts of these tr i al s have shown mar gi nal overal l
benefi t i n ter ms of sur vi val rate. Pr eoperati ve radi ati on therapy
al one i s ther efor e not general l y r ecommended, even i n the face of
cl i ni cal tr i al s.
Al though r esul ts of phase II studi es of i nducti on chemotherapy had
been pr omi si ng, most of the subsequent pr ospecti ve randomi zed
tr i al s usi ng mul ti pl e di ffer ent agents and combi nati ons have fai l ed
to show any advantage i n r ecur r ence or sur vi val . Evi dence that
neoadjuvant chemotherapy was capabl e of si gni fi cant tumor
r esponse and even compl ete r esponses was r epor ted by mul ti pl e
author s. Compl ete r esponder s wer e al so found to have better
sur vi val rates than par ti al or nonr esponder s, and the R0 r esecti on
rate seemed to i mpr ove overal l . However, the net gai n i n sur vi val
was not si gni fi cantl y di ffer ent fr om contr ol s (sur ger y al one).
Conjectur e on the r easons for thi s ar e that nonr esponder s
fr equentl y far e wor se than contr ol s; the overal l r esecti on rate was
l ower i n pati ents under goi ng neoadjuvant therapy, ther eby
abol i shi ng any overal l benefi t; or ther e was a study desi gn fl aw,
possi bl y r epr esenti ng a -er r or. Unfor tunatel y, benefi ts seen i n
phase II tr i al s wer e mai nl y bel i eved to be secondar y to sel ecti on
bi as. In contrast, the l ar gest tr i al on i nducti on chemotherapy
i nvol vi ng mor e than 800 pati ents wi th esophageal car ci noma
(squamous and adeno) per for med i n Eur ope (MRC tr i al , 2002) di d
show a si gni fi cant sur vi val advantage over sur ger y al one. The fact
that the l ar gest U.S. i nter gr oup tr i al , however, fai l ed to fi nd any
advantage i n sur vi val rate wi th the same agents i n mor e than 400
pati ents l eaves the i ssue open for debate. At thi s poi nt, i nter est i n
chemotherapy as monotherapy neoadjuvant tr eatment has been
mostl y di ver ted to combi ned chemoradi otherapy.
Neoadjuvant chemoradi ati on therapy for esophageal car ci noma has
been shown to be feasi bl e and effecti ve. Phase II tr i al s have
r epor ted excel l ent overal l r esponse rates (compl ete r esponses i n
25% 35% ) and r el ati vel y decent compl i ance wi th therapy. Sur vi val
and l ocal contr ol compar e favorabl e to hi stor i cal contr ol s. However,
despi te the fact that ther e have been ei ght pr ospecti ve randomi zed
studi es, onl y one to date has shown a benefi t to thi s therapy over
sur ger y al one. Thi s study has been wi del y cr i ti ci zed, and the r esul ts
have not been r epeated i n any other randomi zed tr i al . Thi s tr i al ,
conducted at the Uni ver si ty of Dubl i n wi th 113 pati ents wi th
adenocar ci noma, eval uated neoadjuvant ci spl ati n pl us 5-F U and 40
G y of radi ati on wi th sur ger y al one. The i nvesti gator s r epor ted a
25% compl ete pathol ogi cal r esponse, as wel l as a si gni fi cant
i ncr ease i n medi an sur vi val (16 vs. 11 months) and 3-year sur vi val
rate (32% vs. 6% ) for the pati ents r ecei vi ng the neoadjuvant
tr eatment. Much of the debate over thi s study has focused on the
poor sur vi val i n the
sur ger y-onl y ar m of 6% at 3 year s, er rati c pr eoperati ve cl i ni cal
stagi ng, and questi ons of mi scal cul ati ons wi thi n the stati sti cs. The
seven other randomi zed tr i al s that have been per for med ar ound the
wor l d as mul ti -i nsti tuti onal and si ngl e i nsti tuti onal tr i al s have not
shown a si gni fi cant sur vi val advantage. The si gni fi cant contr i buti ons
of these wor ks, however, have i mpr oved our under standi ng of
esophageal cancer bi ol ogy. Locor egi onal r ecur r ence i s r epor ted to be
l ow after neoadjuvant chemoradi otherapy, and pati ents that have
had a compl ete r esponse far e ver y wel l . Pati ents who ar e
si gni fi cantl y downstaged (to N0 status) per for m equal to
pathol ogi cal l y si mi l ar l y staged pati ents who have under gone sur ger y
al one. Radi ati on to 50.4 G y i s equi val ent to hi gher doses of
radi ati on and i s wel l tol erated wi thout si gni fi cantl y i ncr easi ng
per i operati ve mor tal i ty (i n exper i enced center s).
Thr ee l ar ge meta-anal yses have been conducted on the use of
neoadjuvant chemoradi otherapy i n esophageal cancer. The tr end
towar d sur vi val advantage i n most of the smal l er tr i al s transl ated to
a si gni fi cant sur vi val advantage i n the thr ee publ i shed meta-
anal yses for tr eated pati ents. It i s pr obabl e that ther e i s an overal l
benefi t to chemoradi otherapy; however, a tr i al that woul d
adequatel y defi ne thi s woul d r equi r e appr oxi matel y 2,000 pati ents
and a decade or mor e to compl ete. F ur ther mor e, many cl i ni ci ans
have questi oned whether i ncl udi ng a sur ger y-onl y ar m i s
sci enti fi cal l y ethi cal for a tr i al thi s l ar ge and, ther efor e, ther e i s
doubt that thi s tr i al wi l l ever be per for med.
Definitive Radiation Therapy and

Chemoradiation Therapy
Al though sur gi cal r esecti on r emai ns the pr efer r ed therapy for
esophageal cancer, defi ni ti ve radi ati on therapy and chemoradi ati on
therapy have been used i n pati ents who ar e not candi dates for
sur gi cal r esecti on. Local contr ol rates ranged between 40% and
75% , and medi an and 2-year sur vi val rates ranged fr om 9 to 24
months and fr om 18% to 38% , r especti vel y. Several pr ospecti ve
randomi zed tr i al s have shown that defi ni ti ve chemoradi ati on
therapy i s super i or to radi ati on therapy al one i n the tr eatment of
esophageal cancer. Al though di r ect compar i sons agai nst sur gi cal
therapy (wi th or wi thout neoadjuvant therapy) have been attempted
i n the Uni ted States and Eur ope, both tr i al s have fai l ed to r ecr ui t
pati ents, l ar gel y because of physi ci ans r el uctance to accept a
nonsur gi cal appr oach i n pati ents who ar e operati ve candi dates. One
tr i al out of Eur ope that sought to eval uate the addi ti onal benefi t of
sur ger y after neoadjuvant chemoradi otherapy showed si gni fi cantl y
i mpr oved l ocor egi onal contr ol i n the sur ger y ar m compar ed wi th
chemoradi otherapy al one. At thi s ti me, ther efor e, defi ni ti ve
chemoradi ati on therapy shoul d be r eser ved for those pati ents who
ar e poor sur gi cal candi dates.
Other Therapeutic Modalities

In cer tai n par ts of the wor l d, par ti cul ar l y i n ar eas wher e esophageal
cancer i s endemi c, mass scr eeni ng and advances i n di agnosti c
techni ques have l ed to the detecti on of i ncr eased number s of
super fi ci al esophageal cancer s. Studi es fr om Japan and the Uni ted
States have suggested that for l esi ons confi ned to the epi thel i um
and l ami na pr opr i a, l ymphati c spr ead i s rar e. In some
of these pati ents, endoscopi c mucosal r esecti on i s a feasi bl e opti on,
al though exper i ence wi th thi s techni que i s sti l l l i mi ted. Abl ati on
therapy wi th Nd-YAG l aser or ar gon-beam coagul ati on ar e pr i mar i l y
used for pal l i ati on, but i n pati ents who ar e not candi dates for
sur ger y wi th super fi ci al cancer s and car ci noma i n si tu, these
methods can al so be useful . Al though exper i ence wi th these
techni ques i s l i mi ted, i nvesti gator s have r epor ted tumor-fr ee
sur vi val for several months after therapy, al though r ecur r ence rates
after about 1 year can be si gni fi cant. Si mi l ar l y, photodynami c
therapy has been used i n nonsur gi cal candi dates, and r esul ts of
pr el i mi nar y studi es i n pati ents wi th ear l y-stage tumor s have
suggested that tumor-fr ee sur vi val can l ast several months and that
compl ete r emi ssi on i s possi bl e i n some pati ents (at 2-year fol l owup). However, l ong-ter m studi es ar e sti l l needed.
Palliation for Unresectable Tumors

Common i ndi cati ons for pal l i ati on i n pati ents wi th advanced di sease
i ncl ude dysphagi a, pr esence of esophagor espi rator y fi stul a,
r ecur r ent bl eedi ng, and pr ol ongati on of sur vi val . Tumor debul ki ng
sur ger y has been per for med, and al though sur vi val durati on seems
somewhat i mpr oved r el ati ve to that i n pati ents who di d not under go
r esecti on, few randomi zed tr i al s have been per for med, and
mor bi di ty can be si gni fi cant. Other opti ons for pal l i ati on i ncl ude (a)
di l ati on, whi ch i s a safe and effecti ve method to r el i eve dysphagi a,
al though i t usual l y r equi r es mul ti pl e pr ocedur es; (b) stents, both
r i gi d and expandabl e, whi ch have become ver y popul ar i n r ecent
year s for r el i evi ng dysphagi a and for tr eati ng fi stul as and bl eedi ng;
(c) l aser therapy, whi ch has been effecti ve i n r el i evi ng dysphagi a
fr om shor ter str i ctur es and those wi th i ntral umi nal rather than
i nfi l trati ve gr owth; (d) photodynami c therapy, whi ch r esul ts i n
fewer per forati ons than do di l ati ons or l aser therapy and i s
tol erated better but r equi r es mor e fr equent sessi ons; (e) bi pol ar
el ectr ocauter y and coagul ati on wi th tumor pr obes that use heat to
destr oy tumor cel l s and cause ci r cumfer enti al i njur y; and (f )
brachytherapy, whi ch del i ver s radi oacti ve seeds i ntral umi nal l y.
Al l of these techni ques have advantages and di sadvantages, and
shor t-ter m success rates of 80% to 100% have been r epor ted. If
these tr eatment opti ons fai l , an endoscopi c pr osthesi s can often be
pl aced wi th good r esul ts. These techni ques ar e not wi thout
compl i cati ons, however, and ul cerati on, obstr ucti on, di sl ocati on, and
aspi rati on have al l been r epor ted. Recentl y, i mpr ovements i n
defi ni ti ve radi ati on therapy and chemotherapy have al so pr ovi ded
excel l ent means for shor t-ter m pal l i ati on. Wi th nonoperati ve
tr eatment, however, l ong-ter m l ocal contr ol i s sti l l poor (40%
l ocor egi onal fai l ur e). Whi ch method to use ther efor e depends on the
exper i ence of the physi ci an and the par ti cul ar needs and condi ti on
of the pati ent.
Surveillance
A bar i um swal l ow study shoul d be obtai ned i n the fi r st pr eoperati ve
month as a basel i ne study. Asymptomati c pati ents can be assessed
wi th year l y physi cal exami nati ons and chest radi ography. Any
symptoms (e.g., pai n, dysphagi a, wei ght l oss) shoul d be eval uated
aggr essi vel y wi th CT scanni ng, bar i um studi es, or
endoscopy. Beni gn str i ctur es at the anastomosi s shoul d be tr eated
wi th di l ati on. Unfor tunatel y, tr eatment opti ons ar e l i mi ted for
l ocor egi onal or di stant r ecur r ences. If radi ati on therapy was not
gi ven pr eoperati vel y or postoperati vel y, i t can be used al ong wi th
the pr evi ousl y menti oned nonoperati ve methods of pal l i ati on (i .e.,
di l ati on, stenti ng, l aser, photodynami c, or ther mal r esecti on).
Recommended Reading
Ajani JA. Cur r ent status of new dr ugs and mul ti di sci pl i nar y
appr oaches i n pati ents wi th car ci noma of the esophagus. Chest
1998;113(suppl 1):112S.
Aki yama H, Tsur umar u M, Udagawa H, et al . Esophageal cancer.
Cur r Pr obl Sur g 1997;34:767.
Bosset JF, G i gnoux M, Tr i boul et JP, et al . Chemoradi otherapy
fol l owed by sur ger y compar ed wi th sur ger y al one i n squamouscel l cancer of the esophagus. N Engl J Med 1997;337:161.
G ol dmi nc M, Madder n G , LePr i se E, et al . Oesophagectomy by
transhi atal appr oach or thoracotomy: a pr ospecti ve randomi zed
contr ol l ed tr i al . Br J Sur g 1993;80:367.
G or e RM. Esophageal cancer : cl i ni cal and pathol ogi c featur es.
Radiol Clin Nor th Am 1997;35:243.
Her skovi c A, Mar tz K, Al -Sar raf M, et al . Combi ned chemotherapy
and radi otherapy compar ed wi th radi otherapy al one i n pati ents
wi th cancer of the esophagus. N Engl J Med 1992;326:1593.
Kel sen DP, G i nsber g R, Pajak TF, et al . Chemotherapy fol l owed by

sur ger y compar ed wi th sur ger y al one for l ocal i zed esophageal
cancer. N Engl J Med 1998;339:1979.
Kol h P, Honor e P, Degauque C, et al . Ear l y stage r esul ts after
oesophageal r esecti on for mal i gnancy-col on i nter posi ti on ver sus
gastr i c pul l -up. Eur J Car diothor ac Sur g 2000;18:293300.
Knyr i m K, Wagner HJ, Bethge N, et al . A contr ol l ed tr i al of an
expansi l e metal stent for pal l i ati on of esophageal obstr ucti on due
to i noperabl e cancer. N Engl J Med 1993;329:1302.
Or r i nger MB, Mar shal l B, Iannettoni MD. Transhi atal
esophagectomy: cl i ni cal exper i ence and r efi nements. Ann Sur g
1999;230:392.
Roth JA, Pass HI, F l anagan MM, et al . Randomi zed cl i ni cal tr i al of
pr eoperati ve and postoperati ve adjuvant chemotherapy wi th
ci spl ati n, vi ndesi ne and bl eomyci n for car ci noma of the
esophagus. J Thor ac Car diovasc Sur g 1988;96:242.
Swi sher SG , Hol mes EC, Hunt KK, et al . The r ol e of neoadjuvant
therapy i n sur gi cal l y r esectabl e esophageal cancer. Ar ch Sur g
1996;131:819.
Swi sher SG , Hunt KK, Hol mes EC, et al . Changes i n the sur gi cal
management of esophageal cancer fr om 1970 to 1993. Am J Sur g
1995;169:609.
Ur ba SG , Or r i nger MB, Tur r i si A, et al . Randomi zed tr i al of
pr eoperati ve chemoradi ati on ver sus sur ger y al one i n pati ents
wi th l ocor egi onal esophageal car ci noma. J Clin Oncol
2001;19:305.
Ur schel JD. Does the i nter ponat affect outcome after
esophagectomy for cancer ? Dis Esophagus 2001;14(2):124130.
Wal sh TN, Noonan N, Hol l ywood D, et al . A compar i son of
mul ti modal therapy and sur ger y for esophageal adenocar ci noma.
N Engl J Med 1996;335:462.

M.
Edition
> Ta ble o f C o nt e nt s > 9 - G a s t ric C a nc e r
9
Gastric Cancer
W addah B. A l-Refaie
Eddie K. A bdalla
Syed A . A hmad
Paul F. Mansfield
Introduction
Because 95% of gastr i c cancer s ar e adenocar ci nomas, they ar e the
pr i mar y focus of thi s chapter on gastr i c cancer. As wi th other
cancer s, evol uti on i n the eval uati on and tr eatment of gastr i c
adenocar ci noma si nce the mi d-1990s has l ed to a shi ft i n the
management of thi s di sease. Now, l apar oscopy i s an essenti al
component of pr etr eatment stagi ng for r esectabl e gastr i c
adenocar ci noma. The Amer i can Joi nt Commi ttee on Cancer (AJCC)
stagi ng system has been al ter ed to consi der the number rather than
the l ocati on of nodes i nvol ved by metastati c tumor, whi ch has been
shown to yi el d a mor e accurate pr ognosi s i n pati ents wi th thi s
di sease. F i nal l y, evi dence that the combi nati on of chemoradi ati on
therapy and potenti al l y curati ve sur gi cal r esecti on i ncr eases
di sease-fr ee and overal l sur vi val durati on has l ed many
i nvesti gator s to r ecommend mul ti modal i ty tr eatment i n pati ents
wi th advanced r esectabl e gastr i c adenocar ci nomas. Thi s chapter
cover s the epi demi ol ogy, pr eoperati ve eval uati on, and sur gi cal and
adjuvant tr eatment of gastr i c cancer, as wel l as management of
advanced di sease. Less common tumor s such as gastr i c l ymphoma,
gastr i c car ci noi ds, and gastr oi ntesti nal str omal tumor s (G ISTs) of
the stomach ar e al so br i efl y di scussed.
Epidemiology
In the Uni ted States i n 2005, 21,860 new cases of adenocar ci noma
of the stomach and 11,550 deaths due to thi s di sease wer e

expected, whi ch woul d make gastr i c cancer the 14th most common
cancer and the 8th l eadi ng cause of cancer death i n the Uni ted
States. Ther e has been a decl i ne i n i ts i nci dence si nce the 1930s,
when gastr i c adenocar ci noma was the most common mal i gnancy i n
the countr y. Al though the r easons for the decr easi ng i nci dence ar e
suspected, they ar e not compl etel y cl ear. Nonethel ess, even though
the i nci dence of di stal gastr i c cancer i s decr easi ng i n the Uni ted
States, the i nci dence of pr oxi mal gastr i c tumor s conti nues to
i ncr ease. Cancer s of the gastr i c car di a cur r entl y account for near l y
50% of al l cases of gastr i c adenocar ci noma. Ther e ar e al so wi de
var i ati ons i n the i nci dence wor l dwi de: The appr oxi mate i nci dence of
gastr i c car ci noma i n the Uni ted States i s 10 cases per 100,000
peopl e, wher eas the i nci dence i n Japan i s upwar d of 78 cases per
100,000 peopl e, al though the i nci dence i s dr oppi ng i n Japan as wel l .
Nonethel ess, rates r emai n hi gh i n Kor ea and Costa Ri ca.
G ender- and ethni c gr oup-r el ated di ffer ences i nfl uence the
pr esentati on and outcome of gastr i c adenocar ci noma pati ents. In
par ti cul ar, gastr i c car di a tumor s ar e fi ve ti mes mor e common, and
noncar di a gastr i c tumor s ar e twi ce as common i n men as
i n women. In addi ti on, whi tes ar e affected twi ce as fr equentl y as
bl acks. However, the i nci dence i s al so hi gher i n l ow soci oeconomi c
popul ati ons, and the popul ati ons of devel opi ng countr i es.
Sur vi val rates i n pati ents wi th gastr i c cancer r emai n poor, wi th
vi r tual l y no change i n the overal l 5-year sur vi val rates rangi ng fr om
53% i n Japan to 10% i n Easter n Eur ope. A r ecent anal ysi s of the
Nati onal Cancer Data Base i n the Uni ted States r eveal ed a 6% to
12% better 5-year sur vi val rate for women than for men, for
pati ents wi th di stal as opposed to pr oxi mal tumor s, and for
Japanese or Japanese Amer i cans compar ed wi th member s of other
ethni c gr oups.
Risk Factors
Many factor s have been associ ated wi th an i ncr eased r i sk for
i ntesti nal -type gastr i c adenocar ci noma, wi th di et bel i eved to pl ay a
major r ol e. For exampl e, the i nci dence of gastr i c car ci noma tends to
be hi gh i n geographi c r egi ons wher e peopl e consume di ets hi gh i n
sal t and smoked foods. Indeed, ani mal studi es have shown that
pol ycycl i c hydr ocar bons and di methyl ni tr osami nes, substances
pr oduced after pr ol onged smoki ng of fi sh and meat, can i nduce
mal i gnant gastr i c tumor s. In contrast, di ets hi gh i n raw vegetabl es,

fr esh fr ui ts, vi tami n C, and anti oxi dants may be pr otecti ve.
In the Uni ted States, mal e gender, bl ack race, and l ow
soci oeconomi c cl ass ar e associ ated wi th a hi gher r i sk of gastr i c
car ci noma. Obesi ty i s associ ated wi th pr oxi mal gastr i c cancer s. A
speci fi c occupati onal haz ar d may exi st for metal wor ker s, mi ner s,
and r ubber wor ker s, as wel l as for wor ker s exposed to wood or
asbestos dust. Ci gar ette smoki ng poses a cl ear r i sk, possi bl y as a
r esul t of the associ ated decr eased vi tami n C l evel s, but al cohol
consumpti on has not been as consi stentl y cor r el ated wi th the
devel opment of gastr i c car ci noma. An associ ati on between gastr i c
car ci noma and bl ood gr oup A was fi r st descr i bed i n 1953, but the
r el ati ve r i sk i s onl y 1.2. Fami l i al cl uster i ng of gastr i c
adenocar ci noma, al though rar e, has been r epor ted and i s di scussed
mor e l ater i n thi s chapter.
Helicobacter pylor i, a gram-negati ve mi cr oaer ophi l i c bacter i um
l i vi ng wi thi n the mucous l ayer i n the gastr i c pi ts, has been
i mpl i cated i n the genesi s of gastr i c car ci noma. In keepi ng wi th thi s,
the i nci dence of H. pylor i i nfecti on i s i ncr eased i n ar eas wher e ther e
i s a hi gh rate of gastr i c cancer and i s i ncr eased among pati ents wi th
gastr i c cancer i n the Uni ted States. H. pylor i i s common i n pati ents
wi th di stal cancer but not i n pati ents wi th pr oxi mal cancer. It al so
appear s that ther e i s a mar ked geographi c associ ati on wi th H. pylor i
i nfecti on, i n that i t i s mor e pr eval ent i n the popul ati ons of
devel opi ng nati ons than i n i ndustr i al i zed nati ons. F ur ther mor e,
near l y 90% of pati ents wi th i ntesti nal -type gastr i c cancer have H.
pylor i detected i n adjacent, hi stol ogi cal l y nor mal mucosa, wher eas
onl y 32% of pati ents wi th di ffuse-type gastr i c cancer have thi s
fi ndi ng. Li kewi se, H. pylor i i s essenti al for the devel opment of
mucosa-associ ated l ymphoi d ti ssue (MALT) and gastr i c l ymphoma.
(Intesti nal - and di ffuse-type gastr i c cancer s ar e di scussed i n the
Pathol ogy secti on.) F i nal l y, the r i sk of adenocar ci noma appear s to
be i ncr eased i n pati ents wi th ser ol ogi c evi dence of i mmunogl obul i n
G anti body to H. pylor i bacter i al
pr otei ns and wi th i nfecti on of gr eater than 10 year s durati on. By
str ongl y i mpai r i ng the bi oavai l abi l i ty of vi tami n C, H. pylor i
i nfecti on appear s to hei ghten the r i sk for gastr i c cancer by causi ng
decr eased l evel s of ci r cul ati ng vi tami n C.
G astr i c pol yps ar e unusual and rar el y pr ecur sor s of gastr i c cancer.
Hyper pl asti c pol yps, the pol yps most commonl y found i n the
stomach, ar e beni gn l esi ons. The fi ndi ng of vi l l ous adenomas does,
however, i ndi cate an i ncr eased r i sk of mal i gnancy, not onl y wi thi n
the pol yp i tsel f, but al so el sewher e i n the stomach. However, vi l l ous
adenomas r epr esent onl y 2% of al l gastr i c pol yps.
Per ni ci ous anemi a i s associ ated wi th a 10% i nci dence of gastr i c
cancer, a r i sk that i s about thr ee to fi ve ti mes that seen i n the
nor mal popul ati on. Even though the r i sk of car ci noma devel opi ng i n
a chr oni c gastr i c ul cer i s smal l , of concer n i s the fact that up to
10% of pati ents wi th gastr i c car ci noma ar e mi sdi agnosed as havi ng
a beni gn gastr i c ul cer when eval uated by onl y a doubl e-contrast
study of the upper gastr oi ntesti nal tract. Al so, i ni ti al endoscopi c
bi opsi es may mi ss the cancer, thus r equi r i ng the endoscopy to be
r epeated to ensur e the ul cer has r esol ved. Operati ons for beni gn
pepti c ul cer s al so appear to be associ ated wi th an i ncr eased r i sk of
stomach cancer. Typi cal l y appear i ng 25 or mor e year s after
gastr ectomy for the tr eatment of gastr i c ul cer s, gastr i c stump
cancer has been var i ousl y r epor ted to occur fr om zer o to fi ve ti mes
mor e often i n pati ents who have had gastr ectomy than i n
i ndi vi dual s wi thout pr evi ous gastr i c r esecti on. Chr oni c atr ophi c
gastr i ti s and the i ntesti nal metapl asi a that often r esul t fr om these
pr ocedur es ar e al so r i sk factor s for gastr i c car ci noma but may not
be di r ect pr ecur sor condi ti ons. To date, no associ ati on has been
demonstrated between l ong-ter m H2 bl ockade and gastr i c cancer
i nci dence.
Mutati ons i n the CDH1 gene that encodes E-cadher in, an epi thel i al
cel l adhesi on mol ecul e, may be found i n i ntesti nal cancer s but ar e
mor e common i n di ffuse-type gastr i c cancer s. F ur ther mor e, defects
i n E-cadher i nmedi ated cel l adhesi on ar e character i sti c of di ffusetype gastr i c tumor s. It al so appear s that a CDH1 gene mutati on
occur s i n a cl uster of pati ents wi th her edi tar y di ffuse gastr i c cancer.
Ther efor e, pr ophyl acti c gastr ectomy i s offer ed to car r i er s of these
mutati ons. Vi r tual l y al l car r i er s of thi s mutati on so far have been
found to har bor an ear l y mal i gnancy i n the r esected speci men,
despi te negati ve i ni ti al endoscopy fi ndi ngs, poi nti ng to the
advi sabi l i ty of the gastr ectomy.
Vascular endothelial gr owth factor C (VEG F -C) i s a gl ycopr otei n that
bel ongs to the VEG F fami l y. VEG F s ar e cytoki nes that pl ay an
i mpor tant r ol e i n angi ogenesi s and, as shown i n r ecent studi es, i n
l ymphangi ogenesi s as wel l . Several i n vi vo and i n vi tr o studi es have
al so demonstrated that VEG F -C and VEG F -D pr omote the for mati on
of new l ymphati c channel s i n sol i d tumor s. In gastr i c
adenocar ci nomas, expr essi on of VEG F -C mRNA i s associ ated wi th
l ymphati c i nvasi on, l ymph node metastasi s, and possi bl y a l ess
favorabl e outcome.
Most r ecentl y, several geneti c al terati ons have been found to be
associ ated wi th gastr i c cancer. A study of p53 expr essi on i n 418
pati ents wi th gastr i c cancer r eveal ed p53 expr essi on i n mor e than
55% of tumor s; however, ther e was no cor r el ati on between p53
expr essi on and depth of i nvasi on, l ymph node i nvol vement,
or sur vi val . Other r epor ted r i sk factor s i ncl ude pr i or radi ati on
therapy and Epstei n-Bar r vi r us i nfecti on.
Pathology
Ni nety-fi ve per cent of gastr i c cancer s ar e adenocar ci nomas that
ar i se al most excl usi vel y fr om the mucous-pr oduci ng rather than the
aci d-pr oduci ng cel l s of the gastr i c mucosa. Lymphoma, car ci noi d,
l ei omyosar coma, G ISTs of the stomach, and adenosquamous and
squamous cel l car ci noma compr i se the r emai ni ng 5% of gastr i c
cancer s. In the Uni ted States, gastr i c cancer i s di vi ded i nto
ul cerati ve (75% ), pol ypoi d (10% ), sci r r hous (10% ), and super fi ci al
(5% ) subtypes on the basi s of macr oscopi c fi ndi ngs.
Adenocar ci noma of the stomach i s an aggr essi ve tumor, often
metastasi z i ng ear l y by both l ymphati c and hematogenous r outes and
di r ectl y extendi ng i nto adjacent str uctur es. Extensi on thr ough the
ser osal sur face can l ead to per i toneal tumor spr ead.
Accor di ng to the Laur en cl assi fi cati on, ther e ar e two hi stol ogi c types
of gastr i c adenocar ci noma: i ntesti nal and di ffuse. Each type has
di sti nct cl i ni cal and pathol ogi cal featur es. The i ntesti nal type i s
found i n geographi c r egi ons wher e ther e i s a hi gh i nci dence of
gastr i c cancer and i s character i zed pathol ogi cal l y by the tendency of
mal i gnant cel l s to for m gl ands. These tumor s ar e usual l y wel l to
moderatel y di ffer enti ated and associ ated wi th metapl asi a or chr oni c
gastr i ti s. They occur mor e commonl y i n ol der pati ents and tend to
spr ead hematol ogi cal l y to di stant or gans. The di ffuse type typi cal l y
l acks or gani zed gl and for mati on, i s usual l y poor l y di ffer enti ated,
and has many si gnet r i ng cel l s. If mor e than 50% of the tumor
contai ns i ntracytopl asmi c muci n, then i t i s desi gnated si gnet r i ng
type. Di ffuse-type tumor s ar e mor e common i n younger pati ents
wi th no hi stor y of gastr i ti s and spr ead transmural l y and by
l ymphati c i nvasi on. Di ffuse-type tumor s appear to be associ ated
wi th obesi ty. Al though the i nci dence of these tumor s var i es l i ttl e
fr om countr y to countr y, thei r overal l i nci dence appear s to be
i ncr easi ng wor l dwi de. Al though Laur en cl assi fi cati on separates
gastr i c tumor s i nto two types, the Wor l d Heal th Or gani z ati on
cl assi fi es them accor di ng to thei r hi stomor phol ogi c appearance,
whi ch i ncl udes tubul ar, muci nous, papi l l ar y, and si gnet r i ng cel l
types.
In the past, most gastr i c car ci nomas (60% 70% ) wer e found i n the
antr um. However, between 1980 and 1990, the pr opor ti on of gastr i c
car ci nomas ar i si ng i n the antr um decr eased, and the pr opor ti on
ar i si ng i n the car di a i ncr eased. Ni ne per cent of pati ents have tumor
that i nvol ves the enti r e stomach; thi s i s known as l i ni ti s pl asti ca or
l eather bottl e stomach, and the pr ognosi s for these pati ents i s
di smal . In general , gastr i c tumor s ar e mor e common on the l esser
cur ve of the stomach than on the gr eater cur ve. In the Uni ted
States, the i nci dence of synchr onous l esi ons i s 2.2% , compar ed wi th
an i nci dence of up to 10% i n Japanese pati ents wi th per ni ci ous
anemi a.
G astr i c adenocar ci noma i s usual l y not associ ated wi th speci fi c
symptoms ear l y i n the cour se of the di sease. Pati ents often i gnor e
the vague epi gastr i c di scomfor t and i ndi gesti on that por tend the
cancer and may be tr eated pr esumpti vel y for beni gn di sease
for 6 to 12 months befor e di agnosti c studi es ar e per for med. Rapi d
wei ght l oss, anor exi a, and vomi ti ng ar e usual l y a si gn of advanced
di sease. These pr esenti ng featur es ar e si mpl y due to the pr esence
of a par ti al l y obstr ucti ng (ei ther mechani cal or physi ol ogi cal ) l esi on.
The most fr equent pr esenti ng symptoms of 1,121 pati ents at
Memor i al Sl oan-Ketter i ng Cancer Center wer e wei ght l oss, pai n,
vomi ti ng, and anor exi a. The epi gastr i c pai n i s usual l y si mi l ar to the
pai n caused by beni gn ul cer s and i s often r el i eved by eati ng food;
however, i t can mi mi c angi na. Dysphagi a i s usual l y associ ated wi th
tumor s of the car di a or gastr oesophageal juncti on. Antral tumor s
may cause symptoms of gastr i c outl et obstr ucti on. Al though ver y
rar e, l ar ge tumor s that di r ectl y i nvade the transver se col on may
pr esent wi th col oni c obstr ucti on. Physi cal exami nati on wi l l r eveal a
pal pabl e mass i n up to 30% of pati ents.
Appr oxi matel y 10% of pati ents pr esent wi th one or mor e si gns of
metastati c di sease. The most common i ndi cati ons of di stant
metastasi s ar e a pal pabl e supracl avi cul ar l ymph node (Vi r chow
node), a mass pal pabl e on r ectal exami nati on (Bl umer shel f ), a
pal pabl e per i umbi l i cal mass (Si ster Mar y Joseph node), asci tes,
jaundi ce, or a l i ver mass. The most common si te of hematogenous

spr ead i s the l i ver ; tumor al so fr equentl y spr eads di r ectl y to the
l i ni ng of the per i toneal cavi ty.
G astr i c tumor s may be associ ated wi th chr oni c bl ood l oss, but
massi ve upper gastr oi ntesti nal bl eedi ng i s rar e. In Japan, the hi gh
i nci dence of gastr i c cancer has l ed to r outi ne endoscopi c scr eeni ng;
as a r esul t, i n that countr y, mor e than 50% of gastr i c cancer s ar e
di agnosed at an ear l y stage.
Preoperative Evaluation
National Comprehensive Cancer Network
Guidelines for Initial Evaluation
The Nati onal Compr ehensi ve Cancer Networ k has devel oped
consensus gui del i nes for the cl i ni cal eval uati on and stagi ng of
pati ents suspected of havi ng gastr i c adenocar ci noma. The
r ecommended i ni ti al eval uati on i ncl udes a compl ete hi stor y and
physi cal exami nati on, l aborator y studi es (e.g., compl ete bl ood cel l
and pl atel et counts; measur ement of el ectr ol ytes, cr eati ni ne, and
l i ver functi on), chest radi ography, and computed tomography (CT) of
the abdomen and pel vi s. For pr oxi mal gastr i c tumor s, CT of the
chest i s al so per for med. Upper gastr oi ntesti nal contrast-enhanced
studi es ar e not mandator y. Esophagogastr oduodenoscopy i s
necessar y, and pr ovi des both ti ssue for a pathol ogi cal di agnosi s and
anatomi cal l y l ocal i zes the pr i mar y tumor i n mor e than 90% of
pati ents. Four to si x bi opsy speci mens and cytol ogi c br ushi ngs ar e
usual l y suffi ci ent for establ i shi ng an accurate di agnosi s. Thi s i ni ti al
wor kup enabl es the strati fi cati on of pati ents i nto two cl i ni cal stage
gr oups: those wi th l ocor egi onal di sease (AJCC stages IIII) and
those wi th systemi c di sease (AJCC stage IV) (Tabl e 9.1). Pal l i ati ve
therapy i s consi der ed i n pati ents wi th systemi c di sease, dependi ng
on thei r symptoms and functi onal status, because several
randomi zed studi es have shown a qual i ty of l i fe benefi t fr om
tr eatment i n pati ents wi th stage IV di sease. Pati ents wi th
l ocor egi onal di sease ar e fur ther strati fi ed on the basi s of thei r
functi onal status and comor bi d
condi ti ons. Addi ti onal studi es i n pati ents wi th l ocal i zed di sease
i ncl ude l apar oscopy and endoscopi c ul trasonography (EUS).
Pul monar y functi on tests may al so be necessar y i n sel ect pati ents.
Pati ents wi th l ocor egi onal di sease who ar e consi der ed candi dates for
sur ger y r ecei ve defi ni ti ve (fr equentl y mul ti modal i ty) therapy,
i ncl udi ng l apar otomy and r esecti on. Pati ents wi th occul t M1 di sease
found at l apar oscopy ar e consi der ed for pal l i ati ve therapy.
Table 9.1. TNM classification of carcinoma

of the stomach
Category Criteria
Primary tumor (T)
Tx
T0
Tis
Carcinoma in situ
T1

submucosa
T2
Tumor invades muscularis propria or

subserosa
T2a
T2b
Tumor invades subserosa
T3
Tumor penetrates serosa (visceral

peritoneum) without invasion of
adjacent structures
T4
Tumor invades adjacent structures

Nx

assessed
N0
N1
Metastases in 16 lymph nodes
N2
Metastases in 715 lymph nodes
N3
Metastases in >15 lymph nodes

Mx
Distant metastasis cannot be

assessed
M0
M1
Distant metastasis
Stage grouping
Stage 0
Tis
N0
M0
Stage IA
T1
N0
M0
T1
N1
M0
Stage IB
Stage II
Stage
IIIA
Stage
IIIB
Stage IV
T2a/b
N0
M0
T1
N2
M0
T2a/b
N1
M0
T3
N0
M0
T2a/b
N2
M0
T3
N1
M0
T4
N0
M0
T3
N2
M0
T4
N13
M0
T13
N3
M0
Any T
Any N
M1
Adapted from Stomach. In: Greene FL, Page

DL, Fleming ID, et al., eds. AJCC Cancer
Staging Manual. 6th ed. New York, NY:
Springer-Verlag; 2002:99103, with
permission.
Upper Gastrointestinal Endoscopy and
Endoscopic Ultrasonography
Upper gastr oi ntesti nal endoscopy wi th bi opsy i s essenti al for the
di agnosi s of gastr i c tumor s and enabl es anatomi cal assessment of
the pr oxi mal extent of the tumor, tumor si ze, and, often, pr ovi ded
that l umi nal obstr ucti on does not pr event passage of the
gastr oscope beyond the tumor, the di stal extent of the tumor. Tumor
l ocati on can gui de sur gi cal or pal l i ati ve tr eatment pl anni ng. In
sel ected pati ents wi th advanced di sease,
esophagogastr oduodenoscopy enabl es pal l i ati ve tr eatment consi sti ng
of l aser abl ati on, di l atati on, or tumor stenti ng to be per for med.
Depth of tumor i nvasi on i s a major deter mi nant of stage and
di r ectl y cor r el ates wi th pr ognosi s. G astr i c mural EUS can achi eve
spati al r esol uti on of 0.1 mm, whi ch al l ows for a r easonabl y accurate
assessment of the degr ee of tumor penetrati on thr ough the l ayer s
of the gastr i c wal l . However, because EUS cannot r el i abl y
di sti ngui sh between tumor and fi br osi s (ei ther tr eatment r el ated or
secondar y to pepti c ul cerati on), EUS has some l i mi tati on and i s thus
used pr i mar i l y for i ni ti al stagi ng rather than for assessi ng r esponse
to neoadjuvant therapy.
Pathol ogi cal confi r mati on of pr eoperati ve EUS fi ndi ngs has shown
the overal l stagi ng accuracy of EUS to be 75% . However, EUS
cor r ectl y i denti fi es T2 l esi ons onl y 38.5% of the ti me; i t i s better at
i denti fyi ng T1 (80% ) and T3 (90% ) l esi ons. Techni cal i mpr ovements
and exper i ence have i mpr oved the accuracy of EUS i n the nodal
eval uati on of N1 di sease to appr oxi matel y 65% . The i nfor mati on
yi el ded by EUS-gui ded fi ne-needl e aspi rati on may fur ther i mpr ove
the accuracy of nodal stagi ng, but thi s techni que i s techni cal l y mor e
chal l engi ng. G i ven the operator dependence of EUS, i t i s l ar gel y
per for med at r egi onal r efer ral center s.
Computed Tomography
Abdomi nal and pel vi c CT i s per for med ear l y i n the overal l stagi ng of
pati ents wi th newl y di agnosed gastr i c cancer. Thi s al l ows
unnecessar y l apar otomy to be avoi ded i n many pati ents wi th
vi sceral metastati c di sease or mal i gnant asci tes. CT of the chest
may be r equi r ed for the compl ete stagi ng of pr oxi mal gastr i c
tumor s.
The major l i mi tati ons of CT as a stagi ng tool ar e i n the eval uati on
of ear l y gastr i c tumor s and smal l (<5 mm) metastases on per i toneal
sur faces or i n the l i ver. Even wi th the use of hel i cal CT scan, the
overal l accuracy i n deter mi ni ng tumor stage i s appr oxi matel y 66%
to 77% . CT can be used to accuratel y deter mi ne nodal stage i n 25%

to 86% of pati ents.
Laparoscopy and Laparoscopic

Ultrasonography
The val ue of fur ther stagi ng wi th l apar oscopy i s appar ent on
r ecogni ti on of the l ow sensi ti vi ty of CTeven hi gh-qual i ty hel i cal
CT per for med wi th gastr i c-speci fi c pr otocol s for the detecti on of
smal l (<5 mm) metastases on the per i toneal sur face. Lapar oscopy i s
done ei ther separatel y or i mmedi atel y befor e sur gi cal r esecti on. A
ful l techni cal descr i pti on of di agnosti c l apar oscopy i s beyond the
scope of thi s chapter. In br i ef, a l apar oscopi c i nspecti on i s usual l y
per for med i n a systemati c manner and i ncl udes a sear ch for
metastases on the per i toneal sur faces and the l i ver. Bi opsy of the
nodal basi n for stagi ng pur poses i s not r outi nel y per for med, but i t
can be done i n sel ected cases. When i t i s done, the l esser sac
shoul d be eval uated vi a the gastr ocol i c omentum. The i denti fi cati on
of advanced di sease affor ded by l apar oscopy al l ows many pati ents to
be spar ed an ul ti matel y nontherapeuti c l apar otomy. Pati ents wi th
smal l -vol ume metastati c di sease i n the per i toneum or l i ver
i denti fi ed at l apar otomy have a l i fe expectancy of onl y 3 to 9
months; thus, despi te some r epor ts that pal l i ati ve gastr ectomy may
confer a sur vi val advantage, such pati ents rar el y benefi t fr om
expectant pal l i ati ve r esecti on. An ar gument for per for mi ng a
second-l ook l apar oscopy can be made i n the case of pati ents who
r ecei ve neoadjuvant chemotherapy for unr esectabl e di sease and
appear to have a good cl i ni cal r esponse.
Resear cher s at Memor i al Sl oan-Ketter i ng Cancer Center and M. D.
Ander son Cancer Center have eval uated the feasi bi l i ty, yi el d, and
cl i ni cal benefi t of l apar oscopi c stagi ng after hi gh-qual i ty abdomi nal
CT stagi ng and found that l apar oscopy i denti fi ed CT-occul t
metastati c di sease i n 23% to 37% of pati ents. Mor eover, l ess than
2% of the pati ents i n whom CT-occul t metastases wer e i denti fi ed by
l apar oscopy r equi r ed subsequent l apar otomy for pal l i ati on. On the
basi s of the avai l abl e data, the Nati onal Compr ehensi ve Cancer
Networ k has i ntegrated l apar oscopy i nto the r ecommended r outi ne
stagi ng al gor i thm for pati ents wi th l ocor egi onal gastr i c cancer s and
sel ect pati ents wi th advanced gastr i c cancer.
Lapar oscopi c ul trasonography (LUS) has been pr oposed as a means
to over come some of the l i mi tati ons of l apar oscopy and to i mpr ove
the di agnosti c yi el d. However, the major i ty of studi es of LUS i n the

stagi ng of gastr i c cancer ar e di ffi cul t to i nter pr et because the use of
state-of-the-ar t pr el apar oscopy stagi ng (par ti cul ar l y CT) has var i ed,
and r esul ts have been r epor ted i n a manner that makes i t di ffi cul t
to deter mi ne the speci fi c added benefi t of LUS over hi gh-qual i ty CT
pl us l apar oscopy al one. G i ven the l i mi tati ons of the avai l abl e data,
the hi gh cost of LUS equi pment, and the operator-dependent natur e
of the techni que, i t i s best to r egar d LUS as r equi r i ng fur ther
i nvesti gati on to defi ne i ts r ol e.
Peritoneal Cytology
Cytol ogi c anal ysi s of per i toneal fl ui d or fl ui d obtai ned by per i toneal
l avage may i denti fy occul t car ci nomatosi s. For thi s r eason, many
i nsti tuti ons have i ncl uded the cytol ogi c assessment of per i toneal
fl ui d i n the pr eoperati ve stagi ng of pati ents. The fl ui d i s usual l y
obtai ned by per cutaneous or l apar oscopi c aspi rati on (wi th or
wi thout per i toneal l avage) per for med at the ti me of stagi ng
l apar oscopy. Per i toneal cytol ogi c anal ysi s can be r el ati vel y si mpl e
and fast and i s ther efor e al so feasi bl e i ntraoperati vel y, al though
one must be on the watch for fal se-posi ti ve r eadi ngs.
In most ser i es, pati ents wi th posi ti ve per i toneal cytol ogy fi ndi ngs
have a pr ognosi s si mi l ar to that of pati ents wi th macr oscopi c
vi sceral or per i toneal di sease (3- to 9-month medi an sur vi val ).
Some r esear cher s have i nvesti gated the i mpact of per i toneal
cytol ogy fi ndi ngs on outcome and noted that the medi an sur vi val i n
those wi th posi ti ve cytol ogy fi ndi ngs was 122 days; other s have
used i t as an i ndi cati on for neoadjuvant tr eatment rather than an
absol ute contrai ndi cati on to r esecti on. The pr i mar y concer ns
r egar di ng the use of per i toneal cytol ogy ar e the possi bi l i ty of fal seposi ti ve r esul ts and the fact that some r epor ts do not confi r m the
uni for ml y poor pr ognosi s i n pati ents wi th posi ti ve fi ndi ngs. G i ven
that cytol ogi c anal ysi s i s ver y much an operator-dependent vi sual
i nter pr etati on, effor ts ar e ongoi ng to devel op mor e sensi ti ve and
speci fi c techni ques for i denti fyi ng per i toneal di ssemi nati on,
i ncl udi ng i mmunostai ni ng and r ever se transcr i ptase-pol ymerase
chai n r eacti on testi ng for car ci noembr yoni c anti gen (CEA) mRNA.
Al though some success has been seen usi ng these techni ques
because they take mor e ti me than per i toneal cytol ogy, they may not
be practi cal for use i n the operati ng r oom.
Lymphatic Mapping
G i ven the essenti al r ol e of nodal status i n gastr i c cancer stagi ng
and the contr over sy that sur r ounds the extent of l ymphadenectomy,
ther e has been i nter est i n eval uati ng the feasi bi l i ty of senti nel
l ymph node mappi ng i n gastr i c cancer. However, unl i ke br east
cancer and mel anoma, l ymphati c drai nage of the stomach i s compl ex
and thus ther e i s a r i sk of a ski p metastasi s i n up to 15% of
cases. Al though l ymphati c mappi ng of stomach tumor s has been
most commonl y per for med vi a an open l apar otomy, i t has al so been
done usi ng a l apar oscopi c appr oach. Mappi ng agents such as
radi ocol l oi d wi th or wi thout vi tal dye and acti vated car bon par ti cl es
have been used. The i denti fi cati on rate var i es fr om 90% to 100% ,
and the sensi ti vi ty of the fi ndi ngs ranges fr om 61% to 100% .
However, l ymphati c mappi ng has several drawbacks. F i r st, the
number of pati ents wi th gastr i c cancer i n whi ch i t has been studi ed
i s smal l i n compar i son wi th mel anoma or br east cancer. Second, i t i s
associ ated wi th a fal se-negati ve rate as hi gh as 39% . Thi r d, the
number of senti nel l ymph nodes per pati ent i s qui te var i ed (two to
seven senti nel nodes per pati ent). Four th, the fi ndi ngs ar e
si gni fi cantl y di ffer ent i n the typi cal l y obese Wester n pati ents fr om
those i n Asi an pati ents, i n whom most of the studi es of l ymphati c
mappi ng have been done. Ther efor e, for these r easons, senti nel
l ymph node mappi ng for stomach cancer r emai ns i nvesti gati onal .
Other Studies
Posi tr on emi ssi on tomography (PET), whi ch esti mates tumor
metabol i sm on the basi s of the uptake of a radi otracermost
commonl y, fl uor odeoxygl ucosei s cur r entl y bei ng eval uated as a
stagi ng tool for gastr i c cancer. Thi s techni que may r eveal CT-occul t
metastases (par ti cul ar l y extra-abdomi nal di sease) and may be used
to assess r esponse to neoadjuvant therapy. Cur r ent drawbacks to
PET ar e i ts hi gh cost and i ts l i mi ted avai l abi l i ty.
Al so, the addi ti onal yi el d of PET over standar d stagi ng studi es i n the
eval uati on of gastr i c cancer has thus far not been shown.
Incr eased l evel s of (CEA) Chor i oembr yoni c Anti gen ar e seen i n onl y
30% of pati ents wi th gastr i c car ci noma. Because the CEA l evel i s
usual l y nor mal i n ear l y gastr i c cancer, CEA i s not a useful scr eeni ng
mar ker. Ser i al deter mi nati ons of the CEA l evel may be hel pful ,
however, i n detecti ng tumor r ecur r ence or i n moni tor i ng r esponse to
tr eatment i n pati ents who pr esent wi th an i ncr eased CEA l evel .
Staging Systems
Many stagi ng systems for gastr i c adenocar ci noma have been
pr oposed. The pathol ogi cal stagi ng system cur r entl y i n use
wor l dwi de i s the Uni on Inter nati onal e Contr el e Cancer
(UICC)/Amer i can Joi nt Commi ttee on Cancer (AJCC) TNM stagi ng
system, wi th the addi ti on of the ter m R status to denote r esi dual
di sease r emai ni ng after r esecti on. Several other l ar gel y abandoned
systems have been devel oped i n an attempt to descr i be both the
extent of disease and the r esul tant extent of r esection or
lymphadenectomy necessar y i n a gi ven pati ent. The var i ous stagi ng
systems i n use ar e expl ai ned as fol l ows.
American Joint Committee on Cancer Staging

System
The stagi ng of gastr i c adenocar ci noma has changed si gni fi cantl y
si nce the mi d-1990s. In 1997, the AJCC r el eased a r evi sed TNM
stagi ng system i n whi ch pati ents ar e strati fi ed on the basi s of the
number rather than the l ocati on of any i nvol ved l ymph nodes. In
2002, thi s TNM stagi ng system under went mi ni mal r evi si on i n the
most cur r ent AJCC stagi ng system (Tabl e 9.1). Sur vi val i s cl osel y
l i nked to the AJCC pathol ogi cal stage, par ti cul ar l y the nodal stage.
The val i di ty of the newer TNM stagi ng system i s now wel l
establ i shed. Because i t i s a pathol ogi cal rather than a cl i ni cal
stagi ng system, however, a pati ent's TNM status i s onl y ful l y known
fol l owi ng r esecti on. Thr ee i mpor tant cl i ni copathol ogi cal factor s have
been shown to r el i abl y strati fy pati ents i nto di sti nct gr oups wi th
di ffer ent r i sks of tumor-r el ated death: the depth of penetrati on of
the pr i mar y tumor thr ough the gastr i c wal l (T), the absence or
pr esence and extent of l ymph node i nvol vement (N), and the
absence or pr esence of di stant metastases (M). To adequatel y assess
N status, no fewer than 15 l ymph nodes shoul d be r etr i eved. If
metastasi s i s found i n mor e than 15 l ymph nodes (N3), thi s i s
consi der ed stage IV di sease. Some i nvesti gator s (e.g., Roder et al .,
1998) ar gued that sur vi val i s al so i ndependentl y pr edi cted by tumor
l ocati on (i .e., car di a as opposed to di stal tumor s) and suggested
that futur e AJCC stagi ng systems shoul d r efl ect the poor er
pr ognosi s for pati ents wi th pr oxi mal tumor s seen i n thei r anal yses.
Residual Disease: R Status

The R status, whi ch was fi r st descr i bed by Her manek and Wi tteki nd
i n 1994, i s commonl y used to descr i be the tumor status i n a pati ent

fol l owi ng r esecti on and i s desi gnated fol l owi ng pathol ogi cal
eval uati on of the r esecti on mar gi ns (Tabl e 9.2). R0 i ndi cates that
mi cr oscopi c mar gi ns ar e fr ee of tumor and that no gr oss or
mi cr oscopi c di sease r emai ns. R1 i ndi cates that al l gr oss di sease has
been exti r pated but that mi cr oscopi c mar gi ns ar e posi ti ve for tumor.
R2 i ndi cates that gr oss r esi dual di sease r emai ns. Long-ter m sur vi val
can be expected onl y i n pati ents who under go an R0 r esecti on for
gastr i c adenocar ci noma, and si gni fi cant effor t i s ther efor e made to
avoi d R1 or R2 r esecti ons.
Table 9.2. Current description of

completeness of resection based on
presence or absence of residual disease
following resection and pathological
evaluation of resection margins
Description
Gross or Pathological Extent of

Residual Disease
R0
No residual gross disease and

negative microscopic margins
R1
Microscopic residual disease only
R2
Gross residual disease
Japanese R System
The R status descr i bed i n the pr evi ous secti on shoul d not be
confused wi th an ol der Japanese cl assi fi cati on of gastr i c r esecti on
that al so i ncl uded an R status. Thi s R status has now been r epl aced
wi th a D status and i s menti oned her e for i nfor mati onal pur poses
onl y because i t has not been used after 1992.
Japanese Classification: Extent of Resection

The extent of pathol ogi cal l ymph node i nvol vement r el ati ve to the
scope of the l ymphadenectomy per for med i s the di sti ngui shi ng
character i sti c of the Japanese cl assi fi cati on scheme, whi ch i s based
on the assumpti on that extended l ymph node cl earance beyond the
l evel of pathol ogi cal i nvol vement may pr ol ong sur vi val . In yet
another Japanese system (Tabl e 9.3), the compl eteness of nodal
di ssecti on i s desi gnated D1 (r emoval of al l nodal ti ssue wi thi n 3 cm
of the pr i mar y tumor ), D2 (D1 pl us cl earance of hepati c, spl eni c,
cel i ac, and l eft gastr i c nodes), or D3 (total gastr ectomy,
omentectomy, spl enectomy, di stal pancr eatectomy, and cel i ac and
por tal l ymphadenectomy). Al though these cl assi fi cati ons ar e not
par t of the AJCC stagi ng system, the D ter mi nol ogy
i s i mpor tant i n compar i ng the r esul ts of sur gi cal therapy, as i s
di scussed l ater i n the chapter.
Table 9.3. D Nomenclature: extent of

surgical resection and lymphadenectomy
Description Regions Included in Resection
D1
Removal of all nodal tissue within

3 cm of the primary tumor
D2
D1 plus clearance of hepatic,

splenic, celiac, and left gastric
lymph nodes
D3
D2 plus omentectomy,
splenectomy, distal pancreatomy,
and clearance of porta hepatis
lymph nodes and para-aortic
lymph nodes
Surgical Treatment
As l ong as ther e i s no documented metastati c di sease, the sur gi cal
r esecti on of gastr i c tumor s i s the mai nstay of tr eatment. We
r ecommend a wi de macr oscopi cal l y negati ve mar gi n of 5 to 6 cm,
al ong wi th the en bl oc r esecti on of l ymph nodes and adher ent
sur r oundi ng or gans. D2 l ymphadenectomy, spar i ng the spl een and
di stal pancr eas, i s empl oyed i f i t can be done wi th l ow mor bi di ty and
mor tal i ty. The appr opr i ate sur gi cal pr ocedur e for a gi ven pati ent
must take i nto account the l ocati on of the l esi on and the known
patter n of spr ead.
Proximal Tumors
Pr oxi mal tumor s account for about 50% of al l gastr i c car ci nomas.
These tumor s ar e usual l y advanced at pr esentati on and ar e
associ ated wi th a poor er l ong-ter m pr ognosi s than ar e di stal
cancer s. Ther e ar e thr ee types of gastr oesophageal juncti on tumor s
accor di ng to the Si ewer t cl assi fi cati on: Type I ar e associ ated wi th
Bar r ett esophagus or tr ue esophageal cancer gr owi ng i nto the
gastr oesophageal juncti on, type II cancer s ar e tr ue juncti onal
tumor s that l i e wi thi n 2 cm of the squamocol umnar juncti on, and
type III cancer s ar e pr esent wi thi n the subcar di al r egi on of the
stomach. The opti mal sur gi cal management of type II and III
cancer s i s contr over si al . The opti ons i ncl ude total gastr ectomy and
pr oxi mal subtotal gastr ectomy. Because of the advanced stage of
most tumor s of the car di a at di agnosi s, some author s ar gue that any
operati on i s r eal i sti cal l y onl y a pal l i ati ve pr ocedur e and that,
ther efor e, one shoul d al ways per for m the si mpl er pr oxi mal subtotal
gastr ectomy, especi al l y because total gastr ectomy does not i mpr ove
pr ognosi s for pati ents wi th stage III and IV di sease. However, some
studi es have shown a poor er qual i ty of l i fe i n pati ents who under go
a pr oxi mal subtotal gastr ectomy than i n pati ents who under go a
total gastr ectomy.
At M. D. Ander son, we usual l y per for m a total gastr ectomy wi th a
Roux-en-Y r econstr ucti on and r egi onal l ymphadenectomy for
pr oxi mal gastr i c l esi ons. Thi s pr ocedur e has the advantage of
avoi di ng the al kal i ne r efl ux esophagi ti s often associ ated wi th
pr oxi mal subtotal gastr ectomy. F ur ther mor e, l ymph nodes al ong the
l esser cur vatur e, a common si te of spr ead, ar e easi l y r emoved
dur i ng a total gastr ectomy. Ther e i s al so no gr eater mor tal i ty or
mor bi di ty i n pati ents who under go total gastr ectomy compar ed wi th

those who under go a pr oxi mal subtotal gastr ectomy.
Midbody Tumors
Mi dstomach tumor s account for 15% to 30% of al l gastr i c cancer s.
For the same r easons as those gi ven for our appr oach to the
tr eatment of pr oxi mal tumor s, we r ecommend total gastr ectomy
wi th r egi onal l ymphadenectomy i f the node di ssecti on can be done
wi th l ow mor bi di ty.
Distal Tumors
Di stal tumor s account for appr oxi matel y 35% of al l gastr i c cancer s.
The standar d operati on for these l esi ons i s a di stal subtotal
gastr ectomy wi th appr opr i ate l ymphadenectomy. Subtotal
gastr ectomy entai l s r esecti on of appr oxi matel y thr ee-four ths of the
stomach, i ncl udi ng the major i ty of the l esser cur vatur e. Thi s
pr ocedur e i s per for med for two r easons. F i r st, randomi zed
pr ospecti ve tr i al s demonstrated no sur vi val benefi t to total
gastr ectomy over subtotal gastr ectomy. Second, the qual i ty of l i fe i s
better i n those who have subtotal gastr ectomy than i n those who
have total gastr ectomy.
Because studi es have shown that mi cr oscopi c i nvasi on beyond 6 cm
fr om the gr oss tumor i s rar e, we ther efor e r ecommend a 5- to 6-cm
l umi nal r esecti on mar gi n when possi bl e. Even i f thi s di stance i s
achi eved, however, the sur gi cal mar gi ns shoul d be eval uated by
fr ozen-secti on pr eparati ons.
Splenectomy
Spl enectomy i s not per for med unl ess the tumor adher es to or
i nvades the spl een or i ts vascul ar suppl y. Routi ne spl enectomy does
not i mpr ove sur vi val but does i ncr ease the mor bi di ty and mor tal i ty
associ ated wi th gastr ectomy i n wester n pati ents. If a spl enectomy i s
anti ci pated pr eoperati vel y because of tumor adher ence shown by CT,
we gi ve pneumococcal pol ysacchar i de, meni ngococcal , and
Haemophilus i nfl uenz a vacci nes befor e sur ger y. Ther e i s a l ar ge
ongoi ng tr i al i n Japan that i s speci fi cal l y exami ni ng the r ol e of
spl enectomy i n the tr eatment of pati ents wi th gastr i c
adenocar ci nomas.
Lymphadenectomy
Despi te pr ospecti ve randomi zed tr i al s, contr over sy sti l l exi sts about
the r ol e of extended l ymphadenectomy i n the tr eatment of gastr i c
cancer. Radi cal l ymphadenectomy was adopted based on an i ni ti al
r epor t publ i shed i n 1981 by Kodama et al . that descr i bed a sur vi val
benefi t for pati ents wi th ser osal or r egi onal l ymph node i nvol vement
who under went a D2 or D3 l ymphadenectomy (R2 or R3 i n the ol d
Japanese nomencl atur e). Speci fi cal l y, the 5-year sur vi val rate i n
pati ents who under went a radi cal l ymphadenectomy was 39% as
opposed to onl y 18% i n pati ents who under went D1
l ymphadenectomy. Many other nonrandomi zed studi es fr om Japan
have shown a si mi l ar l y si gni fi cant sur vi val benefi t i n pati ents
under goi ng radi cal l ymphadenectomy. Unfor tunatel y, Wester n
studi es have not been abl e to r epr oduce the Japanese r esul ts.
The r epor ted di ffer ences i n sur vi val seen i n Japanese and Wester n
studi es may have mul ti pl e r easons. One potenti al r eason i s that
most Japanese pati ents pr esent wi th ear l y-stage di sease, whi ch
makes overal l sur vi val appear better. However, stage for stage, the
di ffer ences ar e not qui te so dramati c. F ur ther mor e, the Japanese
appr oach to nodal di ssecti on and pathol ogi cal anal ysi s i s much mor e
meti cul ous than the appr oach used i n the West, and ther e i s l i kel y
to be an el ement of stage mi grati on. It i s not ver y common for
nodes di stant fr om the stomach to be eval uated i n the Uni ted
States. Al so, pr oxi mal tumor s, whi ch behave mor e aggr essi vel y, ar e
l ess common i n Japan than i n the West. F i nal l y, the mor e aggr essi ve
sur ger y per for med i n Japan may confer a smal l i ncr ease i n sur vi val
rates.
In 1996, Wanebo et al . r evi ewed the outcomes i n 18,346 pati ents
wi th gastr i c cancer whose r ecor ds had been gather ed i n a database
that i ncl uded i nfor mati on fr om 200 tumor r egi str i es i n the Uni ted
States. Compar ed wi th pati ents under goi ng D1 di ssecti on, pati ents
under goi ng D2 nodal di ssecti on (i ncl udi ng l ymph nodes 3 cm fr om
the pr i mar y tumor ) (Tabl e 9.3) had no i ncr ease i n the medi an
sur vi val ti me (D2, 19.7 months; D1, 24.8 months) or i n the 5-year
sur vi val rate (D2, 26.3% ; D1, 30% ). In 1987, Shi u et al .
r etr ospecti vel y r evi ewed 210 pati ents wi th gastr i c cancer tr eated at
Memor i al Sl oan-Ketter i ng Cancer Center and found that a
l ymphadenectomy that di d not i ncl ude l ymph nodes at l east one
echel on beyond the hi stol ogi cal l y i nvol ved nodes was pr edi cti ve of a
poor pr ognosi s. Thi s study al so showed that ther e was not a
si gni fi cant di ffer ence i n the mor bi di ty associ ated wi th D1 and D2

l ymphadenectomi es.
Thus far, fi ve randomi zed tr i al s eval uati ng the extent of
l ymphadenectomy for gastr i c cancer have been conducted. Thr ee
tr i al s compar ed D1 ver sus D2 l ymphadenectomy. Two tr i al s
compar ed D3 ver sus D2 or D1 l ymphadenectomy.
To compar e the mor bi di ty and outcome i n pati ents who under went
D1 and D2 l ymphadenectomy, Dent et al ., fr om South Afr i ca,
randomi zed 43 pati ents i nto each ar m. Those who under went D2
di ssecti on had a hi gher mor bi di ty rate (D1, 15% ; D2, 30% ; P =
0.06), l onger hospi tal stay (D1, 4.2 days; D2, 9.2 days; P <0.008),
and l onger operati ve ti me (D1, 1.8 hour s; D2, 2.5 hour s; P <0.001).
However, the 5-year sur vi val rate was si mi l ar i n both gr oups (D1,
69% ; D2, 67% ). In 2004, Bonenkamp et al . r epor ted on a study
conducted i n the Nether l ands i n whi ch 711 pati ents wer e
pr ospecti vel y randomi zed to under go D1 or D2 l ymphadenectomy.
Pati ents under goi ng the mor e extended l ymphadenectomy (D2) had
a si gni fi cantl y hi gher operati ve mor bi di ty rate (D2, 43% ; D1, 25% ;
P <0.001) and si gni fi cantl y hi gher mor tal i ty rate (D2, 10% ; D1,
4% ; P = 0.004). The 5-year r el apse rates (D1, 43% ; D2, 37% ) and
5-year sur vi val rates (D1, 45% ; D2, 47% ) wer e si mi l ar, however.
Si mi l ar r esul ts wer e obtai ned i n the Medi cal Resear ch Counci l tr i al
r epor ted i n the Uni ted Ki ngdom by Cuschi er i et al . i n 1999. In thi s
study, 400 pati ents wi th gastr i c adenocar ci noma wer e pr ospecti vel y
randomi zed, as i n the Dutch tr i al , to under go D1 or D2
l ymphadenectomy. Si mi l ar l y, ther e was no di ffer ence i n the overal l
5-year sur vi val rate between the two gr oups (D1, 35% ; D2, 33% ).
In thi s study, as i n the Dutch tr i al , pancr eati cospl enectomy
per for med as par t of the D2 r esecti on r esul ted i n i ncr eased
postoperati ve mor bi di ty and mor tal i ty. These data ther efor e do not
suppor t the r outi ne per for mance of D2 l ymphadenectomy i n pati ents
wi th gastr i c adenocar ci noma, par ti cul ar l y i f pancr eati cospl enectomy
i s necessar y to effect the di ssecti on.
In a compar i son of D1 and D3 l ymphadenectomy, Rober tson et al .,
fr om Hong Kong, randomi zed 54 pati ents to under go ei ther D1
l ymphadenectomy wi th subtotal gastr ectomy or D3
l ymphadenectomy wi th total gastr ectomy. In addi ti on to poor er
sur vi val i n the D3 gr oup, the hospi tal stay and bl ood l oss wer e
gr eater i n the pati ents i n the D3 gr oup than i n the D1 gr oup.
In 2004, the Japanese Cooperati ve Oncol ogy G r oup (JCOG 9501)
r epor ted the fi ndi ngs fr om a pr ospecti ve randomi zed tr i al eval uati ng
R0 gastr ectomy wi th D2 l ymphadenectomy ver sus

D2 pl us para-aor ti c l ymphadenectomy. In thi s mul ti center tr i al ,
sur geons exper i enced i n per for mi ng extended l ymphadenectomy
operated on mor e than 500 pati ents. In addi ti on to the pr eoperati ve
stagi ng, age younger than 75 year s and negati ve per i toneal l avage
cytol ogy fi ndi ngs wer e some of the i ncl usi on cr i ter i a. Ther e wer e
two deaths i n each ar m, accounti ng for a r emar kabl y l ow hospi tal
mor tal i ty of 0.8% . Al though the mor bi di ty rate i n pati ents who
under went the D2 pl us para-aor ti c l ymphadenectomy (28.1% ) was
hi gher than that i n the pati ents who under went the D2
l ymphadenectomy (20.9% ), the di ffer ence di d not r each stati sti cal
si gni fi cance. Pati ents who under went the D2 pl us para-aor ti c
l ymphadenectomy al so had l onger operati ons (P <0.001) wi th
i ncr eased bl ood l oss (P <0.001), and hence hi gher bl ood transfusi on
r equi r ements (P <0.001), than di d those who had onl y a D2
l ymphadenectomy. The sur vi val r esul ts of thi s tr i al ar e expected i n
2006.
At M. D. Ander son, spl een-spar i ng D2 l ymphadenectomy i s standar d.
Anal ysi s of pati ents who under went curati ve r esecti on after
neoadjuvant therapy at M. D. Ander son between 1991 and 1998
showed a per i operati ve mor tal i ty rate of 2% . Cur r ent standar d
r ecommendati ons i ncl ude a D1 di ssecti on (per i gastr i c
l ymphadenectomy), al though major center s conti nue to study the
potenti al benefi t and mor bi di ty associ ated wi th mor e extended nodal
di ssecti ons i n the setti ng of l ow operati ve mor tal i ty.
Surgical Technique
Total Gastrectomy
For a total gastr ectomy, the di ssecti on i s begun by separati ng the
omentum fr om the mesocol on. The r i ght gastr oepi pl oi c vessel s ar e
l i gated at thei r or i gi n, and the subpyl or i c nodes ar e r esected wi th
the speci men. The fi r st por ti on of the duodenum i s mobi l i zed and
di vi ded 2 cm di stal to the pyl or us. The gastr ohepati c l i gament i s
opened, and the l eft gastr i c ar ter y i s l i gated at i ts or i gi n. It i s
i mpor tant to r emember that an aber rant or accessor y l eft hepati c
ar ter y may or i gi nate fr om the l eft gastr i c ar ter y and r esi de i n the
gastr ohepati c l i gament. If an extended l ymphadenectomy i s done,
the cel i ac, hepati c ar ter y, and spl eni c ar ter y nodes ar e cl ear ed of
nodal ti ssue and r emoved al ong wi th the speci men. The shor t
gastr i c vessel s ar e l i gated sequenti al l y up to the gastr oesophageal
juncti on. Di ssecti on ar ound the gastr oesophageal juncti on can fr ee

up 7 to 8 cm of di stal esophagus, whi ch faci l i tates transecti on of the
esophagus wi th an adequate pr oxi mal mar gi n. Stay sutur es of 2-0
si l k ar e pl aced, and after the esophagus i s di vi ded, the r esecti on
mar gi ns ar e eval uated by fr ozen-secti on exami nati on. If the tumor
adher es to the spl een, pancr eas, l i ver, di aphragm, col on, or
mesocol on, the i nvol ved or gan or or gans ar e r emoved en bl oc.
Ther e ar e many types of r econstr ucti ons, but the one most
fr equentl y used i s a Roux-en-Y anastomosi s. If a si gni fi cant por ti on
of the di stal esophagus i s r esected, a l eft thoracoabdomi nal or r i ght
thoracotomy (Ivor-Lewi s appr oach) may be used. Al though some
studi es have shown that r econstr ucti on wi th pouches and l oops to
act as r eser voi r s ar e benefi ci al , the data ar e far fr om concl usi ve.
The one mor e advanced r econstr ucti on, whi ch makes
physi ol ogi cal sense and has data suppor ti ng the benefi t of the
pr ocedur e, i s jejunal i nter posi ti on between the esophagus and the
duodenum. In thi s r econstr ucti on, car e i s taken to ensur e the
i nter posi ti on l i mb i s at l east 45 cm l ong. A feedi ng jejunostomy
tube i s pl aced for postoperati ve nutr i ti onal suppor t.
Subtotal Gastrectomy
The mobi l i z ati on for subtotal gastr ectomy i s i denti cal to that for
total gastr ectomy descr i bed i n the pr ecedi ng secti on, except that
onl y appr oxi matel y 80% of the di stal stomach i s r esected. The
di ssecti on of the di stal shor t gastr i c vessel s i s per for med fi r st to
ensur e spl eni c pr eser vati on. The smal l r emnant of stomach that i s
l eft i s suppl i ed by the r emai ni ng shor t gastr i c vessel s and the
poster i or gastr i c ar ter y ar i si ng fr om the spl eni c ar ter y. We often use
Roux-en-Y r econstr ucti on after subtotal gastr ectomy, al though a
l oop gastr ojejunostomy (Bi l l r oth II) i s al so acceptabl e. Other
r ecommendati ons i ncl ude a Bi l l r oth I.
F i gur e 9.1 shows the M. D. Ander son tr eatment al gor i thm for
potenti al l y r esectabl e gastr i c car ci noma.
Complications of Surgery
Compl i cati ons of gastr i c r esecti on and thei r r el ati ve i nci dences ar e
gi ven i n Tabl e 9.4. The most devastati ng compl i cati on i s an
anastomoti c l eak, whi ch occur s i n 3% to 21% of pati ents. Because
l eaks can occur l ate, an i ntact anastomosi s ear l y i n the
postoperati ve per i od i s not a guarantee of an uncompl i cated cour se.
Oral feedi ng i s begun 5 to 7 days postoperati vel y i f the pati ent i s

asymptomati c. Upper gastr oi ntesti nal tract contrast studi es ar e
per for med on the basi s of cl i ni cal i ndi cati ons onl y (e.g., fever,
tachycar di a, tachypnea). Because the food r eser voi r i s gone, many
pati ents must i ni ti al l y change thei r eati ng habi ts such that they
consume si x smal l meal s per day, other wi se cal l ed a
postgastr ectomy di et. Al ter nati vel y, they may eat r egul ar meal s
pl us snacks. Suppl emental jejunostomy feedi ngs ar e star ted the
same day or the day after sur ger y and conti nued unti l oral i ntake i s
adequate. Wi thi n several months, most pati ents ar e abl e to i ncr ease
thei r i ntesti nal capaci ty and eat l ar ger meal s l ess fr equentl y (thr ee
or four meal s per day).
Less than 10% of pati ents wi l l devel op cl i ni cal l y si gni fi cant dumpi ng
syndr ome. Ear l y dumpi ng typi cal l y occur s 15 to 30 mi nutes after a
meal and i ncl udes di aphor esi s, abdomi nal cramps, pal pi tati ons, and
water y di ar r hea. Late dumpi ng i s usual l y associ ated wi th
hypogl ycemi a and hyper i nsul i nemi a. The medi cal management for
dumpi ng symptoms shoul d i ncl ude di etar y modi fi cati on (fi ber di et
and avoi dance of hyper osmol ar l i qui ds) and, i f r efractor y, a
somatostati n anal og.
F i gur e 9.1. The Uni ver si ty of Texas M. D. Ander son Cancer

Center al gor i thm for the eval uati on and tr eatment of potenti al l y
r esectabl e gastr i c adenocar ci noma. *Occasi onal l y, metastati c
di sease i s found at the ti me of open sur gi cal expl orati on for
tumor s bel i eved to be r esectabl e on the basi s of radi ol ogi c and

l apar oscopi c stagi ng. In thi s si tuati on, the deci si on to per for m
pal l i ati ve r esecti on i s made on an i ndi vi dual i zed basi s. Pati ents
wi th metastati c di sease have a di smal pr ognosi s (see text).
Table 9.4. Complications of gastric

resection
Complication
Percentage of Patients
Affected
Pulmonary
355
Infectious
322
Anastomotic
321
Cardiac
110
Renal
Bleeding
Pulmonary
embolus
18
0.35
14
Outcomes of Surgery
The overal l 5-year sur vi val rate i n pati ents wi th gastr i c cancer i n
most Wester n ser i es i s 10% to 21% , whi ch i s a consequence of the
hi gh pr opor ti on of tumor s that ar e at an advanced stage at
pr esentati on. Pati ents who under go potenti al l y curati ve r esecti on

have a sl i ghtl y better pr ognosi s (5-year sur vi val rate of 24% 57% ).
The 5-year sur vi val rate i n pati ents who under go curati ve r esecti on
i n Japan i s r epor ted to be at l east 50% . Overal l 5-year sur vi val
rates i n Japan and the Uni ted States by TNM stage ar e l i sted i n
Tabl e 9.5.
To deter mi ne gastr i c cancer di sease-speci fi c sur vi val fol l owi ng R0
r esecti on, r esear cher s fr om Memor i al Sl oan-Ketter i ng Cancer Center
devel oped an i nter nal l y val i dated pr ognosti c nomogram. In thi s
nomogram, var i abl es i ncl uded age, gender, tumor l ocati on, Laur en
cl assi fi cati on, si ze, number of posi ti ve and negati ve l ymph nodes,
and depth. The pr edi cti ve abi l i ty of thi s nomogram was compar ed
wi th that of the cur r ent AJCC stagi ng system i n 1,039 pati ents, and
the nomogram was found to be super i or i n pr edi cti ng both 5- and 9year di sease-speci fi c sur vi val (concor dance i ndex 0.80 vs. 0.77; P
<0.001). Li mi tati ons of thi s nomogram ar e that i t needs to be
exter nal l y val i dated and i t depends on several postoperati ve factor s.
Di sease r ecur r ence has been anal yzed i n autopsy, r eoperati ve, and
cl i ni cal ser i es. Some component of di sease r ecur r ence can be found
i n up to 80% of pati ents fol l owi ng gastr ectomy. In 1982, G under son
and Sosi n anal yzed patter ns of r ecur r ence i n a pr ospecti ve study of
109 pati ents who under went gastr i c r esecti on and subsequent
r eoperati on at the Uni ver si ty of Mi nnesota. Of the 107 eval uabl e
pati ents, 86 (80% ) had r ecur r ent di sease. Locor egi onal r ecur r ence
al one ar ose i n 22 (25.6% ) of these 86 pati ents, but per i toneal
seedi ng was a component of r ecur r ence i n 54% of pati ents. Isol ated
di stant metastases wer e uncommon but occur r ed as some
component of r ecur r ence i n 29% of pati ents.
In 1990, Landr y et al . fr om Massachusetts G eneral Hospi tal
anal yzed di sease r ecur r ence i n 130 pati ents tr eated by r esecti on
wi th curati ve i ntent. The overal l l ocor egi onal r ecur r ence rate was
38% (49/130); 21 pati ents (16% ) had l ocor egi onal r ecur r ence
al one, 28 pati ents (22% ) had l ocor egi onal r ecur r ence and di stant
metastasi s, and 39 pati ents (30% ) had di stant metastasi s
al one. However, when vi ewed onl y i n ter ms of the pati ents i n whom
tr eatment fai l ed, l ocor egi onal r ecur r ence devel oped i n 57%
(49/88). The r i sk of l ocor egi onal r ecur r ence i ncr eased wi th the
degr ee of tumor penetrati on thr ough the gastr i c wal l . The most
fr equent si tes of l ocor egi onal r ecur r ence wer e the gastr i c r emnant
at the anastomosi s, the gastr i c bed, and the r egi onal nodes. The
overal l i nci dence of di stant metastasi s was 52% (67 pati ents), and
the i nci dence of di stant metastasi s i ncr eased wi th advanci ng stage

of di sease. The overal l r ecur r ence rate was 68% (88 pati ents).
Table 9.5. Five-year survival rates after

gastrectomy with complete resection and >15
lymph nodes examined
5-Year Survival Rate (%)
United Statesa
AJCC
Stage
Japanese
Japan b Germany
All (n =
Americans (n =
(n =
32,532)
(n = 697) 587)
1,017)
IA
78
95
95
86
IB
58
75
86
72
II
34
46
71
47
IIIA
20
48
59
34
IIIB
18
35
25
IV
17
16
Overall
28
42
NR
NR
AJCC, American Joint Committee on Cancer; n,

number of patients; NR, not reported.
a Data
from Hundahl SA, Phillips JL, Menck HR. The

National Cancer Data Base Report on poor survival
of U.S. gastric carcinoma patients treated with
gastrectomy: fifth edition American Joint
Committee on Cancer staging, proximal disease,
and the different disease hypothesis. Cancer
2000;88:921932.
b Data from Ichikura T, Tomimatsu S, Uefuji K, et
al. Evaluation of the New American Joint
Committee on Cancer/International Union against
cancer classification of lymph node metastasis
from gastric carcinoma in comparison with the
Japanese classification. Cancer 1999;86:553558.
c Data from Roder JO, Bottcher K, Busch R, et al.
Classification of regional lymph node metastasis
from gastric carcinoma. German Gastric Cancer
Study Group. Cancer 1998;82:621631.
In 2004, D'Angel i ca r epor ted the patter ns of r ecur r ence i n 1,172
pati ents who under went R0 r esecti on at Memor i al Sl oan-Ketter i ng
Cancer Center. At a medi an fol l ow-up of 22 months, var i ous types of
tumor r ecur r ence had devel oped i n 42.3% of the 1,172 pati ents. In
thi s anal ysi s, di sease r ecur r ed i n 79% of pati ents wi th r ecur r ence
wi thi n the fi r st 2 year s of tr eatment. Locor egi onal r ecur r ence was
the most fr equent (54% ), fol l owed by di stant (51% ) and per i toneal
(29% ) r ecur r ence. On mul ti var i ate anal ysi s, factor s pr edi cti ve of
l ocor egi onal r ecur r ence wer e mal e gender and pr oxi mal l esi ons. The
medi an ti me to death fr om the ti me of r ecur r ence was 6 months.
Inter esti ngl y, the nodal status
and the extent of l ymphadenectomy wer e not associ ated wi th
l ocor egi onal r ecur r ence. Al though thi s anal ysi s i denti fi ed the
r ecur r ence patter n and pr edi ctor s of r ecur r ence, thi s r etr ospecti ve
study had some l i mi tati ons. F i r st, 26% of pati ents wi th r ecur r ence
di d not have a r ecur r ence patter n documented. Second,
postoperati ve fol l ow-up and adjuvant tr eatments wer e not
consi stent. The effect of adjuvant therapy on r ecur r ence was al so

not eval uated.
Early Gastric Cancer

In the ear l y 1960s, the Japanese defi ned ear l y gastr i c cancer as
car ci noma l i mi ted to the mucosa and submucosa, r egar dl ess of
whether ther e wer e l ymph node metastasi s. Thi s pathol ogi cal
cl assi fi cati on was based on the hi gh cur e rate i n thi s gr oup of
pati ents. In the Uni ted States, the pr opor ti on of pati ents wi th ear l y
gastr i c cancer at di agnosi s has i ncr eased si nce the mi d-1980s to
appr oxi matel y 10% to 15% . In Japan, aggr essi ve scr eeni ng has
r esul ted i n ear l y gastr i c cancer bei ng di agnosed i n gr eater than
50% of Japanese pati ents wi th gastr i c cancer. Not sur pr i si ngl y,
ther efor e, the mean age of pati ents at di agnosi s i s 63 year s i n
Wester n studi es, wher eas i t i s 55 year s i n Japanese studi es. Most
pati ents wi th ear l y gastr i c cancer pr esent wi th gastr oi ntesti nal
symptoms si mi l ar to those of pepti c ul cer di sease, i ncl udi ng
epi gastr i c pai n and dyspepsi a or even no symptoms.
Endoscopy i s cr i ti cal for the di agnosi s of ear l y gastr i c cancer. For
exampl e, i n col l ected Wester n ser i es, al though onl y 22% of ear l y
gastr i c cancer s wer e di agnosed wi th an upper gastr oi ntesti nal tract
bar i um study, 80% wer e di agnosed wi th endoscopy. The Japanese
have cl assi fi ed ear l y gastr i c cancer pathol ogi cal l y on the basi s of
gr oss endoscopi c appearance i nto thr ee basi c mor phol ogi c types:
type I, pr otr uded or pol ypoi d; type II, super fi ci al (IIa, el evated; Ii b,
fl at; IIc, depr essed); and type III, excavated or ul cerated. Ear l y
gastr i c cancer s i ncl ude al l TNM T1 tumor s.
Despi te a hi gh potenti al cur e rate, up to 10% to 15% of ear l y
gastr i c tumor s may be associ ated wi th posi ti ve l ymph nodes.
Ther efor e, al though gastr ectomy wi th D1 or D2 l ymphadenectomy
general l y r emai ns the tr eatment of choi ce i n Japan, speci fi c cr i ter i a
have been devel oped for i denti fyi ng pati ents who r equi r e onl y
endoscopi c mucosal r esecti on. Recogni ti on that tumor si ze (mucosal
ar ea), di ffer enti ati on, l ymphovascul ar i nvasi on, and submucosal
i nvasi on ar e si gni fi cant pr edi ctor s of nodal metastases i n pati ents
wi th T1 tumor s has al so pr ovi ded the means of i denti fyi ng sel ect
pati ents wi th ear l y tumor s who r equi r e l ess aggr essi ve tr eatment.
In 1994, Takekoshi r epor ted the fi ndi ngs fr om an anal ysi s of cases
of ear l y gastr i c cancer fr om 104 center s i n Japan. In par ti cul ar,
anal ysi s of the endoscopi c appearance (pr evi ousl y descr i bed) of
ear l y tumor s i n pati ents who under went mucosal r esecti on enabl ed
the for mul ati on of speci fi c cr i ter i a for the mucosal r esecti on of ear l y
gastr i c cancer s wi thout submucosal i nvasi on. Subsequent anal yses

have l ed to r efi nements i n the cr i ter i a that must be met to ensur e
the safe endoscopi c mucosal r esecti on of AJCC T1 gastr i c cancer s.
These cr i ter i a i ncl ude onl y the fol l owi ng: (a) wel l - or moderatel y
di ffer enti ated endoscopi c type I or Ii a tumor that i s l ess than 2 cm
i n ar ea, or (b) wel l - or moderatel y di ffer enti ated endoscopi c type Ii c
tumor, wi thout an ul cer scar, that i s l ess than 1 cm i n ar ea. The
i nci dence of nodal metastases
i n pati ents i denti fi ed by these cr i ter i a was 0.01% . Al though cl ose
endoscopi c fol l ow-up i s necessar y i n pati ents who under go thi s
l ocal i zed tr eatment, the cur e rate has exceeded 90% . Conventi onal
gastr ectomy wi th at l east a D1 l ymphadenectomy i s mandated i f
submucosal i nvasi on i s found on per manent ser i al secti oni ng i n a
pati ent after an endoscopi c mucosal r esecti on.
Adjuvant Therapy
Some for m of r ecur r ence devel ops i n most pati ents who under go a
potenti al l y curati ve r esecti on for gastr i c cancer. However, al though
adjuvant therapy i s needed i n these pati ents, r esul ts have general l y
been i nconsi stent. Onl y r ecentl y has a sur vi val benefi t of adjuvant
therapy been convi nci ngl y demonstrated. Unfor tunatel y, poor
tol erance of postoperati ve tr eatment i s an obstacl e that can
fr equentl y hamper the effecti veness of the tr eatment.
Postoperative Chemotherapy
Randomi zed tr i al s i nvesti gati ng the effects of adjuvant
chemotherapy al one on sur vi val after compl ete r esecti on of gastr i c
adenocar ci noma have pr oduced i nconsi stent r esul ts. Meta-anal yses
per for med to r esol ve thi s i ssue have al so yi el ded i nconsi stent
fi ndi ngs r egar di ng the i mpact of postoperati ve chemotherapy i n
gastr i c cancer. For exampl e, i n 2002, Janunger conducted a metaanal ysi s of 21 randomi zed studi es of adjuvant systemi c
chemotherapy and found sur vi val durati on was si gni fi cantl y better
i n those who r ecei ved postoperati ve chemotherapy than i n contr ol s
(odds rati o [OR] 0.84, 95% confi dence i nter val [CI] 0.740.96).
However, when the data fr om Asi an and Wester n studi es wer e
anal yzed separatel y, no sur vi val benefi ts wer e seen for the Wester n
pati ents tr eated wi th chemotherapy (OR 0.96; 95% CI 0.831.12).
G i ven the fl aws i n the conduct of some of the randomi zed tr i al s, the
author s noted that the r esul ts of thei r meta-anal ysi s shoul d be
i nter pr eted wi th cauti on when i t came to r ecommendi ng
postoperati ve chemotherapy i n pati ents wi th gastr i c cancer.

Li kewi se, Mar i et al . noted i n thei r 2000 meta-anal ysi s of 20
randomi zed tr i al s that adjuvant chemotherapy was associ ated wi th a
sur vi val benefi t (haz ar d rati o 0.82, 95% CI 0.750.89, P <0.001).
However, these author s wer e al so r el uctant to r ecommend adjuvant
chemotherapy i n pati ents wi th gastr i c cancer because of the
i nconsi stenci es i n the fi ndi ngs fr om meta-anal yses.
Postoperative External-beam Radiation

Therapy
Most studi es of radi ati on therapy for gastr i c cancer have exami ned
radi ati on therapy as an adjuvant to sur ger y or combi ned wi th
sensi ti z i ng chemotherapy (usual l y 5-fl uor ouraci l [5-F U]).
Studi es fr om the Mayo Cl i ni c i n the 1960s of l ow-dose bol us 5-F U
wi th 40 G y exter nal -beam radi ati on therapy ver sus radi ati on
therapy al one showed that combi nati on therapy i mpr oved sur vi val .
The i mpr ovement i n sur vi val was attr i buted to a radi ati onsensi ti z i ng effect of the chemotherapy because the 5-F U dose was
r el ati vel y l ow.
Two randomi zed studi es have exami ned pati ents assi gned to r ecei ve
no addi ti onal therapy or radi ati on therapy wi th concur r ent 5-F U
after compl ete tumor r esecti on. In thei r 1979 study of 142 pati ents,
Dent et al . found no benefi t fr om thi s combi ned
r egi men, al though the fi ndi ngs may have been i nfl uenced by the
fact that some pati ents may have had an i ncompl ete r esecti on and
the radi ati on therapy dose was onl y 20 G y. In a second study i n
1984, Moer tel et al . found a benefi t to chemotherapy pl us radi ati on
therapy, but the study r esul ts may have been skewed because ten
pati ents who wer e randomi zed to the exper i mental ar m r efused
tr eatment. Nonethel ess, i nter est was generated by thi s study
because the 5-year sur vi val rate was sl i ghtl y hi gher and the l ocal
r ecur r ence rate was l ower i n the adjuvant therapy gr oup than i n the
sur ger y-onl y gr oup.
Many i nvesti gator s bel i eve that the standar d of car e for pati ents
wi th r esectabl e gastr i c cancer has changed i n the past 5 year s on
the basi s of the nati onal i nter gr oup tr i al (INT-0116) i ni ti ated by the
Southwest Oncol ogy G r oup that eval uated two cycl es of 5-F U and
l eucovor i n fol l owed by radi ati on therapy wi th concur r ent
chemotherapy fol l owi ng R0 r esecti on of gastr i c adenocar ci noma
(MacDonal d et al ., 2001). Mor e than 600 pati ents wer e randomi zed;
of these, 556 wer e eval uabl e and wer e randoml y assi gned to
curati ve r esecti on (n = 275 pati ents) or curati ve r esecti on wi th
chemoradi ati on therapy (n = 281 pati ents) consi sti ng of 45 G y
exter nal -beam radi ati on therapy del i ver ed concur r entl y wi th 5-F U
and l eucovor i n. The fi r st cycl e used the Mayo Cl i ni c r egi men (425
mg/m 2 5-F U and 20 mg/m2 l eucovor i n) for 4 consecuti ve days,
fol l owed by concur r ent chemoradi ati on therapy, wi th chemotherapy
doses decr eased at thi s poi nt and near the end of radi ati on therapy.
One month after the compl eti on of radi ati on therapy, two addi ti onal
cycl es of 5-F U and l eucovor i n wer e gi ven. Thr ee deaths wer e
attr i buted to the adjuvant therapy (1% ), and mor bi di ty was
acceptabl e; however, onl y 65% of the pati ents wer e abl e to
compl ete the adjuvant tr eatment. Nonethel ess, adjuvant therapy
pr oduced a si gni fi cant i mpr ovement i n the di sease-fr ee and overal l
3-year sur vi val rates. The medi an sur vi val i n the sur ger y-onl y
gr oup was 27 months, compar ed wi th 36 months i n the
chemoradi ati on therapy gr oup; the 3-year sur vi val rates wer e 41%
and 52% , r especti vel y. Concer ns have been voi ced r egar di ng the
sur ger y per for med and the hi gh per centage of D0
l ymphadenectomi es, wi th some i nvesti gator s ar gui ng that the
pr i nci pal benefi t of thi s r egi men i s that i t makes up for subopti mal
sur ger y. Al though 54% of pati ents had what was descr i bed as l ess
than a D1 l ymphadenectomy, thi s tr i al di d not demonstrate any
di ffer ence i n overal l or r el apse-fr ee sur vi val among the thr ee node
di ssecti on gr oups (P = 0.80).
Intraoperative Radiation Therapy

Most of the data avai l abl e on i ntraoperati ve radi ati on therapy
(IORT) for gastr i c cancer comes fr om the 1981 r epor t of Abe and
Takahashi fr om Japan. In a pr ospecti ve nonrandomi zed tr i al , these
author s compar ed 110 pati ents tr eated wi th sur ger y al one wi th 84
pati ents tr eated wi th sur ger y pl us IORT. The 5-year sur vi val rates
wer e si mi l ar i n pati ents wi th stage I di sease; however, a suggesti on
of a sur vi val benefi t fr om IORT was seen i n pati ents wi th stage II,
III, or IV di sease. In contrast, a smal l (<40 pati ents) randomi zed
study of IORT done at the Nati onal Cancer Insti tute showed nei ther
a di sease-fr ee nor an overal l sur vi val benefi t fr om IORT, despi te a
mar ked decr ease i n the fr equency of l ocor egi onal
r ecur r ence. Other studi es of IORT have general l y exami ned i t i n
combi nati on wi th other therapi es (see the next secti on).
Neoadjuvant Therapy
The use of neoadjuvant chemotherapy i n the tr eatment of gastr i c
cancer evol ved fr om pr eoperati ve tr eatment strategi es used for
esophageal and r ectal cancer s. Wi l ke et al . al so spar ked i nter est i n
thi s tr eatment as a r esul t of thei r fi ndi ngs i n pati ents wi th l ocal l y
advanced gastr i c cancer (deemed unr esectabl e ei ther cl i ni cal l y or
i ntraoperati vel y) who under went R0 r esecti on after r ecei vi ng
systemi c pr eoperati ve chemotherapy. Ther e ar e several potenti al
advantages of neoadjuvant chemotherapy for gastr i c cancer (Ajani ,
1998; Mi nsky, 1996). These i ncl ude theor eti cal bi ol ogi cal
advantages (decr eased tumor seedi ng at sur ger y), and the potenti al
oppor tuni ty to assess tumor sensi ti vi ty to a chemotherapeuti c
r egi men. That i s, i f the tumor r esponds to the neoadjuvant therapy,
the same tr eatment can be conti nued postoperati vel y. Another
theor eti cal advantage i s an i mpr oved R0 r esecti on rate. An
advantage to pr eoperati ve radi ati on therapy i s smal l er tr eatment
vol ume and di spl acement of conti guous str uctur es by the i ntact
tumor l eadi ng to r educed radi ati on therapy toxi ci ty. F i nal l y, the
i nter val r equi r ed for neoadjuvant therapy pr ovi des a ti me i n whi ch
to eval uate for pr ogr essi on of di sease, thus i mpr ovi ng pati ent
sel ecti on for r esecti on. A potenti al di sadvantage of neoadjuvant
tr eatment i s that ther e i s a r i sk of over tr eati ng pati ents wi th ear l ystage di sease, al though i mpr oved pr etr eatment stagi ng wi th EUS
mi ni mi zes thi s r i sk.
The combi nati on of etoposi de, ci spl ati n, and ei ther 5-F U (ECF ) or
doxor ubi ci n as neoadjuvant tr eatment has been eval uated i n several
tr i al s. Cl i ni cal r esponse rates have ranged fr om 21% to 31% , and
compl ete pathol ogi cal r esponse rates have ranged fr om 0% to 15% .
Mul ti var i ate anal ysi s of the thr ee phase II tr i al s of neoadjuvant
therapy at M. D. Ander son (Lowy et al ., 1999) r eveal ed that the
r esponse to neoadjuvant chemotherapy was the si ngl e most
i mpor tant pr edi ctor of overal l sur vi val after such tr eatment for
gastr i c cancer.
Several i mpor tant l essons have been l ear ned fr om phase II tr i al s
r egar di ng the r ol e of neoadjuvant chemotherapy; the most
i mpor tant one has been that the tr eatment-r el ated toxi ci ti es ar e
acceptabl e. F ur ther mor e, as pr evi ousl y menti oned, the outcome i n
those who r espond to pr eoperati ve tr eatment i s better than that i n
nonr esponder s.
In 2005, sur vi val r esul ts of the UK Medi cal Resear ch Counci l
Adjuvant G astr i c Infusi on Chemotherapy (MAG IC) tr i al wer e
pr esented at the Amer i can Soci ety of Cl i ni cal Oncol ogy annual
meeti ng. In thi s mul ti -i nsti tuti onal , pr ospecti ve randomi zed tr i al ,
503 pati ents wi th stage II or hi gher gastr i c cancer wer e randomi zed
to r ecei ve pr eoperati ve chemotherapy fol l owed by sur ger y or to
under go sur ger y al one. Those randomi zed to the pr eoperati ve
tr eatment ar m r ecei ved thr ee cycl es of ECF, fol l owed by sur ger y and
then thr ee cycl es of ECF. Onl y 42% of pati ents compl eted thei r
postoperati ve r egi men. Both pr ogr essi on-fr ee sur vi val and overal l
sur vi val wer e i mpr oved i n the tr eatment ar m (0.001 and P = 0.009
r especti vel y). The 5-year sur vi val rate was 36% i n the tr eatment
pl us sur ger y gr oup and 23% i n the
sur ger y-onl y gr oup. Despi te these pr omi si ng r esul ts, the MAG IC
tr i al i s not wi thout some cr i ti ci sm. F i r st, the tr i al i ncl uded pati ents
wi th di stal esophageal cancer s, whi ch may affect the r esul ts of the
tr i al . Second, the stagi ng i n thi s tr i al may have been subopti mal
due to l ack of EUS or stagi ng l apar oscopy.
The appr oach to adjuvant therapy for gastr i c adenocar ci noma at M.
D. Ander son has been l ar gel y to del i ver the therapy pr eoperati vel y.
Mul ti modal i ty neoadjuvant therapy combi ni ng chemotherapy wi th
exter nal -beam radi ati on therapy i s conti nui ng to be studi ed. These
studi es ar e best exempl i fi ed by a pi l ot study of pr eoperati ve
chemoradi ati on therapy wi th IORT for r esectabl e gastr i c cancer done
at M. D. Ander son (Lowy et al ., 2001) i n whi ch 24 pati ents wer e
tr eated wi th 45 G y exter nal -beam radi ati on therapy and concur r ent
i nfusi onal 5-F U (300 mg/m2 ). Pati ents wer e r estaged 4 to 6 weeks
after compl eti ng tr eatment and, i f fr ee of di sease, under went
r esecti on and IORT (10 G y). Several fi ndi ngs wer e of si gni fi cant
i nter est. Twenty-thr ee (96% ) of the 24 pati ents compl eted
chemoradi ati on therapy, a rate si gni fi cantl y hi gher than that i n
tr i al s of postoperati ve adjuvant therapy. Four pati ents had
pr ogr essi on of di sease and di d not under go r esecti on; the r emai ni ng
19 pati ents under went r esecti on wi th D2 l ymphadenectomy and
IORT. The mor bi di ty and mor tal i ty rates wer e acceptabl e (32% and
one death; r especti vel y). Of the pati ents who under went r esecti on,
two (11% ) had compl ete pathol ogi cal r esponses, and 12 (63% ) had
si gni fi cant pathol ogi cal evi dence of a tr eatment effect.
In 2004, Ajani et al . demonstrated that a pathol ogi cal compl ete
r esponse (30% ) can be achi eved thr ough a thr ee-step appr oach i n
pati ents wi th l ocal i zed gastr i c adenocar ci noma. In thi s tr i al , 28 of
34 pati ents r ecei ved i nducti on chemotherapy (5-F U [200 mg/m2 /d],
l eucovor i n [20 mg/m2 ], and ci spl ati n [20 mg/m2 /d]), fol l owed by
chemoradi ati on therapy (45 G y pl us concur r ent 5-F U) and

gastr ectomy. R0 r esecti on was achi eved i n 70% of pati ents, and a
compl ete pathol ogi cal r esponse was noted i n 30% . At a medi an
fol l ow-up of 50 months, the medi an sur vi val was 33.7 months, and
2-year sur vi val rate was 54% . Ther e wer e two tr eatment-r el ated
deaths. Thi s mul ti -i nsti tuti onal tr i al thus al so demonstrated that a
pathol ogi cal r esponse to tr eatment i s associ ated wi th a si gni fcant
sur vi val benefi t.
To di scer n whether i t i s the pathol ogi cal r esponse to pr eoperati ve
chemotherapy, and not pr etr eatment parameter s, that deter mi ne a
pati ent's outcome, i n 2005, Ajani et al . r epor ted a pr ospecti ve
nonrandomi zed study of pr eoperati ve pacl i taxel -based
chemoradi ati on therapy. In thi s anal ysi s, 43 pati ents r ecei ved two
cycl es of 5-F U, ci spl ati n, and pacl i taxel for 28 days, fol l owed by
chemoradi ati on therapy. The radi ati on r egi men i ncl uded 25 fracti ons
of 1.8 G y up to a total dose of 45 G y. Then, pati ents under went
gastr ectomy wi th spl een-pr eser vi ng D2 l ymphadenectomy after
radi ographi c and endoscopi c r estagi ng. At the ti me of anal ysi s, 78%
of pati ents had under gone an R0 r esecti on, 20% had had a compl ete
pathol ogi cal r esponse, and 15% had had a par ti al pathol ogi cal
r esponse. In thi s study, R0 r esecti on (P <0.001), pathol ogi cal
compl ete r esponse (P = 0.02), pathol ogi cal par ti al r esponse (P =
0.006), and postsur gi cal T and N status (P = 0.01 and P <0.001,
r especti vel y) wer e factor s associ ated wi th
overal l sur vi val . Al though the author s acknowl edged the i mpor tance
of pr etr eatment parameter s i n the stagi ng of gastr i c cancer,
pathol ogi cal r esponse was a major deter mi nant of outcome.
In summar y, cur r ent tr i al s of neoadjuvant chemoradi ati on therapy
ar e yi el di ng pr omi si ng r esul ts; however, these r esul ts need to be
val i dated i n the setti ng of l ar ge, pr ospecti ve randomi zed tr i al s.
Management of Advanced Disease

Many pati ents (20% 30% ) pr esent wi th stage IV di sease, and an
addi ti onal 28% to 37% i ni ti al l y bel i eved to have l ocal i zed di sease
ar e found to have metastati c di sease after compl ete stagi ng. The 5year sur vi val rate for pati ents wi th stage IV di sease appr oaches
zer ohence, a l ar ge per centage of newl y di agnosed gastr i c cancer
pati ents ar e i ncurabl e. Because of thi s overal l l ow cur e rate for
gastr i c cancer and the advanced di sease stage at pr esentati on i n
many pati ents, pal l i ati on i s an essenti al component of gastr i c cancer
management. An appr opr i ate under standi ng and use of pal l i ati ve
techni ques i s ther efor e essenti al .
Opti mal pal l i ati on r el i eves or abates symptoms, whi l e causi ng
mi ni mal mor bi di ty and i mpr ovi ng the pati ent's qual i ty of l i fe.
Pr ol onged sur vi val i s general l y not a goal of pal l i ati ve tr eatment,
but pal l i ati on may r el i eve debi l i tati ng and potenti al l y l i fethr eateni ng pr obl ems, such as gastr oi ntesti nal bl eedi ng or gastr i c
outl et obstr ucti on, whi ch may di mi ni sh sur vi val .
Palliative Surgery
Sur gi cal pal l i ati on of advanced gastr i c cancer may i ncl ude r esecti on
or bypass al one or i n combi nati on wi th other i nter venti ons.
Compl ete stagi ng i s r equi r ed for deter mi nati on of the best pal l i ati ve
appr oach.
Pal l i ati on by endoscopi c means may be appr opr i ate for pati ents wi th
per i toneal di sease, hepati c metastases, extensi ve nodal metastases,
or asci tes and for pati ents wi th pr obl ems that i ncl ude bl eedi ng or
pr oxi mal or di stal gastr i c obstr ucti on. Both mor bi di ty and mor tal i ty
ar e r el ati vel y hi gh i n these pati ents wi th a shor t l i fe expectancy.
Laser r ecanal i z ati on or si mpl e di l atati on wi th or wi thout stent
pl acement can be used to tr eat obstr ucti on. Repeat endoscopy may
be r equi r ed at per i odi c i nter val s. Pati ents who under go stent
pl acement for gastr i c outl et obstr ucti on ar e fr equentl y abl e to eat
sol i d or semi sol i d food and may not r equi r e any fur ther i nter venti on
befor e death.
The sel ecti on of pati ents for pal l i ati ve r esecti on i s compl ex. In
pati ents wi th an excel l ent per for mance status, exper i enced
sur geons can per for m pal l i ati ve di stal gastr ectomy wi th mi ni mal
mor bi di ty and acceptabl e mor tal i ty rates. Pal l i ati ve total
gastr ectomy and esophagogastr ectomy, however, shoul d be
appr oached wi th gr eater cauti on because the mor bi di ty fr om these
pr ocedur es i s hi gher. Sur ger y achi eves good pal l i ati on l ess than
50% of the ti me. In 2004, Mi nor r etr ospecti vel y r evi ewed pati ents
who under went R1 or R2 r esecti ons and di vi ded them i nto pal l i ati ve
(R1/R2) r esecti ons and nonpal l i ati ve r esecti ons (R1/R2). They
r epor ted a per i operati ve mor tal i ty rate of 7% associ ated wi th
pal l i ati ve r esecti ons ver sus 4% associ ated
wi th nonpal l i ati ve r esecti ons; the medi an sur vi val was 8.3 and 13.5
months, r especti vel y (P <0.001).
Speci fi c i ndi cati ons for pal l i ati ve r esecti on, sur gi cal bypass (open or
l apar oscopi c), and endoscopi c pal l i ati on r emai n undefi ned. However,
assessment of mor bi di ty, mor tal i ty, and qual i ty of l i fe has r eveal ed
that car eful l y sel ected pati ents (par ti cul ar l y those wi thout
macr oscopi c metastati c di sease) may benefi t fr om pal l i ati ve
r esecti on. Advanced endoscopi c techni ques, i ncl udi ng l aser or
ar gon-beam tumor abl ati on and endoscopi c pl acement of coated
metal l i c stents, pr ovi de better pal l i ati on of dysphagi a than sur gi cal
bypass wi th l ower mor bi di ty. Mul ti modal i ty therapy consi sti ng of
radi otherapy, sur ger y, and endoscopy i s l i kel y to l ead to
i mpr ovements i n qual i ty of l i fe and l ower mor bi di ty wi th pal l i ati ve
therapy. However, ear l i er di agnosi s and advances i n curati ve
therapy ar e ul ti matel y the onl y way i n whi ch the hi gh i nci dence and
mor bi di ty associ ated wi th advanced di sease i n pati ents wi th gastr i c
adenocar ci noma wi l l be defi ni ti vel y r educed.
Palliative Chemotherapy
G i ven the mi ni mal sur vi val benefi t fr om combi nati on chemotherapy
i n pati ents wi th advanced gastr i c cancer, i nvesti gator s have debated
i ts r ol e ver sus that of best suppor ti ve car e. As a r esul t, four
randomi zed tr i al s have been conducted to assess the i mpact of
combi nati on chemotherapy on sur vi val and qual i ty of l i fe. The
combi nati on r egi mens i ncl uded FAMTX (5-F U, doxor ubi ci n, and hi ghdose methotr exate), F EMTX (5-F U, epi r ubi ci n, and hi gh-dose
methotr exate), and ELF (etoposi de, l eucovor i n, and 5-F U). Pati ents
who r ecei ved combi nati on chemotherapy had both better sur vi val
(39 months) and qual i ty of l i fe than di d pati ents gi ven best
suppor ti ve car e. Despi te thi s, the outcome fr om advanced gastr i c
cancer r emai ns poor.
Palliative Radiation Therapy

Ther e ar e several i sol ated case r epor ts descr i bi ng the benefi t of
radi ati on therapy for the pal l i ati ve tr eatment of advanced gastr i c
car ci noma. However, no l ar ge pr ospecti ve tr i al has demonstrated a
l ong-ter m benefi t fr om radi ati on therapy al one i n pati ents wi th
advanced di sease. Thi s modal i ty i s most l i kel y best used i n
combi nati on wi th chemotherapy, as descr i bed pr evi ousl y i n thi s
chapter.
Intraperitoneal Hyperthermic Perfusion

Intraper i toneal hyper ther mi c per fusi on has been exami ned i n
several tr i al s as a tr eatment for advanced gastr i c cancer. For
exampl e, i n 1988, Koga et al . r evi ewed thei r exper i ence wi th a

combi nati on of hyper ther mi a and mi tomyci n C as adjuvant
tr eatment for pati ents wi th per i toneal r ecur r ence of gastr i c cancer.
These r esear cher s r epor ted that thi s pr ocedur e was techni cal l y
feasi bl e and safe. In 1990, F uji moto et al . eval uated 59 pati ents
wi th advanced gastr i c cancer who under went gastr ectomy and wer e
then randoml y assi gned to r ecei ve ei ther no fur ther therapy or
i ntraper i toneal hyper ther mi c per fusi on. The pati ents tr eated wi th
per fusi on sur vi ved l onger than di d the contr ol s (1-year sur vi val rate
of 80% vs. 34% ). A si gni fi cant sur vi val benefi t was al so seen i n
pati ents wi th per i toneal seedi ng who under went per fusi on
wi th hyper ther mi c mi tomyci n C. Si mi l ar l y, i n 1996, Yonemura et al .
r epor ted that adjuvant hyper ther mi c i ntraper i toneal chemotherapy
wi th mi tomyci n C, etoposi de, and ci spl ati n after gastr i c r esecti on i n
pati ents wi th per i toneal seedi ng r esul ted i n compl ete r esponse i n 8
(19% ) of 43 pati ents and par ti al r esponses i n 9 (21% ) of 43
pati ents. A randomi zed tr i al conducted by Yu i n pati ents who wer e
tr eated at the ti me of compl ete r esecti on of tumor s that penetrated
the gastr i c ser osa but had no evi dence of per i toneal metastases
showed that hyper ther mi c i ntraper i toneal chemotherapy wi th
mi tomyci n C l ed to a r educed i nci dence of per i toneal r ecur r ence and
a smal l sur vi val advantage at 3 year s. In 2005, Yonemura et al .
pr ospecti vel y r evi ewed 107 pati ents wi th per i toneal di ssemi nati on
fr om gastr i c adenocar ci nomas. Over a 10-year per i od, 65 pati ents
under went cytor educti ve sur ger y i n combi nati on wi th
i ntraper i toneal hyper ther mi c per fusi on befor e 1995, and 42 pati ents
under went cytor educti ve sur ger y i n combi nati on wi th
i ntraper i toneal hyper ther mi c per fusi on wi th per i tonectomy after
1995. The per fusi on r egi men i ncl uded mi tomyci n C, ci spl ati n, and
etoposi de. Compl ete cytor educti ve sur ger y was achi eved i n 43% of
107 pati ents. Ther e was a 21% postoperati ve compl i cati on rate, and
ther e wer e thr ee postoperati ve deaths (al l i n the per i tonectomy
gr oup), accounti ng for 7% of the pati ents i n thi s gr oup. At a medi an
fol l ow-up of 46 months, the 5-year sur vi val rates i n those who had
compl ete and i ncompl ete cytor educti ve sur ger y wer e 13% and 2% ,
r especti vel y (P <0.001), wi th a medi an sur vi val of 19 and 7.8
months, r especti vel y. F ur ther mor e, the 5-year sur vi val rate for
pati ents who under went cytor educti ve sur ger y by per i tonectomy was
27% (P <0.001). Mul ti var i ate anal ysi s showed that compl ete
cytor educti ve sur ger y (P = 0.010) and per i tonectomy (P = 0.012)
wer e associ ated wi th a mor e favorabl e outcome. However,
per i tonectomy was al so associ ated wi th hi gher postoperati ve
mor bi di ty (43% ) and mor tal i ty (7% ) rates. Other center s, however,
have not found such encouragi ng r esul ts. Thi s techni que i s cur r entl y
under i nvesti gati on i n a few center s ar ound the wor l d.
In summar y, ther e i s no standar d tr eatment for pati ents wi th
per i toneal car ci nomatosi s stemmi ng fr om gastr i c adenocar ci noma
other than systemi c chemotherapy i n sel ected cases. Pr ospecti ve
randomi zed studi es ar e r equi r ed to cl ar i fy the r ol e of
i ntraper i toneal therapy i n thi s setti ng.
Immunotherapy and Hormonal Therapy

Numer ous i nvesti gator s have exami ned the use of i mmunol ogi c
agents al one and i n combi nati on wi th chemotherapy as adjuvant
tr eatment i n pati ents wi th advanced gastr i c adenocar ci noma, but
the fi ndi ngs have been confl i cti ng. In 1994, Maehara et al . r epor ted
that the rates of per i toneal r ecur r ence wer e si gni fi cantl y l ower and
sur vi val ti mes si gni fi cantl y l onger i n pati ents randoml y assi gned to
r ecei ve standar d chemotherapy pl us i ntraper i toneal i njecti ons of the
str eptococcal pr eparati on OK-432 than i n pati ents who r ecei ved
chemotherapy al one. Si mi l ar l y, data fr om Japan and Kor ea
suggested that i mmunochemotherapy consi sti ng of Micr obacter iumder i ved pol ysacchar i des pr ovi des a sur vi val benefi t i n pati ents
fol l owi ng potenti al l y curati ve r esecti on. However, mor e r ecent tr i al s
have not demonstrated any
di ffer ence i n sur vi val . For exampl e, i n 2004, Sato et al . conducted a
pr ospecti ve randomi zed tr i al i n pati ents wi th gastr i c
adenocar ci noma who under went ei ther R0 r esecti on fol l owed by
adjuvant OK-432 and 5-deoxy-5 fl uor our i di ne tr eatment (n = 144)
or R0 r esecti on onl y (n = 143). The 5-year sur vi val rate i n both
gr oups was vi r tual l y the same: 63.8% and 62.9% , r especti vel y (P =
0.7996). The outcome fr om adjuvant hor monal therapy wi th
tamoxi fen i n pati ents wi th advanced gastr i c cancer has al so been
di sappoi nti ng. Never thel ess, studi es of i mmunotherapy and
hor monal therapy ar e ongoi ng. The r ol e of i mmunomodul ator s i n
gastr i c cancer r emai ns to be defi ned.
Surveillance
We typi cal l y see pati ents ever y 3 months for the fi r st 2 year s
fol l owi ng curati ve r esecti on of gastr i c adenocar ci noma. At each
fol l ow-up, a car eful hi stor y and physi cal exami nati on ar e per for med,
al ong wi th l aborator y studi es (compl ete bl ood cel l count and l i ver
functi on tests). Chest radi ographs ar e obtai ned ever y 6 months, and
abdomi nal and pel vi c CT i s per for med 6 months after sur ger y and
then year l y ther eafter. Endoscopy shoul d be consi der ed at the end
of the fi r st year i n pati ents who have under gone subtotal
gastr ectomy and can then be done year l y for 4 to 5 year s. Pati ents
who r ecei ve pr otocol -based therapy often have mor e fr equent
stagi ng studi es, but thi s has never been pr oven to i mpact pati ent
sur vi val . Per haps the most i mpor tant r easons to fol l ow pati ents
cl osel y ar e to enabl e any postgastr ectomy sequel ae to be deal t wi th
and to acqui r e accurate r ecur r ence and sur vi val data on pati ents i n
cl i ni cal tr i al s.
Gastric Lymphoma
In contrast to the decr easi ng i nci dence of gastr i c adenocar ci noma,
the i nci dence of gastr i c l ymphoma i s steadi l y i ncr easi ng, wi th nonHodgki n l ymphomas now the second most common mal i gnancy of the
stomach after adenocar ci noma. H. pylor i appear s to be a causati ve
agent i n the devel opment of both gastr i c l ymphoma and MALT
l ymphoma. The stomach i s the most common si te of l ymphoma i n
the gastr oi ntesti nal tract, accounti ng for two-thi r ds of
gastr oi ntesti nal l ymphomas. The average age of pati ents wi th
gastr i c l ymphoma i s 60 year s. The most fr equent symptoms at the
ti me of pr esentati on ar e pai n (68% ), wei ght l oss (28% ), bl eedi ng
(28% ), and fati gue (16% ). Obstr ucti on, per forati on, and massi ve
bl eedi ng ar e uncommon.
Befor e the advent of endoscopy, the di agnosi s of gastr i c l ymphoma
was usual l y made at operati on. Endoscopy now per mi ts a cor r ect
ti ssue di agnosi s to be made i n appr oxi matel y 80% of cases. Most
l esi ons ar e l ocated i n the di stal stomach and spr ead l ocal l y by
submucosal i nfi l trati on. Once the di agnosi s has been made, a
car eful wor kupi ncl udi ng a physi cal exami nati on (wi th speci al
attenti on to adenopathy); r outi ne l aborator y tests, al ong wi th
l actate dehydr ogenase and 2-mi cr ogl obul i n deter mi nati ons; a bone
mar r ow bi opsy; chest radi ograph; and CT scan of the chest,
abdomen, and pel vi sshoul d be done to ful l y deter mi ne the extent
of di sease. Pathol ogi cal exami nati on shows most cases to be B-cel l
non-Hodgki n l ymphoma, and the di ffuse hi sti ocyti c subtype i s
pr edomi nant. The di sease i s staged usi ng the modi fi ed
Ann Ar bor stagi ng system (see Chapter 17). Hi stol ogi c grade and
pathol ogi cal stage ar e two var i abl es that i ndependentl y pr edi ct
sur vi val . However, one shoul d be fami l i ar wi th the i nter nati onal
i ndex when car i ng for these pati ents.

Tr eatment for MALT l ymphoma typi cal l y i ncl udes aci d suppr essi on
therapy (pr oton pump i nhi bi tor s or H2 bl ocker s), metr oni dazol e, and
other anti bi oti cs. Pati ents need cl ose endoscopi c sur vei l l ance to
both document r egr essi on and detect r el apse, as wel l as to
deter mi ne when anti -H. pylor i tr eatment shoul d be r epeated.
Exter nal -beam radi ati on (30 G y) and/or chemotherapy i s offer ed to
(a) those who do not r espond to an anti bi oti c eradi cati on r egi men
and (b) hi gh-r i sk pati ents (i .e., those wi th l ymph node i nvol vement
or t[11;18] chr omosomal transl ocati on). At pr esent, gastr i c
r esecti on i s rar el y per for med for pati ents wi th MALT l ymphomas.
The tr eatment of gastr i c l ymphoma var i es among i nsti tuti ons, wi th
some center s advocati ng sur ger y al one, al though the number s of
such i nsti tuti ons ar e decr easi ng, and other s advocati ng
chemotherapy and radi ati on therapy al one. Sur ger y i s necessar y i n
some cases to confi r m the di agnosi s. Sur gi cal r esecti on i s curati ve
i n pati ents wi th l ocal i zed di sease, al though hal f of r esected pati ents
r equi r e chemotherapy. Al though mor e accurate stagi ng i s obtai ned
at sur ger y, thi s i s not a suffi ci ent r eason to per for m r esecti on. If
sur ger y i s per for med, an attempt shoul d be made to r esect the ar ea
gr ossl y i nvol ved wi th l ymphoma but l eave gr ossl y nor mal stomach
i ntact. Negati ve mar gi ns ar e not necessar y for cur e. In a 1990
nonrandomi zed study of pati ents wi th stage I and II gastr oi ntesti nal
l ymphomas, Tal amonti et al . noted that sur ger y al one pr oduced a 5year sur vi val rate of 82% , wher eas radi ati on therapy pr oduced a 5year sur vi val rate of onl y 50% .
Many pati ents wi th gastr i c l ymphoma who under go i ni ti al r esecti on
al so r ecei ve chemotherapy. However, some author s have found no
sur vi val benefi t associ ated wi th adjuvant chemotherapy. Sti l l other
author s bel i eve that pati ents can benefi t fr om a combi nati on of
radi ati on therapy and chemotherapy wi thout any need for sur ger y.
In fact, 10-year sur vi val rates of 80% have been seen i n pati ents
wi th Ann Ar bor stage IE and IIE gastr i c l ymphoma tr eated wi th
chemotherapy al one.
At M. D. Ander son, pati ents wi th gastr i c l ymphoma ar e i ni ti al l y
tr eated wi th a chemotherapeuti c r egi men based on doxor ubi ci n and
cycl ophosphami de, wi th a compl ete r esponse documented i n mor e
than 80% of pati ents tr eated wi th thi s pr otocol . Pati ents wi th a hi gh
i nter nati onal i ndex (i ndi cati ve of aggr essi ve di sease) may be
candi dates for bone mar r ow transpl ant. Radi ati on therapy and
sur ger y ar e r eser ved for pati ents who do not have a compl ete
r esponse to chemotherapy or who have r ecur r ent di sease.
Gastric Carcinoids
Car ci noi ds of the stomach, fi r st r epor ted i n 1923, ar e a rar e enti ty
and di sti nct fr om other car ci noi d tumor s. Despi te ear l i er r epor ts i n
whi ch gastr i c car ci noi ds wer e r epor ted to consti tute onl y 2% of
car ci noi d tumor s, evi dence fr om the Sur vei l l ance, Epi demi ol ogy, and
End Resul ts database i s now suggesti ng that gastr i c car ci noi ds
consti tute up to 5% of al l car ci noi ds. Contemporar y data
fr om case ser i es ar e al so suggesti ng a r i si ng i nci dence of these
tumor s.
G astr i c car ci noi ds ar i se fr om enter ochr omaffi n-l i ke cel l s of the
fundus of the stomach. Owi ng to the r epor ted r el ati onshi p between
pr oton pump i nhi bi tor s and car ci noi ds seen i n rats, gastr i c
car ci noi ds have gai ned wi der r ecogni ti on. The pr esenti ng featur es of
gastr i c car ci noi ds ar e var i abl e; however, they ar e commonl y
di scover ed as an i nci dental fi ndi ng dur i ng the wor kup for other
symptoms, when a yel l ow nodul e i s found i n the fundus of the
stomach.
G astr i c car ci noi ds ar e cl assi fi ed i nto thr ee types: Type I car ci noi ds
ar e associ ated wi th type A chr oni c atr ophi c gastr i ti s, type II
car ci noi ds ar e associ ated wi th Zol l i nger-El l i son syndr ome wi th
mul ti pl e endocr i ne neopl asi a-I (MEN-I) syndr ome, and type III ar e
sporadi c gastr i c car ci noi ds. Type I car ci noi ds ar e the most common
type of gastr i c car ci noi d (65% 83% ) and ar e found pr edomi nantl y
i n women. These pati ents typi cal l y have el evated pl asma gastr i n
l evel s and l ow gastr i c aci d pr oducti on. On macr oscopi c exami nati on,
the l esi ons ar e mul ti centr i c, smal l (<1 cm), and l ocated i n the
fundus. Overal l , they gr ow sl owl y and rar el y metastasi ze to other
or gans. Type II gastr i c car ci noi ds ar e the l east common type,
accounti ng for 8% of cases wi th an equal gender di str i buti on.
Al though type II gastr i c car ci noi ds ar e associ ated wi th Zol l i ngerEl l i son syndr ome i n conjuncti on wi th MEN-1 syndr ome, they shar e
featur es wi th type I car ci noi ds, such as l ocati on i n the fundus,
mul ti centr i ci ty, el evated pl asma gastr i n l evel , and smal l si ze (<1
cm). Type III gastr i c car ci noi ds, whi ch ar e sporadi c car ci noi ds,
r epr esent 23% of cases and ar e found pr edomi nantl y i n men (80% );
the mean age of pati ents at di agnosi s i s 49 year s. Pati ents may
compl ai n of hi stami ne-pr oduci ng symptoms, such as cutaneous
fl ushi ng, br onchospasm, i tchi ng, and l acr i mati on. Unl i ke the other
two types of gastr i c car ci noi ds, sporadi c tumor s ar e si ngl e, sol i tar y,
often l ar ge (25 cm), and l ocated i n the antr um or fundus of the
stomach. F ur ther mor e, the natural cour se of type III gastr i c
car ci noi ds i s mor e aggr essi ve, wi th hepati c metastasi s found at
di agnosi s i n up to 50% of cases.
G astr i c car ci noi ds ar e di agnosed by both bi ochemi cal and hi stol ogi c
means. Upper gastr oi ntesti nal endoscopy, i ncl udi ng EUS, i s al so
essenti al to eval uate the number, si ze, extent, and l ocati on of
l esi ons. In addi ti on, the endoscopi st shoul d car eful l y l ook for
duodenal car ci noi ds, especi al l y i n pati ents wi th type II gastr i c
car ci noi ds associ ated wi th Zol l i nger-El l i sonMEN-I syndr ome.
Extensi ve gastr i c bi opsy shoul d be per for med i n those wi th
suspected gastr i c car ci noi ds, checki ng for hi stol ogi c chr omograni n,
featur es of dyspl asi a, mucosal atr ophy, and the degr ee of mucosal
i nvasi on. It appear s that the rate of di agnosi s cor r el ates wi th the
number of bi opsi es per for med. F ur ther mor e, CT of the abdomen i s
essenti al to excl ude metastasi s to the l i ver and nodal i nvol vement.
The type of gastr i c car ci noi d di ctates the natur e of tr eatment. For
pati ents wi th ei ther type I or II car ci noi ds, and wi th tumor s l ess
than 1 cm or wi th fewer than thr ee to fi ve l esi ons, tr eatment
typi cal l y consi sts of an endoscopi c pol ypectomy or endoscopi c
mucosal r esecti on, wi th endoscopi c sur vei l l ance ever y 6 months.
Endoscopi c mucosal r esecti on shoul d be appr oached wi th cauti on,
however, gi ven the r epor ts of posi ti ve mar gi ns i n tumor s r emoved
by thi s means. Antr ectomy or l ocal exci si on may be per for med i n a
young pati ent wi th an el evated gastr i n l evel who has r ecur r ent or
mul ti focal di sease. Thi s tr eatment wi l l decr ease gastr i n l evel s and
fr equentl y l eads to the r egr essi on of other tumor s. Ol der pati ents
wi th many l esi ons may be fol l owed i f the l esi ons ar e smal l . For
di ffuse or r ecur r ent di sease, a compl eti on gastr ectomy may be
r ecommended, dependi ng on the pati ent's age and cour se of
di sease. In contrast, those wi th type III di sease shoul d be
consi der ed for en bl oc r esecti on wi th l ymphadenectomy, dependi ng
on the tumor si ze, al though the hi gh i nci dence of hepati c metastasi s
shoul d temper thi s deci si on.
The pr ognosi s for pati ents wi th gastr i c car ci noi ds i s var i abl e and
depends mai nl y on the type. Several studi es have suggested that
the 5-year sur vi val rates for al l types of gastr i c car ci noi ds ar e
between 48% and 52% ; these studi es di d not categor i ze the
car ci noi ds accor di ng to thei r types, so di ffer ences i n the sur vi val
rates between the types wer e not shown. It appear s that the 5-year
sur vi val rates for pati ents wi th type I or II gastr i c car ci noi ds ar e
between 60% and 75% , al though l ymph node i nvol vement i s mor e
common i n type II di sease, whi ch woul d l i kel y transl ate i nto a l ower
rate. In contrast, the 5-year sur vi val rate i n pati ents wi th type III
gastr i c car ci noi ds i s l ess than 50% .
Fol l ow-up i n pati ents wi th gastr i c car ci noi ds pr i mar i l y consi sts of
pl asma chr omograni n deter mi nati ons. Pl asma gastr i n and ur i nar y 5hydr oxyi ndol eaceti c aci d (5-HIAA) l evel s may al so be eval uated,
al though ur i nar y 5-HIAA l evel s ar e l ess sensi ti ve.
Gastric Intestinal Stromal Tumors of the

Stomach
G ISTs ar e the most common mesenchymal tumor s of the stomach,
wi th the stomach bei ng the most common l ocati on of these tumor s
i n the gastr oi ntesti nal tract (40% ), fol l owed by the smal l i ntesti ne
(32% ). G ISTs of the stomach ar e pr edomi nantl y found i n mal es,
wi th a medi an age at di agnosi s of 63 year s. The pr esenti ng featur es
i n these pati ents ar e var i ed and i ncl ude bl eedi ng (38% ), abdomi nal
pai n (11.8% ), and r uptur e (1% ); 12% of pati ents have no
symptoms. The medi an si ze of G ISTs of the stomach i s 6 cm.
Regar dl ess of the l ocati on of these tumor s i n the stomach, R0
r esecti on r emai ns the tr eatment of choi ce, confer r i ng a 5-year
sur vi val of 55% . Several studi es have shown that the featur es
r ecommended i n the NIH gui del i nes, tumor si ze (>5 cm) and mi toti c
i ndex (>5/50 hpf ), ar e associ ated wi th a l ess favorabl e outcome. In
the l ar gest r etr ospecti ve anal ysi s of G ISTs of the stomach
per for med by Mi etti ten et al . i n 2005, tumor l ocati on i n the
gastr oesophageal juncti on or fundus, ul cerati on, coagul ati ve
necr osi s, and mucosal i nvasi on wer e found to be associ ated wi th a
poor outcome (P <0.001). Antral tumor s, however, wer e found to be
associ ated wi th a mor e favorabl e outcome (P <0.001).
Those pati ents wi th unr esectabl e or metastati c di sease ar e offer ed
tr eatment wi th Imati ni b (G l eevec, an oral tyr osi ne ki nase i nhi bi tor ).
They may then be r e-eval uated for potenti al r esecti on i f they
demonstrate r esponse to tr eatment. F ur ther speci fi c detai l s
r egar di ng G ISTs ar e di scussed i n Chapter 5.
Conclusion
Str i des ar e bei ng made i n the tr eatment of gastr i c cancer. However,
al though several di agnosti c modal i ti es ar e avai l abl e for stagi ng

gastr i c cancer and ongoi ng tr i al s of neoadjuvant tr eatment ar e
yi el di ng pr omi si ng r esul ts, better systemi c agents and betterdesi gned tr i al s ar e sti l l needed. Despi te the cur r ent pr ogr ess, the
outcome i n pati ents wi th gastr i c cancer general l y r emai ns poor. As
we enter the era of tar geted therapy, i t i s i mperati ve that such
therapy al so be devel oped for gastr i c cancer and that mol ecul ar
pr edi ctor s ar e i denti fi ed to hel p i n sel ecti ng appr opr i ate tr eatment
for pati ents.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 0 - Sm a ll Bo w e l M a ligna nc ie s a nd C a rc ino id Tum o rs
10
Small Bowel Malignancies and Carcinoid
Tumors
Keith D. A mos
Rosa F. Hw ang
Epidemiology
Mal i gnanci es of the smal l i ntesti ne ar e rar e, wi th an esti mated
5,400 new cases di agnosed i n the Uni ted States i n 2006. The smal l
i ntesti ne r epr esents 75% of the l ength and 90% of the sur face ar ea
of the al i mentar y tract, accounti ng for onl y 1% of gastr oi ntesti nal
(G I) neopl asms. Adenocar ci noma, car ci noi d, l ymphoma, and sar coma
account for the major i ty of smal l bowel mal i gnanci es. The i nci dence
of thi s rar e mal i gnancy i s 0.7 to 1.6 per 100,000 per sons, wi th a
sl i ght mal e pr edomi nance. Mean age at pr esentati on i s 57 year s.
Associ ated condi ti ons i ncl ude fami l i al pol yposi s, G ar dner syndr ome,
Peutz-Jegher s syndr ome, adul t (nontr opi cal ) cel i ac spr ue, von
Reckl i nghausen neur ofi br omatosi s, and Cr ohn di sease. In addi ti on,
i mmunosuppr essed pati ents such as those wi th i mmunogl obul i n A
(IgA) defi ci ency ar e bel i eved to be at i ncr eased r i sk of smal l bowel
mal i gnanci es. As many as 25% of affected pati ents have
synchr onous mal i gnanci es, i ncl udi ng neopl asms of the col on,
endometr i um, br east, and pr ostate gl and.
The peak i nci dence of car ci noi d tumor s i s i n the si xth and seventh
decades of l i fe, al though these tumor s have been r epor ted i n
pati ents as young as 10 year s. The si tes of or i gi n of car ci noi d
tumor s ar e shown i n Tabl e 10.1. Appr oxi matel y 85% of car ci noi d
tumor s ar e found i n the G I tract, wi th the appendi x bei ng the most
common si te. Noni ntesti nal si tes i ncl ude the l ungs, pancr eas, bi l i ar y
tract, thymus, and ovar y. Il eal car ci noi ds ar e the most l i kel y to
metastasi ze, even when smal l , i n contrast to appendi ceal car ci noi ds,
whi ch rar el y metastasi ze.
Risk Factors
Several di sti ncti ve character i sti cs of the smal l i ntesti ne may expl ai n
i ts r el ati ve spar i ng fr om mal i gnancy. Benzopyr ene hydr oxyl ase, an
enz yme that conver ts benzopyr ene to a l ess car ci nogeni c compound,
i s found i n l ar ge amounts i n the mucosa of the smal l i ntesti ne. In
contrast, anaer obi c bacter i a, whi ch conver t bi l e sal ts i nto potenti al
car ci nogens, ar e general l y l acki ng i n the smal l i ntesti ne. Unl i ke the
stomach or col on, the smal l i ntesti ne i s pr otected fr om the
tumor i geni c effects of an aci di c envi r onment and fr om the i r r i tati ng
effects of sol i d G I contents. In addi ti on, the rapi d transi t of l i qui d
succus enter i cus thr ough the smal l bowel i s bel i eved to r educe i ts
tumor i geni ci ty by mi ni mi z i ng the contact ti me between potenti al
enter i c car ci nogens and the mucosa. Secr etor y IgA, al so found i n
l ar ge quanti ti es i n the smal l i ntesti ne, safeguar ds agai nst oncogeni c
vi r uses.
G I dysfuncti on may pr edi spose the smal l i ntesti ne mucosa to
tumor i genesi s. Stasi s secondar y to par ti al obstr ucti on or bl i nd
l oop syndr ome l eads to bacter i al over gr owth and has been
i mpl i cated i n the devel opment of smal l i ntesti ne mal i gnanci es.
Table 10.1. Sites of origin of carcinoid

tumors
Tumor Site
Percentage of Cases
Stomach
2.8
Duodenum
2.9
Jejunoileum
25.5
Appendix
36.2
Colon
6.0
Rectum
16.4
Bronchus
9.9
Ovary
0.5
Miscellaneous
0.2
Unknown primary
3.3
Small Bowel Malignancy
G I symptoms devel op i n 75% of pati ents wi th mal i gnant l esi ons of
the smal l bowel , compar ed wi th onl y 50% of pati ents wi th beni gn
tumor s. Si xty-fi ve per cent wi l l pr esent wi th i nter mi ttent abdomi nal
pai n that i s dul l and crampy and radi ates to the back, 50% wi th
anor exi a and wei ght l oss, and 25% wi th si gns and symptoms of
bowel obstr ucti on. Onl y 10% of pati ents wi th smal l bowel
mal i gnanci es wi l l devel op bowel per forati on, most commonl y those
wi th l ymphomas or sar comas. A pal pabl e abdomi nal mass i s pr esent
i n 25% of pati ents. Jaundi ce may be pr esent i n pati ents wi th
common bi l e duct obstr ucti on fr om ampul l ar y cancer. Epi sodi c
jaundi ce associ ated wi th guai ac-posi ti ve stool suggests an ampul l ar y
mal i gnancy.
The nonspeci fi ci ty of symptoms, when pr esent, fr equentl y r esul ts i n
a 6- to 8-month del ay i n di agnosi s. The cor r ect di agnosi s i s
establ i shed pr eoperati vel y i n onl y 50% of cases. Late detecti on and
i naccurate di agnosi s contr i bute not onl y to the advanced stage of
di sease at the ti me of sur ger y, but al so to a 50% rate of metastasi s
at pr esentati on and thus to the overal l poor pr ognosi s for pati ents
wi th mal i gnant tumor s of the smal l i ntesti ne.
Carcinoid Tumors
The pr esentati on of car ci noi ds var i es, dependi ng not onl y on thei r
physi cal character i sti cs and si te of or i gi n, but al so on whether they
ar e pr oduci ng substances that ar e hor monal l y acti ve. In general ,
most car ci noi ds ar e smal l , i ndol ent tumor s that ar e categor i zed
pathol ogi cal l y ei ther by mi cr oscopi c featur es or accor di ng to thei r
embr yol ogi c si te of or i gi n. The embr yol ogi c cl assi fi cati on of
car ci noi ds i s mor e commonl y used and i s outl i ned i n Tabl e 10.2.
Table 10.2. Characteristics of carcinoid tumor

by embryologic site of origin
Characteristics Foregut
Location
Histology
Midgut
Hindgut
Bronchus
Jejunum
Colon
Stomach
Ileum
Rectum
Pancreas
Appendix
Trabecular
Nodular,
solid
nest of
cells
Trabecula
Low
High
None
High
High
Normal
Secretion
Tumor 5-HT
Urinary 5HIAA
Carcinoid
syndrome
Other
endocrine
secretions
Yes
Yes
No
Frequent
Frequent
No
5-HIAA, 5-hydroxyindoleacetic acid; 5-HT, 5hydroxytryptamin or serotonin.

Thi s cl assi fi cati on system subdi vi des car ci noi ds i nto those of the
for egut (stomach, pancr eas, and l ungs), mi dgut (smal l bowel and
appendi x), or hi ndgut (col on and r ectum).
For egut car ci noi ds ar e mor e commonl y associ ated wi th an atypi cal
pr esentati on due to secr eti on of pepti de hor mone pr oducts other
than ser otoni n, such as gastr i n, adr enocor ti cotr opi c hor mone, or
gr owth hor mone. Pul monar y car ci noi ds ar e usual l y per i hi l ar, and
pati ents pr esent wi th r ecur r ent pneumoni a, cough, hemoptysi s, or
chest pai n. Ectopi c secr eti on of cor ti cotr opi n or gr owth hor moner el easi ng factor fr om these tumor s can pr oduce Cushi ng syndr ome
or acr omegal y, r especti vel y. G astr i c car ci noi ds ar e associ ated wi th
chr oni c atr ophi c gastr i ti s type A (CAG -A) i n 75% of cases,
pr edomi nantl y women, of whi ch hal f have per ni ci ous anemi a. These
tumor s ar e usual l y i denti fi ed on endoscopi c eval uati on for anemi a
or abdomi nal pai n and ar e l ocated i n the body or fundus of the
stomach. Another 5% to 10% of gastr i c car ci noi ds ar e associ ated
wi th Zol l i nger-El l i son syndr ome i n pati ents wi th mul ti pl e endocr i ne
neopl asi a type I. The r emai ni ng 15% to 25% of gastr i c car ci noi ds
ar e sporadi c and mor e fr equentl y appear i n men. Sporadi c for egut
car ci noi ds ar e associ ated wi th an atypi cal car ci noi d syndr ome, whi ch
i s bel i eved to be hi stami ne medi ated and exhi bi ted mai nl y as
i ntense er ythematous fl ushi ng, i tchi ng, conjuncti val suffusi on, faci al
edema, and occasi onal ur ti car i a.
Mi dgut car ci noi ds pr oduce symptoms of hor mone excess onl y when
bul ky or metastati c. Because 75% of the tumor s ar e l ocated i n the
di stal one-thi r d of the appendi x, l ess than 10% cause symptoms,
and the vast major i ty of appendi ceal car ci noi ds ar e found
i nci dental l y. Pati ents wi th smal l bowel car ci noi ds usual l y pr esent
wi th symptoms si mi l ar to those descr i bed for other smal l bowel

tumor s. Not uncommonl y, as a smal l bowel car ci noi d pr ogr esses, i t
i nduces fi br osi s of the mesenter y, whi ch may by i tsel f cause
i ntesti nal obstr ucti on and l ead to var yi ng degr ees of mesenter i c
i schemi a. Most pati ents wi th smal l bowel car ci noi ds pr esent wi th
metastases to l ymph nodes or to the l i ver.
Hi ndgut car ci noi ds tend to be cl i ni cal l y si l ent tumor s unti l they ar e
advanced. Two-thi r ds ar e found i n the r i ght col on wi th the average
tumor di ameter at pr esentati on bei ng 5 cm. They rar el y pr oduce
ser otoni n, even i n the pr esence of metastati c di sease. Pati ents wi th
hi ndgut tumor s most commonl y pr esent wi th bl eedi ng and
occasi onal l y exper i ence abdomi nal pai n.
The hor monal mani festati ons of car ci noi d tumor s (car ci noi d
syndr ome) ar e seen i n onl y 10% of pati ents and occur when the
secr etor y pr oducts of these tumor s gai n di r ect access to the
systemi c ci r cul ati on and avoi d metabol i sm i n the l i ver. Thi s cl i ni cal
syndr ome occur s i n the fol l owi ng si tuati ons: (a) when hepati c
metastases ar e pr esent; (b) when r etr oper i toneal di sease i s
extensi ve, wi th venous drai nage di r ectl y i nto the paraver tebral
vei ns; and (c) when the pr i mar y car ci noi d tumor i s outsi de the G I
tract, as wi th br onchi al , ovar i an, or testi cul ar tumor s. Ni nety
per cent of cases of car ci noi d syndr ome ar e seen i n pati ents wi th
mi dgut tumor s.
The mai n symptoms of car ci noi d syndr ome ar e water y di ar r hea,
fl ushi ng, sweati ng, wheez i ng, dyspnea, abdomi nal pai n,
hypotensi on, or r i ght hear t fai l ur e due to tr i cuspi d r egur gi tati on or
pul moni c stenosi s caused by endocar di al fi br osi s. The fl ush i s often
dramati c and i s an i ntense pur pl i sh col or on the upper body and
ar ms. Faci al edema i s often pr esent. Repeated attacks can l ead to
the devel opment of tel angi ectasi as and per manent ski n
di scol orati on. The fl ush can be pr eci pi tated by consumi ng al cohol ,
bl ue cheese, chocol ate, or r ed wi ne, and by exer ci se. The medi ator s
of these symptoms ar e shown i n Tabl e 10.3.
A l i fe-thr eateni ng for m of car ci noi d syndr ome cal l ed car cinoid cr isis
i s usual l y pr eci pi tated by a speci fi c event such as anesthesi a,
sur ger y, or chemotherapy. The mani festati ons i ncl ude an
i ntense fl ush, di ar r hea, tachycar di a, hyper tensi on or hypotensi on,
br onchospasm, and al terati on of mental status. The symptoms ar e
usual l y r efractor y to fl ui d r esusci tati on and admi ni strati on of
vasopr essor s.
Table 10.3. Clinical symptoms of carcinoid

syndrome and tumor products suspected of
causing them
Symptom
Tumor Product
Bradykinin
Flushing
Hydroxytryptophan
Prostaglandins
Vasoactive intestinal
polypeptide
Telangiectasia
Serotonin
Prostaglandins
Bradykinin
Bradykinin
Bronchospasm
Histamine
Prostaglandins
Endocardial
fibrosis
Serotonin
Glucose
intolerance
Serotonin
Arthropathy
Serotonin
Hypotension
Serotonin
Diagnostic Workup
Small Bowel Malignancies
A hi gh i ndex of suspi ci on i s essenti al to the ear l y di agnosi s and
tr eatment of smal l i ntesti ne mal i gnanci es. The pati ent pr esenti ng
wi th nonspeci fi c abdomi nal symptoms shoul d under go a compl ete
hi stor y, physi cal exami nati on, and scr eeni ng for occul t fecal bl ood.
Laborator y wor kup shoul d i ncl ude a compl ete bl ood cel l count,
measur ement of ser um el ectr ol yte l evel s, and l i ver functi on tests.
F ur ther l aborator y testi ng, i ncl udi ng measur ement of ur i nar y 5hydr oxyi ndol eaceti c aci d (5-HIAA), shoul d be di r ected by cl i ni cal
suspi ci on.
Retr ospecti ve r evi ews r epor t that 50% to 60% of smal l i ntesti ne
neopl asms ar e detected by usi ng conventi onal radi ographi c
techni ques, i ncl udi ng upper G I ser i es wi th smal l bowel
fol l owthr ough (UG I/SBF T) and enter ocl ysi s. Hypotoni c
duodenography, usi ng anti chol i ner gi c agents or gl ucagon to r educe
duodenal per i stal si s, may enhance di agnosti c yi el d to as hi gh as
86% for mor e pr oxi mal l y l ocated duodenal mal i gnanci es.
Tradi ti onal l y, computed tomography (CT) was not bel i eved to be
hel pful i n di agnosi ng smal l bowel neopl asms. However, several
r ecent r evi ews have shown that CT was abl e to detect abnor mal i ti es
i n 97% of pati ents wi th smal l bowel tumor s. Angi ography
demonstrates a tumor bl ush i n speci fi c subtypes of smal l bowel
mal i gnanci es, most notabl y, car ci noi d and l ei omyosar coma, but i s
rar el y i ndi cated i n the i ni ti al di agnosti c wor kup.
Enter oscopy shoul d be consi der ed when al l pr evi ous di agnosti c
studi es ar e negati ve. In 1991, Lewi s et al . r evi ewed the exper i ence
at Mt. Si nai Medi cal Center i n New Yor k wi th two endoscopi c
techni quespush enter oscopy and smal l bowel enter oscopyi n 258
pati ents wi th obscur e G I bl eedi ng. Push enter oscopy uses a
pedi atr i c col onoscope that i s passed oral l y and then pushed di stal l y
thr ough the smal l i ntesti ne, faci l i tati ng i ntubati on of the jejunum
60 cm di stal to the l i gament of Tr ei tz . Thi s techni que establ i shed a
di agnosi s i n 50% of pati ents exami ned. Smal l bowel enter oscopy,
whi ch uses a 120-degr ee, for war d-vi ewi ng, 2,560-mm, bal l oonti pped endoscope that i s car r i ed di stal l y by per i stal si s, per mi tted
i ntubati on of the ter mi nal i l eum i n 77% of cases wi thi n 8 hour s.
Upper G I endoscopy, when per for med to the l i gament of Tr ei tz , was
di agnosti c i n ei ght of ni ne pati ents wi th duodenal mal i gnanci es
r evi ewed by Our i el and Adams i n 2000.
Most r etr ospecti ve studi es r epor t onl y moderate success i n
di agnosi ng smal l bowel neopl asms pr eoperati vel y, wi th l ar ge ser i es
r epor ti ng a cor r ect pr eoperati ve di agnosi s i n onl y 50% of cases, the
r emai nder di agnosed at l apar otomy. Expl orator y l apar otomy r emai ns
the most sensi ti ve di agnosti c modal i ty i n eval uati ng a pati ent i n
whom smal l bowel neopl asm i s suspected and shoul d be consi der ed
i n the di agnosti c eval uati on of a pati ent wi th occul t G I bl eedi ng,
unexpl ai ned wei ght l oss, or vague abdomi nal
pai n. Di stal l y l ocated smal l bowel adenocar ci noma at or near the
i l eum i s di agnosed wi th l apar otomy i n 57% of pati ents, wi th UG I i n
21% of pati ents, and CT scan i n onl y 7% of pati ents. Because most
tumor s pr esent as l ar ge, bul ky l esi ons wi th l ymph node metastasi s,
l apar oscopy i s potenti al l y useful for establ i shi ng the di agnosi s of
mal i gnancy when the wor kup i s other wi se negati ve and for
obtai ni ng adequate ti ssue sampl es i f a di agnosi s of l ymphoma i s
suspected. Ear l y detecti on and tr eatment r emai n the most
si gni fi cant var i abl es i n i mpr ovi ng outcome fr om smal l bowel
mal i gnancy, necessi tati ng thoughtful and expedi ent di agnosti c
wor kup of pati ents pr esenti ng wi th vague abdomi nal symptoms.
Carcinoids
The di agnosi s of car ci noi d tumor i s made usi ng a combi nati on of
bi ochemi cal tests and i magi ng studi es. Overal l , appr oxi matel y 50%
of pati ents wi th car ci noi ds have el evated ur i nar y l evel s of 5-HIAA,
i r r especti ve of whether they have symptoms of car ci noi d syndr ome.
One study r epor ted 100% speci fi ci ty and 70% sensi ti vi ty of ur i nar y
5-HIAA for the pr esence of car ci noi d syndr ome and 5-HIAA l evel s
seem to cor r el ate wi th tumor bur den. Ur i nar y 5-HIAA l evel s can be
al ter ed by medi cati ons and cer tai n foods (e.g., bananas, wal nuts,
pi neappl es). When ur i nar y 5-HIAA l evel s ar e nondi agnosti c, a mor e

extensi ve wor kup shoul d be under taken, consi sti ng of measur ement
of ur i nar y 5-hydr oxytr yptami ne (5-HT, ser otoni n) and 5hydr oxytr yptophan (5-HPT), pl asma 5-HPT, pl atel et 5-HT, and ser um
l evel s of other secr etor y pr oducts such as chr omograni n A, neur onspeci fi c enol ase (NSE), substance P, and neur opepti de K. In wel l di ffer enti ated tumor s, the sensi ti vi ty of ser um chr omograni n A i s
between 80% and 100% and al so r efl ects tumor l oad. Chr omograni n
A can be used i n the detecti on of functi onal and nonfuncti onal
tumor s. An over vi ew of ser otoni n metabol i sm i s shown i n F i gur e
10.1.
Local i z ati on of the tumor may al so hel p confi r m the di agnosi s.
Br onchi al car ci noi ds ar e best vi sual i zed wi th a chest radi ograph or
CT scan. G astr i c, duodenal , col oni c, and r ectal car ci noi ds ar e
usual l y seen on endoscopy and bar i um studi es. Smal l i ntesti ne
car ci noi ds ar e i ni ti al l y eval uated as descr i bed for other smal l bowel
mal i gnanci es. Abdomi nal CT scan i s useful for assessi ng i nvol vement
of the r etr oper i toneum and pr esence of l i ver metastasi s. In
addi ti on, smal l bowel car ci noi ds have a spoke-wheel appearance on
CT due to extensi ve mesenter i c fi br osi s, and 70% of cases
demonstrate cal ci fi cati ons.
Nucl ear medi ci ne scans have al so been used i n l ocal i z ati on. Scans
usi ng Indi um 111 (1 1 1 In-penetr eoti de) or metai odobenz yl guani di ne
(MIBG ) radi ol abel ed wi th i odi ne 131 (1 3 1 I) can i denti fy pr i mar y or
metastati c car ci noi d tumor s appr oxi matel y 70% of the ti me, when
MIBG i s taken up by the tumor and stor ed i n i ts neur osecr etor y
granul es. The combi nati on of these two i magi ng modal i ti es
i ncr eases sensi ti vi ty to 95% . However, the sensi ti vi ty of detecti ng
bone metastases i s onl y 20% to 50% .
On occasi on, a pati ent may benefi t fr om angi ography or sel ecti ve
venous sampl i ng i f other di agnosti c maneuver s pr ove unsuccessful .
F i gur e 10.1. Bi ochemi cal steps i n the pr oducti on of 5hydr oxytr yptami ne (5-HT, ser otoni n) and 5-hydr oxyi ndol eaceti c
aci d (5-HIAA).
Staging
The Amer i can Joi nt Commi ttee on Cancer stagi ng system for smal l
bowel mal i gnanci es i s shown i n Tabl e 10.4.
Malignant Neoplasms
The di str i buti on of smal l bowel mal i gnanci es (r epor ted by Wei ss and
Yang i n a 1987 r evi ew of ni ne popul ati on-based cancer r egi str i es
par ti ci pati ng i n the Nati onal Cancer Insti tute's Sur vei l l ance,
Epi demi ol ogy, and End Resul ts Pr ogram) i s shown i n Tabl e 10.5.
Infor mati on on tumor bi ol ogy, modes of l ymphati c spr ead, and
patter ns of r ecur r ence for smal l bowel mal i gnanci es i s l i mi ted.
The most common hi stol ogi c types of mal i gnant tumor s of the smal l
i ntesti ne ar e adenocar ci noma (45.3% ), car ci noi d (29.3% ),
l ymphoma (14.8% ), and sar coma (10.4% ). Adenocar ci noma i s the
most common mal i gnancy i n the pr oxi mal smal l i ntesti ne, wher eas
car ci noi d i s the most common mal i gnancy i n the i l eum. Sar coma and
l ymphoma may devel op thr oughout the smal l i ntesti ne but ar e mor e
pr eval ent i n the di stal smal l bowel . Mutati ons of the Ki -r as gene ar e
found i n 14% to 53% of smal l i ntesti ne adenocar ci nomas and ar e
mor e pr eval ent i n duodenal , rather than jejunal or i l eal ,
adenocar ci nomas. In contrast, mutati ons of the APC gene ar e
uncommon i n smal l bowel car ci nomas, suggesti ng that these tumor s
ar i se thr ough a di ffer ent geneti c pathway than col or ectal
car ci nomas.
Adenocarcinoma
Pathology
Adenocar ci noma of the smal l i ntesti ne occur s most commonl y i n the
duodenum, wi th 65% of these neopl asms cl uster ed i n the
per i ampul l ar y r egi on. These tumor s i nfi l trate i nto the muscul ar i s
pr opr i a and may extend thr ough the ser osa and i nto adjacent
ti ssues. Ul cerati on i s common, causi ng occul t G I bl eedi ng and
chr oni c anemi a. Obstr ucti on may devel op fr om pr ogr essi ve gr owth
of appl e cor e l esi ons or l ar ge i ntral umi nal pol ypoi d masses. It can
mani fest as gastr i c outl et obstr ucti on i n cases of duodenal l esi ons
or sever e crampi ng pai n i n cases of mor e di stal l y l ocated l esi ons.
Appr oxi matel y 60% of tumor s ar e wel l - or moderatel y di ffer enti ated
tumor s, and 37% ar e si gnet r i ng and poor l y di ffer enti ated tumor s.

Cancer staging of small intestine
malignancies
Primary tumor (T)
T0
Tis
Carcinoma in situ
T1

submucosa
T2
T3
Tumor invades through the muscularis

propria into the subserosa or into the
nonperitonealized perimuscular tissue
(mesentery or retroperitoneum) with
extension 2 cm
T4
Tumor perforates the visceral

peritoneum or directly invades other
organs or structures (includes other
loops of the small intestine, mesentery,
or retroperitoneum >2 cm, and
abdominal wall by way of serosa; for
duodenum only, invasion of the
pancreas)

N0
N1

M0
M1
Distant metastasis
Staging
Stage
0
Tis
N0
M0
Stage
I
T1-T2
N0
M0
Stage
II
T3-T4
N0
M0
Stage
III
Any T
N1
M0
Stage
IV
Any T
Any N
M1

et al., eds. AJCC Manual for Staging of Cancer.
6th ed. Philadelphia, Pa: Springer-Verlag, with
permission.
Table 10.5. Distribution of primary malignant

in the small intestine by subsite of cancer an
type as percentages of total (N = 1,4
Subsite
Specified
Adenocarcinoma
Carcinoid
Lymphom
Duodenum
21.9
1.3
0.8
Jejunum
14.7
2.5
5.1
Ileum
Total
8.7
25.5
8.9
45.3
29.3
14.8
Adapted from NCI SEER Registries 19731982. In:

Yang C. Incidence of histologic types of cancer of t
intestine. J Natl Cancer Inst 1987;78:653, with per
Clinical Course
Adenocar ci noma of the smal l bowel fol l ows a patter n of tumor
pr ogr essi on si mi l ar to that of col on cancer, wi th si mi l ar sur vi val
rates when compar ed stage for stage. Seventy per cent to 80% of
smal l bowel l esi ons ar e r esectabl e at the ti me of di agnosi s, wi th a
5-year sur vi val rate of 20% to 30% r epor ted for pati ents
under goi ng r esecti on. Appr oxi matel y 35% of pati ents have
metastasi s to r egi onal l ymph nodes at the ti me of di agnosi s, and an
addi ti onal 20% have di stant metastasi s. Mural penetrati on, nodal
i nvol vement, di stant metastasi s, and per i neural i nvasi on cor r el ate
wi th a poor pr ognosi s. Lar ge tumor si ze and poor hi stol ogi c grade
wer e al so associ ated wi th decr eased sur vi val i n a study fr om the
Uni ver si ty of Cal i for ni a, Los Angel es, but other s have not found the
same r el ati onshi p.
Adenocar ci noma of the smal l bowel i s known to be associ ated wi th
Cr ohn di sease, usual l y occur r i ng i n the di stal i l eum. Ri sk factor s
associ ated wi th devel opment of a smal l bowel cancer i n Cr ohn
di sease i ncl ude durati on of di sease, mal e gender, associ ated
fi stul ous di sease, and the pr esence of sur gi cal l y excl uded bowel
l oops.
Treatment
Wi de exci si on of the mal i gnancy and sur r oundi ng zones of
conti guous spr ead i s per for med to pr ovi de compl ete tumor cl earance
for l esi ons l ocated i n the jejunum and the i l eum. A r etr ospecti ve
r evi ew of 217 pati ents di agnosed wi th smal l bowel adenocar ci noma
tr eated at The Uni ver si ty of Texas M. D. Ander son Cancer Center
found that sur ger y was the pr i mar y defi ni ti ve tr eatment modal i ty i n
67% of pati ents. Tr eatment strategi es rangi ng fr om
pancr eati coduodenectomy to l ocal exci si on have been pr oposed for

the management of duodenal adenocar ci noma.
Pancr eati coduodenectomy has been touted as a super i or operati on
for duodenal adenocar ci noma because of i ts mor e radi cal cl earance
of the tumor bed and r egi onal l ymph nodes. In fact, some author s,
i ncl udi ng Lai et al . i n 1988, conti nue to r ecommend
pancr eati coduodenectomy for al l pr i mar y duodenal
adenocar ci nomas. However, segmental r esecti on for adenocar ci noma
of the duodenum sati sfi es the pr i nci pl es of en bl oc r esecti on,
wi thout the mor bi di ty of a pancr eati coduodenectomy, and shoul d be
consi der ed when techni cal l y feasi bl e.
Unl i ke pancr eati c cancer, whi ch di ffusel y i nfi l trates i nto the
sur r oundi ng soft ti ssues, adenocar ci noma of the duodenum extends
i nto adjacent ti ssues as a mor e l ocal i zed pr ocess. Ther efor e, tumorfr ee r esecti on mar gi ns, cr i ti cal to a curati ve exti r pati on,
may be achi eved wi thout necessar i l y r esecti ng a gener ous por ti on of
the sur r oundi ng soft ti ssues and adjacent or gans; however, the
tumor-fr ee status of r esecti on mar gi ns must be confi r med on
fr ozen-secti on eval uati on of the r esected speci men.
In a 1994 compar i son of pancr eati coduodenectomy to segmental
r esecti on for management of duodenal adenocar ci noma at M. D.
Ander son Cancer Center, Bar nes et al . found no si gni fi cant
di ffer ence i n sur vi val rates, but di d fi nd a di ffer ence i n 5-year l ocal
contr ol rates76% for pancr eati coduodenectomy and 49% for
segmental r esecti on. Several other r evi ews, i ncl udi ng those of
Lowel l et al . i n 1992, Joestl i ng et al . i n 1981, and van Ooi jen and
Kal sbeek i n 1988, whi ch compar ed sur vi val fol l owi ng
pancr eati coduodenectomy or segmental r esecti on for l esi ons i n the
thi r d and four th por ti ons of the duodenum, have demonstrated no
si gni fi cant di ffer ence i n 5-year sur vi val . In these studi es, a mor e
l i mi ted r esecti on, wi th a l ower rate of associ ated mor bi di ty and
mor tal i ty, pr ovi ded a sur vi val benefi t equal to that of a mor e
extensi ve r esecti on.
At M. D. Ander son, a pancr eati coduodenectomy i s per for med for
l esi ons i nvol vi ng the pr oxi mal duodenum to the r i ght of the super i or
mesenter i c ar ter y (SMA). A segmental r esecti on i s per for med for
duodenal l esi ons to the l eft of the SMA. Local exci si on i s consi der ed
for smal l l esi ons on the anti mesenter i c wal l of the second por ti on of
the duodenum. Two studi es have found a hi gher rate of
postoperati ve compl i cati ons fr om pancr eati coduodenectomy i n
pati ents wi th per i ampul l ar y mal i gnanci es than i n those wi th
pancr eati c adenocar ci noma, al though thi s di d not r esul t i n a hi gher

rate of per i operati ve mor tal i ty i n ei ther study. An i ncr eased
pancr eati c anastomoti c l eak rate was pr esent i n the gr oup wi th
duodenal car ci noma, pr esumabl y due to the fact that the pancr eas
i n these pati ents woul d be nor mal wi th a soft textur e, ther eby
i ncr easi ng the techni cal di ffi cul ty of the pancr eati c anastomosi s.
Experimental Therapy
El ectr on-beam i ntraoperati ve radi ati on therapy and exter nal -beam
radi ati on therapy have been admi ni ster ed at M. D. Ander son i n a
l i mi ted number of cases of mi cr oscopi c i nvol vement of r esecti on
mar gi ns or unr esectabl e di sease. However, adenocar ci noma of the
smal l i ntesti ne i s general l y consi der ed to be radi ati on r esi stant.
Chemotherapy, based on 5-fl uor ouraci l (5-F U) and ni tr osour eas, has
been r ecommended i n both the adjuvant setti ng and i n cases of
unr esectabl e di sease, yet most r etr ospecti ve studi es have fai l ed to
demonstrate a si gni fi cant r esponse to chemotherapy. Because most
center s have onl y l i mi ted exper i ence tr eati ng adenocar ci noma of
the smal l i ntesti ne, the effi cacy of chemotherapy needs fur ther
study, and pati ents shoul d conti nue to be enr ol l ed i n pr ospecti ve
randomi zed cl i ni cal tr i al s.
Carcinoid
Pathology
Car ci noi ds ar e known mai nl y for thei r abi l i ty to secr ete ser otoni n
and ar e the most common endocr i ne tumor s of the G I system. They
ar i se fr om enter ochr omaffi n cel l s, whi ch ar e l ocated
pr edomi nantl y i n the G I tract and mai nstem br onchi . In addi ti on to
ser otoni n, these tumor s can secr ete a number of bi ol ogi cal l y acti ve
substances (Tabl e 10.6), i ncl udi ng ami nes, tachyki ni ns, pepti des,
and pr ostagl andi ns.
Table 10.6. Biologically active substances

that can be secreted by carcinoid tumors
Amines
5-HT
5-HIAA
5-HTP
Histamine
Dopamine
Tachykinins
Kallikrein
Substance P
Neuropeptide K
Others
Prostaglandins
Pancreatic polypeptide
Chromogranins
Neurotensin
hCGa
hCGb
5-HT, 5-hydroxytryptamine; 5-HIAA, 5hydroxyindoleacetic acid; 5-HTP, 5hydroxytryptophan; hCG, human chorionic
gonadotropin.
Car ci noi d tumor s occur most fr equentl y i n the appendi x (40% ),
smal l i ntesti ne (27% ), r ectum (15% ), and br onchus (11% ). Smal l
bowel car ci noi ds occur most commonl y i n the ter mi nal 60 cm of the
i l eum as tan, yel l ow, or gray-br own i ntramural or submucosal
nodul es. The pr esence of mul ti pl e synchr onous nodul es i n 30% of
pati ents mandates car eful i nspecti on of the enti r e smal l i ntesti ne i n
these pati ents.
Clinical Course
Pr i mar y car ci noi d tumor s ar e i ndol ent, sl ow-gr owi ng l esi ons that
become symptomati c l ate i n the cour se of the di sease. Rar el y
ul cerati ve, these tumor s i nfi l trate the muscul ar i s pr opr i a and may
extend thr ough the ser osa to i nvol ve the mesenter y or

r etr oper i toneum and to pr oduce a character i sti cal l y i ntense
desmopl asti c r eacti on.
Metastati c di sease, pr esent i n 90% of symptomati c pati ents,
cor r el ates not onl y wi th the depth of i nvasi on, but al so wi th the si ze
of the pr i mar y l esi on. For car ci noi ds l ess than 1 cm, the r i sk of
metastasi s i s 2% for appendi ceal , 15% to 18% for smal l bowel , and
20% for r ectal pr i mar i es. If car ci noi d tumor s ar e gr eater than 2 cm,
33% of appendi ceal , 86% to 95% of smal l bowel , and al most al l
r ectal pr i mar i es have metastasi zed.
Di stant si tes of metastases i ncl ude the l i ver and, to a l esser degr ee,
the l ungs and bone. Ther e i s no wi del y accepted hi stol ogi c
cl assi fi cati on of car ci noi ds that accuratel y pr edi cts metastati c
behavi or. Mor phol ogi c cr i ter i a such as mi toti c acti vi ty, cytol ogi c
atypi a, and tumor necr osi s have been eval uated; however, these
featur es can be affected by i schemi a secondar y to mesenter i c
scl er osi s i n G I car ci noi ds. An anal ysi s of G I car ci noi ds by Moyana et
al . i n 2000 r eveal ed that posi ti ve i mmunohi stochemi cal stai ni ng for
MIB-1 (a mar ker of pr ol i ferati on) and p53 was associ ated wi th
metastati c behavi or. In addi ti on, hi gh l evel s of the nucl ear anti gen
Ki -67 appear s to cor r el ate wi th decr eased sur vi val i n pati ents wi th
car ci noi d tumor s.
Treatment of Localized Disease

Sur gi cal exti r pati on i s the defi ni ti ve tr eatment for l ocal i zed pr i mar y
car ci noi d tumor s. The extent of r esecti on i s deter mi ned by the si ze
of the pr i mar y l esi on and i s based on the l i kel i hood of mesenter i c
l ymph node i nvol vement. The i nci dence of metastasi s depends on
the l ocati on of the tumor, i ts depth of i nvasi on, and i ts si ze.
Appendi ceal car ci noi ds smal l er than 1 cm rar el y metastasi ze and ar e
adequatel y tr eated by appendectomy al one unl ess the base of the
appendi x i s i nvol ved, i n whi ch case a par ti al cecectomy may be
necessar y. Because the i nci dence of metastasi s i ncr eases wi th
pr i mar y tumor si ze, tr eatment of appendi ceal car ci noi ds between 1
and 2 cm i s mor e contr over si al . In general , most author s
r ecommend appendectomy al one for l esi ons smal l er than 1.5 cm and
r i ght hemi col ectomy for l esi ons l ar ger than 1.5 cm or for any l esi on
wi th i nvasi on of the mesoappendi x, bl ood vessel s, or r egi onal l ymph
nodes.
In contrast to appendi ceal car ci noi ds, car ci noi ds of the smal l bowel
ar e mor e l i kel y to metastasi ze even when smal l er than 1 cm. As a

r esul t, most sur geons r ecommend a wi de en bl oc r esecti on that
i ncl udes the adjacent mesenter y and l ymph nodes. Such a r esecti on
may be di ffi cul t at ti mes; the smal l bowel mesenter y i s fr equentl y
fi br oti c and for eshor tened secondar y to a desmopl asti c r eacti on
seen wi th these tumor s. Al though some sur geons advocate l ocal
exci si on for smal l mi dgut car ci noi ds, up to 70% of these tumor s
metastasi ze to the l ymph nodes. Ther efor e, a wi de r esecti on may
not onl y cur e some of these pati ents, but shoul d al so pr ovi de better
l ocal di sease contr ol than l ocal exci si on. F ur ther mor e, a car eful and
thor ough exami nati on of the enti r e l ength of bowel i s i mpor tant
because 20% to 40% of smal l bowel car ci noi ds ar e mul ti centr i c.
Because of the sl ow-gr owi ng natur e of these tumor s, wi de exci si on
i s advocated even when di stant metastases ar e pr esent. In addi ti on,
appr oxi matel y 40% of pati ents wi th mi dgut car ci noi ds have a second
G I mal i gnancy. Ther efor e, the enti r e bowel and col on shoul d be
eval uated befor e any pl anned sur gi cal i nter venti on.
Rectal car ci noi ds l ess than 1 cm, whi ch compr i se two-thi r ds of al l
r ectal car ci noi ds, ar e adequatel y tr eated by wi de l ocal exci si on
al one. Tumor s between 1 and 2 cm shoul d be l ocal l y r esected by a
wi de, l ocal , ful l -thi ckness exci si on wi th abdomi noper i neal r esecti on
or l ow anter i or r esecti on r ecommended for tumor s that i nvade the
muscul ar i s pr opr i a. The tr eatment of pati ents wi th r ectal car ci noi ds
gr eater than 2 cm r emai ns contr over si al . Even though major
oncol ogi c operati ons wer e once r ecommended for r ectal car ci noi ds
gr eater than 2 cm, i t i s now appr eci ated that the
r i sk of di stant metastasi s i s so hi gh that radi cal sur ger y shoul d not
be consi der ed i f the tumor can be r emoved by wi de l ocal exci si on.
Ever y attempt shoul d be made for sphi ncter pr eser vati on i n pati ents
wi th car ci noi ds of the r ectum of gr eater than 2 cm because of the
hi gh l i kel i hood of di stant fai l ur e and the mar gi nal benefi t obtai ned
fr om radi cal l ocal therapy.
Long-ter m pr ognosi s after sur gi cal tr eatment of pati ents wi th G I
car ci noi ds was eval uated i n a study fr om the Mayo Cl i ni c. Wi th a
medi an fol l ow-up of 18 year s, sur vi val was si gni fi cantl y associ ated
wi th embr yol ogi c or i gi n of the tumor and pati ent age. Incr eased
sur vi val was found i n those pati ents wi th mi dgut car ci noi ds,
compar ed wi th those wi th for egut tumor s, as wel l as i n pati ents
younger than 62 year s. Overal l sur vi val rates at 5 and 10 year s
wer e 69% and 53% , r especti vel y.
Treatment of Advanced Disease

The r ol e of sur ger y for unr esectabl e and metastati c di sease i s not
cl ear l y defi ned, but i t appear s that sur ger y may benefi t some
pati ents. When metastati c di sease i s pr esent, i t i s necessar y to
establ i sh whether the pati ent has symptoms of car ci noi d syndr ome
and whether curati ve r esecti on i s possi bl e. If the pati ent has no
contrai ndi cati ons to sur ger y, then an attempt at compl ete
exti r pati on shoul d be made because i t may l ead to pr ol onged
di sease-fr ee sur vi val and symptomati c r el i ef. Pati ents wi th
metastati c car ci noi d shoul d al l begi n r ecei vi ng octr eoti de therapy
pr eoperati vel y to pr event a car ci noi d cr i si s. Sur gi cal r esecti on of
l i ver metastases has r esul ted i n l ong-ter m r el i ef of symptoms.
Ei ghty-two per cent of pati ents wi th mi dgut car ci noi ds metastati c to
the l i ver who under went r esecti on demonstrated par ti al or compl ete
r el i ef of symptoms wi th a mean durati on of 5.3 year s. Pati ents i n
whom l i ver metastases fr om car ci noi d tumor ar e suspected shoul d
under go an abdomi nal CT scan. The study shoul d be done befor e and
after i ntravenous (IV) contrast mater i al to better vi sual i ze car ci noi d
l i ver metastases, whi ch ar e usual l y hyper vascul ar and can be
di ffi cul t to di sti ngui sh fr om nor mal l i ver after i njecti on of IV
contrast mater i al .
Pati ents wi th mi l dl y symptomati c car ci noi d syndr ome can be tr eated
medi cal l y. Di ar r hea can usual l y be contr ol l ed wi th l operami de,
di phenoxyl ate, or the ser otoni n r eceptor antagoni st cypr oheptadi ne.
F l ushi ng can fr equentl y be contr ol l ed wi th ei ther adr ener gi c
bl ocki ng agents (e.g., cl oni di ne or phenoxybenz ami ne) or a
combi nati on of type 1 and 2 hi stami ne r eceptor antagoni sts.
Al buter ol (a beta-adr ener gi c bl ocki ng agent) and ami nophyl l i ne ar e
effecti ve i n r el i evi ng br onchospasm and wheez i ng.
For pati ents whose symptoms cannot be contr ol l ed wi th these
conser vati ve measur es or i n whom a car ci noi d cr i si s devel ops, the
somatostati n anal og octr eoti de has shown tr emendous pr omi se. A
tr i al fr om the Mayo Cl i ni c found that fl ushi ng and di ar r hea coul d be
contr ol l ed i n the vast major i ty of pati ents wi th as l i ttl e as 150 g of
octr eoti de admi ni ster ed subcutaneousl y thr ee ti mes per day. The
durati on of the r esponses was on the average mor e than 1 year.
Inter esti ngl y, a number of studi es have now shown that octr eoti de
i s al so abl e to sl ow tumor gr owth si gni fi cantl y i n mor e than 50% of
pati ents and to cause tumor r egr essi on for var i abl e per i ods i n
another 10% to 20% of i ndi vi dual s. Lanr eoti de, another
l ong-acti ng somatostati n anal og, i s avai l abl e i n sl ow-r el ease

for mul ati on. Tr eatment wi th l anr eoti de by i njecti on ever y 10 to 14
days appear s to be as effecti ve as dai l y octr eoti de for mal i gnant and
nonmal i gnant endocr i ne di sor der s. F ur ther mor e, tr eatment wi th a
depot for mul ati on of octr eoti de, 20 mg i ntramuscul ar l y ever y 4
weeks, r esul ted i n symptomati c r el i ef and tumor r egr essi on i n a
pati ent wi th di ssemi nated car ci noi d who had pr ogr essed dur i ng
tr eatment wi th l anr eoti de combi ned wi th i nter fer on al fa.
Because such good r esul ts can be achi eved wi th octr eoti de,
i nter fer on, or hepati c ar ter y chemoembol i z ati on, sur gi cal debul ki ng
pr ocedur es, whi ch used to be r ecommended for pati ents wi th
symptomati c car ci noi d syndr ome and l i ver metastasi s, ar e rar el y
r equi r ed. Pati ents wi th unr esectabl e di sease, i f asymptomati c,
shoul d just be moni tor ed. Local compl i cati ons r el ated to the tumor
can be addr essed i f and when they devel op. Our cur r ent i ndi cati ons
for sur gi cal i nter venti on i n unr esectabl e and wi del y metastati c
di sease i ncl ude compl i cati ons of bul ky car ci noi d tumor s such as
obstr ucti on and per forati on. In addi ti on, sur gi cal debul ki ng i s
consi der ed for sever e i ntractabl e symptoms unr esponsi ve to medi cal
tr eatment, i f a domi nant mass or l i ver metastasi s can be i denti fi ed.
For pati ents who have under gone l i ver r esecti on for metastati c
car ci noi d tumor s, R2 (vs. R0) r esecti on and pancr eati c l ocati on of
the car ci noi d have been associ ated wi th poor er pr ognosi s.
Despi te the advanced stage of di sease at pr esentati on and the
l i mi ted effecti veness of cur r entl y avai l abl e therapi es, the natural
hi stor y of car ci noi ds affor ds affected pati ents a better pr ognosi s
than other mal i gnanci es of the smal l bowel . The 5-year sur vi val
rate for l ocal i zed di sease appr oaches 100% after compl ete
r esecti on. Resecti on of metastati c di sease i s associ ated wi th a 68%
5-year sur vi val rate, wher eas unr esectabl e di sease has a 38% 5year sur vi val rate.
A number of chemotherapeuti c agents have been studi ed i n pati ents
wi th car ci noi d tumor s. Resul ts of chemotherapy tr i al s wi th such
agents as doxor ubi ci n, dacar baz i ne, and str eptozotoci n, ei ther al one
or i n combi nati on, have been di sappoi nti ng. Most chemotherapy
tr i al s show r esponse rates of l ess than 30% , wi th r esponses l asti ng
onl y a few months. The r ol e of chemotherapy i s sti l l i nvesti gati onal ,
but for pati ents wi th advanced di sease that cannot be contr ol l ed
wi th standar d measur es, moni tor ed cl i ni cal tr i al s shoul d be
r ecommended.
One bi ol ogi cal agent, i nter fer on, i n both al fa-2a and al fa-2b for ms,
has demonstrated pr omi si ng r esul ts i n di mi ni shi ng ur i nar y l evel s of
5-HIAA and symptoms of car ci noi d syndr ome. Most pati ents i n
var i ous studi es exper i enced ei ther par ti al r egr essi on or stabi l i z ati on
of thei r di sease for a pr ol onged per i od. Unfor tunatel y, objecti ve
r esponses wi th r educti on of tumor si ze occur r ed i n onl y
appr oxi matel y 15% of pati ents.
In some center s, hepati c ar ter y occl usi on or embol i z ati on has been
used wi th some success to di mi ni sh the si ze of l i ver metastases and
decr ease l evel s of bi ol ogi cal l y acti ve medi ator s of car ci noi d
syndr ome. However, durati on of r esponse i s usual l y shor t, wi th
medi an durati on rangi ng fr om 7 months for hepati c ar ter y
occl usi on al one to 20 months i n a study usi ng hepati c ar ter y
occl usi on fol l owed by systemi c chemotherapy. F ur ther mor e, si de
effects may be substanti al . Li ver embol i z ati on wi th G el foam
per for med i n pati ents wi th neur oendocr i ne tumor s r esul ted i n
ser i ous compl i cati ons i n 10% , i ncl udi ng r enal fai l ur e, l i ver necr osi s,
and bowel i schemi a. Another opti on for management of car ci noi d
hepati c metastases i s radi ofr equency abl ati on (RFA). In one smal l
ser i es, RFA was used as sal vage therapy i n pati ents wi th hepati c
metastases who wer e not amenabl e to sur gi cal r esecti on and
unr esponsi ve to embol i z ati on. Al though onl y thr ee pati ents wer e
tr eated, al l thr ee demonstrated decr eases i n both the si ze of the
l esi ons and the sever i ty of symptoms. Because RFA can be
per for med per cutaneousl y or l apar oscopi cal l y, thi s may be a useful
tr eatment al ter nati ve for pati ents wi th di ssemi nated car ci noi d
tumor s.
Al though exter nal -beam radi ati on has not pr oven effecti ve i n
tr eati ng car ci noi d tumor s, tar geted radi ati on i n the for m of
radi oacti ve i odi ne coupl ed to ei ther MIBG or octr eoti de i s a
therapeuti c strategy that may hol d some pr omi se for the futur e.
Sarcoma
Pathology
Sar comas of the smal l i ntesti ne ar e typi cal l y sl ow-gr owi ng l esi ons;
they occur mor e fr equentl y i n the jejunum and i l eum than i n the
duodenum. Shar i ng a si mi l ar gr owth patter n wi th other G I
sar comas, these mal i gnanci es i nvade adjacent ti ssues, wi th
metastasi s occur r i ng pr edomi nantl y vi a the hematogenous r oute to
the l i ver, l ungs, and bones. The most common cl i ni cal pr esentati ons
ar e pai n (65% ), abdomi nal mass (50% ), and bl eedi ng. Mor e than
75% of tumor s exceed 5 cm i n di ameter at di agnosi s, wi th
extramural extensi on, rather than i ntramural or i ntral umi nal
extensi on, r epr esenti ng the typi cal gr owth patter n. For thi s r eason,
obstr ucti on i s rar el y a mani festati on of thi s di sease pr ocess.
CT scan of these l esi ons typi cal l y demonstrates a heter ogeneous
mass wi th focal ar eas of necr osi s wher e the tumor has outgr own i ts
nutr i ent bl ood suppl y and for med l ocal i zed abscesses.
Lei omyosar coma and gastr oi ntesti nal str omal tumor (G IST) account
for 75% of smal l i ntesti ne sar comas; fi br osar coma, l i posar coma, and
angi osar coma ar e seen l ess fr equentl y. In summar y, sar coma
r epr esents onl y 10% of smal l bowel mal i gnanci es, yet the var i ous
subtypes encompass a br oad range of bi ol ogi cal behavi or, the scope
of whi ch exceeds thi s r evi ew.
Treatment
Sur gi cal r esecti on i s the pr i mar y tr eatment modal i ty for sar coma of
the smal l bowel . Because sar coma i nfr equentl y metastasi zes to
r egi onal mesenter i c l ymph nodes, unl i ke adenocar ci noma and
car ci noi d, an extensi ve mesenter i c l ymphadenectomy i s unnecessar y
and wi l l not pr ol ong sur vi val . En bl oc r esecti on of the l esi on wi th
tumor-fr ee mar gi ns i s r ecommended for a potenti al l y curati ve
r esecti on; however, at the ti me of di agnosi s, 50% of l esi ons ar e
unr esectabl e and most exceed 5 cm i n di ameter. Local r esecti on
shoul d be consi der ed i n the pr esence of wi del y metastati c di sease
for contr ol of bl eedi ng and r el i ef of obstr ucti on.
Lei omyosar comas of the smal l bowel ar e r esi stant to chemotherapy
and radi ati on therapy. Combi ned chemotherapy and radi ati on
therapy shoul d be offer ed to pati ents wi th l ei omyosar comas onl y as
par t of an exper i mental pr otocol i n an attempt to downstage the
di sease or possi bl y make an unr esectabl e l esi on r esectabl e.
Chemotherapy can be used i n the tr eatment of r ecur r ent or
metastati c di sease, but agai n, onl y as par t of an exper i mental
pr otocol . Cur r entl y at M. D. Ander son, chemoembol i z ati on wi th
ci spl ati n i s used i n pati ents wi th metastati c di sease to the l i ver.
Sar comas of other hi stol ogi c subtypes, most i mpor tantl y, the G ISTs,
ar e di scussed i n Chapter 5.
Lymphoma
Pathology
The di str i buti on of l ymphoma i n the smal l i ntesti ne paral l el s the
di str i buti on of l ymphoi d fol l i cl es i n the smal l i ntesti ne, wi th the
l ymphoi d-r i ch i l eum r epr esenti ng the most common l ocati on of smal l
bowel l ymphoma. Lymphoma ar i ses fr om the l ymphoi d aggr egates i n
the submucosa; i nfi l trati on of the mucosa can r esul t i n ul cerati on
and bl eedi ng. The tumor may al so extend to the ser osa and adjacent
ti ssues, pr oduci ng a l ar ge obstr ucti ng mass associ ated wi th
crampi ng abdomi nal pai n. Per forati on occur s i n as many as 25% of
pati ents. Lymphoma may ar i se as a pr i mar y neopl asm or as a
component of systemi c di sease wi th G I i nvol vement. As wi th
sar coma, bul ky di sease i s a character i sti c of l ymphoma, wi th
appr oxi matel y 70% of tumor s l ar ger than 5 cm i n di ameter.
Pr i mar y tumor s ar e staged accor di ng to the Ki el cl assi fi cati on (see
Chapter 17) as l ow, i nter medi ate, or hi gh grade, wi th hi gh-grade
l esi ons bei ng di agnosed most fr equentl y. Pr ognosti c factor s i ncl ude
tumor grade, extent of tumor penetrati on, nodal i nvol vement,
per i toneal di sease, and di stant metastasi s. The 5-year sur vi val rate
ranges fr om 20% to 33% .
Treatment
The i ni ti al tr eatment for pr i mar y l ymphoma of the smal l bowel i s
chemotherapy. Unfor tunatel y, chemotherapy i s not al ways abl e to be
admi ni ster ed due to i ntra-abdomi nal compl i cati ons of the tumor,
most notabl y obstr ucti on and per forati on. In addi ti on, per forati on of
the bowel may r esul t after i ni ti ati ng chemotherapy due to the
i nher ent thi n wal l of the smal l i ntesti ne. In these cl i ni cal si tuati ons,
extended sur gi cal r esecti on of the pr i mar y l esi on may be a safer
i ni ti al appr oach. Resecti on shoul d extend to gr ossl y nor mal bowel ;
ther e i s no r ol e for fr ozen-secti on eval uati on of mar gi ns because
potenti al mi cr oscopi c di sease wi l l be adequatel y tr eated by adjuvant
chemotherapy. Lymph node metastases ar e fr equent; however, en
bl oc r esecti on of the adjoi ni ng mesenter y i s onl y i ndi cated i f i t i s
necessi tated by the pr i mar y tumor mass for techni cal
consi derati ons. Other wi se, the tumor bur den i n the l ymph nodes i s
better tr eated wi th adjuvant chemotherapy. The fi r st-l i ne
chemotherapy r egi men cur r entl y used at the M. D. Ander son Cancer
Center i s cycl ophosphami de, doxor ubi ci n, vi ncr i sti ne, and
pr edni sone.
Chemoradi ati on has been used at some i nsti tuti ons for nodal
metastasi s, posi ti ve r esecti on mar gi ns, and unr esectabl e di sease.
However, a sur vi val benefi t fr om such tr eatment r egi mens has not
been demonstrated. The use of radi ati on therapy al one has been
associ ated wi th si gni fi cant tumor necr osi s, bl eedi ng, and bowel
per forati on, but may be consi der ed i n el der l y pati ents unabl e to
tol erate the toxi ci ty of chemotherapy.
Metastatic Malignancies
Pathology
Metastases ar e the most common for m of mal i gnancy i n the smal l
i ntesti ne and devel op as a r esul t of hematogenous or l ymphati c
spr ead fr om a pr i mar y tumor to the mucosa or submucosal
l ymphati cs of the smal l i ntesti ne. The pr i mar y tumor s that most
commonl y metastasi ze to the smal l bowel i ncl ude ovar i an, col on,
l ung, and mel anoma. Metastati c mel anoma i s uni que i n that once
l ocal i zed i n the smal l bowel , the metastati c focus may fur ther
di ssemi nate to the smal l bowel mesenter y and drai ni ng l ymph
nodes. In general , however, smal l bowel metastases r emai n
l ocal i zed to the bowel wal l , and they may pr oduce smal l bowel
obstr ucti on (fr equentl y due to i ntussuscepti on wi th mel anoma
metastases) or per forati on.
Al though the typi cal pr esentati on of metastati c l esi ons i s
obstr ucti on or per forati on, the mor e common cause of obstr ucti on
and per forati on i n pati ents who have pr evi ousl y under gone
r esecti on of a G I pr i mar y tumor i s r el ated to the i ni ti al pr ocedur e
that i s, ei ther r ecur r ence of the pr i mar y tumor or adhesi ons
r esul ti ng fr om the i ni ti al expl orati on.
Segmental bowel r esecti on i s the pr i mar y tr eatment for smal l bowel
metastases. Except for mel anoma metastases, whi ch may functi on
as a sour ce of fur ther l ymphati c di ssemi nati on, a r egi onal
l ymphadenectomy i s not per for med for metastati c tumor s of the
smal l i ntesti ne.
Palliation
At the ti me of di agnosi s, most smal l bowel mal i gnanci es ar e l ocal l y

advanced, wi th si gni fi cant bul ky di sease or metastases. When the
advanced stage of di sease pr ecl udes sur gi cal r esecti on, enter i c
bypass shoul d be per for med to pr event obstr ucti on. In the event of
bl eedi ng fr om an unr esectabl e smal l bowel mal i gnancy, i ntraar ter i al embol i z ati on of nutr i ent ar ter i es may be consi der ed, but the
benefi ts must be wei ghed agai nst the si gni fi cant r i sks of thi s
pr ocedur e. Our exper i ence wi th thi s techni que at M. D. Ander son
Cancer Center has been di scouragi ng because of the si gni fi cant rate
of bowel i schemi a and per forati on associ ated wi th embol i z ati on of
the smal l bowel mesenter y.
Chemotherapy or chemoradi ati on may offer effecti ve contr ol of
l ocal l y advanced unr esectabl e di sease, par ti cul ar l y i n the case of
l ymphoma, and shoul d be consi der ed as a pal l i ati ve tr eatment
opti on.
Surveillance
Routi ne fol l ow-up for pati ents shoul d i ncl ude a compl ete hi stor y and
physi cal exami nati on, compl ete bl ood cel l count, ser um el ectr ol yte
deter mi nati on, and l i ver functi on tests per for med at r egul ar
i nter val s. A chest radi ograph shoul d be obtai ned ever y 6 months for
the fi r st 3 year s after r esecti on, fol l owed by subsequent year l y
exami nati ons. Assessment of l ocor egi onal r ecur r ence i n pati ents
who have under gone a r i ght hemi col ectomy for i l eal mal i gnancy or
segmental r esecti on for duodenal mal i gnancy shoul d i ncl ude
endoscopy at 6-month i nter val s. Assessment for r ecur r ence at other
si tes may i ncl ude CT scan, UG I/SBF T, angi ography, or enter oscopy
and must be di r ected by cl i ni cal suspi ci on based on pati ent hi stor y
and physi cal and l aborator y fi ndi ngs.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 1 - C a nc e r o f t he C o lo n, Re c t um , a nd Anus
11
Cancer of the Colon, Rectum, and Anus
George J. Chang
Barry W . Feig
Epidemiology
Col or ectal cancer i s the four th most common cancer and the second
l eadi ng cause of cancer deaths. In 2005, ther e wer e an esti mated
145,000 cases di agnosed i n the Uni ted States, i ncl udi ng 104,950
cases of col on cancer and 40,340 cases of r ectal cancer. Col or ectal
cancer i nci dence rates have conti nued to decl i ne si nce 1985, a
decl i ne par tl y bel i eved to be due to i mpr oved scr eeni ng and
tr eatment of pol yps befor e thei r pr ogr essi on to i nvasi ve cancer s.
However, col or ectal cancer sti l l accounts for 10% of cancer deaths.
Esti mates for the year 2005 show 54,290 deaths fr om col on and
r ectal cancer.
In the Uni ted States, the cumul ati ve l i feti me r i sk of devel opi ng
col or ectal cancer i s about 6% . The mean age of onset i s 65. The
r i sk of col or ectal cancer cl ear l y i ncr eases wi th age. Except i n the
setti ng of her edi tar y for ms of col or ectal cancer, thi s di sease rar el y
occur s befor e age 40. After age 50, ther e i s a rapi d i ncr ease i n the
rate of di sease, and 90% of the cases occur i n pati ents ol der than
50. These facts ar e r esponsi bl e for the r ecommendati ons to begi n
scr eeni ng at age 50.
When di agnosed, 39% of pati ents have l ocal i zed di sease, 38% have
r egi onal di sease, 19% have di stant metastasi s, and 5% ar e
unstaged. The sur vi val rates for l ocal , r egi onal , and di stant di sease
at 5 year s ar e 90% , 66% , and 9.0% , r especti vel y, and at 10 year s
ar e 85% , 58% , and 6.6% , r especti vel y.
Appr oxi matel y 75% of col or ectal cancer cases ar e sporadi c, wi th the
r emai nder of cases occur r i ng i n pati ents who ar e at i ncr eased r i sk.
The pati ents wi th i ncr eased r i sk i ncl ude those wi th i nfl ammator y
bowel di sease, fami l i al adenomatous pol yposi s (FAP), and her edi tar y
nonpol yposi s col or ectal cancer (HNPCC), as wel l as pati ents wi th a
str ong fami l y hi stor y of col or ectal cancer. Men ar e at sl i ghtl y
i ncr eased r i sk as the age-adjusted i nci dence i s 58.5 per 100,000 i n
men and 44.2 per 100,000 i n women.
Risk Factors
Diet
Many di etar y factor s have been studi ed r egar di ng thei r effect on
col or ectal cancer. Consumpti on of r ed meat and ani mal fat, as wel l
as the pr esence of hi gh fecal l evel s of chol ester ol , cor r el ate wi th
and may be causal l y r el ated to an i ncr eased r i sk of col or ectal
car ci noma. Fol ate suppl ements have been shown to be pr otecti ve
agai nst col or ectal cancer. Cal ci um suppl ements have been shown to
decr ease the for mati on of new adenomas i n pati ents wi th a hi stor y
of adenomas. Vi tami ns wi th anti oxi dant pr oper ti es i ncl udi ng betacar otene, vi tami n C, and vi tami n E have been studi ed, and at
pr esent ther e ar e no pr ospecti ve data that demonstrate a
pr otecti ve effect fr om col or ectal cancer wi th thei r use. Di etar y fi ber
has al so been studi ed and i s epi demi ol ogi cal l y associ ated wi th a
decr eased col or ectal cancer r i sk; however, no pr ospecti ve data
suppor t i ts use for pr otecti on fr om the devel opment of col or ectal
cancer.
Medications
Several medi cati ons have demonstrated pr otecti ve effects for
col or ectal cancer. Hor mone r epl acement therapy has been shown to
si gni fi cantl y decr ease mor tal i ty fr om col or ectal cancer i n women.
Aspi r i n and other nonster oi dal anti -i nfl ammator y dr ugs have al so
demonstrated pr otecti ve effects. Recent studi es wi th sul i ndac and
the sel ecti ve cycl ooxygenase-2 (COX-2) i nhi bi tor cel ecoxi b
demonstrated the abi l i ty of these agents to cause r egr essi on of
col on pol yps i n pati ents wi th FAP. However, the COX-2 i nhi bi tor s
have been associ ated wi th an i ncr eased r i sk for car di ovascul ar
compl i cati ons; ther efor e, thei r r ol e i n chemopr eventi on r emai ns
uncl ear.
Polyps
Most col or ectal cancer s ar i se fr om pol yps. Col or ectal pol yps ar e
cl assi fi ed hi stol ogi cal l y as ei ther neopl asti c (adenomatous i ncl udi ng
ser rated adenomatous) pol yps (whi ch may be beni gn or mal i gnant)
or nonneopl asti c (i ncl udi ng hyper pl asti c, mucosal , i nfl ammator y,
and hamar tomatous) pol yps. Adenomatous pol yps ar e found i n
appr oxi matel y 33% of the general popul ati on by age 50 and i n
appr oxi matel y 50% of the general popul ati on by age 70. Most
l esi ons ar e l ess than 1 cm i n si ze, wi th 60% of peopl e havi ng a
si ngl e adenoma and 40% havi ng mul ti pl e l esi ons. Si xty per cent of
l esi ons wi l l be l ocated di stal to the spl eni c fl exur e.
A geneti c model for col on car ci nogenesi s has been devel oped fr om
the geneti c anal ysi s of col or ectal adenomas and car ci nomas. Thi s
model demonstrates a sequence of geneti c al terati ons r esponsi bl e
for the devel opment of col or ectal adenomas and thei r pr ogr essi on to
i nvasi ve car ci noma. The Nati onal Pol yp Study showed that
col onoscopi c r emoval of adenomatous pol yps si gni fi cantl y r educed
the r i sk of devel opi ng col or ectal cancer.
Pol yps coexi st wi th col or ectal cancer i n 60% of pati ents and ar e
associ ated wi th an i ncr eased i nci dence of synchr onous and
metachr onous col oni c neopl asms. Pati ents wi th a pr i mar y cancer
and a sol i tar y associ ated pol yp have a l ower i nci dence of
synchr onous and metachr onous l esi ons when compar ed to pati ents
wi th mul ti pl e pol yps. The natural hi stor y of pol yps suppor ts an
aggr essi ve appr oach to thei r tr eatment: i nvasi ve cancer wi l l devel op
i n 24% of pati ents wi th untr eated pol yps at the si te of that pol yp
wi thi n 20 year s.
Ther e ar e thr ee hi stol ogi c var i ants of adenomatous pol yps. Tubular
adenomas r epr esent 75% to 87% of pol yps and ar e found wi th equal
fr equency thr oughout al l segments of the bowel . Less than 5% of
tubul ar adenomas ar e mal i gnant. Tubulovillous adenomas consti tute
8% to 15% of pol yps. They ar e al so equal l y di str i buted thr oughout
the bowel , and 20% to 25% ar e mal i gnant. The r emai ni ng 5% to
10% of pol yps ar e villous adenomas, whi ch ar e most commonl y
found i n the r ectum; 35% to 40% of these pol yps ar e mal i gnant.
Pol yps may be peduncul ated (usual l y
tubul ar or tubul ovi l l ous) or sessi l e (usual l y tubul ovi l l ous or vi l l ous).
Besi des hi stol ogi c character i sti cs, the si ze of a pol yp and the degr ee
of dyspl asi a has been associ ated wi th mal i gnant potenti al .
Mal i gnancy was found i n 1.3% of adenomas l ess than 1 cm, 9.5%
between 1 and 2 cm, and 46% gr eater than 2 cm. Si mi l ar l y, 5.7% of
mi l d, 18% of moderate, and 34.5% of adenomatous pol yps wi th
sever e dyspl asi a wer e found to have mal i gnant cel l s on compl ete
exci si on of the pol yp. Ther efor e, al though onl y 2% to 5% of
adenomatous pol yps har bor mal i gnancy at the ti me of di agnosi s, the
hi stol ogi c character i sti cs, si ze, and degr ee of dyspl asi a can hel p
pr edi ct whi ch pol yps wi l l be mal i gnant.
The ter ms car cinoma in situ, intr amucosal car cinoma, and highgr ade dysplasia ar e used to descr i be sever el y dyspl asti c adenomas
wher e the cancer ous cel l s have not i nvaded thr ough the muscul ar i s
mucosae and ther efor e have no r i sk of l ymph node metastases. In
an effor t to avoi d confusi on, standar di zed use of the ter m highgr ade dysplasia i s advocated. Appr oxi matel y 5% to 7% of
adenomatous pol yps contai n hi gh-grade dyspl asi a. If a pol yp
contai ni ng hi gh-grade dyspl asi a i s compl etel y exci sed
endoscopi cal l y, the pati ent shoul d be consi der ed cur ed.
Overal l , 8.5% to 25% of pol yps har bor i ng i nvasi ve car ci noma wi l l
metastasi ze to r egi onal l ymph nodes. Unfavorabl e pathol ogi cal
featur es of mal i gnant col or ectal pol yps i ncr ease the pr obabi l i ty that
r egi onal l ymph nodes wi l l be i nvol ved wi th tumor and i ncl ude (a)
poor di ffer enti ati on, (b) vascul ar and/or l ymphati c i nvasi on, (c)
i nvasi on bel ow the submucosa, and (d) posi ti ve r esecti on mar gi n.
Poor l y di ffer enti ated l esi ons (grade 3) ar e associ ated wi th a hi gher
i nci dence of l ymphovascul ar i nvol vement and r ecur r ent di sease
when compar ed wi th wel l - and moderatel y di ffer enti ated l esi ons
(grades 1 and 2, r especti vel y). Appr oxi matel y 4% to 8% of
mal i gnant pol yps wi l l be poor l y di ffer enti ated. The pr esence of one
or mor e of these adver se featur es shoul d pr ompt eval uati on for
sur gi cal r esecti on. Depth of i nvasi on i s an i mpor tant pr ognosti c
factor for mesenter i c l ymph node i nvol vement wi th i nvasi ve cancer
ar i si ng i n a pol yp. In 1985, Haggi tt et al . cl assi fi ed the l evel of
i nvasi on fr om the head of the pol yp to the submucosa of the
under l yi ng col oni c wal l (Tabl e 11.1). In a mul ti var i ate anal ysi s, onl y
i nvasi on i nto the submucosa of the under l yi ng bowel wal l (l evel 4)
was a si gni fi cant pr ognosti c factor. Thi s i s i n keepi ng wi th pr evi ous
pathol ogi cal studi es that have shown that the l ymphati c channel s do
not penetrate above the muscul ar i s
mucosa. Al though these fi ndi ngs have been confi r med by other
studi es, ther e ar e fr equentl y mul ti pl e adver se pr ognosti c factor s
seen i n pati ents wi th hi gher l evel s of i nvasi on (i .e., l evel s 3 and 4),
whi ch makes i t di ffi cul t to assi gn depth as the most i mpor tant
factor. A negati ve r esecti on mar gi n has consi stentl y been shown to
be associ ated wi th a decr eased r i sk for adver se outcome
(r ecur r ence, r esi dual car ci noma, l ymph node metastases, decr eased
sur vi val ). Twenty-seven per cent of pati ents wi th posi ti ve or
i ndeter mi nate tumor mar gi ns wi l l have adver se outcomes, compar ed
wi th 18% wi th negati ve mar gi ns and poor pr ognosti c featur es and
0.8% wi th negati ve mar gi ns and no other poor pr ognosti c featur es.
Ther efor e, a negati ve mar gi n i s onl y one component i n r i sk factor
assessment.
Table 11.1. Haggitt's classification for

colorectal carcinomas arising in adenomas
Classification Depth of Invasion
0
Carcinoma confined to the

mucosa
Head of polyp
Neck of polyp
Stalk of polyp
Submucosa of the underlying

colonic wall
An addi ti onal cl assi fi cati on system for mal i gnant col or ectal pol yps
has been popul ar i zed i n Japan and may be appl i cabl e to mal i gnant
sessi l e pol yps and was descr i bed by Ki kuchi i n 1995. It cl assi fi es
i nvasi ve cancer as Sm1 (sl i ght car ci noma i nvasi on of the muscul ar i s
mucosa, 200300 m), Sm2 (i nter medi ate i nvasi on), or Sm3 (deep
submucosal i nvasi on extendi ng to the i nner sur face of the
muscul ar i s pr opr i a). Sm1 depth of i nvasi on i s associ ated wi th a l ow
r i sk for l ocal r ecur r ence or l ymph node metastasi s. Nasci mbeni et
al ., have r epor ted thei r ser i es fr om the Mayo Cl i ni c wher e Sm3
depth of i nvasi on was associ ated wi th a 23% r i sk for l ymph node

metastasi s.
Al though cl i ni cal factor s such as age, l ocati on, number of pol yps,
and gender ar e col l ecti vel y known to be pr ognosti c factor s, onl y age
of ol der than 60 year s has been i denti fi ed as an i ndependent r i sk
factor for i nvasi on.
Treatment
When adenomatous pol yps ar e found by si gmoi doscopy, we
r ecommend compl ete col onoscopy wi th col onoscopi c r emoval of the
pol yp and col onoscopi c sur vei l l ance ever y 1 to 3 year s unti l the
exami nati on r esul t i s nor mal . Col onoscopi c pol ypectomy i s a safe,
effecti ve tr eatment for near l y al l peduncul ated pol yps. A bi opsy i s
per for med on those pol yps not amenabl e to safe pol ypectomy;
subsequentl y, sur gi cal r esecti on i s r ecommended (usual l y for l ar ge
sessi l e vi l l ous l esi ons). F ungati on, ul cerati on, and di stor ti on of the
sur r oundi ng bowel wal l i ndi cate the pr esence of i nvasi ve cancer and
ar e contrai ndi cati ons to pol ypectomy.
Col ectomy i s i ndi cated for pati ents wi th r esi dual car ci noma and for
those at hi gh r i sk for l ymph node metastases despi te compl ete
endoscopi c pol ypectomy. The hi gh-r i sk pathol ogi cal featur es
pr evi ousl y descr i bed (mar gi n <3 mm, poor di ffer enti ati on, Haggi tt
l evel 4, and vascul ar or l ymphati c i nvasi on) and the r esul tant
i ncr eased r i sk of l ymph node metastasi s shoul d be wei ghed agai nst
the r i sk of sur gi cal r esecti on.
In a r evi ew of 17 studi es to eval uate the fr equency of l ymph node
metastases or r esi dual car ci noma i n l ow-r i sk pati ents wi th
peduncul ated pol yps, onl y a 1% i nci dence was found. In sessi l e
pol yps wi th l ow-r i sk featur es, the i nci dence was i ncr eased to 4.1% .
Because the i nci dence of nodal metastases i s hi gher i n sessi l e
pol yps wi th i nvasi ve cancer, those pati ents at l ow operati ve r i sk
shoul d be consi der ed for r esecti on even i f no hi gh-r i sk pathol ogi cal
featur es ar e obser ved. Stal k i nvasi on i n peduncul ated
pol yps i s not consi der ed an adver se hi stol ogi c featur e, and
tr eatment of pol yps wi th stal k i nvasi on i s the same as that of pol yps
wi thout stal k i nvasi on (based on r i sk strati fi cati on). Pol ypoi d
cancer s (al most al l the pol yp i s i nvaded wi th car ci noma) ar e tr eated
no di ffer entl y fr om other mal i gnant pol ypoi d l esi ons. Lar ge vi l l ous
adenomas of the r ectum may be amenabl e to transanal l ocal
exci si on. Thi s pr ovi des a compl ete di agnosti c eval uati on for
mal i gnancy, and i f exci sed wi th negati ve mar gi ns (wi th other

favorabl e pr ognosti c featur es), may be the onl y therapeuti c
pr ocedur e needed.
Hereditary Colorectal Cancer Syndromes

The major i ty of col or ectal cancer s ar e sporadi c cancer s that occur i n
pati ents wi thout a si gni fi cant fami l y hi stor y of col or ectal cancer.
Appr oxi matel y 5% to 10% of al l col or ectal cancer s ar e associ ated
wi th a fami l i al col or ectal r ectal cancer syndr ome, and an addi ti onal
15% to 20% ar e associ ated wi th a fami l i al pr edi sposi ti on.
F amilial adenomatous polyposis (F AP) i s the best character i zed of
the syndr omes; 1% to 2% of pati ents di agnosed wi th col on
car ci noma wi l l have FAP. G er m-l i ne mutati ons i n the adenomatous
pol yposi s col i (APC) gene on chr omosome 5q ar e character i sti c of
FAP. The major i ty of the mutati ons r esul t i n a tr uncated APC
pr otei n; however, some mutati ons do not and can onl y be i denti fi ed
wi th gene sequenci ng. The patter n of i nher i tance i s autosomal
domi nant, wi th 90% penetrance. The i nci dence of new mutati ons i n
FAP pati ents i s hi gh; appr oxi matel y 25% of al l FAP cases ar e the
r esul t of a de novo ger m-l i ne mutati on. In pati ents wi th FAP,
thousands of pol yps devel op thr oughout the gastr oi ntesti nal (G I)
tract but ar e most common i n the col on. The medi an age of
adenoma di agnosi s i s 15 year s. Wi thout pr ophyl acti c col ectomy,
col or ectal cancer wi l l devel op i n vi r tual l y al l affected i ndi vi dual s by
the end of the thi r d decade of l i fe. A mi l der phenotype known as
attenuated FAP i s associ ated wi th fewer pol yps wi th the typi cal age
of onset for col or ectal cancer by the ear l y fi fti es. Pati ents wi th FAP
may al so devel op extracol oni c mani festati ons i ncl udi ng gastr i c
pol yps, duodenal adenomas and car ci nomas, desmoi d tumor s,
thyr oi d car ci noma, mandi bul ar osteomas, congeni tal hyper tr ophy of
the r eti nal pi gmented epi thel i um, sebaceous and epi der moi d cysts
and fi br omas (pr evi ousl y G ar dner syndr ome), or central ner vous
system tumor s (Tur cot syndr ome). Commer ci al geneti c testi ng can
now i denti fy the APC gene mutati on by sequenci ng. Si nce the
compl ete sequenci ng of the APC gene, studi es have cor r el ated the
speci fi c geneti c mutati ons wi th the di ffer i ng phenotypes of
extrai ntesti nal mani festati ons of FAP. G eneti c testi ng and
counsel i ng shoul d be offer ed to al l pati ents i n whom FAP i s
suspected. Sur vei l l ance for FAP shoul d begi n at the age of 10 to 12
wi th annual endoscopi c eval uati ons. Once a mutati on i s i denti fi ed
wi thi n a fami l y, unaffected i ndi vi dual s can be spar ed such an
i ntensi ve sur vei l l ance r egi men.
The pr i mar y tr eatment for FAP i s pr ophyl acti c col ectomy. Sur gi cal
opti ons i ncl ude abdomi nal col ectomy wi th i l eor ectal anastomosi s
(IRA), r estorati ve pr octocol ectomy wi th i l eal -pouch anal
anastomosi s (IPAA), and l ess commonl y pr octocol ectomy wi th end
i l eostomy. Pati ents who have pol yp bur dens wi thi n the r ectum that
cannot be endoscopi cal l y contr ol l ed shoul d not under go IRA.
It shoul d be emphasi zed that after pr ophyl acti c col ectomy or
pr octocol ectomy, these pati ents must conti nue l i fe-l ong sur vei l l ance
because ther e r emai ns a r i sk for cancer i n the r emai ni ng r ectum
after IRA or at the anastomosi s or wi thi n the i l eal pouch i tsel f after
IPAA.
MYH (mutY homolog)-associated polyposis syndr ome has r ecentl y
been i denti fi ed fr om subgr oups of pati ents i n FAP r egi str i es who
have tested negati ve for APC gene mutati ons. The patter n or
i nher i tance i s autosomal r ecessi ve, and the phenotype demonstrates
mul ti pl e col or ectal pol yps (>10) but typi cal l y fewer than i n
i ndi vi dual s wi th cl assi c FAP. An age of onset of col or ectal cancer i n
pati ents younger than 50 year s has been r epor ted i n those wi th
bi al l el i c MYH mutati ons. Col or ectal cancer s i n MYH pol yposi s
syndr ome ar e associ ated wi th G :C to T:A transver si ons r esul ti ng
fr om defects i n base exci si on r epai r. Thi s col or ectal cancerassoci ated pol yposi s syndr ome conti nues to be defi ned.
Her editar y nonpolyposis color ectal cancer syndr ome (HNPCC), al so
cl assi cal l y known as the Lynch I and II syndr omes, i s a nonpol yposi s
autosomal domi nant di sease that occur s fi ve ti mes mor e fr equentl y
than fami l i al pol yposi s. HNPCC accounts for 5% to 7% of col on
cancer s. Isol ated, ear l y onset col or ectal cancer occur s i n the Lynch I
syndr ome. Col or ectal cancer and tumor s of the endometr i um, ovar y,
stomach, smal l bowel , hepatobi l i ar y tract, pancr eas, ur eter, and
r enal pel vi s character i ze the Lynch II syndr ome. Penetrance i s
between 30% and 70% . Ther e i s an esti mated 85% l i feti me r i sk of
col on cancer. Compar ed wi th pati ents wi th sporadi c col on cancer,
pati ents wi th HNPCC have cancer s that ar e mor e r i ght si ded (60%
70% occur pr oxi mal to the spl eni c fl exur e), occur ear l i er (at about
45 year s of age), have a l ower stage, have better sur vi val , and have
an i ncr eased rate of metachr onous and synchr onous tumor s (20% ).
The geneti c mutati ons causi ng HNPCC ar e i n DNA mi smatch r epai r
(MMR) genes that pr event r epl i cati on er r or s, and hence geneti c
i nstabi l i ty. F i ve of the DNA MMR genes have been l i nked to HNPCC.
These genes ar e hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2. The
fi r st two genes account for the 50% and 39% of the cases of
HNPCC, r especti vel y. Mutati ons i n tumor suppr essor genes such as
p53, DCC, and APC can be associ ated wi th HNPCC because
r epl i cati on er r or s ar e pr oduced i n these tumor suppr essor genes.
One of the mai n di ffi cul ti es i n the management of pati ents wi th
HNPCC i s the i denti fi cati on of those i ndi vi dual s who shoul d be
tested. A detai l ed fami l y hi stor y shoul d be obtai ned i n al l pati ents
wi th col or ectal cancer and may i denti fy potenti al l y affected
i ndi vi dual s usi ng Amster dam cr i ter i a or Bethesda gui del i nes (Tabl e
11.2). Al though l acki ng i n speci fi ci ty, the use of these cr i ter i a and
gui del i nes i s associ ated wi th 60% to 94% sensi ti vi ty for i denti fyi ng
i ndi vi dual s wi th HNPCC. F ur ther mor e, hi stopathol ogi cal eval uati on
of the sur gi cal speci men may r eveal the pr esence of featur es
associ ated wi th HNPCC, i ncl udi ng a Cr ohn's-l i ke i nfl ammator y cel l
i nfi l trate and si gnet r i ng cel l s. At M. D. Ander son Cancer Center
(MDACC), i mmunohi stochemi str y for mi smatch r epai r gene pr otei n
expr essi on i s per for med i n the col or ectal tumor s of suspected
i ndi vi dual s. If l oss of one of the r epai r pr otei ns i s noted, geneti c
testi ng i s per for med.
Table 11.2. Amsterdam criteria and

Bethesda guidelines
Amsterdam I
At least three
relatives must have
histologically verified
colorectal cancer
1. One must be a firstdegree relative of

the other two
2. At least two
successive
generations must be
affected
3. At least one of the
relatives must have
received the
diagnosis before age
50
Amsterdam II
Similar to Amsterdam I, but may include any
combination of cancers associated with HNPCC
(e.g., colorectal, endometrial, gastric, ovarian,
ureter or renal pelvis, brain, small bowel,
hepatobiliary tract, sebaceous gland adenomas,
keratoacanthomas)
Bethesda guidelines
1. Amsterdam criteria are met
2. Two colorectal or HNPCC-related cancers,
including synchronous and metachronous
presentation
3. Colorectal cancer and a first-degree relative
with colorectal and/or an HNPCC-related
cancer and/or a colonic adenoma; one of the
cancers must be diagnosed before age 45
and the adenoma diagnosed before age 40
4. Colorectal or endometrial cancer diagnosed
before age 45
5. Right-sided colorectal cancer with an
undifferentiated pattern (solid/cribriform) on
histopathology, diagnosed before age 45
6. Signet ring cell-type colorectal cancer
diagnosed before age 45 (>50% signet ring
cells)
7. Colorectal adenomas diagnosed before age
40
Revised Bethesda guidelines

1. Early onset colorectal cancer (before age 50)
2. Synchronous, metachronous, or other
HNPCC-associated tumors, regardless of age
3. Colorectal cancer with high microsatellite
instability diagnosed before age 60
4. Colorectal cancer diagnosed in one or more
first-degree relatives with an HNPCC-related
tumor, with one of the cancers being
diagnosed before age 50
5. Colorectal cancer diagnosed in two or more
first- or second-degree relatives with
HNPCC-related tumors, regardless of age
HNPCC, hereditary nonpolyposis colorectal
cancer.
Other l ess common her edi tar y col or ectal cancer syndr omes may be
associ ated wi th hamar tomatous pol yposi s such as Peutz-Jegher s
syndr ome (PJS), juveni l e pol yposi s syndr ome (JPS), Cowden
syndr ome, and Bannayan-Ruval caba-Ri l ey syndr ome. G er m-l i ne
mutati ons i n STK11 (LKB1) ar e associ ated wi th PJS, mutati ons i n
SMAD4 and BMPR1-A ar e associ ated wi th JPS, and PTEN mutati ons
ar e associ ated wi th Cowden syndr ome and Bannayan-Ruval cabaRi l ey syndr ome. The hamar tomatous pol yposi s syndr omes ar e
associ ated wi th a si gni fi cantl y i ncr eased r i sk for col or ectal cancer
and ar e pr esent i n <1% of col or ectal cancer i n Nor th Amer i ca.
Peopl e wi th a fi r st-degr ee r el ati ve wi th col or ectal cancer have a

1.8- to 8-fol d hi gher r i sk of col or ectal cancer than the general
popul ati on. The r i sk i s hi gher i f mor e than one r el ati ve i s affected,
and hi gher i f the cancer devel oped i n the r el ati ve at a young age
(<45). The r ol e of i nher i tabl e geneti c defects i n pr edi sposi ti on to
col or ectal cancer i n such pati ents i s not wel l under stood.
Inflammatory Bowel Disease

Chr oni c ul cerati ve col i ti s (CUC) car r i es a r i sk of col or ectal
car ci noma that i s 30 ti mes gr eater than that of the general
popul ati on. The r i sk of cancer i ncr eases 0.5% to 1% per year after
10 year s and i s 18% to 35% at 30 year s. The sever i ty, extent, and
durati on of i nfl ammati on, as wel l as fami l y hi stor y of col or ectal
cancer and hi stor y of pr i mar y scl er osi ng chol angi ti s, ar e r i sk factor s
for the devel opment of cancer. In contrast to sporadi c col or ectal
cancer s, CUC-r el ated cancer s ar e mor e often mul ti pl e, br oadl y
i nfi l trati ng, and poor l y di ffer enti ated. It can be extr emel y di ffi cul t
to i denti fy smal l tumor s i n a CUC col on due to the chr oni c changes
r esul ti ng fr om the i nfl ammator y pr ocess. Ther efor e, random
sur vei l l ance bi opsi es shoul d be r outi nel y per for med i n pati ents wi th
CUC, and pr ophyl acti c col ectomy or pr octocol ectomy shoul d be
r ecommended for hi gh-grade dyspl asi a and consi der ed for l ow-grade
dyspl asi a. Cr ohn di sease i s al so associ ated wi th an i ncr eased r i sk
for col or ectal cancer that i s r el ated to the durati on and sever i ty of
di sease. Its r i sk i s si mi l ar to that wi th CUC. The r i sk associ ated wi th
i nfl ammator y bowel di sease under scor es the i mpor tance of
sur vei l l ance i n thi s pati ent popul ati on.
Previous Colon Carcinoma

A second pr i mar y col on car ci noma i s thr ee ti mes mor e l i kel y to
devel op i n pati ents wi th a hi stor y of col on cancer than i n the
general popul ati on; metachr onous l esi ons devel op i n 5% to 8% of
these pati ents.
Screening
The val ue of r outi ne scr eeni ng of asymptomati c popul ati ons who
l ack hi gh-r i sk factor s for devel opment of col or ectal cancer has been
establ i shed. Scr eeni ng shoul d be i ni ti ated at age 50. As many as
19% of the general popul ati on ar e at r i sk of devel opi ng
adenomatous pol yps, and 5% of sporadi c pol yps may pr ogr ess to
col or ectal car ci noma. The goal s of scr eeni ng ar e detecti on of ear l y
cancer s and pr eventi on of cancer by fi ndi ng and r emovi ng

adenomas. Thr ee randomi zed tr i al s have shown that fecal occul t
bl ood scr eeni ng fol l owed by col onoscopy has been shown to detect
cancer s at an ear l i er stage. One of these tr i al s, the Mi nnesota Col on
Cancer Contr ol Study, has demonstrated a si gni fi cantl y i mpr oved
cancer-r el ated sur vi val , and a meta-anal ysi s of the randomi zed
tr i al s i ndi cates that Hemoccul t testi ng i s associ ated wi th a 19%
r educti on i n the mor tal i ty rate fr om col or ectal car ci noma. However,
the sensi ti vi ty of fecal occul t bl ood tests (F OBTs) has been r epor ted
to be 30% to 90% . Ther efor e, al ter nati ve methods have been
i nvesti gated, i ncl udi ng i mmunochemi cal F OBTs and fecal tests for
DNA mutati ons. If F OBT i s posi ti ve, total col onoscopy shoul d be
per for med.
Four case-contr ol studi es have demonstrated that si gmoi doscopy i s
associ ated wi th a r educed mor tal i ty for col or ectal cancer. The
Nati onal Cancer Insti tute funded Pr ostate, Lung, Col or ectal , and
Ovar i an scr eeni ng tr i al and the UK F l exi Scope Tr i al ar e bei ng
per for med wi th an anti ci pated 250,000 subjects to eval uate
scr eeni ng fl exi bl e si gmoi doscopy, but outcomes data ar e not yet
avai l abl e. The uti l i ty of fl exi bl e si gmoi doscopy as a scr eeni ng test
for col or ectal neopl asi a i s l i mi ted by the amount of col on vi sual i zed
wi th a 70-cm si gmoi doscope. Ther efor e, fl exi bl e si gmoi doscopy
shoul d be used i n conjuncti on wi th radi ographi c eval uati on of the
mor e pr oxi mal col on or annual fecal occul t bl ood testi ng. As a
scr eeni ng test, fl exi bl e si gmoi doscopy, when nor mal , shoul d be
r epeated ever y 5 year s.
The val ue of col onoscopy i n scr eeni ng can be appr eci ated i f one
consi der s that appr oxi matel y 40% of col on cancer s ar i se pr oxi mal to
the spl eni c fl exur e and that 75% of pr oxi mal col on cancer s do not
have an i ndex l esi on wi thi n r each of the fl exi bl e si gmoi doscope. Al l
r oads eventual l y l ead to col onoscopy for di agnosi s or therapy (as i n
the case of a l esi on on bar i um enema). Most studi es usi ng scr eeni ng
col onoscopy i n average-r i sk pati ents r epor t an average of 30% of
neopl asti c l esi ons detected. Cost i s an i mpor tant i ssue, however, i f
col onoscopy i s consi der ed the ul ti mate scr eeni ng tool . Cur r entl y,
scr eeni ng col onoscopy i s cost-effecti ve i f a 10-year i nter val i s used
once the col on i s cl ear ed of pol yps.
Doubl e-contrast bar i um enema i s used l ess fr equentl y than
col onoscopy for scr eeni ng and can detect col or ectal car ci noma and
pol yps gr eater than 1 cm wi th accuracy equal to that of
col onoscopy. It has been used i n pati ents who r efuse or cannot have
ful l col onoscopy to the cecum, as an adjunct to fl exi bl e

si gmoi doscopy to eval uate the r emai nder of the col on, and for
di ffi cul t-to-vi sual i ze tur ns i n the col on. The di ffi cul ty wi th thi s
method i s that l esi ons detected by doubl e-contrast bar i um enema
r equi r e fur ther eval uati on, decr easi ng the cost-effecti veness of the
method.
CT col onography (vi r tual col onoscopy) i s an emer gi ng techni que for
the di agnosi s of col oni c pol yps i n the scr eeni ng popul ati on that uses
thr ee-di mensi onal r econstr ucti on of the ai r di stended col on. At the
Nati onal Naval Medi cal Center, i n 1,223 average-r i sk adul ts who
subsequentl y under went conventi onal (opti cal ) col onoscopy, vi r tual
col onoscopy was as good or better at detecti ng r el evant l esi ons.
However, i t may be l ess accurate i n sur vei l l ance popul ati ons, and
subsequent mul ti -i nsti tuti onal studi es have fai l ed to confi r m the
excel l ent r esul ts fr om thi s ser i es. The major l i mi tati ons i ncl ude
uncer tai n accuracy, the need for ful l bowel pr eparati on, and fol l owup col onoscopy for
ti ssue di agnosi s of radi ographi c abnor mal i ti es. Because vi r tual
col onoscopy i s consi derabl y ti me and l abor i ntensi ve fr om the
standpoi nt of the radi ol ogi st, acti ve i nvesti gati ons i nto methods of
automati ng the eval uati on pr ocess ar e ongoi ng.
Car cinoembr yonic antigen (CEA) i s a gl ycopr otei n found i n the cel l
membranes of many ti ssues, i ncl udi ng col or ectal cancer. Some of
the anti gen enter s the ci r cul ati on and i s detected by
radi oi mmunoassay of ser um; CEA i s al so detectabl e i n var i ous other
body fl ui ds, ur i ne, and feces. El evated ser um CEA i s not speci fi cal l y
associ ated wi th col or ectal cancer ; abnor mal l y hi gh l evel s ar e al so
found i n sera of pati ents wi th mal i gnanci es of the pancr eas, br east,
ovar y, pr ostate gl and, head and neck, bl adder, and ki dney. CEA
l evel s ar e hi gh i n appr oxi matel y 30% to 80% of pati ents wi th
cancer of the l ar ge i ntesti ne, but l ess than hal f of pati ents wi th
l ocal i zed di sease ar e CEA posi ti ve. Ther efor e, CEA has no r ol e i n
scr eeni ng for pr i mar y l esi ons. Fal se-posi ti ve r esul ts occur i n beni gn
di sease (l ung, l i ver, and bowel ). The CEA l evel i s al so i ncr eased i n
smoker s. Overal l , 60% of tumor s wi l l be mi ssed by CEA scr eeni ng
al one.
Screening Recommendations
Recentl y, the U.S. Mul ti soci ety Task For ce on Col or ectal cancer met
to update the or i gi nal 1997 consensus gui del i nes for col or ectal
cancer scr eeni ng and sur vei l l ance and made r ecommendati ons
r egar di ng scr eeni ng (Tabl e 11.3).
Pathology
Hi stol ogi cal l y, mor e than 90% of col on cancer s ar e
adenocar ci nomas. On gr oss appearance, ther e ar e four mor phol ogi c
var i ants of adenocar ci noma. Ul cerati ve adenocar ci noma i s the most
common confi gurati on seen and i s most character i sti c of tumor s i n
the descendi ng and si gmoi d col on. Exophyti c (al so known as
pol ypoi d or fungati ng) tumor s ar e most commonl y found i n the
ascendi ng col on, par ti cul ar l y i n the cecum. These tumor s tend to
pr oject i nto the bowel l umen, and pati ents often pr esent wi th a
r i ght-si ded abdomi nal mass and anemi a. Annul ar (sci r r hous)
adenocar ci noma tends to gr ow ci r cumfer enti al l y i nto the wal l of the
col on, r esul ti ng i n the cl assi c appl e cor e l esi on seen on bar i um
enema radi ol ogi c study. Rar el y, a submucosal i nfi l trati ve patter n
can be obser ved that i s si mi l ar to l i ni ti s pl asti ca seen wi th gastr i c
adenocar ci noma.
Other epi thel i al hi stol ogi c var i ants of col on cancer that ar e
occasi onal l y seen i ncl ude muci nous (col l oi d) car ci noma, si gnet-r i ng
cel l car ci noma, adenosquamous and squamous cel l car ci noma (SCC),
and undi ffer enti ated car ci noma. Other rar e tumor s i ncl ude
car ci noi ds and l ei omyosar comas.
A commonl y used gradi ng system i s based on the degr ee of
for mati on of gl andul ar str uctur es, nucl ear pl eomor phi sm, and
number of mi toses. G rade 1 tumor s have the most devel oped
gl andul ar str uctur es wi th the fewest mi toses, grade 3 i s the l east
di ffer enti ated wi th a hi gh i nci dence of mi toses, and grade 2 i s
i nter medi ate between grades 1 and 3.
Table 11.3. Colorectal cancer screening

recommendations
Risk Category
Screening
Recommendations
FOBT each year (full

colonoscopy or
DCBE/flex sig if +)
Average risk,
asymptomatic (age 50)
Flex sig every 5

years (consider full
colonoscopy if +)
FOBT each year +
flex sig every 5
years
DCBE every 5 years
Colonoscopy every
10 years
First-degree relative
with CRC or
adenomatous polyps at
age 60 years, or two
second-degree relatives
affected with CRC
Same as for average

risk but starting at
age 40 years
Two or more firstdegree relatives with

CRC or single firstdegree relative with
CRC or adenomatous
polyps diagnosed at age
<60 years
Colonoscopy every 5
years beginning at
age 40 or 10 years
younger than the
earliest diagnosis in
the family
One second-degree or
any third-degree
relative with CRC
Same as for average

risk
Gene carrier or at risk

for FAP
Annual flexible
sigmoidoscopy
beginning at 1012
years
Gene carrier or at risk

for HNPCC
Colonoscopy every
12 years beginning
at age 2025 years
or 10 years younger
than the earliest
case in the family
FOBT, fecal occult blood test; DCBE, double

contrast barium enema; CRC, colorectal
cancer; FAP, familial adenomatous polyposis;
HNPCC, hereditary nonpolyposis colorectal
cancer.
Staging
The Dukes and TNM stagi ng systems for col or ectal car ci noma ar e
pr esented i n Tabl es 11.4 and 11.5. Al though most cl i ni ci ans ar e
fami l i ar wi th both stagi ng systems, cl i ni cal tr i al and tr eatment
pl anni ng shoul d be based on the TNM stagi ng system. The Dukes
stagi ng system i s i mpor tant for hi stor i cal per specti ve.
Pati ents wi th col or ectal cancer pr esent wi th bl eedi ng, anemi a,
abdomi nal pai n, change i n bowel habi ts, anor exi a, wei ght l oss,
nausea, vomi ti ng, fati gue, and anemi a. Pel vi c pai n or tenesmus i n
r ectal cancer may be associ ated wi th an advanced stage of di sease

i ndi cati ng i nvol vement of the pel vi c fl oor muscl es or ner ves.
Metastati c di sease i s suspected i n pati ents wi th r i ght upper
quadrant pai n, fever s and sweats, hepatomegal y, asci tes, effusi ons,
and supracl avi cul ar adenopathy. Central ner vous system and bone
metastases ar e seen i n l ess than 10% of autopsy cases, and ar e
ver y rar e i n the absence of advanced l i ver or l ung di sease. The
i nci dence of compl ete obstr ucti on i n newl y di agnosed col or ectal
cancer i s 5% to 15% . In a l ar ge study fr om the Uni ted Ki ngdom,
49% of obstr ucti ons occur r ed at the spl eni c fl exur e, 23% occur r ed
i n the l eft col on, 23% occur r ed i n the r i ght col on, and 7% occur r ed
i n the r ectum. Obstr ucti on i ncr eases the r i sk of death fr om
col or ectal cancer 1.4-fol d and i s an i ndependent co-var i ate i n
mul ti var i ate anal yses. Per forati on occur s i n 6% to 8% of col or ectal
car ci noma cases. Per forati on i ncr eases the r i sk of death fr om cancer
3.4-fol d. Usi ng TMN stagi ng and Sur vei l l ance, Epi demi ol ogy, and
End Resul ts (SEER) Pr ogram data, 15% of pati ents pr esent wi th
stage I di sease, 30% wi th stage II, 20% wi th stage III, and 25%
wi th stage IV. The r emai nder have unknown stagi ng.
Table 11.4. Modified Astler-Coller

classification of the Dukes staging system
for colorectal cancer
Stage Description
A
Lesion not penetrating submucosa
B1
Lesion invades but not through the

muscularis propria
B2
Lesion through intestinal wall, no

adjacent organ involvement
B3
Lesion involves adjacent organs
C1
Lesion B1 invasion depth; regional

C2

C3

Distant metastatic disease
Table 11.5. TNM staging classification of

colorectal cancer
Primary tumor (T)
TX
T0
Tis
Carcinoma in situ: intraepithelial or

invasion of the lamina propria without
invasion through the muscularis mucosae
into the submucosa
T1
Tumor invades submucosa
T2
T3
Tumor invades through the muscularis

propria into the subserosa, or into
nonperitonealized pericolic or perirectal
tissues
T4
Tumor directly invades other organs or

structures and/or perforates visceral
peritoneum

NX
N0
N1
Metastasis in one to three regional lymph

nodes
N2
Metastasis in four or more regional lymph

nodes
Distant metastases (M)

MX
M0
M1
Distant metastases present
Diagnosis
Colon Cancer
Cl i ni cal eval uati on of car ci noma of the col on shoul d i ncl ude
col onoscopy and bi opsy, ai r-contrast bar i um enema i f the enti r e
col on coul d not be vi sual i zed by col onoscopy, chest radi ograph,
compl ete bl ood cel l count, CEA deter mi nati on, ur i nal ysi s, and l i ver
functi on tests (LF Ts).
The use of computed tomography (CT) i n the pr eoperati ve
eval uati on of pati ents wi th col on cancer i s contr over si al . We
eval uate the abdomen and pel vi s wi th CT to detect i nvol vement of
conti guous or gans, para-aor ti c l ymph nodes, and the l i ver. Abnor mal
LF Ts ar e pr esent i n onl y appr oxi matel y 15% of pati ents wi th l i ver
metastases and may be el evated wi thout l i ver metastases i n up to
40% ; ther efor e, LF Ts ar e not a useful scr een for deter mi ni ng the
need for obtai ni ng a CT scan.
The pr eoperati ve CEA l evel can al so r efl ect di sease extent and
pr ognosi s: CEA l evel s sur passi ng 10 to 20 ng per mL ar e associ ated
wi th i ncr eased chances of di sease fai l ur e for both node-negati ve
and node-posi ti ve pati ents. F i fteen to 20% of l i ver metastases wi l l
be nonpal pabl e at the ti me of sur ger y. However, up to 15% of
l esi ons can be mi ssed by combi ned pr eoperati ve and operati ve
eval uati on. Intraoperati ve ul trasonography has been shown to be
the most accurate method of detecti ng l i ver metastasi s.
Appr oxi matel y 20% of pati ents wi l l have synchr onous l i ver
metastasi s at the ti me of di agnosi s; ther efor e, the pr eoperati ve
i denti fi cati on of l i ver metastasi s i s necessar y for the sur gi cal
pl anni ng of combi ned r esecti ons of the pr i mar y tumor and the l i ver
metastasi s or for the tr eatment of tumor s i nvol vi ng conti guous
or gans. Magneti c r esonance i magi ng (MRI) may be hel pful i n
ci r cumstances when i ntravenous contrast-enhanced CT scanni ng i s
contrai ndi cated.
The r ol e of r outi ne pr eoperati ve ur i nar y tract eval uati on i s
contr over si al . Pati ents who ar e symptomati c or have l ar ge, bul ky
l esi ons shoul d have a pr eoperati ve i ntravenous pyel ogram, CT scan,
or cystoscopy to eval uate the ur i nar y tract.
Posi tr on emi ssi on tomography (PET), and now PET-CT, has emer ged
as a potenti al l y i mpor tant i magi ng modal i ty for col or ectal cancer.
The techni que uses the gl ucose anal og
fl uor odeoxygl ucose, whi ch accumul ates i n metabol i cal l y acti ve

ti ssues. The standar di zed uptake val ue can pr ovi de a
semi quanti tati ve deter mi nati on to hel p di scr i mi nate beni gn fr om
mal i gnant di sease. Al though potenti al l y useful i n r ecur r ent cancer,
i t has not been hel pful i n the pr i mar y eval uati on of pati ents wi th
col on cancer due to fal se posi ti ves and hi gh costs.
Rectal Cancer
In addi ti on to the hi stor y and physi cal exami nati on, chest
radi ograph, compl ete bl ood cel l count, and CEA, pr octoscopi c
exami nati on, endor ectal ul trasound (ERUS), ful l col onoscopy, and
CT scan of the abdomen and pel vi s shoul d be per for med to
accuratel y stage pati ents wi th r ectal cancer. Symptomati c pati ents
under go eval uati on of thei r ur i nar y tract as descr i bed ear l i er for
col on cancer.
Accurate pr eoperati ve stagi ng tool s ar e cr i ti cal i n r ectal cancer
because di sease stage may i nfl uence tr eatment deci si ons such as
transanal r esecti on or pr eoperati ve mul ti modal i ty therapy. ERUS i s
the most accurate tool i n deter mi ni ng tumor (T) stage. Per for med
usi ng r i gi d or fl exi bl e pr obes, the l ayer s of the r ectal wal l can be
i denti fi ed wi th 67% to 93% accuracy. The ERUS character i sti cs of
T1 and T3 tumor s make them r el ati vel y easy to di ffer enti ate.
However, the di sti ncti on between T2 and T3 tumor s i s mor e di ffi cul t,
yet i t i s vi tal i n deter mi ni ng tr eatment pl anni ng. ERUS i s hi ghl y
operator dependent, and i t can be di ffi cul t to di ffer enti ate l ymph
nodes fr om bl ood vessel s and other str uctur es or per i tumoral edema
fr om tumor. F ur ther mor e, ERUS i s l i mi ted i n i ts abi l i ty to eval uate
tumor s that ar e l ar ge or bul ky, associ ated wi th l ar ge vi l l ous tumor s,
or have been tr eated wi th radi ati on therapy. As a r esul t of these
factor s, over stagi ng occur s i n appr oxi matel y 20% of cases and
under stagi ng i n appr oxi matel y 10% to 20% . Stenoti c l esi ons may
make ERUS i mpossi bl e secondar y to the i nabi l i ty to pass the pr obe.
ERUS eval uati on of T stage i s super i or to that of CT scanni ng (52%
83% accuracy) and i n r ecent r epor ts compar es to endor ectal coi l
MRI (59% 95% accuracy). The r el ati ve accuracy of ERUS or MRI for
r ectal cancer stagi ng i s i nsti tuti on dependent, and ERUS i s
pr efer r ed at MDACC. CT and MRI can del i neate the r el ati onshi p of
the tumor to sur r oundi ng vi scera and pel vi c str uctur es. Nei ther CT
nor MRI i s mor e useful for the eval uati on of l ocor egi onal di sease
after neoadjuvant chemoradi ati on tr eatment because radi ati on
changes can be di ffi cul t to accuratel y di ffer enti ate fr om tumor.
Lymph node stagi ng i n r ectal cancer has pr oven mor e di ffi cul t than
pr i mar y tumor stagi ng, wi th ERUS accuraci es of 62% to 83% , CT

accuraci es of 35% to 73% , and MRI accuraci es of 39% to 84%
r epor ted. Despi te descr i pti ons of methods to radi ol ogi cal l y pr edi ct
metastases i n l ymph nodes, onl y nodal enl ar gements can be
detected wi th most cur r ent technol ogi es. F i fty to 75% of posi ti ve
l ymph nodes i n r ectal cancer may be nor mal i n si ze, ther eby
l i mi ti ng accurate eval uati on. Si mi l ar l y, l ymph nodes may be
enl ar ged fr om i nfl ammati on, gi vi ng fal se-posi ti ve r esul ts. Combi ni ng
si ze and ul trasonographi c character i sti cs can i ncr ease accuracy.
Lymph nodes that ar e gr eater than 3 mm and hypoechoi c ar e mor e
l i kel y to contai n metastati c deposi ts. In addi ti on, i t i s possi bl e to
per for m fi ne-needl e aspi rati on of suspi ci ous l ymph
nodes under ERUS gui dance. ERUS i s i nval uabl e when eval uati ng
pati ents for pr eoperati ve adjuvant therapy, but i t cannot accuratel y
assess r esponse to pr eoperati ve adjuvant therapy due to the
obl i terati on of ti ssue pl anes by edema and fi br osi s.
Abdomi nopel vi c CT scanni ng i s i mpor tant i n assessi ng the pr esence
of di stant spr ead of di sease and i nvol vement of adjacent or gans. In
the management of r ectal cancer, i t i s extr emel y i mpor tant to
accuratel y assess the l ocal spr ead of di sease, i ncl udi ng the potenti al
i nvol vement of the l evator muscl es and other pel vi c str uctur es.
Al though ERUS i s super i or to CT i n detecti ng depth of penetrati on,
CT pr ovi des a better assessment of conti guous or gan i nvol vement.
MRI i s a useful adjunct i n the eval uati on of l ocal l y advanced r ectal
cancer by pr ovi di ng mul ti pl e vi ews of the r el ati onshi ps of the tumor
to adjacent pel vi c str uctur es.
The stagi ng of r ecur r ent r ectal cancer i s compl i cated by radi ati on
and postoperati ve changes that ar e often di ffi cul t to di sti ngui sh
fr om tumor. Due to the di ffi cul ty i n di sti ngui shi ng scar fr om tumor,
the use of ERUS for postoperati ve sur vei l l ance i s contr over si al and
i s not r outi nel y per for med. Ther e i s poor cor r el ati on of
postradi ati on therapy ERUS i n pr eoperati ve r egi mens to fi nal
pathol ogi cal fi ndi ngs (postr esecti on), i ndi cati ng the l i mi ted val ue of
ERUS i n assessi ng tumor i n an i r radi ated mi l i eu. CT i s useful to
assess extent of di sease and adjacent or gan i nvol vement i f
r ecur r ent tumor i s obvi ous. MRI may yi el d added i nfor mati on by
pr ovi di ng sagi ttal i mages that gi ve addi ti onal i nfor mati on on
r esectabi l i ty. In cases wher e r ecur r ence i s unknown but suspected,
CT i s mor e useful i f a basel i ne study i s avai l abl e for compar i son.
PET has r ecentl y been i ntr oduced wi th ear l y r epor ts of i ncr eased
accuracy i n di sti ngui shi ng postoperati ve changes fr om r ecur r ent
tumor. In a sel ected ser i es, i t has been shown to be up to 95%

sensi ti ve, 98% speci fi c, and 96% accurate i n the detecti on of cancer
r ecur r ence. When used appr opr i atel y, i t can hel p di sti ngui sh
pati ents who woul d benefi t fr om sur ger y for r ecur r ent cancer fr om
those who have unr esectabl e di sease, par ti cul ar l y when the other
i magi ng modal i ti es fai l to l ocal i ze the di sease. However, fur ther
studi es ar e r equi r ed befor e thi s test can be r ecommended for use on
a r outi ne basi s. Cur r entl y at MDACC, we obtai n both a CT scan and
an MRI of the pel vi s i n cases of i sol ated r ecur r ent r ectal car ci noma
because we bel i eve these studi es ar e compl ementar y i n thei r
pr ovi si on of cr i ti cal stagi ng and r esectabi l i ty i nfor mati on.
Management of Colon Cancer

The goal of pr i mar y sur gi cal tr eatment of col on car ci noma i s to
eradi cate di sease i n the col on, the drai ni ng nodal basi ns, and
conti guous or gans. Car eful sur gi cal pl anni ng i s essenti al . The stage
of di sease, pr esence of synchr onous col oni c tumor s, and the
pr esence of under l yi ng col or ectal cancer syndr omes ar e si gni fi cant
factor s i n deter mi ni ng the opti mal sur gi cal appr oach. The pati ent's
general medi cal condi ti on i s al so i mpor tant because most
per i operati ve deaths r esul t fr om car di ovascul ar or pul monar y
compl i cati ons.
Anatomy
Thor ough knowl edge of the ar ter i al , venous, and l ymphati c anatomy
of the col on and r ectum i s essenti al to appr opr i ate sur gi cal
management (F i g. 11.1). The ascendi ng and pr oxi mal transver se
col ons ar e embr yol ogi cal l y der i ved fr om the mi dgut and r ecei ve
thei r ar ter i al bl ood suppl y fr om the super i or mesenter i c ar ter y vi a
the i l eocol i c, r i ght, and mi ddl e col i c ar ter i es. The di stal transver se,
descendi ng, and si gmoi d col on ar e hi ndgut der i vati ves whose
ar ter i al bl ood suppl y ar i ses fr om the i nfer i or mesenter i c ar ter y
(IMA) thr ough the l eft col i c and si gmoi d ar ter i es. The r ectum, al so a
hi ndgut der i vati ve, r ecei ves i ts bl ood suppl y to the upper thi r d fr om
the IMA vi a the super i or hemor r hoi dal ar ter y. The mi ddl e and l ower
thi r ds of the r ectum ar e suppl i ed by the mi ddl e and i nfer i or
hemor r hoi dal ar ter i es, whi ch ar e branches of the hypogastr i c ar ter y.
Col l ateral bl ood suppl y for the col on i s pr ovi ded thr ough the
mar gi nal ar ter y of Dr ummond. The venous drai nage of the col on and
r ectum paral l el s the ar ter i al suppl y, wi th the major i ty drai ni ng
di r ectl y i nto the por tal venous system. Thi s pr ovi des a di r ect r oute
for metastati c spr ead of tumor to the l i ver. The onl y mi nor
anatomi cal var i ati on i n the venous drai nage compar ed wi th the
ar ter i al suppl y i s that the i nfer i or mesenter i c vei n (IMV) joi ns the
spl eni c vei n befor e emptyi ng i nto the por tal system. The r ectum has
dual venous drai nage; the upper r ectum drai ns i nto the por tal
system, and the di stal one-thi r d of the r ectum drai ns i nto the
i nfer i or vena cava vi a the mi ddl e and i nfer i or hemor r hoi dal vei ns,
pr ovi di ng a di r ect r oute for hematogenous spr ead outsi de the
abdomen.
The l ymphati c drai nage of the bowel i s mor e compl ex than the
vascul ar suppl y. Lymphati cs begi n i n the bowel wal l as a pl exus
beneath the l ami na pr opr i a and drai n i nto the submucosal and
i ntramuscul ar l ymphati cs. The epi col i c l ymph nodes drai n the
subser osa and ar e l ocated i n the col on wal l . Thi s nodal gr oup r uns
al ong the i nner bowel mar gi n between the i ntesti nal wal l and the
ar ter i al ar cades. These nodes i n tur n drai n i nto the paracol i c nodes,
whi ch fol l ow the r outes of the mar gi nal ar ter i es. The epi col i c and
paracol i c nodes r epr esent the major i ty of the col oni c l ymph nodes
and ar e the most l i kel y si tes of r egi onal metastati c di sease. The
paracol i c nodes drai n i nto the i nter medi ate nodes, whi ch fol l ow the
mai n col i c vessel s. F i nal l y, the i nter medi ate nodes drai n i nto the
pr i nci pal nodes, whi ch begi n at the or i gi ns of the super i or and
i nfer i or mesenter i c ar ter i es and ar e conti guous wi th the para-aor ti c
chai n.
The r oute of l ymphati c fl ow paral l el s the ar ter i al and venous
di str i buti on of the col on. The r i ght col on wi l l drai n to the super i or
mesenter i c nodes thr ough the i nter medi ate nodes or to the por tal
system vi a the l ymphati cs of the super i or mesenter i c vei n. The l eft
col on's l ymphati c drai nage fol l ows the mar gi nal ar ter y to the l eft
col i c i nter medi ate nodes and fi nal l y to the i nfer i or mesenter i c
nodes. The l ymphati c drai nage of the upper thi r d of the r ectum
fol l ows the IMV, wher eas the l ower two-thi r ds drai n i nto the
hypogastr i c nodes, whi ch, i n tur n, drai n i nto the para-aor ti c nodes.
The l ower thi r d of the r ectum can al so drai n al ong the pudendal
vessel s to the i ngui nal nodes.
Surgical Options
At r esecti on, the pr i mar y tumor and i ts l ymphati c, venous, and
ar ter i al suppl y ar e exti r pated, as wel l as any conti guousl y i nvol ved
or gans. Our cur r ent use of i ntraoperati ve ul trasound i s
l i mi ted to the eval uati on of nonpal pabl e hepati c abnor mal i ti es

i denti fi ed on pr eoperati ve CT scan. We do not bel i eve that the no
touch i sol ati on techni que i s necessar y; we suppor t hi gh l i gati on of
appr opr i ate vessel s i n col on cancer r esecti ons.
F i gur e 11.1. Anatomy of col oni c bl ood suppl y al ong wi th a

pi ctor i al descr i pti on of the var i ous anatomi cal r esecti ons used
for col on car ci noma. A: Ri ght hemi col ectomy. B: Extended r i ght
hemi col ectomy. C: Transver se col ectomy. D: Left hemi col ectomy.
E: Low anter i or r esecti on. (F r om Sugar baker PH, MacDonal d J,
G under son L. Col or ectal cancer. In: DeVi ta VT, Hel l man S,
Rosenber g SA, eds. Cancer : Pr inciples and Pr actice of Oncology.
3r d ed. Phi l adel phi a, Pa: Li ppi ncott; 1984, wi th per mi ssi on.)
The var i ous sur gi cal opti ons, as wel l as thei r i ndi cati ons and major
mor bi di ti es, ar e br i efl y di scussed next.
Right Hemicolectomy
Thi s operati on i nvol ves r emoval of the di stal 5 to 8 cm of the i l eum,
r i ght col on, hepati c fl exur e, and transver se col on just pr oxi mal to
the mi ddl e col i c ar ter y. Thi s pr ocedur e i s i ndi cated for cecal and
ascendi ng col oni c l esi ons. Major mor bi di ti es i ncl ude ur eteral i njur y,
duodenal i njur y, and rar el y bi l e aci d defi ci ency. Anastomoti c
dehi scence i s a r i sk wi th al l bowel r esecti ons that i ncl ude
r econstr ucti on.
Extended Right Hemicolectomy

Thi s pr ocedur e i ncl udes r esecti on of the transver se col on (i ncl udi ng
r esecti on of the mi ddl e col i c ar ter y at i ts or i gi n) i n addi ti on to the
str uctur es r emoved i n the r i ght hemi col ectomy. It general l y r equi r es
mobi l i z ati on of the spl eni c fl exur e to al l ow a tensi on-fr ee
anastomosi s. Indi cati ons for the pr ocedur e ar e hepati c fl exur e or
transver se col on l esi ons. Mor bi di ti es i ncl ude spl eni c i njur y i n
addi ti on to the compl i cati ons associ ated wi th r i ght hemi col ectomy.
Ni nety per cent of the fecal water i s absor bed i n the pr oxi mal col on;
ther efor e, extended r esecti ons ar e associ ated wi th the potenti al for
di ar r hea.
Transverse Colectomy
Thi s pr ocedur e i nvol ves the segmental r esecti on of the transver se
col on and i s i ndi cated for mi ddl e transver se col on l esi ons. Thi s
operati on i s i nfr equentl y per for med because the mi dtransver se
col on i s one of the l east common l ocati ons for pr i mar y col on
cancer s. To pr event anastomoti c dehi scence, a wel l -vascul ar i zed and
tensi on-fr ee anastomosi s i s mandated. Thi s r equi r es mobi l i z ati on of
both the r i ght and the l eft col ons, al ong wi th both fl exur es wi th an
ascendi ng-to-descendi ng col on anastomosi s.
Left Hemicolectomy
Thi s r esecti on i nvol ves the r emoval of the transver se col on di stal to
the r i ght branch of the mi ddl e col i c ar ter y and the descendi ng col on
up to, but not i ncl udi ng, the r ectum and pr oxi mal l i gati on and
di vi si on of the l eft col i c vessel s or IMA. Thi s operati on may be
tai l or ed to the l ocati on of the l esi on. Indi cati ons for the pr ocedur e
ar e l eft col on and spl eni c fl exur e l esi ons. Mor bi di ti es i ncl ude spl eni c
and ur eteral i njur y.
Low Anterior Resection

When per for med for l esi ons wi thi n the si gmoi d col on or pr oxi mal
r ectum, thi s pr ocedur e i ncl udes r emoval of the si gmoi d col on and
the i nvol ved r ectum, and l i gati on of super i or r ectal vessel s at thei r
or i gi n. The spl eni c fl exur e i s r outi nel y mobi l i zed and the
r econstr ucti on i s per for med usi ng the descendi ng col on. The use of
the si gmoi d col on i s di scouraged, especi al l y for di stal
r econstr ucti on as the thi ckened and hyper tr ophi c muscl e of the
si gmoi d i s l ess compl i ant and wel l vascul ar i zed than the descendi ng
col on. To achi eve a tensi on-fr ee anastomosi s, the IMA may need to
be di vi ded at i ts or i gi n, al ong wi th the IMV at the i nfer i or bor der of
the pancr eas. For l esi ons i nvol vi ng the r ectum, the mesor ectum
shoul d be di vi ded at l east 5 cm di stal to the di stal aspect of the
tumor. Mor bi di ti es i ncl ude anastomoti c dehi scence, whi ch i s hi gher
wi th mor e di stal r econstr ucti on and has been r epor ted to be l ess
than 10% , and bowel i schemi a (secondar y to i nadequate fl ow
thr ough the mar gi nal ar ter y of Dr ummond). For r outi ne l ow anter i or
r esecti ons for si gmoi d or upper r ectal l esi ons wi thout radi ati on, a
defuncti oni ng i l eostomy i s not typi cal l y necessar y.
Subtotal Colectomy
Thi s r esecti on i nvol ves the r emoval of the enti r e col on to the
r ectum wi th an i l eor ectal anastomosi s. Thi s pr ocedur e i s i ndi cated
for mul ti pl e synchr onous col oni c tumor s that ar e not confi ned to a
si ngl e anatomi cal di str i buti on, for sel ected pati ents wi th FAP wi th
mi ni mal r ectal i nvol vement, or for sel ected pati ents wi th HNPCC and
col on cancer. Al though an excel l ent qual i ty of l i fe can be achi eved
after i l eor ectostomy, fr equent l oose bowel movements ar e the nor m.
Pati ents shoul d be counsel ed r egar di ng a bowel r egi men and
per i anal car e. The r i sk for anastomoti c l eak after i l eor ectal
anastomosi s i s appr oxi matel y 5% or l ess.
The sur gi cal tr eatment of the fami l i al pol yposi s syndr omes depends
on the age of the pati ent and the pol yp densi ty i n the r ectum.
Sur gi cal opti ons i ncl ude pr octocol ectomy wi th Br ooke i l eostomy,
total abdomi nal col ectomy wi th IRA, or r estorati ve pr octocol ectomy
wi th IPAA. Pr octocol ectomy wi th conti nent i l eostomy i s rar el y
per for med today. Total abdomi nal col ectomy wi th i l eor ectal
anastomosi s has a l ow compl i cati on rate, pr ovi des good functi onal
r esul ts, and i s a vi abl e opti on for pati ents wi th fewer than 20
adenomas i n the r ectum. These pati ents must be obser ved wi th 6month pr octoscopi c exami nati ons to r emove pol yps and detect si gns
of cancer. If r ectal pol yps become too numer ous, compl eti on
pr octectomy wi th Br ooke i l eostomy or IPAA, when techni cal l y
possi bl e, i s war ranted. The Cl evel and Cl i ni c Foundati on r ecentl y
eval uated thei r r egi str y of pati ents wi th FAP who wer e tr eated wi th
IRA or IPAA. Pr i or to the use of IPAA for pati ents wi th hi gh r ectal
pol yp bur dens, the r i sk of cancer i n the r etai ned r ectum was 12.9%
at a medi an fol l ow-up of 212 months. Because of the use of IPAA for
pati ents wi th l ar ge r ectal pol yp bur dens and the sel ected use of IRA
for those wi th smal l r ectal pol yp bur dens, no pati ent has devel oped
r ectal cancer i n the r emai ni ng r ectum at a medi an fol l ow-up of 60
months. Restorati ve pr octocol ectomy wi th IPAA has the advantage
of r emovi ng al l or near l y al l l ar ge i ntesti ne mucosa at r i sk for
cancer, whi l e pr eser vi ng transanal defecati on. Compl i cati on rates
ar e l ow when thi s pr ocedur e i s done i n l ar ge center s. Mor bi di ty fr om
the pr ocedur e i ncl udes i nconti nence, mul ti pl e l oose stool s,
i mpotence, r etr ograde ejacul ati on, dyspar euni a, and pouchi ti s.
Appr oxi matel y 7% of pati ents have to be conver ted to a per manent
i l eostomy due to compl i cati ons after the pr ocedur e.
Laparoscopic Resection for Colorectal

Carcinoma
Recent studi es have confi r med that l apar oscopy for col or ectal
car ci noma r esecti on i s techni cal l y feasi bl e and safe, yi el di ng an
equi val ent number of r esected l ymph nodes and l ength of r esected
bowel when compar ed wi th open col ectomy. Ear l y concer ns
r egar di ng por t-si te metastases have now been l ai d to r est. The fi r st
adequatel y power ed randomi zed tr i al was conducted i n Bar cel ona,
Spai n. Thi s tr i al randomi zed 219 pati ents to l apar oscopi c ver sus
open col ectomy for cancer and demonstrated oncol ogi c equi val ency
and a tr end towar d i mpr oved oncol ogi c outcomes i n a smal l subset
of stage III pati ents.
The Nati onal Cancer Insti tute (NCI)-sponsor ed mul ti center ed
Cl i ni cal Outcomes of Sur gi cal Therapy (COST) tr i al enr ol l ed near l y
800 pati ents and val i dated the oncol ogi c safety and effi cacy of
l apar oscopy for col on cancer. Lapar oscopi c assi sted col ectomy for
cancer was associ ated wi th equi val ent r ecur r ence-fr ee and overal l
sur vi val when compar ed wi th open sur ger y wi th no i ncr ease i n
wound r ecur r ences. Pati ent r el ated benefi ts i ncl uded r educed l ength
of hospi tal stay, decr eased pai n, faster r esol uti on of i l eus, i mpr oved
cosmesi s, and a smal l i mpr ovement i n shor t-ter m qual i ty of l i fe.
The Medi cal Resear ch Counci l -sponsor ed Conventi onal ver sus
Lapar oscopi c-Assi sted Sur ger y In pati ents wi th Col or ectal Cancer
(CLASICC) mul ti center ed tr i al i n the Uni ted Ki ngdom has fi ni shed
accr ual and has r epor ted thei r shor t-ter m outcomes, whi ch ar e
oncol ogi cal l y equi val ent for l apar oscopi c ver sus open col ectomy for
cancer. Si mi l ar pati ent-r el ated benefi ts as i n the COST tr i al wer e
obser ved. The Eur opean Mul ti center ed Col on Car ci noma
Lapar oscopi c or Open Resecti on tr i al i s sti l l ongoi ng. An addi ti onal
tr i al fr om Hong Kong demonstrated oncol ogi c equi val ency wi th
l apar oscopy for si gmoi d and r ectosi gmoi d tumor s. The l apar oscopi cassi sted appr oach has consi stentl y been associ ated wi th r educti ons
i n hospi tal stay, postoperati ve pai n, and durati on of postoperati ve
i l eus when compar ed wi th open sur ger y. However, the magni tude of
these effects i n randomi zed tr i al s have been modest, appr oxi matel y
20% to 35% , and r emai ns the subject of fur ther i nvesti gati on.
Unpr oven addi ti onal benefi ts of l apar oscopy i ncl ude potenti al l y
decr eased mor bi di ty, decr eased conval escence, i mpr oved qual i ty of
l i fe, and decr eased costs.
Wi th r espect to cl i ni cal tr i al s of l apar oscopy for col or ectal cancer, i t
shoul d be noted that exper i enced sur geons who have demonstrated
pr ofi ci ency i n l apar oscopi c col ectomy for cancer obtai ned these
r esul ts. F ur ther mor e, al though l apar oscopi c-assi sted techni ques
have been val i dated for col on car ci noma, i ts use for r ectal cancer
has not yet been defi ni ti vel y establ i shed. Addi ti onal i ndi cati ons for
l apar oscopy i ncl ude r esecti on of pol yps, cr eati on of i ntesti nal
stomas, and di agnosti c pr ocedur es.
The appeal of l apar oscopi c col on sur ger y i s a si mpl e one: mi ni mal l y
i nvasi ve techni ques r esul t i n faster r ecover y and ther efor e may
r esul t i n i mpr oved qual i ty of l i fe and l ower heal th car e costs when
compar ed wi th open l apar otomy. These benefi ts have been
dramati cal l y r eal i zed wi th sur ger y for other si tes such as for beni gn
gal l bl adder di sease. When consi der i ng col ectomy,
r educti on i n postoperati ve pai n and nar coti c use, faster r esol uti on
of i l eus, and shor ter durati on of hospi tal i z ati on ar e uni fyi ng
featur es of the l apar oscopi c appr oach. Added benefi ts may i ncl ude
the potenti al for i mpr oved shor t- and l ong-ter m compl i cati ons and a
r educti on i n costs. However, owi ng to the r el ati vel y i ncr eased
compl exi ty of l apar oscopi c col ectomy and the ongoi ng evol uti on of
the techni ques, the magni tude of these benefi ts i s sti l l bei ng
deter mi ned.
F ur ther mor e, the i mpor tance of these effects may i n par t depend on
the under l yi ng di agnosi s. Most pati ents wi th col on cancer ar e
candi dates for l apar oscopi c-assi sted techni ques. Transver se col on
tumor s r equi r e extensi ve bi l ateral col oni c mobi l i z ati on and
ther efor e ar e techni cal l y mor e di ffi cul t. Factor s associ ated wi th an
i ncr eased need for conver si on i ncl ude tumor-r el ated factor s such as
pr oxi mal l eft-si ded l esi ons and l ar ge bul ky tumor s, as wel l as
pati ent obesi ty, adhesi ons, and the pr esence of an associ ated
abscess that was not pr eoperati vel y i denti fi ed. Cancer s wi th
per forati on, obstr ucti on, or i nvasi on of the r etr oper i toneum or
abdomi nal wal l ar e not appr oached l apar oscopi cal l y.
Obstructing Colorectal Cancers

Obstr ucti ng col or ectal cancer s ar e usual l y tr eated i n two stages:
r esecti on and Har tmann's pr ocedur e, fol l owed by col ostomy
takedown and anastomosi s. An al ter nati ve i s a one-stage pr ocedur e
wi th ei ther subtotal col ectomy and pr i mar y anastomosi s or a
segmental r esecti on and i ntraoperati ve col oni c l avage for car eful l y
sel ected pati ents. (Contrai ndi cati ons i ncl ude mul ti pl e pr i mar y
cancer s, advanced per i toni ti s, hemodynami c i nstabi l i ty, poor general
heal th, ster oi d therapy, or i mmunosuppr essed state.) In the SCOTIA
pr ospecti ve randomi zed tr i al usi ng these two tr eatment modal i ti es
i n 91 pati ents wi th mal i gnant l eft-si ded col oni c obstr ucti on, the
mor bi di ty and mor tal i ty rates wer e si mi l ar. Laser ful gurati on and
endoscopi c stenti ng of obstr ucti ve l esi ons can be used for pal l i ati on
and to al l ow for bowel pr eparati on and subsequent si ngl e-step
r esecti on. Obstr ucti ng r i ght-si ded cancer s can be effecti vel y tr eated
wi th r esecti on and anastomosi s i n one stage.
Survival
Nodal i nvol vement i s the pr i mar y deter mi nant of 5-year sur vi val . In
node-negati ve di sease, the 5-year sur vi val rate i s 90% for pati ents
wi th T1 and T2 l esi ons and 80% for those wi th T3 l esi ons. For nodeposi ti ve cancer s, the 5-year sur vi val ranges fr om 74% wi th N1
di sease to 51% wi th N2 di sease. These fi gur es al so var y dependi ng
on the number of l ymph nodes eval uated i n the sur gi cal speci men,
wi th i mpr oved sur vi val associ ated wi th a hi gher number of l ymph
nodes eval uated. Other factor s that ar e pr oven pr ognosti c i ndi cator s
i ncl ude grade, bowel per forati on, and obstr ucti on. Pati ents who
pr esent wi th unr esectabl e metastati c di sease have hi stor i cal l y had
an 8% 5-year sur vi val rate.
Adjuvant Therapy
Most pati ents wi th col on cancer pr esent wi th di sease that appear s
l ocal i zed and can be compl etel y r esected wi th sur ger y. However,
al most 33% of pati ents under goi ng curati ve r esecti on wi l l r el apse
wi th r ecur r ent di sease secondar y to unr esected occul t mi cr oscopi c
metastasi s. Adjuvant therapy i s admi ni ster ed to tr eat and hopeful l y
eradi cate thi s r esi dual mi cr ometastati c di sease. Unti l r ecentl y, 5fl uor ouraci l (5-F U) was the onl y effecti ve agent for col on car ci noma,
wi th r esponse rates of 15% to 30% i n pati ents wi th advanced
di sease. In the past 5 year s, several new agents have shown
excel l ent acti vi ty i n col or ectal cancer, i ncl udi ng i r i notecan,
oxal i pl ati n, and bi ol ogi cal agents.
History
Wi th the i denti fi cati on of the anti cancer acti vi ty of 5-F U i n pati ents
wi th col or ectal cancer s, ther e have been numer ous studi es of 5-F U
i n combi nati on therapi es. Adjuvant tr i al s usi ng 5-F U and semusti ne
(MeCCNU; Veterans Admi ni strati on Sur gi cal Oncol ogy G r oup, VASOG
no. 5) fai l ed to demonstrate an overal l sur vi val benefi t fr om
adjuvant therapy wi th thi s combi nati on. However, subset anal ysi s of
pati ents wi th one to four posi ti ve l ymph nodes di d r eveal a
si gni fi cant i mpr ovement i n 5-year sur vi val i n pati ents r ecei vi ng
sur ger y and 5-F U/semusti ne ver sus sur ger y al one (51% 31% ,
r especti vel y). A second l ar ge tr i al was the Nati onal Sur gi cal
Adjuvant Br east and Bowel Pr oject (NSABP) C-01 pr otocol , whi ch
compar ed sur ger y al one wi th sur ger y fol l owed by MOF
chemotherapy (MeCCNU, vi ncr i sti ne, and 5-F U). Wi th mor e than
1,100 pati ents randomi zed, the study demonstrated an 8%
i mpr ovement i n 5-year sur vi val i n the adjuvant therapy ar m.
Al though these i ni ti al r esul ts wer e posi ti ve, they wer e not suffi ci ent
to r ecommend adjuvant therapy for col or ectal cancer. They di d,
however, sti mul ate fur ther studi es combi ni ng 5-F U wi th other
agents.
5-Fluorouracil/Levamisole
The fi r st major success of adjuvant therapy for col on cancer was
demonstrated i n tr i al s of 5-F U i n combi nati on wi th l evami sol e, an
anti hel mi nthi c agent wi th i mmunosti mul ator y pr oper ti es. A pi l ot
pr ospecti ve randomi zed study compar i ng 5-F U/l evami sol e,

l evami sol e, and sur ger y al one conducted by the Nor th Central
Cancer Tr eatment G r oup (NCCTG ) demonstrated i mpr oved 5-year
di sease-fr ee sur vi val wi th l evami sol e and 5-F U/l evami sol e gi ven for
1 year as compar ed wi th sur ger y al one. The i mpr ovement i n the
l evami sol e-onl y ar m was l ess si gni fi cant than that of the 5F U/l evami sol e ar m when exami ni ng overal l 5-year sur vi val . These
r esul ts wer e confi r med by the Nati onal Cancer Insti tute Inter gr oup
Tr i al (NCI-INT) pr otocol 035, a l ar ger study compar i ng the same
tr eatment ar ms. In thi s study, pati ents wi th stage III di sease wer e
shown to have a 41% r educti on i n the r i sk of r ecur r ence when
tr eated wi th 5-F U/l evami sol e. These pati ents al so demonstrated a
33% i mpr ovement i n overal l 5-year sur vi val . Inter esti ngl y, the
l evami sol e-onl y ar m fai l ed to show any i mpr ovement i n di sease-fr ee
and overal l 5-year sur vi val rates compar ed wi th the sur ger y-onl y
ar m. In addi ti on, the data suggested an i mpr ovement i n di seasefr ee and overal l sur vi val for pati ents wi th stage II col on car ci noma;
however, stati sti cal si gni fi cance was not r eached for thi s gr oup of
pati ents. Based on these r esul ts, the Nati onal Insti tutes of Heal th
Consensus Confer ence i n 1990
r ecommended that al l pati ents wi th stage III col on car ci noma
r ecei ve adjuvant chemotherapy wi th 5-F U and l evami sol e. Adjuvant
chemotherapy for pati ents wi th stage II col on car ci noma r emai ned
of unpr oven benefi t.
5-Fluorouracil/Leucovorin
The addi ti on of l eucovor i n (LV) to 5-F U has been shown to i ncr ease
anti tumor acti vi ty i n both i n vi tr o and i n vi vo model s. LV wor ks by
stabi l i z i ng the 5-F U thymi dyl ate synthase compl ex, thus pr ol ongi ng
the i nhi bi ti on of thymi dyl ate synthase and i ncr easi ng tumor
cytotoxi ci ty. In the Uni ted States, the two most commonl y used
r egi mens wer e the Mayo Cl i ni c r egi men of bol us 5-F U 425 mg/m2 /d
and l eucovor i n 20 mg/m2 /d days 1 to 5 ever y 28 days and the
Roswel l Par k r egi men usi ng bol us 5-F U 500 mg per m2 and
l eucovor i n 500 mg per m2 weekl y for 6 weeks ever y 8 weeks. These
r egi mens showed effi cacy i n the metastati c cancer setti ng. These
fi ndi ngs qui ckl y l ed to study of thi s combi nati on i n the adjuvant
setti ng. Ini ti al effi cacy of thi s combi nati on was demonstrated i n the
NCI-INT pr otocol 089, whi ch demonstrated a 30% i mpr ovement i n
5-year sur vi val when compar ed wi th sur ger y al one. An Ital i an study
al so demonstrated both i mpr oved di sease-fr ee and overal l sur vi val
usi ng the 5-F U/LV combi nati on. Mor e r ecent studi es have compar ed
5-F U/LV to pr evi ousl y tested combi nati ons. The NSABP C-03 tr i al
compar ed 5-F U/LV to MOF chemotherapy (MOF was used i n NSABP
C-01). Thi s study was r epor ted ear l y because 5-F U/LV was
si gni fi cantl y super i or to MOF i n ter ms of overal l sur vi val , and i t was
much l ess toxi c than MOF. NSABP C-04 compar ed 5-F U/LV wi th 5F U/l evami sol e and 5-F U/LV/l evami sol e. Durati on of therapy for thi s
tr i al was 1 year. The r esul ts showed that the 5-F U/LV combi nati on
was super i or to 5-F U/l evami sol e, wi th di sease-fr ee sur vi val of 64%
ver sus 60% and overal l sur vi val of 74% ver sus 69% , r especti vel y
(p = 0.05). The 5-F U/LV/l evami sol e combi nati on di d not i mpr ove
outcome but had mar ked i ncr eased toxi ci ty. F i nal l y, NSABP C-05
compar ed 5-F U/LV wi th 5-F U/LV and i nter fer on (IF N). No di ffer ence
i n di sease-fr ee and overal l sur vi val was demonstrated wi th the
addi ti on of IF N.
Oral Fluoropyrimidines
Two new oral agents, UF T and capeci tabi ne, have been tested i n
l ar ge, wel l -desi gned tr i al s. UF T, a combi nati on of oral uraci l and the
5-F U pr odr ug Tegafur, has been studi ed i n the NSABP C-06 tr i al
compar i ng 6 months of UF T wi th l eucovor i n to 5-F U and l eucovor i n
usi ng the Roswel l Par k r egi men. No di ffer ences wer e seen i n 5-year
sur vi val wi th these r egi mens.
Capeci tabi ne i s a dr ug wi th rapi d G I absor pti on that under goes a
thr ee-step enz ymati c conver si on to 5-F U i n tumor ti ssue. When
used i n fi r st-l i ne tr eatment of metastati c col or ectal cancer, i t was
associ ated wi th a better toxi ci ty pr ofi l e than 5-F U. The phase III XACT tr i al i nvesti gated the use of capeci tabi ne i n the adjuvant
setti ng for r esected stage III col on cancer and al so noted an
i mpr oved safety pr ofi l e when compar ed wi th 5-F U and l eucovor i n
usi ng the Mayo Cl i ni c r egi men, wi th si gni fi cantl y l ess di ar r hea,
nausea/vomi ti ng, stomati ti s, and neutr openi a. Capeci tabi ne was
associ ated wi th an i ncr eased r i sk for sever e hand and foot
syndr ome.
Irinotecan
Ir i notecan has shown si gni fi cant acti vi ty i n metastati c col or ectal
cancer and i ts use i n the adjuvant setti ng has been studi ed by
several tr i al s. The most i mpor tant ar e the Cancer and Leukemi a
G r oup B (CALG B) C89803 tr i al and Eur opean PETACC-3 tr i al . In the
CALG B study, 1,260 pati ents wi th r esected stage III col on cancer
wer e randomi zed to Roswel l Par k r egi men 5-F U and l eucovor i n wi th
or wi thout i r i notecan (IF L). The IF L ar m noted an i ncr eased 60-day
mor tal i ty of 2.5% ver sus 0.8% i n the contr ol gr oup, pr i mar i l y due
to gastr oi ntesti nal and thr omboembol i c toxi ci ti es. The PETACC-3
tr i al usi ng two di ffer ent schedul es of 5-F U i nfusi on al one or wi th
i r i notecan for 6 months i n the adjuvant setti ng for stages II and III
col on cancer has not yet r epor ted i ts fi nal data.
Oxaliplatin
Oxal i pl ati n, a new pl ati num der i vati ve wi th acti vi ty agai nst
col or ectal cancer, has shown i mpr essi ve anti tumor acti vi ty agai nst
advanced col or ectal cancer. The Mul ti center Inter nati onal Study of
Oxal i pl ati n, 5-F U and l eucovor i n i n the Adjuvant Tr eatment of Col on
Cancer (MOSAIC) tr i al has r ecentl y publ i shed i ts r esul ts. Thi s study
enr ol l ed 2,246 pati ents wi th compl etel y r esected stage II/III
col or ectal cancer to the i nfusi onal LV5-F U2 r egi men or to F OLF OX-4,
whi ch i s LV5-F U2 pl us oxal i pl ati n (85 mg per m2 ) gi ven ever y 2
weeks for 12 cycl es. The pr i mar y endpoi nt of 3-year di sease-fr ee
sur vi val was si gni fi cantl y better for the F OLF OX-4 ar m (78.2% vs.
72.9% , p = 0.002). These r esul ts wer e mor e si gni fi cant i n stage III
pati ents than i n stage II pati ents. The NSABP C-07 tr i al i s studyi ng
Roswel l Par k r egi men bol us 5-F U and l eucovor i n wi th or wi thout
oxal i pl ati n.
Monoclonal Antibodies
One of the most i mpor tant r ecent advances i n the tr eatment of
advanced col or ectal cancer has been the avai l abi l i ty of bi ol ogi cal
agents di r ected agai nst tumor-speci fi c tar gets. The epi der mal
gr owth factor r eceptor (EG F R)-medi ated pathways ar e i mpor tant for
tumor pr ol i ferati on and metastases. Monocl onal anti bodi es di r ected
agai nst EG F R i ncl ude cetuxi mab, pani tumomab, and other s.
Cetuxi mab i s a chi mer i c anti body wi th acti vi ty agai nst col or ectal
cancer that has been demonstrated by the Eur opean randomi zed
phase II BOND tr i al , whi ch randomi zed i r i notecan fai l ur e pati ents
to r ecei ve cetuxi mab and i r i notecan or cetuxi mab monotherapy. The
r esponse rate was 10.8% wi th cetuxi mab al one and 22.9% wi th
combi nati on therapy. Cur r entl y, cetuxi mab i s the onl y anti -EG F R
anti body appr oved for use for col or ectal cancer. Its r ol e i n the
adjuvant setti ng has not yet been establ i shed.
The vascul ar endothel i al gr owth factor (VEG F ) fami l y of
gl ycopr otei ns i s al so i mpor tant for tumor gr owth. Bevaci z umab i s a

humani zed monocl onal anti body that tar gets ci r cul ati ng VEG F. In
pr evi ousl y untr eated metastati c col or ectal cancer, the addi ti on of
bevaci z umab to IF L i mpr oved the r esponse rate fr om 35% to 45% (p
= 0.0029) and the overal l sur vi val fr om 15.6 to 20.3 months
(p = 0.00003). The ECOG 3200 tr i al compar es F OLF OX wi th si ngl eagent bevaci z umab or F OLF OX and bevaci z umab as second l i ne for
metastati c col or ectal cancer. Addi ti on of bevaci z umab pr ol onged
medi an sur vi val fr om 10.7 months for F OLF OX to 12.5 months for
the combi nati on r egi men. As wi th cetuxi mab, the r ol e of
bevaci z umab i n the adjuvant setti ng has not yet been establ i shed.
Duration of Therapy
Most of the adjuvant tr i al s used 1 year of tr eatment for the
adjuvant tr eatment ar ms. Opti mal tr eatment durati on was exami ned
i n two tr i al s: the NCI-INT pr otocol 089 and an NCCTG tr i al . These
studi es exami ned 12- and 6-month tr eatment cour ses for 5-F U/LV
and 5-F U/l evami sol e. Reducti on of tr eatment fr om 12 to 6 months
for 5-F U/l evami sol e r esul ted i n an 8% i ncr ease i n mor tal i ty. No
i ncr ease i n mor tal i ty was noted compar i ng 12- and 6-month
tr eatment wi th 5-F U/LV. Overal l , 6 months of 5-F U/LV was shown to
be equi val ent to 1 year of 5-F U/l evami sol e. For 5-F U/LV, maxi mal
benefi t of adjuvant therapy for the pati ent i s achi eved wi th 6
months of therapy. The method of admi ni strati on has been under
some debate. However, the bol us r egi mens have been associ ated
wi th hi gher i nci dence of toxi ci ty; ther efor e, the pr otracted r egi mens
of i ntravenous 5-F U or the oral fl uor opyr i mi di ne, capeci tabi ne, ar e
cur r entl y favor ed.
Adjuvant Therapy for Stage II Disease

Al though adjuvant therapy has been pr oven to benefi t pati ents wi th
stage III di sease, the i ssue of benefi t for pati ents wi th stage II
di sease r emai ns contr over si al . Al though many of the adjuvant tr i al s
i ncl uded pati ents wi th stage II di sease, subgr oup anal ysi s shows
tr ends towar d benefi t wi thout r eachi ng stati sti cal si gni fi cance. Thi s
i ssue has been addr essed i n thr ee meta-anal yses fr om NSABP,
NCCTG , and IMPACT (Inter nati onal Mul ti -center Pool ed Anal ysi s of
Col on cancer Tr i al s). Al l have suggested mar gi nal i mpr ovements i n
di sease-fr ee and overal l sur vi val wi th 5-F U and l eucovor i n i n stage
II col on cancer pati ents. Adjuvant chemotherapy i n stage II pati ents
pr ovi des a r el ati ve i mpr ovement i n overal l 5-year sur vi val that was
comparabl e to that of stage III pati ents (appr oxi matel y 30%
r el ati ve i mpr ovement). However, the absol ute i mpr ovement i n
overal l sur vi val i s onl y 2% to 7% . Ther efor e, the r outi ne use of
adjuvant chemotherapy for stage II pati ents i s sti l l not common
practi ce. G eneral l y, pati ents wi th stage II di sease ar e offer ed
chemotherapy i f adver se pr ognosti c featur es such as l ymphovascul ar
i nvasi on, T4 status, obstr ucti on, or poor di ffer enti ati on ar e pr esent.
The deter mi nati on of mol ecul ar and geneti c pr ognosti c mar ker s that
wi l l be useful i n sel ecti ng those stage II pati ents who woul d benefi t
most fr om r outi ne use of adjuvant therapy i s an ar ea of acti ve
i nvesti gati on.
Treatment of Locally Advanced Colon Cancer

Col on cancer s that ar e adher ent to adjacent str uctur es have a 36%
to 53% chance of l ocal fai l ur e after compl ete r esecti on.
Appr oxi matel y 10% of car ci nomas pr esent i n thi s fashi on.
Strategi es desi gned to r educe l ocal r ecur r ence woul d benefi t these
pati ents.
Surgical Strategy
Resecti on of col or ectal cancer that has i nvaded adjacent str uctur es
i nvol ves en bl oc r esecti on of al l i nvol ved str uctur es; fai l ur e to do so
r esul ts i n si gni fi cantl y i ncr eased l ocal r ecur r ence and decr eased
sur vi val . Impor tantl y, al l adhesi ons between the car ci noma and
adjacent str uctur es shoul d be assumed to be mal i gnant and not
taken down because 33% to 84% ar e mal i gnant when exami ned
hi stol ogi cal l y. The affected or gan shoul d have r esecti on l i mi ted to
the i nvol ved ar ea wi th a r i m of nor mal ti ssue. A pati ent who has a
mar gi n-negati ve mul ti vi sceral r esecti on has the same sur vi val as a
pati ent wi th no adjacent or gan i nvol vement on a stage-matched
basi s.
Adjuvant Radiation Therapy

Retr ospecti ve ser i es have shown subsets of pati ents who have
benefi ted fr om postoperati ve radi ati on therapy wi th or wi thout 5F Ubased chemotherapy. Unfor tunatel y, ther e ar e no consi stent
cr i ter i a to use i n assessi ng i ncr eased r i sk of l ocal fai l ur e. The val ue
of adjuvant radi ati on therapy after compl ete r esecti on of hi gh-r i sk
col on cancer i s cur r entl y bei ng eval uated i n a randomi zed
pr ospecti ve fashi on (NCCTG 91-46-52). In thi s tr i al , pati ents wi th
B3 or C3 (modi fi ed Astl er-Col l er ) tumor s ar e randomi zed to r ecei ve

postoperati ve 5-F U/l evami sol e or 5-F U/l evami sol e and radi ati on
therapy. Pati ents wi th subtotal l y r esected cancer s far e wor se than
those wi th posi ti ve mi cr oscopi c di sease, as one woul d expect. It has
been found that radi ati on therapy i s mor e effecti ve i n mi cr oscopi c
than i n macr oscopi c di sease, and that i t i s mor e effecti ve when
combi ned wi th 5-F U. In a r ecent r etr ospecti ve Mayo Cl i ni c study of
103 mostl y stage B3 and C3 (modi fi ed Astl er-Col l er ) pati ents, i n
whi ch 49% had no r esi dual di sease, 17% had mi cr oscopi c r esi dual
di sease, and 34% had gr oss r esi dual di sease; the l ocal fai l ur e rate
was 10% for pati ents wi th no r esi dual di sease, 54% for those wi th
mi cr oscopi c r esi dual di sease, and 79% for those wi th gr oss r esi dual
di sease. Mor e r ecentl y, i mpr oved l ocal contr ol wi th adjuvant
radi ati on has been demonstrated i n a smal l set of pati ents wi th T4
cancer s wi th per forati on or fi stul a. If ther e i s any questi on
r egar di ng the abi l i ty to achi eve a mar gi n-negati ve r esecti on,
sur gi cal cl i ps shoul d be used to outl i ne the ar ea of the tumor bed. If
the mar gi n i s posi ti ve on fi nal pathol ogi cal studi es, radi ati on shoul d
be admi ni ster ed wi th concomi tant 5-F Ubased chemotherapy.
Management of Rectal Cancer

The pr i mar y pr i nci pl e i n the management of l ocal i zed r ectal cancer
i s si mi l ar to that for col on cancer (i .e., compl ete oncol ogi c
r esecti on). In l i ne wi th thi s pr i nci pl e ar e the goal s of cancer contr ol
(negati ve mar gi n r esecti on of tumor, and r esecti on of al l drai ni ng
l ymph nodes), r estorati on of i ntesti nal conti nui ty, and pr eser vati on
of anor ectal sphi ncter, sexual , and ur i nar y functi on. Achi evi ng these
goal s i s made di ffi cul t due to the anatomi cal constrai nts of the bony
pel vi s. Local contr ol i s cl ear l y r el ated to the adequacy of the
sur gi cal pr ocedur e. Al though l ocal contr ol i s cr i ti cal for i ncr easi ng
the chances of cur e, many pati ent- and tumor-r el ated factor s ar e
associ ated wi th overal l outcome. Data suggest that
ther e i s a si gni fi cant sur geon- and center-r el ated var i abi l i ty i n
pati ent outcome after tr eatment for r ectal cancer. The Stockhol m
Rectal Cancer Study G r oup found that speci al i sts and center s wi th
hi gher vol umes of r ectal cancer cases had l ower l ocal fai l ur e rates
and i ncr eased sur vi val rates. It i s not unusual to see l ocal
r ecur r ence rates rangi ng fr om 3.7% to 43% i n var i ous ser i es for
curati ve sur gi cal r esecti on, wi th or wi thout adjuvant therapy.
Obvi ousl y, other factor s ar e i nvol ved, such as methods of adjuvant
therapy, pati ent sel ecti on, and di sease factor s. These var yi ng
r esul ts have hi nder ed an accurate assessment of the vi tal

components of an adequate oncol ogi c operati on and pr evented an
accurate assessment of the val ue of adjuvant chemoradi ati on i n
r ectal cancer. Consequentl y, ther e ar e some who bel i eve that wi th
an adequate oncol ogi c pr ocedur e by an exper i enced sur geon, onl y
l ar ge T3 and T4 (fi xed) l esi ons need adjuvant chemoradi ati on
tr eatment. Tr eati ng al l other T3 pati ents and those wi th N1N2
di sease mer el y attempts to make up for bad sur ger y. Other s
contend that the si gni fi cant decr ease i n l ocal r ecur r ence and
possi bl y some i mpr ovement i n sur vi val associ ated wi th adjuvant
radi ati on or chemoradi ati on justi fy i ts appl i cati on i n al l pati ents
wi th tumor s that ar e T3 or gr eater, or those wi th node-posi ti ve
di sease. Never thel ess, sur gi cal techni que i s cr i ti cal to the success of
the tr eatment of r ectal cancer.
When pl anni ng sur gi cal tr eatment of a r ectal cancer, the r ectum can
be general l y di vi ded i nto thr ee r egi ons: l ower, mi ddl e, and upper
thi r ds. The upper r ectum i s general l y defi ned as extendi ng 11 to 15
cm fr om the anal ver ge. The l ength of the r ectum var i es
si gni fi cantl y, dependi ng on the si ze of the i ndi vi dual , and ther efor e
these di sti ncti ons shoul d be i ndi vi dual i zed. Tumor s of the pr oxi mal
r ectum, at the l evel of the sacral pr omontor y, behave si mi l ar l y to
col oni c cancer s and ar e ther efor e general l y consi der ed to be
r ectosi gmoi d cancer s. Tumor s 6 to 10 cm fr om the anal ver ge ar e
defi ned as mi ddl e r ectal cancer s, and tumor s fr om 0 to 5 cm ar e
defi ned as l ow r ectal cancer s. Note that l ow r ectal cancer s can be
associ ated wi th the i nter nal and exter nal sphi ncter s, anal canal , or
l evator muscl es, or can be above the pel vi c fl oor.
Surgical Aspects
In addi ti on to under standi ng the anatomi cal si te of the tumor, i t i s
i mpor tant to under stand the pr i nci pl es i nfl uenci ng the extent of
radi cal exti r pati ve sur ger y, r egar dl ess of the type of r esecti on
pl anned.
Resection Margin
Opti mal tr eatment of al l mal i gnanci es r equi r es an adequate mar gi n
of r esecti on. Hi stol ogi c exami nati on of the bowel wal l di stal to the
gr oss r ectal tumor r eveal s that onl y 2.5% of pati ents wi l l have
submucosal spr ead of di sease gr eater than 2.5 cm. However, the
most i mpor tant mar gi n i s the radi al mar gi n. For many, par ti cul ar l y
di stal , r ectal cancer s, thi s i s the most di ffi cul t mar gi n to achi eve. In
1986 Qui r ke et al . wer e the fi r st to character i ze the cr i ti cal

i mpor tance of the negati ve radi al mar gi n i n pr eventi ng r ectal cancer
r ecur r ence. In thei r ser i es, the rate of l ocal r ecur r ence was 86% i n
the setti ng of a posi ti ve radi al r esecti on mar gi n.
At MDACC, we tr y to obtai n a di stal r esecti on mar gi n of at l east 2
cm. Ir r i gati on of the r ectal stump has not shown to affect
r ecur r ence and i s not mandator y.
Lymphadenectomy
An adequate l ymphadenectomy shoul d be per for med for accurate
stagi ng and l ocal contr ol , and shoul d i ncl ude pr oxi mal vascul ar
l i gati on at the or i gi n of the super i or r ectal vessel s fr om the IMA
just di stal to the or i gi n of the l eft col i c. Spr ead fr om the pr i mar y
tumor occur s al ong the mesor ectum and i n a l ateral and upwar d
di r ecti on. Ther efor e, al though a 2-cm bowel mar gi n i s consi der ed
adequate for r ectal cancer, the mesor ectal mar gi n shoul d be at l east
5 cm di stal to the i nfer i or aspect of the tumor or to the end of the
mesor ectum at the pel vi c fl oor. The techni que of total mesor ectal
exci si on (TME) pr ovi des an adequate l ymphadenectomy for r ectal
cancer. It i nvol ves shar p exci si on and exti r pati on of the mesor ectum
by di ssecti ng outsi de the i nvesti ng fasci a of the mesor ectum. TME
opti mi zes the oncol ogi c operati on by not onl y r emovi ng drai ni ng
l ymph nodes, but al so maxi mi z i ng l ateral r esecti on mar gi ns ar ound
the tumor. Al though no randomi zed pr ospecti ve tr i al has compar ed
TME wi th conventi onal mesor ectal exci si on, some i nsti tuti ons have
shown a si gni fi cant decr ease i n the l ocal r ecur r ence rate compar ed
wi th hi stor i cal contr ol s usi ng conventi onal sur ger y (i n the range of
6.3% 7.3% ). The major mor bi di ty associ ated wi th TME i s an
i ncr eased rate of anastomoti c l eak bel i eved to be due to
devascul ar i z ati on of the r ectal stump. Leak rates of 11% to 16%
have been r epor ted for TME as compar ed wi th 8% for non-TME
r esecti ons done by the same gr oup of sur geons.
The TME di ssecti on can be faci l i tated by l i gati on of the IMA (and
IMV) at or near i ts or i gi n (hi gh l i gati on). Thi s al l ows for maxi mal
mobi l i z ati on of the pr oxi mal bowel to faci l i tate a tensi on-fr ee di stal
l ow pel vi c or col oanal anastomosi s. The data on whether hi gh
l i gati on r esul ts i n a decr eased l ocal r ecur r ence r emai n equi vocal . It
has been wel l documented that negati ve l ateral (radi al ) mar gi ns ar e
major deter mi nants of l ocal r ecur r ence and sur vi val , and may be
mor e i mpor tant than l ongi tudi nal r esecti on mar gi ns. Lateral mar gi n
cl earance can be maxi mi zed by shar p di ssecti on between the fasci a
pr opr i a of the mesor ectum and the endopel vi c fasci a. The bony
pel vi s, whi ch i nher entl y l i mi ts the maxi mal extent of l ateral
di ssecti on, may ser ve as the best expl anati on of why di stal r ectal
cancer s have a hi gher l ocal r ecur r ence rate than thei r mor e
pr oxi mal counter par ts when compar i ng pati ents wi th tumor s of
si mi l ar stage. It i s contr over si al whether the enti r e mesor ectum
must be exci sed for al l r ectal cancer s or whether the mesor ectum
can be shar pl y di vi ded at the di stal r esecti on mar gi n. At MDACC, we
per for m a tumor -specific mesor ectal exci si on. The mesor ectum i s
transected 5 cm di stal to the di stal aspect of the tumor. Thi s woul d
i ncl ude the enti r e mesor ectum for the l ower and l ower-mi ddl e r ectal
cancer s, whi l e pr eser vi ng a por ti on of the mesor ectum for the upper
and upper-mi ddl e r ectal cancer s. Thi s tumor -specific mesor ectal
exci si on does not compr omi se an adequate oncol ogi c operati on and
may decr ease the r i sk for anastomoti c dehi scence fr om
devascul ar i z ati on of the r ectum. No benefi t i n sur vi val or l ocal
di sease
contr ol has been attai nabl e wi th the use of mor e extended
l ymphadenectomy (i l i ac/per i aor ti c nodes, obturator ), and the
compl i cati on rates ar e hi gher wi th these mor e extensi ve sur gi cal
pr ocedur es.
Surgical Approaches to Rectal Cancer

Sur gi cal appr oaches to the r ectum i ncl ude transabdomi nal
pr ocedur es (abdomi noper i neal r esecti on [APR], l ow anter i or
r esecti on [LAR], col oanal anastomosi s [CAA]), transanal
appr oaches, and trans-sacral appr oaches (Yor k-Mason, Kraske).
These l atter two appr oaches wi l l be di scussed i n detai l i n the
secti on on l ocal tr eatment of r ectal cancer. APR, an operati on
devi sed by Er nest Mi l es i n the 1930s, was the onl y pr evi ous
tr eatment for al l r ectal cancer s. Wi th the advent of better
pr eoperati ve stagi ng, neoadjuvant therapy, and i mpr oved sur gi cal
techni ques and stapl er technol ogy, the use of APR has decr eased
si gni fi cantl y. APR i s now r eser ved for pati ents wi th pr i mar y
sphi ncter dysfuncti on and i nconti nence, pati ents wi th di r ect tumor
i nvasi on i nto the sphi ncter compl ex, and pati ents wi th l ar ge or
poor l y di ffer enti ated l esi ons i n the l ower thi r d of the r ectum that do
not have adequate tumor cl earance for sphi ncter pr eser vati on.
Sphincter Preservation Procedures

Besi des l ocal exci si on, sphi ncter pr eser vati on pr ocedur es i ncl ude
LAR and pr octectomy/CAA ei ther al one or combi ned wi th

neoadjuvant radi ati on and chemoradi ati on. Another opti on i ncl udes
the addi ti on of a col oni c r eser voi r for i mpr oved shor t-ter m functi on.
These pr ocedur es can onl y be per for med i f the oncol ogi c r esul t i s
not compr omi sed and the functi onal r esul ts ar e acceptabl e. It was
demonstrated mor e than 20 year s ago that ther e i s no di ffer ence i n
l ocal r ecur r ence rate or sur vi val i n pati ents wi th mi dr ectal cancer s
who under go LAR rather than APR. The techni cal feasi bi l i ty of LAR
i n thi s setti ng was i ncr eased wi th the advent of ci r cul ar stapl i ng
devi ces and the knowl edge that di stal mucosal mar gi ns of r esecti on
of 2 cm wer e adequate. Sur vi val was found to depend on the
di stance of the tumor fr om the anal ver ge, the pr esence of posi ti ve
l ymph nodes, and the l ateral extent of di ssecti on. An al ter nati ve to
LAR i s pr octectomy wi th CAA. It i s used i n l ow r ectal cancer s, wi th
the stapl ed or hand-sewn anastomosi s just above or at the dentate
l i ne. Temporar y fecal di ver si on i s r outi nel y per for med. The use of
pr octectomy and CAA for l ow r ectal cancer s i s usual l y i n the context
of pr eoperati ve radi ati on or chemoradi ati on. Usi ng ei ther LAR or
pr octectomy wi th CAA (and adjuvant therapy), l ocal r ecur r ence
rates of 3% to 6.5% have been r epor ted by MDACC and other s.
F uncti onal r esul ts have been good, wi th 60% to 86% of pati ents
attai ni ng conti nence by 1 year, 10% to 15% r equi r i ng l axati ve use,
and some wi th mi l d soi l i ng at ni ght. Pr eoperati ve chemoradi ati on
does not seem to have a negati ve i mpact on these functi onal
r esul ts. Obvi ousl y, the l ower the anastomosi s (i .e., col oanal ), the
gr eater the potenti al for bowel dysfuncti on. Many pati ent factor s
ar e r el ated to the deci si on to avoi d a col ostomy; however, ther e
have been no randomi zed comparati ve studi es of qual i ty of l i fe after
col oanal anastomosi s ver sus APR.
Colonic J Pouch
Al though conti nence can be mai ntai ned i n pati ents wi th a CAA,
ther e i s a degr ee of i nconti nence i n some pati ents, and other s
r equi r e anti di ar r heal agents. Thi s i s par tl y due to l ack of compl i ance
i n the neor ectum. Thi s l ed to the i ntr oducti on of the col oni c J pouch
for l ow r ectal cancer s that showed better r esul ts i n ter ms of stool
fr equency, ur gency, noctur nal movements, and conti nence than
strai ght col oanal anastomoses. These advantages ar e pr i nci pal l y
dur i ng the fi r st 12 to 24 months after whi ch ti me functi onal
i mpr ovements after strai ght anastomosi s i mpr oves. One potenti al
pr obl em, especi al l y when the pouch i s l onger than 5 or 6 cm, i s
di ffi cul ty i n pouch evacuati on (appr oxi matel y 20% of pati ents). As
i n anter i or r esecti on, the functi onal outcome of pati ents wi th CAA
(wi th or wi thout a J pouch) may take 1 to 3 year s to stabi l i ze and i s
r el ated to the l evel of the anastomosi s (l ower anastomoses tend to
have poor er functi on). Unfor tunatel y, many pati ents wi th l ow r ectal
cancer s do not have enough r oom wi thi n the pel vi s to accommodate
a col oni c J pouch. An al ter nati ve appr oach i s a transver se col opl asty
pouch i n whi ch a l ongi tudi nal i nci si on on the neor ectum pr oxi mal to
the anastomosi s i s cl osed i n a transver se fashi on. Some studi es
compar i ng col oni c J pouch r econstr ucti on to transver se col opl asty
pouch have demonstrated both si mi l ar functi onal r esul ts but sl i ghtl y
i ncr eased compl i cati on rates fol l owi ng the transver se col opl asty;
however, other studi es have shown equi val ent outcomes.
Postoperati ve radi ati on therapy has not been shown to have a
si gni fi cant adver se effect on pouch functi on.
Proximal Diversion
Pr oxi mal di ver si on after sphi ncter pr eser vati on i s i ndi cated i n the
fol l owi ng ci r cumstances: (a) anastomosi s l ess than 5 cm above the
anal ver ge, (b) pati ents who have r ecei ved pr eoperati ve radi ati on
therapy, (c) pati ents on cor ti coster oi ds, (d) when the i ntegr i ty of
the anastomosi s i s i n questi on, and (e) any case of i ntraoperati ve
hemodynami c i nstabi l i ty.
Local Approaches to Rectal Cancer

Local tr eatment al one as defi ni ti ve therapy of r ectal cancer was fi r st
appl i ed to pati ents wi th sever e coexi sti ng medi cal condi ti ons unabl e
to tol erate radi cal sur ger y. Cur r entl y, conser vati ve, sphi nctersavi ng l ocal appr oaches ar e bei ng mor e wi del y consi der ed. Ear l y
studi es of l ocal exci si on demonstrate up to a 97% l ocal contr ol rate
and 80% di sease-fr ee sur vi val for pr oper l y sel ected i ndi vi dual s.
Local tr eatment i s best appl i ed to r ectal cancer s wi thi n 10 cm of the
anal ver ge, tumor s l ess than 3 cm i n di ameter i nvol vi ng l ess than
one-four th of the ci r cumfer ence of the r ectal wal l , exophyti c
tumor s, tumor s staged l ess than T2 by EUS, hi ghl y mobi l e tumor s,
and tumor s of l ow hi stol ogi c grade. The deci si on to use l ocal
exci si on al one or to empl oy adjuvant therapy after l ocal exci si on i s
based on the pathol ogi cal character i sti cs of the pr i mar y cancer
(wi th negati ve mar gi ns) and the potenti al mi cr ometastases i n
drai ni ng l ymph nodes. T1 l esi ons have posi ti ve l ymph nodes i n up to
18% of cases, wher eas the rate for T2 and T3 l esi ons i s up to 38%
and 70% , r especti vel y. T2 tumor s
tr eated wi th l ocal r esecti on al one can have l ocal r ecur r ence rates of
15% to 44% . T1 l esi ons wi th poor pr ognosti c featur es and al l T2
tumor s shoul d be r esected wi th radi cal sur ger y; however, when l ocal
exci si on i s per for med, adjuvant chemoradi ati on and cl ose
sur vei l l ance shoul d al so be per for med. Two phase II cooperati ve
gr oup studi es eval uated l ocal exci si on for T1 l esi ons and l ocal
exci si on wi th adjuvant chemoradi ati on usi ng a 5-F Ubased r egi men
for T2 l esi ons. The CALG B tr i al eval uated 177 pati ents wi th a
medi an 48 months of fol l ow-up. At a medi an fol l ow-up of 48
months, 59 pati ents wi th T1 l esi ons and 51 pati ents wi th T2 l esi ons
met el i gi bi l i ty cr i ter i a. Four of 59 pati ents wi th T1 l esi ons (2 l ocal ,
1 l ocal and di stant, 1 di stant) and 10 of 51 pati ents wi th T2 l esi ons
(5 l ocal , 2 l ocal and di stant, 3 di stant) had r ecur r ences. Overal l and
di sease-fr ee sur vi val rates wer e 85% and 78% , r especti vel y, at 48
months. The RTOG pr otocol 89-02 used a si mi l ar strategy wi th a
medi an fol l ow-up of 6.1 year s i n 52 pati ents wi th T1/T2 r ectal
cancer s and demonstrated a 4% l ocal fai l ur e rate for T1 l esi ons and
16% l ocal fai l ur e rate for T2 l esi ons. An addi ti onal 3 of 13 (23% )
pati ents wi th T3 di sease tr eated wi th l ocal exci si on and
chemoradi ati on wer e noted to have l ocal fai l ur e. Thi s data shoul d be
consi der ed i n the backgr ound of data fr om the Uni ver si ty of
Mi nnesota that r eveal ed a r ecur r ence rate of 18% and 37% i n
pati ents under goi ng l ocal exci si on al one for T1 and T2 tumor s,
r especti vel y.
Local therapy of di stal r ectal cancer s can be accompl i shed by
transanal exci si on, poster i or pr octectomy, ful gurati on, or
endocavi tar y i r radi ati on.
Tr ansanal excision i s the most strai ghtfor war d appr oach to r emovi ng
di stal r ectal cancer s. The deep pl ane of the di ssecti on i s the
per i r ectal fat. Tumor s shoul d be exci sed wi th an adequate
ci r cumfer enti al mar gi n.
Poster ior pr octotomy (Kraske pr ocedur e) can be used for tumor s i n
the mi ddl e and upper r ectum and i s mor e sui tabl e for l ar ger, l ow
r ectal l esi ons. In thi s pr ocedur e, a per i neal i nci si on i s made just
above the anus, the coccyx i s r emoved, and the fasci a i s di vi ded.
The r ectum can then be mobi l i zed for a sl eeve r esecti on, or a
pr octotomy i s per for med for exci si on of the tumor. The
di sadvantages of thi s pr ocedur e ar e fi stul a for mati on and the
potenti al to seed the poster i or wound wi th mal i gnant cel l s.
F ulgur ation uses ei ther standar d el ectr ocauter y or l aser to abl ate
the tumor. Endocavitar y r adiation i s a hi gh-dose, l ow-vol tage

i r radi ati on techni que that appl i es contact radi ati on to a smal l r ectal
cancer thr ough a speci al pr octoscope. F ul gurati on and endocavi tar y
radi ati on ar e used for pal l i ati on and do not have a r ol e i n
tr eatments wi th curati ve i ntent.
Tr ansanal endoscopic micr osur ger y (TEM) pr ovi des accessi bi l i ty to
tumor s of the mi ddl e and upper r ectum that woul d other wi se r equi r e
a l apar otomy or transsacral appr oach, wi th i mpr oved vi si bi l i ty and
i nstr umentati on. Thi s appr oach can be used for sel ected l esi ons up
to 15 cm fr om the anal ver ge. Cauti on must be taken wi th hi gher
l esi ons because ful l -thi ckness exci si on can r esul t i n per forati on i nto
the abdomen that wi l l r esul t i n l eakage of gas i nto the abdomi nal
cavi ty and l oss of r ectal i nsuffl ati on, as wel l as potenti al for i njur y
to i ntraper i toneal or gans. The pr ocedur e i s techni cal l y demandi ng
and r equi r es speci al equi pment,
whi ch i s expensi ve and ther efor e has l i mi ted i ts acceptance i n the
Uni ted States. Thi s pr ocedur e i s not r ecommended for tumor s wi thi n
5 cm of the anal ver ge. These tumor s ar e opti mal l y tr eated wi th a
standar d transanal appr oach. Pati ent sel ecti on i s i mpor tant, and i t
i s r ecommended that pati ents have pr eoperati ve EUS to sel ect
super fi ci al l esi ons. Pati ents wi th deeper l esi ons and metastati c
di sease or comor bi d condi ti ons that woul d pr ecl ude l apar otomy ar e
al so candi dates. Al though l ocal pr ocedur es have become mor e
commonl y used, few randomi zed pr ospecti ve tr i al s have eval uated
oncol ogi c and functi onal outcomes compar ed wi th anter i or r esecti on
or APR. In 1996, Wi nde et al . pr ospecti vel y randomi zed 50 pati ents
wi th T1 adenocar ci noma of the r ectum to ei ther anter i or r esecti on
or TEM. Si mi l ar l ocal r ecur r ence and sur vi val rates, as wel l as
decr eased mor bi di ty rates for l ocal exci si on, wer e found i n the two
study ar ms, confi r mi ng the advantages of l ocal exci si on.
At MDACC, transanal exci si on i s used for l ow r ectal cancer s,
wher eas a Kraske pr ocedur e i s used for hi gher r ectal l esi ons.
Opti mal l ocal exci si on i ncl udes at l east a 1-cm r esecti on mar gi n
ci r cumfer enti al l y, a ful l -thi ckness exci si on, and an exci si on that i s
not fragmented or pi ecemeal . An i nadequate l ocal exci si on mandates
an al ter nate r esecti on strategy, not mer el y the addi ti on of adjuvant
therapy. If pr eoperati ve T stage i s i ncr eased after pathol ogi cal
eval uati on fol l owi ng l ocal exci si on, the appr opr i ate standar d
r esecti on i s r ecommended. T1 tumor s ar e tr eated wi th l ocal therapy
al one unl ess any of the fol l owi ng poor pr ognosti c featur es ar e
i denti fi ed: tumor gr eater than 4 cm, poor l y di ffer enti ated hi stol ogi c
type, l ymphati c or vascul ar i nvasi on, or cl i ni cal or radi ol ogi c

evi dence of enl ar ged l ymph nodes. Those T1 tumor s wi th poor
pr ognosti c featur es and tumor s T2 and gr eater ar e tr eated wi th
radi cal sur ger y. T2 and T3 l esi ons ar e tr eated wi th l ocal exci si on
al one onl y i f the pati ent r efuses standar d r esecti on. Adjuvant
chemoradi ati on tr eatment fol l owed by chemotherapy i s str ongl y
r ecommended postoperati vel y.
Treatment for Locally Advanced Rectal Cancer

Occasi onal l y, pati ents wi l l pr esent wi th i nvol vement of adjacent
str uctur es (bl adder, vagi na, ur eter s, semi nal vesi cl es, sacr um).
These pati ents benefi t fr om mul ti modal i ty therapy, i ncl udi ng
pr eoperati ve or postoperati ve chemoradi ati on tr eatment.
Intraoperati ve radi ati on therapy (IORT) or brachytherapy has been
shown to pr ovi de addi ti onal benefi t. The goal of sur gi cal therapy i s
r esecti on of the pr i mar y tumor, wi th en bl oc r esecti on of adjacent
i nvol ved str uctur es to obtai n negati ve mar gi ns. The confi nes of the
pel vi s and the pr oxi mi ty to ner ves and bl ood vessel s that cannot be
r esected decr ease the r esectabi l i ty of r ectal tumor s compar ed wi th
l ocal l y advanced col on cancer. Impr oved r esectabi l i ty and decr eased
l ocor egi onal r ecur r ence have been demonstrated for l ocal l y
advanced r ectal cancer s after pr eoperati ve chemoradi ati on
tr eatment. As r epor ted by G under son et al . fr om the Mayo Cl i ni c,
the addi ti on of IORT to standar d exter nal -beam radi ati on therapy
wi th 5-F U i n pati ents wi th l ocal l y advanced r ectal cancer has shown
si gni fi cantl y i mpr oved l ocal di sease contr ol and possi bl y some
i mpr ovement i n sur vi val . Pr eoperati ve chemoradi ati on has al so been
shown to i mpr ove rates of sphi ncter pr eser vati on
i n pati ents who wer e i ni ti al l y bel i eved to need APR for curati ve
r esecti on by as much as twofol d when compar ed wi th postoperati ve
chemoradi ati on r egi mens. The best chance of cur e i n pati ents wi th
l ocal l y advanced di sease appear s to i nvol ve pr eoperati ve
chemoradi ati on tr eatment, maxi mal sur gi cal r esecti on, and IORT i n
sel ected cases.
At MDACC pr eoperati ve chemoradi ati on i s standar d tr eatment for
l ocal l y advanced r ectal cancer. An eval uati on of 40 pati ents (29 wi th
l ocal l y advanced di sease; 11 wi th r ecur r ence) r equi r i ng pel vi c
exenterati on for l ocal di sease contr ol wi th negati ve mar gi ns
demonstrated that chemoradi ati on may si gni fi cantl y i mpr ove
sur vi val and that chemoradi ati on r esponse and S-phase fracti on
wer e i mpor tant deter mi nants of sur vi val . Pati ents wi th l ow-r i sk
factor s had a 65% 5-year sur vi val , wher eas hi gh-r i sk pati ents had
onl y a 20% sur vi val . Tabl e 11.6 summar i zes the tr eatment strategy
for pati ents wi th r ectal cancer at MDACC.
Survival after Surgical Therapy

Seventy-fi ve per cent to 90% of node-negati ve r ectal cancer s ar e
cur ed by radi cal sur gi cal r esecti on. F i ve-year di sease-fr ee sur vi val
i n stage III pati ents r emai ns appr oxi matel y 60% or l ess. Local
fai l ur e sti l l r emai ns a si gni fi cant pr obl em, al though i ts r i sk has
decr eased i n the era of TME.
The sur vi val rate after l ocal therapy var i es fr om 70% to 86% , wi th
r ecur r ence rates of 10% to 50% . The overal l l ocal r ecur r ence rate
i s 30% , and i ncr easi ng r ecur r ence rates ar e seen wi th i ncr easi ng
stage of di sease and decr easi ng di stance fr om the anal ver ge. Many
of these pati ents can be sal vaged wi th radi cal sur ger y after a l ocal
r ecur r ence; however, sur vi val after sal vage sur ger y may not be as
good as after i ni ti al curati ve radi cal sur ger y. When consi der i ng l ocal
therapy for r ectal cancer, pati ent sel ecti on i s of paramount
i mpor tance.
Complications of Surgical and Adjuvant

Therapy for Rectal Cancer
Compl i cati ons of sur gi cal and adjuvant therapy for r ectal cancer
i ncl ude al l compl i cati ons associ ated wi th major abdomi nal sur ger y
(e.g., bl eedi ng, i nfecti on, adjacent or gan i njur y, ur eteral i njur y,
bowel obstr ucti on), wi th the addi ti on of some compl i cati ons that ar e
uni que to pel vi c sur ger y. Speci fi cal l y, anastomoti c l eak occur s i n 5%
to 10% of cases overal l , wi th i ncr easi ng rates seen i n l ower
anastomoses, those associ ated wi th i mmunocompr omi sed states, and
those associ ated wi th pr eoperati ve radi ati on therapy. A
defuncti oni ng stoma wi l l decr ease the consequences of such a l eak
and may decr ease l eak i nci dence. At MDACC, a defuncti oni ng l oop
i l eostomy i s used i n al l anastomoses bel ow the per i toneal r efl ecti on
i n pati ents who have r ecei ved pr eoperati ve radi otherapy and i n
pati ents wi th CAA. Autonomi c ner ve pr eser vati on i s al ways
per for med dur i ng pel vi c di ssecti ons, unl ess tumor i nvol vement
necessi tates the sacr i fi ce of these str uctur es. Wi th car eful
di ssecti on dur i ng TME, 75% to 85% of pati ents have a r etur n to
pr eoperati ve sexual and ur i nar y functi on. Other compl i cati ons
i ncl ude ur i nar y dysfuncti on, stoma dysfuncti on, per i neal wound
compl i cati ons, hemor r hage fr om pr esacral vessel s,
and anastomoti c str i ctur e. The mor tal i ty rate fr om sur gi cal
r esecti on var i es fr om l ess than 2% to 6% .
Table 11.6. Recommended surgical treatm

strategy for rectal cancer
T
N
Location
Resection
Stage Stage
Upper
rectum
Mes
Exci
to
T1
N0
TEM or Kraske
T2
N0
LAR
5 cm
to tu
T1
T2
N1
N2
CXRT followed by
LAR
5 cm
to tu
T3
N0
N2
CXRT followed
by LAR
5 cm
to tu
T1
N0
TAE, Kraske
LAR a
5 cm
to
rese
mar
enti
T2
N0
Middle
rectum
Low
rectum
T1
T2
N1
N2
CXRT followed by
LAR a
5 cm
to
rese
mar
enti
T3
N0
N2
CXRT followed by
LAR a
5 cm
to
rese
mar
enti
T1
N0
TAE
T2
N0
Proctectomy/CAA, b
(J pouch), APR
Enti
T1
T2
N1
N2
CXRT followed by
proctectomy/CAA, b
(J pouch), APR
Enti
T3
N0
N2
CXRT followed by
proctectomy/CAA, b
(J pouch), APR
Enti
TEM, transanal endoscopic microsurgery; LAR, low

anterior resection; CXRT, preoperative chemoradiat
TAE, transanal excision; CAA, coloanal anastomosis
abdominoperineal resection.
a LAR distal bowel resection margin >2 cm.
b CAA with protective ileostomy.
The compl i cati ons associ ated wi th chemoradi ati on tr eatment i ncl ude
radi ati on enter i ti s and der mati ti s, autonomi c neur opathy,
hematol ogi c toxi ci ty, stomati ti s (mostl y wi th conti nuous 5-F U
i nfusi ons), and venous access i nfecti ons. The fr equency and
i ntensi ty of these compl i cati ons depend on mul ti pl e factor s,
i ncl udi ng radi ati on therapy total dosi ng, fracti onati on, fi el d
techni que, and whether the radi ati on therapy i s gi ven
pr eoperati vel y or postoperati vel y. Ther e ar e no good pr edi ctor s of
whi ch pati ents wi l l have these compl i cati ons and to what degr ee
they wi l l have them.
Adjuvant Therapy of Rectal Cancer

The two mai n components of adjuvant therapy for r ectal cancer ar e
radi ati on therapy to the pel vi s and 5-F Ubased chemotherapy. The
goal of chemotherapy i s to i ncr ease tumor radi ati on sensi ti vi ty and
to decr ease the chance of di stant fai l ur e. The goal of radi ati on
therapy i s to i ncr ease l ocal contr ol , and i n the pr eoperati ve setti ng,
to i ncr ease mar gi n-negati ve r esecti on rates and sphi ncter
pr eser vati on. It must be emphasi zed that successful mul ti modal i ty
tr eatment of r ectal cancer r equi r es cl ose col l aborati on between
radi ati on therapi sts, medi cal oncol ogi sts, and sur geons.
Postoperative Radiation
Thr ee randomi zed tr i al s have been per for med compar i ng sur ger y
al one wi th sur ger y pl us postoperati ve radi ati on therapy for T3 or
N1N2 r ectal cancer. The onl y tr i al to show a decr ease i n l ocal
r ecur r ence rate was the NSABP R-01 tr i al . Local r ecur r ence was
decr eased fr om 25% i n the sur gi cal ar m to 16% i n the
postoperati ve radi ati on therapy ar m (p = 0.06). Several
nonrandomi zed tr i al s have shown a decr ease i n l ocal r ecur r ence
rates to the 6% to 8% l evel ; the di ffer ences between these tr i al s
may r efl ect radi otherapy dosi ng and pati ent sel ecti on. These tr i al s
showed that postoperati ve radi ati on therapy coul d r educe l ocal
r ecur r ence, but total radi ati on therapy dose and techni que wer e
i mpor tant to achi eve thi s effect. Despi te the per for mance of several
l ar ge pr ospecti ve tr i al s, sur vi val , and extrapel vi c r ecur r ence rates
have not been i mpr oved consi stentl y by radi ati on doses of 45 to 50
G y. Thi s pr ompted the addi ti on of chemotherapy to radi ati on
therapy i n the postoperati ve per i od. The subsequent NSABP R-02
study was devel oped to answer r emai ni ng questi ons about combi ned
modal i ty therapy and MOF chemotherapy ver sus 5-F Ubased
r egi mens. In the NASBP R-02 study, radi otherapy i mpr oved l ocal
contr ol to 8% fr om 13% wi thout radi otherapy (p = 0.02). However,
as i n pr evi ous studi es, no di ffer ences wer e seen i n di sease-fr ee or
overal l sur vi val wi th addi ti on of radi ati on to chemotherapy al one.
Postoperative Radiation Therapy and

Chemotherapy
The addi ti on of chemotherapy to radi ati on therapy has been used to
enhance the radi ati on r esponsi veness of tumor s and i mpact di stant
fai l ur e. Several studi es have shown both i mpr oved l ocal contr ol and
sur vi val . The G astr oi ntesti nal Tumor Study G r oup
tr i al was an ear l y tr i al that compar ed the fol l owi ng tr eatment ar ms:
(a) sur ger y al one, (b) sur ger y fol l owed by postoperati ve
radi otherapy (4048 G y), (c) sur ger y fol l owed by postoperati ve
chemotherapy (bol us 5-F U and semusti ne), and (d) sur ger y fol l owed
by concur r ent chemotherapy and radi otherapy. It demonstrated a
decr ease i n pel vi c fai l ur e for the gr oup tr eated by sur ger y and
postoperati ve chemoradi ati on therapy (11% vs. 24% for sur ger y
al one). In addi ti on, a stati sti cal l y si gni fi cant sur vi val advantage was
found at 7 year s usi ng the combi nati on of r esecti on, radi ati on, and
chemotherapy. The NCCTG subsequentl y conducted a tr i al
randomi z i ng 204 pati ents to radi otherapy (4550.4 G y i n 2528
fracti ons) wi th or wi thout concur r ent chemotherapy (bol us 5-F U).
Ther e was a si gni fi cant decr ease i n pel vi c r ecur r ence (14% vs.
25% ) and a si gni fi cant decr ease i n cancer-r el ated deaths for the
gr oup tr eated by r esecti on, radi ati on, and chemotherapy compar ed
wi th the gr oup tr eated wi th r esecti on and radi ati on therapy.
The fi ndi ngs fr om these studi es pr ompted the publ i cati on of a
cl i ni cal advi sor y by the NCI Consensus Confer ence i n 1990
r ecommendi ng adjuvant tr eatment for pati ents wi th Dukes B2 and C
r ectal car ci noma (T3T4, N0; T3T4, N1N3, now stage IIIII)
consi sti ng of si x cycl es of fl uor ouraci l -based chemotherapy and
concur r ent radi ati on therapy to the pel vi s. Thi s r egi men has
r emai ned the standar d by whi ch al l cur r ent adjuvant r ectal cancer
pr otocol s ar e compar ed. In the Uni ted States, postoperati ve
chemoradi ati on i s by far the most common mode of del i ver i ng
adjuvant therapy. Thi s i s usual l y gi ven as a conti nuous i nfusi on of
5-F U and appr oxi matel y 50.4 G y of i r radi ati on del i ver ed to the
pel vi s i n 1.8 to 2.0 G y fracti ons (6-week tr eatment). Al though the
tr end i n Eur ope has been tr eatment wi th radi ati on therapy and no
chemotherapy, the addi ti on of chemotherapy i n the Uni ted States
has been shown to decr ease the rate of di stant metastases,

somethi ng not attai nabl e wi th radi ati on therapy al one. In addi ti on,
ther e has consi stentl y been a 10% to 15% sur vi val advantage when
radi otherapy wi th chemotherapy i s compar ed to radi otherapy al one.
The Inter gr oup 0114 tr i al was desi gned to study the effects of
bi ochemi cal modul ati on of 5-F U dur i ng radi otherapy. It
demonstrated no si gni fi cant sur vi val advantage to the addi ti on of
l evami sol e and/or l eucovor i n to adjuvant bol us 5-F U and pel vi c
radi ati on i n the postoperati ve per i od. Pr otracted i nfusi on 5-F U has
been compar ed to bol us 5-F U by the NCCTG and has been
demonstrated to r esul t i n i mpr oved di sease-fr ee and overal l
sur vi val . Thi s fi ndi ng has been confi r med i n subsequent studi es.
Preoperative Radiation Therapy (

Chemotherapy)
Several advantages to the use of pr eoperati ve compar ed wi th
postoperati ve radi ati on therapy have been i denti fi ed:
1. A r educti on i n tumor si ze i ncr eases rates of sphi ncter
pr eser vati on i n those pati ents i ni ti al l y deemed to r equi r e an APR
and i mpr oves overal l r esectabi l i ty.
2. Ther e i s a decr eased r i sk of l ocal fai l ur e due to i mpr oved
compl i ance wi th the chemoradi ati on r egi men and i mpr oved
tumor r esponse i n the pr eoperati ve setti ng.
3. Ther e i s a decr eased r i sk of toxi ci ty because the smal l bowel can
mor e r eadi l y be excl uded fr om the radi ati on fi el d i n a
pr eoperati ve setti ng.
4. Ther e i s l ess bowel dysfuncti on because the col on used for
r econstr ucti on i s not i n the radi ati on fi el d.
5. Ther e i s no del ay of therapy as i n some cases of postoperati ve
therapy due to operati ve mor bi di ty.
Unti l now, ther e have been several randomi zed tr i al s eval uati ng the
r ol e of pr eoperati ve radi ati on therapy i n r esectabl e r ectal cancer.
Al though most r epor t si gni fi cant decr eases i n l ocal r ecur r ence, onl y
the 1997 Swedi sh Rectal Cancer Tr i al has shown a si gni fi cant
sur vi val advantage for the total pati ent gr oup. Thi s tr i al gave shor tcour se radi otherapy (25 G y i n fi ve fracti ons, 1 week), fol l owed by
curati ve r esecti on to the exper i mental gr oup, and curati ve sur ger y
al one to the contr ol gr oup. The l ocal r ecur r ence rate and 9-year
di sease-speci fi c sur vi val wer e 11% and 74% , r especti vel y, ver sus
27% and 65% for the contr ol gr oup. One l i mi tati on of thi s study
compar ed to mor e r ecent tr i al s i s the l ack of sur gi cal qual i ty
contr ol , whi ch i s bel i eved to be the r eason for the hi gh l ocal
r ecur r ence rate i n the contr ol gr oup. Thi s was addr essed i n the
Dutch Col or ectal Cancer G r oup tr i al i n whi ch mor e than 1,800
pati ents wi th r ectal cancer l ocated wi thi n 15 cm fr om the anal ver ge
wer e randomi zed to r ecei ve pr eoperati ve shor t-cour se radi otherapy
fol l owed by TME ver sus TME al one. The l ocal r ecur r ence rate i n the
sur ger y al one gr oup was 8.2% . Pr eoperati ve radi otherapy i mpr oved
thi s to 2.4% . However, ther e was no di ffer ence i n overal l sur vi val .
Al so, subgr oup anal ysi s of data fr om thi s tr i al showed no si gni fi cant
benefi t for i r radi ati on of l esi ons l ocated i n the upper r ectum gr eater
than 10 cm fr om the anal ver ge (p = 0.17).
In the Uni ted States, pr eoperati ve radi ati on therapy tr i al s have
usual l y i ncl uded chemotherapy i n a mor e pr otracted cour se rather
than usi ng shor t-cour se radi otherapy al one. Thi s practi ce has been
based on data demonstrati ng the i mpor tance of the addi ti on of
chemotherapy to radi ati on i n the adjuvant setti ng. Mor eover,
general l y a 6-week i nter val i s gi ven after the compl eti on of
chemoradi ati on befor e sur ger y. Longer i nter val s after radi otherapy
have been associ ated wi th i mpr oved pathol ogi cal compl ete r esponse
rates. Two mul ti center ed randomi zed tr i al s have attempted to
addr ess the questi on of pr eoperati ve ver sus postoperati ve
chemoradi ati on for r ectal cancer, RTOG 94-01 and NSABP R-03.
However, both have been cl osed due to a fai l ur e to accr ue pati ents.
The most defi ni ti ve randomi zed data demonstrati ng the super i or i ty
of pr eoperati ve ver sus postoperati ve chemoradi ati on comes fr om the
G er man Rectal Cancer Study G r oup. Four-hundr ed and twenty-one
pati ents wi th tumor s l ocated wi thi n 16 cm fr om the anal ver ge wer e
randoml y assi gned to pr eoperati ve l ong-cour se radi ati on (50.4 G y i n
28 fracti ons) wi th concur r ent i nfusi onal 5-F U (1,000 mg/m2 /d)
dur i ng weeks 1 and 5 fol l owed by TME or to TME fol l owed by
postoperati ve radi ati on (45 G y i n 25 fracti ons) and concur r ent
i nfusi onal 5-F U. Al l pati ents i n the pr eoperati ve gr oup and those
pati ents wi th stage II or gr eater di sease i n the postoperati ve gr oup
al so r ecei ved four cycl es of bol us 5-F U i n the adjuvant setti ng.
Pati ents assi gned to the
pr eoperati ve ar m had a l ower 5-year cumul ati ve r i sk of l ocal fai l ur e
(6% vs. 13% , p = 0.006), and decr eased toxi ci ty, both sever e acute
(27% vs. 40% , p = 0.001) and l ate (14% vs. 24% , p = 0.01).
Mor eover, i mpr oved sphi ncter pr eser vati on rates wer e noted i n
those pati ents who wer e i ni ti al l y deemed to r equi r e APR (39% vs.
19% , p = 0.004), pr eoperati ve ver sus postoperati ve, r especti vel y.
However, ther e was no di ffer ence i n sur vi val between the two ar ms.
The mai n di sadvantage of the pr eoperati ve r egi mens i s that
appr oxi matel y 20% of pati ents wi th r ectal cancer wi l l be
pr eoperati vel y over staged, and ther efor e may under go potenti al l y
unnecessar y radi ati on and chemotherapy. In the G er man study, 20%
of the pati ents randomi zed to the postoperati ve ar m wer e noted to
actual l y have stage I di sease once the speci men was avai l abl e for
eval uati on. These pati ents do not need adjuvant therapy and woul d
have been over tr eated i f they wer e tr eated pr eoperati vel y. Recentl y,
a number of gr oups have demonstrated effi cacy of the oral
fl uor opyr i mi di ne, capeci tabi ne, as the chemotherapeuti c radi ati on
sensi ti zer i n neoadjuvant r egi mens. Capeci tabi ne has the
advantages of conveni ent oral admi ni strati on and r educed toxi ci ty
when compar ed to i ntravenous 5-F U. The NSABP R-04 study hopes
to addr ess thi s i ssue i n a mul ti -i nsti tuti onal tr i al .
Intraoperative Radiation Therapy

IORT i s used for both r ecur r ent and l ocal l y advanced r ectal cancer.
Its advantages i ncl ude i ncr eased l ocal contr ol i n hi gh-r i sk cancer s,
accurate tr eatment of focal ar eas at r i sk, abi l i ty to adjust the depth
of the radi ati on beam, and abi l i ty to shi el d sensi ti ve str uctur es.
Even pr eoperati ve chemoradi ati on i n hi gh-r i sk tumor s can r esul t i n
hi gh l ocal r ecur r ence rates. IORT al l ows tr eatment of ar eas wi th
cl ose or mi cr oscopi cal l y posi ti ve mar gi ns i n thi s si tuati on. At the
Massachusetts G eneral Hospi tal , IORT i s used for focal ar eas of
tumor adher ence, cl ose or posi ti ve mar gi ns, and ar eas of gr oss
r esi dual di sease. IORT dosi ng depends on the cl i ni cal si tuati on: 10
to 13 G y i s gi ven for cl ose mar gi ns (<5 mm), 15 G y i s gi ven for
mi cr oscopi cal l y posi ti ve mar gi ns, and 17 to 20 G y i s used for ar eas
of gr oss r esi dual di sease. In a r ecent 2-year anal ysi s of IORT i n the
RTOG study of l ocal l y advanced di sease, the l ocal contr ol rate was
77% , wi th a 2-year sur vi val of 88% and a compl i cati on rate of 16% .
For faci l i ti es abl e to del i ver thi s type of therapy, ther e i s a cl ear
advantage i n l ocal contr ol i n sel ect pati ents wi th advanced and
r ecur r ent di sease. An al ter nati ve appr oach i s i ntraoperati ve
brachytherapy. Thi s al l ows radi ati on access i n ar eas wher e the IORT
beam cannot be focused due to anatomi cal constrai nts of the pel vi s.
At MDACC, i ntraoperati ve brachytherapy (1020 G y) i s used
sel ecti vel y i n pati ents wi th l ocal l y advanced or r ecur r ent di sease
wher e ther e i s a cl ose or posi ti ve mar gi n as demonstrated by fr ozen
secti on.
M. D. Anderson Experience
Our pr efer r ed management of l ocal l y advanced r ectal cancer (T3
T4, N0, or any T, N1N2) i ncl udes pr eoperati ve radi ati on therapy
wi th a pr otracted i ntravenous i nfusi on of 5-F U or capeci tabi ne.
We del i ver 45 G y of pr eoperati ve radi ati on therapy i n 25 fracti ons
wi th a boost to the tumor bed of 5.4 G y i n 3 fracti ons for a total of
50.4 G y i n 28 fracti ons. A conti nuous i nfusi on of 5-F U at a dose of
300 mg/m2 /d or capeci tabi ne 850 mg/m2 /d i s gi ven 5 days per
week. Sur ger y i s per for med 6 to 8 weeks after compl eti on of
therapy. Wi th thi s r egi men, mor e than 60% of pati ents exper i ence a
T-stage decr ease and 11% achi eve a pathol ogi cal compl ete
r esponse. In pati ents wi th T3 di sease, 44% of pati ents wi th r ectal
cancer s l ocated wi thi n 3 cm of the anal ver ge ar e now abl e to
under go sphi ncter-pr eser vi ng pr ocedur es, wi th a l ocal contr ol rate
i n excess of 90% and a 3-year sur vi val rate of 88% i n nodenegati ve pati ents. In pati ents wi th fi xed T3 and T4 tumor s, the
same r egi men was used wi th the addi ti on of an IORT boost for
posi ti ve or cl ose mar gi ns. The l ocal contr ol rate was 97% wi th an
82% 5-year sur vi val .
Al though some i nsti tuti ons wi l l advocate TME al one for most r ectal
cancer s, sur geons gl obal l y ar e now l ooki ng to i denti fy those
pati ents who wi l l benefi t most fr om adjuvant therapy and what
therapy shoul d be used (chemotherapy and radi ati on therapy
dosi ng). Ongoi ng studi es ar e i nvesti gati ng combi nati ons of di ffer ent
agents and the ti mi ng of sur ger y fol l owi ng mul ti modal therapy i n an
effor t to i mpr ove the pathol ogi cal r esponse rate. The r ol e of l ocal
exci si on wi th mul ti modal therapy i s sti l l contr over si al , par ti cul ar l y
i n the era of newer bi ol ogi cal l y acti ve chemotherapeuti c agents.
Some center s ar e expl or i ng the use of IORT and brachytherapy as
adjuncts to neoadjuvant chemoradi ati on tr eatments to i ncr ease the
l ocal di sease contr ol i n sel ect pati ents who ar e at hi gh r i sk for l ocal
r ecur r ence. Var i ous mol ecul ar mar ker s ar e bei ng eval uated i n fr esh
or ar chi val speci mens to ai d i n i denti fyi ng pati ents who wi l l benefi t
fr om tr eatment.
Surveillance
Pati ents wi th a hi stor y of col or ectal car ci noma r equi r e cl ose

sur vei l l ance. The data to suppor t thi s, however, ar e l acki ng. In a
Dani sh pr ospecti ve randomi zed study i n 597 col or ectal cancer
pati ents, pati ents had ei ther cl ose fol l ow-up (ever y 6 months for
the fi r st 3 year s) or year l y for 3 year s (i ncl udi ng exami nati on/stool
heme test, col onoscopy, l aborator y testi ng [except CEA], and chest
radi ograph). The fr equency of r ecur r ent cancer was the same i n
both gr oups, but i t was di agnosed ear l i er i n the cl ose fol l ow-up
gr oup. The cl ose fol l ow-up gr oup had mor e r esecti ons for curati ve
i ntent (l ocal and di stant), but cancer-speci fi c sur vi val di ffer ences
have been mor e di ffi cul t to demonstrate. Mul ti pl e sur vei l l ance
r egi mens have been advocated by several nati onal soci eti es. In
general , cl ose fol l ow-up i ncl udi ng CEA l evel deter mi nati on dur i ng
the fi r st 2 year s fol l owed by l ess i ntensi ve fol l ow-up dur i ng year s 3
to 5 ar e advocated.
Hi stor y and physi cal exami nati on and l aborator y tests i ncl udi ng a
CEA ar e per for med at MDACC ever y 3 to 4 months for the fi r st 2
year s after sur ger y, ever y 6 months dur i ng year s 3 thr ough 5, and
year l y ther eafter. Col onoscopy shoul d be per for med after 1 year,
and then at 3 year s i f nor mal . A basel i ne CT scan of the abdomen
and pel vi s i s obtai ned pr eoperati vel y fol l owed by annual i nter val s
unl ess other wi se i ndi cated by di sease bi ol ogy. A chest radi ograph i s
obtai ned ever y 6 months for the fi r st
2 year s and year l y ther eafter. It has tradi ti onal l y been pr oposed
that pati ents shoul d be moni tor ed cl osel y for l ocal r ecur r ence
dur i ng the fi r st 2 year s postoperati vel y (the ti me at whi ch most
l ocal r ecur r ences appear ). Recent data show that the addi ti on of
adjuvant radi ati on therapy may extend thi s per i od of vul nerabi l i ty
such that 50% of l ocal r ecur r ences may occur mor e than 2 year s
fr om sur ger y. F i nal l y, i t shoul d be noted that these ar e gener al
gui del i nes that may need to be tai l or ed to i ndi vi dual pati ents.
Recurrent and Metastatic Disease

Mor e than 50% of pati ents who under go curati ve sur ger y for
col or ectal cancer have tumor r ecur r ences. Of the pati ents who have
r ecur r ences, 85% do so dur i ng the fi r st 2.5 year s after sur ger y. The
r emai ni ng 15% exper i ence r ecur r ence dur i ng the subsequent 2.5
year s. Recur r ence devel ops i n l ess than 5% of pati ents who ar e
di sease-fr ee at 5 year s. The r i sk of r ecur r ence i s hi gher wi th stage
II or III di sease. Other r ecur r ence r i sk modi fi er s i ncl ude race,
pr esentati on, grade of tumor, aneupl oi dy, and adjacent or gan
i nvasi on. Many mol ecul ar mar ker s ar e cur r entl y bei ng eval uated for
thei r useful ness i n pr edi cti ng r ecur r ence r i sk. Recur r ences may be
l ocal , r egi onal , or di stant. Di stant di sease r ecur r ence, the most
common pr esentati on, occur s ei ther al one or concomi tantl y wi th
l ocor egi onal r ecur r ence. Local r ecur r ence devel ops i n 20% to 30%
of pati ents who under go i ni ti al curati ve r esecti ons for r ectal cancer,
and i n 50% to 80% of these pati ents, the l ocal r ecur r ence i s the
onl y si te of di sease. For al l r ecur r ence si tes, compl ete r esecti on
r esul ts i n a 25% to 30% cur e rate. Recur r ence i sol ated to the
anastomosi s (i ntramural ) i s rar e and can i ndi cate i nadequate
sur gi cal r esecti on. Li ver i nvol vement occur s i n appr oxi matel y 50%
of pati ents wi th col on cancer, wher eas l ung, bone, and brai n
i nvol vement occur s i n 10% , 5% , and l ess than 5% , r especti vel y.
Symptomati c r ecur r ences pr esent wi th a constel l ati on of symptoms
rangi ng fr om the vague and nonspeci fi c to the cl i ni cal l y over t.
CEA i s i nval uabl e for postoperati ve moni tor i ng. It i s most useful i n
pati ents i n whom l evel s ar e i ncr eased pr eoperati vel y and r etur n to
nor mal fol l owi ng sur ger y. Level s shoul d be deter mi ned
pr eoperati vel y, 6 weeks postoperati vel y, and then accor di ng to the
schedul e descr i bed i n the sur vei l l ance secti on. The absol ute l evel
and rate of i ncr ease i n CEA and the pati ent's cl i ni cal status ar e
i mpor tant i n deter mi ni ng pr ognosi s and tr eatment. Postoperati ve
CEA l evel s that do not nor mal i ze wi thi n 4 to 6 weeks suggest
i ncompl ete r esecti on or r ecur r ent di sease, al though fal se-posi ti ve
r esul ts do occur. CEA l evel s that nor mal i ze postoperati vel y and then
star t to i ncr ease ar e i ndi cati ve of r ecur r ence. Thi s may r epr esent
occul t or cl i ni cal l y obvi ous di sease. A rapi dl y i ncr easi ng CEA l evel
suggests l i ver or l ung i nvol vement, wher eas a sl ow, gradual r i se i s
associ ated wi th l ocor egi onal di sease. Despi te the r el i abi l i ty of an
i ncr eased CEA l evel i n pr edi cti ng tumor r ecur r ence, 20% to 30% of
pati ents wi th l ocor egi onal l y r ecur r ent tumor s have a nor mal CEA
l evel . Poor l y di ffer enti ated tumor s may not make CEA, whi ch i s one
expl anati on for such fal se-negati ve r esul ts. In contrast, CEA i s
i ncr eased i n 80% to 90% of pati ents wi th hepati c r ecur r ences. A
pr ospecti ve randomi zed tr i al
of the val ue of CEA i n fol l ow-up was under taken i n 311 pati ents and
r epor ted by McCal l et al . The study fol l owed asymptomati c pati ents
wi th i ncr eased CEA l evel s unti l symptoms devel oped; then, a ful l
wor kup was i ni ti ated. The pur pose was to defi ne the natural
hi stor y of an el evated CEA. The sensi ti vi ty, speci fi ci ty, and posi ti ve
pr edi cti ve val ues of an i ncr eased CEA l evel wer e 58% , 93% , and
79% , r especti vel y. The medi an l ead-ti me of the i ncr eased CEA to
detecti on by other means was 6 months, a r esul t found i n other

studi es. Seven per cent of pati ents who had an i ncr eased CEA fai l ed
to have i denti fi abl e r ecur r ent di sease on wor kup. Two metaanal yses have been per for med pool i ng r esul ts fr om fi ve randomi zed
studi es and found a sur vi val advantage i n pati ents al l ocated to
i ntensi ve fol l ow-up, i ncl udi ng CEA. The G er man Col or ectal Cancer
Study G r oup eval uated fol l ow-up CEA l evel s i n 1,321 pati ents after
curati ve r esecti on. They deter mi ned that CEA moni tor i ng was
benefi ci al i n 47% of pati ents wi th r ecur r ence and 11% of pati ents
overal l ; however, onl y 2.3% under went a curati ve R0 r esecti on of
r ecur r ent di sease. A mor e r ecent anal ysi s of data fr om a UK
mul ti center randomi zed pr ospecti ve tr i al of pr otracted i nfusi on 5-F U
ver sus bol us 5-F U i n the adjuvant setti ng demonstrated that both
CT and CEA wer e val uabl e components for postoperati ve fol l ow-up
and r esul ted i n i mpr oved sur vi val .
In an effor t to i mpr ove the detecti on of r ecur r ences, r adiolabeled
monoclonal antibodies (mAb) di r ected agai nst tumor-speci fi c
anti gens and CEA have been used for i magi ng the extent and
l ocati on of metastases wi th di sappoi nti ng r esul ts. Thi s modal i ty i s
par ti cul ar l y useful i n the eval uati on of r ecur r ent di sease wher e
postsur gi cal or postradi ati on changes ar e not easi l y di ffer enti ated
fr om tumor on CT or MRI. One agent OncoSci nt CR/OV (Cytogen
Cor p., Pr i nceton, NJ) i s an i ndi um-111l abel ed mAb to B72.3 that
tar gets the tumor-associ ated gl ycopr otei n TAG -72, whi ch i s r eacti ve
wi th appr oxi matel y 83% of col or ectal tumor s. A techneti um l abel ed
anti -CEA pr eparati on i s al so avai l abl e (CEA-Scan). These agents
wer e found to be super i or to CT i n eval uati ng extrahepati c and
pel vi c di sease, wher eas CT was better for detecti ng metastati c
di sease to the l i ver. Most studi es of l abel ed mAbs show a sensi ti vi ty
range of 70% to 86% , wi th a hi gher speci fi ci ty, and posi ti ve
pr edi cti ve val ues gr eater than 90% . These studi es ar e most useful
for the detecti on of r ecur r ent di sease i n a pati ent wi th an
i ncr easi ng CEA l evel and negati ve radi ographi c wor kup, or to r ul e
out metastati c di sease i n a pati ent wi th l ocor egi onal r ecur r ence who
may be sui tabl e for sur gi cal therapy (i .e., hepati c
r esecti on/cr yotherapy, pel vi c exenterati on).
Recentl y, PET wi th 2-( 1 8 F )fl uor odeoxy-D-gl ucose (F DG ) has been
r epor ted to have an 89% posi ti ve pr edi cti ve val ue and 100%
negati ve pr edi cti ve val ue i n pati ents who had a r i si ng CEA and
nor mal conventi onal radi ography. F DG -PET i magi ng r el i es on the
i ncr eased metabol i c uptake of gl ucose (fl uor i ne-l abel ed anal og of 2deoxygl ucose or F DG ) i n tumor s compar ed wi th nor mal ti ssues and
may be abl e to di sti ngui sh postsur gi cal and postradi ati on changes
fr om r ecur r ent tumor. It has al so been shown to be effecti ve at
i denti fyi ng r esectabl e r ecur r ences i n a pr ospecti ve bl i nded study of
second-l ook l apar otomy.
Tr eatment of the asymptomati c pati ent wi th an i ncr eased CEA l evel
can be chal l engi ng. An i ncr eased l evel shoul d be confi r med by a
r epeat CEA deter mi nati on. A thor ough cl i ni cal i nvesti gati on shoul d
i ncl ude LF Ts; CT scan of the chest, abdomen, pel vi s, and brai n
(when i ndi cated); and col onoscopy. At MDACC, we r outi nel y moni tor
CEA val ues because of the potenti al to detect r esectabl e
metastases, especi al l y wi thi n the l i ver, i n a subgr oup of pati ents
who may benefi t fr om ear l y r ecur r ence detecti on. PET scans ar e
per for med to eval uate pati ents wi th r i si ng CEA val ues wher e
conventi onal radi ography i s not abl e to i denti fy the si te of
r ecur r ence.
If the metastati c eval uati on i s negati ve i n the face of an i ncr eased
CEA l evel , a second-l ook l apar otomy may be i ndi cated. In ol der
studi es, appr oxi matel y 60% to 90% of pati ents wi th
asymptomati cal l y i ncr eased CEA l evel s wi l l have r ecur r ent di sease
at l apar otomy; 12% to 60% of these pati ents wi l l have r esectabl e
di sease at the ti me of l apar otomy; and 30% to 40% wi l l sur vi ve 5
year s fol l owi ng r esecti on of the r ecur r ence. Ear l y detecti on of
asymptomati c di sease r esul ts i n a hi gher r esectabi l i ty rate than
when r esecti on i s per for med for symptomati c di sease (60% vs.
27% ). The l i ver i s the most common si te of r ecur r ence, fol l owed by
adjacent or gans, the anastomoti c si te, and the mesenter y.
Resectabi l i ty rates cor r espond to the l evel of CEA el evati on, wi th
CEA l evel s l ess than 11 ng per mL bei ng associ ated wi th hi gher
r esectabi l i ty rates.
Treatment
The appr opr i ate tr eatment of r esectabl e r ecur r ent di sease depends
on the l ocati on of di sease. If two di sease si tes ar e detected that ar e
compl etel y r esectabl e, the pr ocedur e i s under taken i n sel ect
pati ents. Other wi se, i ndi vi dual tr eatment modal i ti es ar e used as
needed for pal l i ati on of pel vi c symptoms. As i n l ocal l y advanced
di sease, potenti al l y r esectabl e r ecur r ent di sease i s tr eated i n a
mul ti modal i ty fashi on usi ng pr eoperati ve chemotherapy (wi th our
wi thout radi ati on), sur ger y, IORT (i f avai l abl e), and brachytherapy.
For r ecur r ence i nvol vi ng the sacr um, en bl oc sacral r esecti on can
someti mes r esul t i n 4-year sur vi val rates of 30% . Contrai ndi cati ons
to sacral r esecti on i ncl ude pel vi c si dewal l i nvol vement, sci ati c notch
i nvol vement, bi l ateral S2 i nvol vement, encasement of i l i ac vessel s,
and extrapel vi c di sease. A r evi ew of pel vi c r ecur r ence at Memor i al
Sl oan-Ketter i ng Cancer Center r eveal ed no pr edi ctor s ei ther i n the
i ni ti al tumor or i n the r ecur r ent tumor to i ndi cate sur vi val other
than compl ete r esecti on. Symptoms of r ecur r ent di sease coul d be
adequatel y pal l i ated wi th sur ger y. At MDACC, potenti al l y r esectabl e
pel vi c r ecur r ences ar e tr eated wi th pr eoperati ve chemoradi ati on,
fol l owed by sur ger y and the use of IORT and brachytherapy as
needed for cl ose or posi ti ve mar gi ns. Usi ng thi s appr oach i n 43
pati ents, the overal l r esecti on rate was 77% , wi th an 88% mar gi nnegati ve r esecti on rate, a 64% l ocal contr ol rate, and a 58% 5-year
sur vi val rate. Al though the usual sur gi cal pr ocedur e for r esectabl e
r ecur r ent r ectal cancer i s APR, sel ect cases can be tr eated wi th
sphi ncter pr eser vati on.
Medi an sur vi val for metastati c col or ectal cancer wi thout systemi c
chemotherapy ranges fr om 6 to 9 months i n ear l y ser i es.
The addi ti on of 5-F Ubased r egi mens i mpr oves sur vi val to 10 to 12
months. The addi ti on of i r i notecan or oxal i pl ati n to 5-F U fur ther
i mpr oves sur vi val to 14 to 17 months. As descr i bed pr evi ousl y, the
addi ti on of the monocl onal anti bodi es have i mpr oved medi an
sur vi val to gr eater than 20 months.
Liver
The l i ver i s the most common si te of vi sceral metastases, and i t i s
the onl y si te affected i n up to 20% of pati ents. Recent data fr om
MDACC demonstrates that sur gi cal r esecti on of hepati c metastases
now offer s the potenti al for 5-year sur vi val up to 58% . Col or ectal
hepati c metastases ar e di scussed i n detai l i n Chapter 12.
Lung
Pul monar y metastases occur i n 10% to 20% of pati ents wi th
col or ectal cancer. They ar e most commonl y seen i n the setti ng of a
l ar ge hepati c tumor bur den or extensi ve metastati c di sease.
Isol ated pul monar y metastases occur most commonl y wi th di stal
r ectal l esi ons because the venous drai nage of the di stal r ectum
bypasses the por tal system and al l ows metastasi s to travel di r ectl y
to the l ungs.
The fi ndi ng of a sol i tar y l esi on on a chest radi ograph shoul d pr ompt
eval uati on wi th thoraci c CT scanni ng and, for a central l y l ocated

l esi on, br onchoscopy wi th bi opsy. Per i pheral l esi ons may be
amenabl e to CT-gui ded needl e bi opsy or vi deo-assi sted
thoracoscopi c sur ger y. F i fty per cent of pati ents wi th sol i tar y
pul monar y nodul es wi l l have pr i mar y l ung tumor s rather than
col or ectal metastases.
Pati ents wi th l ocal l y contr ol l ed pr i mar y tumor s, no evi dence of
metastases el sewher e, good pul monar y r eser ve, and good medi cal
condi ti on ar e candi dates for r esecti on. Pati ents wi th sol i tar y
metastases exper i ence the best sur vi val , but pati ents wi th as many
as thr ee l esi ons (uni l ateral or bi l ateral ) can exper i ence up to a 40%
5-year sur vi val . The opti mum sur gi cal appr oach i s a medi an
ster notomy to al l ow for bi l ateral pul monar y expl orati on because
contrast-enhanced CT scan has up to a 25% fal se-negati ve and
fal se-posi ti ve rate for the detecti on of metastases. As i n l i ver
r esecti on for metastati c di sease, the opti mum sur ger y i nvol ves the
mi ni mal pr ocedur e to obtai n negati ve mar gi ns (i .e., wedge r esecti on
vs. pneumonectomy).
The overal l 5-year sur vi val rate fol l owi ng r esecti on of pul monar y
metastases ranges fr om 20% to 40% . In newer ser i es i nvol vi ng onl y
col or ectal cancer metastases, the rate i s cl oser to 40% to 43% 5year sur vi val . Age, gender, l ocati on of the pr i mar y di sease, di seasefr ee i nter val , or i nvol vement of hi l ar or medi asti nal l ymph nodes
does not seem to i nfl uence sur vi val . The number of metastases i n
most ser i es i s i nver sel y cor r el ated wi th 5-year sur vi val . Recur r ence
confi ned to the l ung after r esecti on i s an i ndi cati on by some for
r epeat r esecti on.
Bone and Brain

Metastati c di sease to the brai n i s uncommon and usual l y occur s
after establ i shed l ung i nvol vement. Symptomati c sol i tar y l esi ons
can be tr eated by pal l i ati ve crani otomy and r esecti on. In a ver y
smal l subpopul ati on of pati ents, crani al di sease may be the onl y
si te of i nvol vement, and exci si on i n thi s setti ng may i ncr ease
sur vi val . Bone metastases ar e qui te uncommon and ar e best
managed wi th radi ati on therapy.
Ovary
Because 1% to 8% of women who under go potenti al l y curati ve
r esecti ons subsequentl y devel op ovar i an metastases, pr ophyl acti c
oophor ectomy at the ti me of col ectomy has been consi der ed for
femal e pati ents. However, pr ophyl acti c oophor ectomy has not been
shown to i mpr ove sur vi val and ther efor e i s not r outi nel y per for med.
The pr el i mi nar y r esul ts of a pr ospecti ve randomi zed tr i al of 155
pati ents at the Mayo Cl i ni c r epor ted an i ni ti al tr end towar d
i mpr oved sur vi val wi th pr ophyl acti c oophor ectomy; however, thi s
di ffer ence di d not per si st at 5 year s, and the tr i al r esul ts have not
si nce been updated. When i sol ated metastati c di sease to the one
ovar y i s i denti fi ed, a bi l ateral oophor ectomy i s per for med because
ther e i s a hi gh r i sk for bi l ateral i nvol vement.
Pelvis
Local r ecur r ence i n the pel vi s i s a major pr obl em after tr eatment for
r ectal cancer. Radi cal sur gi cal pr ocedur es, i ncl udi ng pel vi c
exenterati on and sacr ectomy, may benefi t a sel ect gr oup of pati ents
whose di sease can be compl etel y exti r pated by these pr ocedur es.
Pr eoperati ve chemoradi ati on, even i n the setti ng of pr i or radi ati on,
IORT, and brachytherapy, i s useful i n the setti ng of radi cal sur ger y
for r ecur r ent di sease.
Uncommon Colorectal Tumors

Lymphoma
Lymphoma i s an uncommon tumor that occur s i n 0.4% of pati ents
wi th i ntesti nal l ymphoma pr esenti ng anywher e between the second
and ei ghth decades. Al most al l ar e non-Hodgki n l ymphomas.
Twenty-fi ve per cent of pati ents may pr esent wi th fever, occul t bl ood
l oss, anemi a, a pal pabl e mass, or an acute abdomen. The di agnosi s
i s often made i ntraoperati vel y. A hi stor y of abdomi nal pai n, fever,
and wei ght l oss i n a pati ent who i s younger than the expected age
for a col or ectal tumor shoul d rai se the suspi ci on of i ntesti nal
l ymphoma.
Abdomi nal CT and endoscopy wi th bi opsy ar e the most useful
di agnosti c tests because l esi ons ar e often mi ssed on bar i um enema
exami nati on. A thi ckened bowel , adjacent or gan extensi on, or nodal
enl ar gement may be seen. If the l esi on i s i ntral umi nal , endoscopi c
bi opsy wi l l faci l i tate the di agnosi s. Most of these l esi ons ar e
i nter medi ate- to hi gh-grade B-cel l l ymphomas. If a di agnosi s i s
made pr eoperati vel y i n an other wi se asymptomati c pati ent, bone
mar r ow bi opsy shoul d be per for med. A pr i mar y l esi on i s defi ned as a
l esi on wi th no associ ated or gan or l ymphati c i nvol vement, negati ve
chest CT, and a negati ve per i pheral bl ood smear and bone mar r ow.
Sur ger y i s per for med i n the cl i ni cal setti ng of obstr ucti on, bl eedi ng,
per forati on, or an uncer tai n di agnosi s. In rar e cases, sur ger y may
be per for med for compl ete r esecti on of a pr i mar y l esi on. A thor ough
expl orati on i s per for med, and al l suspi ci ous
nodes or or gans ar e bi opsi ed to assess the stage of di sease. The
pr i mar y i ntesti nal l esi on shoul d be r esected wi th negati ve mar gi ns
whenever possi bl e. The bowel mesenter y shoul d be r esected wi th
the tumor so r egi onal nodes can be assessed pathol ogi cal l y.
Intesti nal conti nui ty shoul d be r estor ed whenever possi bl e. If a
l ar ge tumor i s found to be unr esectabl e and i s not obstr ucti ng the
bowel , a bypass can be per for med. Sur gi cal cl i ps shoul d be pl aced to
faci l i tate i denti fi cati on of the tumor by the radi ati on oncol ogi st.
Intesti nal l ymphoma r equi r es a combi ned-modal i ty appr oach usi ng
sur ger y and chemotherapy wi th or wi thout radi ati on. For r ectal
l ymphoma, compl ete r esecti on i s fol l owed by radi ati on tr eatments to
the pel vi s. Chemoradi ati on i s used i f the r esecti on was i ncompl ete.
The overal l sur vi val for stages I and II di sease i s appr oxi matel y
80% . Thi s decr eases to 35% wi th advanced di sease.
Gastrointestinal Stromal Tumors

G astr oi ntesti nal str omal tumor s (G ISTs) account for most
mesenchymal tumor s ar i si ng i n the wal l of the col on or r ectum.
Pr i mar y col or ectal G ISTs ar e rar e and compr i se l ess than 1% of
col oni c tumor s. G ISTs have r ecentl y been character i zed, but
hi stor i cal l y cl assi fi ed, as l ei omyomas, l ei omyosar comas,
neur ofi br omas, and schwannomas, and ar e fur ther di scussed i n
detai l el sewher e i n thi s text. In a r evi ew of 1,458 cases of
mal i gnant G ISTs fr om 1992 to 2000 i n the SEER database, 7% wer e
l ocated i n the col on and 5% i n the r ectum. These tumor s can
pr esent as smal l submucosal or as l ar ge i ntramural masses. Pati ents
can pr esent wi th pai n, bl eedi ng, obstr ucti on, nausea, vomi ti ng,
anemi a, tenesmus, or hematur i a. Ul cerati on may be pr esent i n 30%
to 50% of pati ents. A thor ough cl i ni cal eval uati on shoul d be
conducted to excl ude metastati c di sease. Exci si on wi th negati ve
sur gi cal mar gi ns i s the tr eatment of choi ce. Col oni c tumor s ar e
exci sed wi th adjacent mesenter y. Wi de nodal exci si on i s not
i ndi cated i n the absence of cl i ni cal l y evi dent di sease. Smal l tumor s
of the r ectum and anal canal can be r emoved transr ectal l y or
endoscopi cal l y. Cr i ter i a si mi l ar to G ISTs el sewher e i n the
gastr oi ntesti nal tract ar e used for deter mi ni ng the need for
adjuvant therapy wi th i mati ni b mesyl ate (STI-571, G l eevec), a
monocl onal anti body to the tyr osi ne ki nase r eceptor. F ur ther detai l s
r egar di ng G ISTS ar e di scussed i n Chapter 5.
Carcinoid
Car ci noi ds ar e neur oendocr i ne tumor s der i ved fr om Kul chi tsky's
cel l s, whi ch ar e uncommonl y found i n the col on and r ectum.
Appr oxi matel y 18% to 30% of i ntesti nal car ci noi ds occur i n the
r ectum or r ectosi gmoi d, 4% to 15% occur i n the col on, and 4% to
50% have been r epor ted to occur i n the appendi x. They ar e usual l y
di scover ed i nci dental l y unl ess they ar e l ar ge. Si ze and depth of
i nvasi on ar e the best pr edi ctor s of cl i ni cal behavi or. Hi ndgut
car ci noi ds al most never pr oduce the car ci noi d syndr ome. Al though
l ar ge tumor s may pr esent wi th bl eedi ng, obstr ucti on, or
consti pati on, tumor s l ess than 2 cm ar e fr equentl y asymptomati c.
Di agnosi s i s made by endoscopi c bi opsy. In general , tumor s l ess
than 1 cm rar el y metastasi ze, wher eas those gr eater than 2 cm
have
i ncr eased metastati c potenti al ; i n the 1- to 2-cm range, 10% to
20% wi l l metastasi ze. Thi s makes tr eatment deci si ons for tumor s i n
the 1- to 2-cm range pr obl emati c. Smal l l esi ons (<1 cm) ar e
commonl y wel l di ffer enti ated and can be adequatel y tr eated wi th
endoscopi c exci si on. Lesi ons l ess than 2 cm can be tr eated wi th ful l thi ckness l ocal exci si on. It i s r ecommended that l ar ger l esi ons,
those that demonstrate i nvasi on thr ough the muscl e wal l , or
i nadequate r esecti on mar gi ns be tr eated wi th standar d r esecti on
techni ques usi ng ei ther an anter i or appr oach or APR. However, a
r ecent r etr ospecti ve r evi ew fr om thi s i nsti tuti on on 44 r ectal
car ci noi ds r eveal ed that extensi ve sur ger y offer ed no sur vi val
advantage over l ocal exci si on. At MDACC, we l ocal l y exci se tumor s
l ess than 2 cm and r esect those gr eater than 2 cm i f sphi ncter
pr eser vati on i s possi bl e. The exper i ence wi th radi ati on therapy and
chemotherapy i n r ectal car ci noi ds i s cur r entl y i nadequate to make
r ecommendati ons r egar di ng i ts use.
Anal Cancer
Squamous Carcinoma of the Anus

Anal SCC i s a r el ati vel y uncommon cancer wi th an annual i nci dence
of appr oxi matel y 9 per mi l l i on i n the Uni ted States and an
esti mated 3,400 new cases i n 2000. However, thi s r epr esents a near
doubl i ng i n r ecent decades. Si nce the mi d 1970s, the i nci dence has
i ncr eased 96% i n men and 39% i n women. The i nci dence i s of
epi demi c pr opor ti ons i n men who have sex wi th men (MSM),
r eachi ng 35/100,000, and among the HIV-posi ti ve popul ati on wher e
the i nci dence i s r epor ted to be twi ce that of HIV-negati ve MSM
(70/100,000). Other causes of i mmunocompr omi se such as
transpl antati on or i mmunotherapy for autoi mmune di seases ar e
addi ti onal r i sk factor s. Ki dney transpl ant pati ents have at l east a
four fol d i ncr eased i nci dence of the di sease. In the general
popul ati on, el der l y women and men i n thei r si xti es ar e at the
hi ghest r i sk for anal cancer, wi th women havi ng the gr eater r i sk.
Popul ati on-based evi dence has establ i shed that anal cancer i s a
sexual l y transmi tted di sease (STD) i n much the same way that
cer vi cal cancer i s an STD. Women wi th anal cancer ar e mor e l i kel y
to have had a hi stor y of geni tal war ts or other STDs and men wi th
anal cancer ar e mor e l i kel y to have r epor ted homosexual acti vi ty or
to have a hi stor y of geni tal war ts or gonor r hea. As wi th cer vi cal
cancer, anal cancer has been l i nked to human papi l l omavi r us (HPV)
i nfecti on. Studi es have shown that 40% to 95% of anal cancer s
har bor HPV DNA, wi th the str ongest associ ati on seen wi th
nonkerati ni z i ng squamous cel l types or i gi nati ng fr om the squamous
mucosa of the anal canal . Thi s associ ati on has pr oven to be even
str onger wi th advances i n HPV detecti on techni ques.
The nati onal cancer r egi str i es i n Denmar k and Sweden i denti fi ed
417 pati ents wi th anal cancer between 1991 and 1994 and
compar ed them wi th 534 contr ol s wi th r ectal adenocar ci noma and
554 popul ati on contr ol s. Usi ng mul ti var i ate anal ysi s adjusti ng for
smoki ng and educati on, the l i feti me number of sexual par tner s;
hi stor y of anal i nter cour se; a hi stor y of anogeni tal war ts,
gonor r hea, or cer vi cal neopl asi a; testi ng for HIV; and a hi stor y
of par tner s wi th STDs wer e al l associ ated wi th a si gni fi cantl y
i ncr eased r i sk for anal cancer i n women. Ri sk factor s for men
i ncl uded l i feti me number of sexual par tner s, homosexual i ty, hi stor y
of anal war ts or syphi l i s, and bei ng unmar r i ed wi th or wi thout a
cur r ent sexual par tner. The associ ati ons wer e si mi l ar when data
fr om Denmar k and Sweden wer e consi der ed separatel y or together.
When pol ymerase chai n r eacti on for HPV DNA was per for med on
ar chi ved ti ssue speci mens fr om these pati ents, 88% of pati ents
overal l wer e posi ti ve for HPV, and HPV-16 was i denti fi ed i n 83% of
those wi th HPV. Thi s compar es to cer vi cal cancer wher e HPV-16 i s
r esponsi bl e for about 50% of cases, HPV 18, 31, and 45 i s
r esponsi bl e for an addi ti onal 30% and addi ti onal HPV types account
for the r emai ni ng 20% of cases. Anal ysi s of the data fr om the SEER
pr ogram r eveal ed that the r el ati ve r i sks of anal cancer and vagi nal
cancer i n women who had been di agnosed wi th i nvasi ve cer vi cal
cancer wer e 4.6 and 5.6, r especti vel y. Thi s i ncr eased r i sk for anal
cancer i n women wi th cer vi cal dyspl asi a or cancer, and thei r sexual
par tner s, i s l i kel y thr ough autoi nocul ati on by the vi r us that caused
the cer vi cal dyspl asi a.
Anal cancer s can be l ocated wi thi n the anal canal or i n the per i anal
ski n (anal mar gi n). Anal canal cancer s ar e thr ee to four ti mes mor e
common i n women than i n men. Anal mar gi n cancer s (tumor s of the
hai r-bear i ng per i anal ski n) ar e mor e common i n mal es. Ther e ar e
si gni fi cantl y mor e cases of anal mar gi n cancer s i n homosexual
mal es.
Pathological Characteristics
Mor e than 80% of mal i gnant anal l esi ons ar e hi stol ogi cal l y SCCs.
Wi th the excepti on of mel anoma, smal l cel l car ci noma, and anal
adenocar ci noma, al l other hi stol ogi c subtypes behave si mi l ar l y and
ar e tr eated accor di ng to thei r anatomi cal l ocati on. Basal oi d
car ci noma (basal cel l car ci noma wi th a massi ve squamous
component), mucoepi der moi d car ci noma (or i gi nati ng i n anal cr ypt
gl ands), and cl oacogeni c car ci noma ar e al l var i ants of squamous
car ci noma. As wi th cer vi cal cancer, SCC of the anus may be
pr eceded by or coexi st wi th pr emal i gnant dyspl asi a or anal
i ntraepi thel i al neopl asi a.
The pr ognosi s of anal mar gi n cancer s i s favorabl e. The rate of l ocal
r ecur r ence i s hi gher than the rate of di stant metastases, whi ch ar e
rar e. When they do occur, metastases ar e most commonl y found i n
the super fi ci al i ngui nal l ymph nodes (appr oxi matel y 15% of cases).
It i s unusual for anal mar gi n cancer s to metastasi ze to mesenter i c
or i nter nal i l i ac nodes.
Anal canal cancer s ar e associ ated wi th aggr essi ve l ocal gr owth and
i f untr eated wi l l extend to the r ectal mucosa and submucosa,
subcutaneous per i anal ti ssue and per i anal ski n, i schi or ectal fat,
l ocal skel etal muscl e, per i neum, geni tal i a, l ower ur i nar y system,
and even the pel vi c per i toneum and the br oad l i gament.
Hi stor i cal l y, mesenter i c l ymph node metastases have been detected
i n 30% to 50% of sur gi cal speci mens. Mor e than 50% of pati ents
wi l l pr esent wi th l ocal l y advanced di sease. The most common si tes
of di stant metastases ar e the l i ver, l ung, and abdomi nal cavi ty.
However, most cancer-r el ated deaths ar e due to uncontr ol l ed pel vi c
or per i neal di sease.
Diagnosis
The i ni ti al symptoms of anal cancer i ncl ude bl eedi ng, pai n, and l ocal
ful l ness. These symptoms ar e si mi l ar to those caused by the
common beni gn anal di seases, whi ch accompany anal cancer i n mor e
than 50% of cases. A detai l ed hi stor y, i ncl udi ng pr evi ous anal
pathol ogy and sexual habi ts, shoul d pr ecede a meti cul ous physi cal
exami nati on. Physi cal exami nati on shoul d attempt to i denti fy the
l esi on, i ts si ze and anatomi cal boundar i es, and any associ ated
scar r i ng or condyl omata. It i s al so i mpor tant to deter mi ne the
r esti ng and vol untar y anal sphi ncter tone. Occasi onal l y, an
exami nati on under general anesthesi a may be necessar y to
compl ete the l ocal eval uati on. Pel vi c and abdomi nal CT scans and a
chest radi ograph ar e i mpor tant i n assessi ng extent of l ocal di sease
and di stant spr ead. Pr octosi gmoi doscopy i s essenti al to assess the
pr oxi mal extent of di sease and to obtai n ti ssue for bi opsy. Pal pabl e
i ngui nal l ymph nodes shoul d be eval uated by fi ne-needl e aspi rati on.
Staging
The cur r ent Amer i can Joi nt Commi ttee on Cancer (AJCC) stagi ng
system for anal mar gi n and anal canal cancer s i s depi cted i n Tabl es
11.7 and 11.8.
Treatment
Anal Canal
Unti l the 1980s, APR wi th per manent col ostomy was the
r ecommended tr eatment for al l SCCs of the anal canal . Thi s
tr eatment, however, was attended by l ow sur vi val rates as a r esul t
of di stant fai l ur e. Radi ati on therapy i n the range of 50 to 60 G y was
al so used as defi ni ti ve tr eatment of these cancer s, wi th r ecur r ence
and sur vi val rates si mi l ar to those seen usi ng APR. The pi oneer i ng
chemoradi ati on pr otocol devel oped by Ni gr o et al . i n 1983, whi ch
has si nce been confi r med and modi fi ed by other s, has radi cal l y
changed the appr oach to thi s di sease. Cur r entl y, sur ger y i s r eser ved
for (a) T1 and smal l T2 l esi ons, whi ch may be l ocal l y exci sed; (b)
sal vage tr eatment for pati ents wi th per si stent di sease (wi thi n 6
months of chemoradi ati on) or r ecur r ent di sease (after 6 months);
(c) sever el y symptomati c pati ents (per i neal sepsi s, i ntractabl e
ur i nar y or fecal fi stul ae, i ntol erabl e i nconti nence); (d) i ngui nal
l ymph node di ssecti on for per si stent i ngui nal di sease, r ecur r ent
i ngui nal di sease (tr eated fi r st wi th radi ati on therapy unl ess
associ ated wi th l ocal r ecur r ence), or pr i mar y di sease i n the i ngui nal
basi n, wher e the di sease i s bul ky or fungati ng; and (e) temporar y
fecal di ver si on i n pati ents wi th near l y obstr ucti ng l esi ons.
Si nce the i ni ti al wor k of Ni gr o et al . i n 1983, studi es have been
per for med to di ssect out the vi tal components and doses of the
chemoradi ati on tr eatments to opti mi ze tr eatment. Ther e i s evi dence
that (a) hi gher doses of radi ati on pr oduce better l ocal contr ol rates
usi ng a constant mi tomyci n-C dose (Ri ch, 1997); (b) 5-F U and
mi tomyci n-C wi th radi ati on therapy pr oduces better l ocal contr ol
rates than radi ati on therapy al one; (c) 5-F U, mi tomyci n-C wi th
radi ati on therapy pr oduces better l ocal contr ol rates than 5-F U wi th
radi ati on therapy; and (d) ci spl ati n wi th 5-F U and radi ati on therapy
pr oduces l ocal contr ol and sur vi val
rates si mi l ar to 5-F U, mi tomyci n-C, and radi ati on therapy, possi bl y

wi th l ess toxi ci ty.

Cancer staging of anal canal cancer
Primary tumor (T)
TX
T0
Tis
Carcinoma in situ
T1
T2
Tumor >2 cm but not >5 cm in greatest

dimension
T3
T4
Tumor of any size invades adjacent

organ(s)
Lymph nodes (N)

NX

assessed
N0
N1
Metastasis in perirectal lymph node(s)
N2
Metastasis in unilateral internal iliac

and/or inguinal lymph node(s)
Metastasis in perirectal and inguinal
lymph nodes and/or bilateral internal
iliac and/or inguinal lymph nodes

MX

assessed
M0
M1
Distant metastasis
Stage grouping
0
Tis
N0
M0
T1
N0
M0
T2
N0
M0
T3
N0
M0
T1
N1
M0
T2
N1
M0
T3
N1
M0
T4
N0
M0
T4
N1
M0
Any T
N2
M0
Any T
N3
M0
Any T
Any N
M1
II
IIIA
IIIB
IV
Table 11.8. AJCC staging of anal margin

cancer
Primary tumor (T)
TX
T0
Tis
Carcinoma in situ
T1
T2
Tumor >2 cm but not >5 cm in greatest

dimension
T3
T4
Tumor invades deep extradermal

structures (i.e., cartilage, skeletal muscle,
or bone)
Lymph nodes (N)

NX
N0
N1
MX

assessed
M0
M1
Distant metastasis
Stage grouping
0
Tis
N0
M0
T1
N0
M0
T2
N0
M0
T3
N0
M0
T4
N0
M0
Any T
N1
M0
Any T
Any N
M1
II
III
IV
The cur r ent r egi men for pr i mar y tr eatment of SCC of the anal canal
i s chemoradi ati on therapy (Tabl e 11.9). At MDACC, thi s has r ecentl y
been changed fr om the 5-F U mi tomyci n-Cbased chemoradi ati on
therapy pr otocol to one that i s 5-F U and ci spl ati n-based, because
of decr eased toxi ci ty, and si mi l ar r esponse and sur vi val data.
Compl ete r esponses wi th thi s tr eatment can be expected i n up to
90% of pati ents, wi th 5-year sur vi val rates appr oachi ng 85% .
Pati ents wi th advanced AIDS and anal cancer ar e poor candi dates
for hi gh-dose radi ati on therapy and the use of mi tomyci n. Cur r ent
r esear ch i s bei ng di r ected at di ffer ent chemotherapy r egi mes wi th

radi ati on for thi s gr oup.
The pr esence of a per si stent mass on exami nati on 12 to 14 weeks
after chemoradi ati on i s an i ndi cati on for bi opsy because a per si stent
mass after therapy wi l l demonstrate cancer on bi opsy i n 18% to
34% of cases. Ther e ar e r epor ts of posi ti ve bi opsy speci men r esul ts
6 to 8 weeks after therapy (per si stent di sease), whi ch wi l l r ever t to
negati ve bi opsy r esul ts i n pati ents
who have r efused sur ger y. Thi s i mpl i es that ther e may be a del ayed
radi ati on effect for up to several months after tr eatment. At
MDACC, we do not r outi nel y obtai n a bi opsy speci men of the tr eated
tumor si te unl ess obvi ous di sease per si stence exi sts; i nstead, we
wai t for cl i ni cal evi dence of l ocal l y r ecur r ent di sease i n fol l ow-up
vi si ts.
Table 11.9. Current and classic treatment

protocols for anal canal cancer
External-beam radiation therapy 5

d/wk for total dose of 4555 Gy
Current
5-FU, 250 mg/m2 /day, MF for the

entire duration of radiation
Cis-platin, 4 g/m2 /day, MF for the
entire duration of radiation
Classic
Days 1
5-FU, 7501,000 mg/m2 over 24-h
continuous IV infusion
Day 1
Mitomycin C, 1015 mg/m2 , IV bolus
Days 1
35
Radiation therapy 5 d/wk for total

dose of 4555 Gy; boosts of up to
60 Gy may be given to the anus
and/or inguinal basins
Days
2932
5-FU, 7501,000 mg/m2 over 24-h

continuous IV infusion
5-FU, 5-fluorouracil; IV, intravenous.

Pati ents wi th l ocal r ecur r ence or per si stent di sease ar e sal vaged
wi th APR, wi th a r esul tant 50% 5-year sur vi val . However, ci spl ati nbased chemotherapy wi th addi ti onal radi ati on therapy has been
used successful l y to sal vage up to one-thi r d of pati ents wi th l ocal l y
r ecur r ent di sease and i s cur r entl y under i nvesti gati on.
Anal Margin
SCC of the anal mar gi n i s defi ned cur r entl y by the AJCC as a l esi on
or i gi nati ng i n an ar ea between the anal mar gi n and 5 cm i n any
di r ecti on onto the per i anal ski n and i s cl assi fi ed wi th ski n tumor s.
Note that the data suppor ti ng the tr eatment of these uncommon,
heter ogeneous l esi ons der i ve fr om smal l , si ngl e-i nsti tuti on, mostl y
r etr ospecti ve studi es. Mor eover, many of these studi es i ncl ude
l esi ons of the l ower anal canal (dentate to anal ver ge) that wer e
i ncl uded pr evi ousl y i n ol der defi ni ti ons of the anal mar gi n. The
rati onal e for any modal i ty of therapy der i ves fr om the pr opor ti onal
i ncr ease i n chance of metastases wi th i ncr easi ng tumor si ze; i n
tumor s l ess than 2 cm, l ymph node metastases ar e rar el y found. For
l esi ons between 2 and 5 cm, and those gr eater than 5 cm, the rates
ar e 24% and 25% to 67% , r especti vel y.
Smal l (<5 cm), super fi ci al (T1T2) anal mar gi n cancer s that do not
i nvade the sphi ncter compl ex can be tr eated by a negati ve-mar gi n

wi de l ocal exci si on al one, wi th a 5-year sur vi val rate
gr eater than 80% . Wi de l ocal exci si on may i ncl ude par ts of the
super fi ci al i nter nal and exter nal anal sphi ncter s wi thout
compr omi si ng anal conti nence.
Lar ger T2, T3 to T4, or T1 to T2, N-posi ti ve l esi ons ar e best tr eated
wi th mul ti modal i ty therapy, as i n anal canal cancer s, gi ven the
hi gher l ocal r ecur r ence rate. Pr ophyl acti c i ngui nal node radi ati on i s
gi ven to pati ents wi th T3 to T4, N0 l esi ons, and hi gher doses of
radi ati on ar e gi ven to pati ents wi th posi ti ve i ngui nal nodes. Lymph
node di ssecti on i s r eser ved for those pati ents wi th r esi dual or
r ecur r ent di sease. It i s not known whether the tr eatment of i ngui nal
di sease transl ates i nto i mpr oved sur vi val . Pati ents wi th T3 to T4
and poor sphi ncter functi on may r equi r e APR. For al l pati ents, the
5-year di sease-speci fi c sur vi val i s 71% to 88% , and the l ocal
contr ol rate after i ni ti al therapy i s 70% to 100% .
Surveillance
Pati ents shoul d be fol l owed for detecti on of l ocal and systemi c
fai l ur es and tr eatment compl i cati ons. Local i nspecti on, di gi tal
exami nati on, anoscopy, and bi opsy of any suspi ci ous ar ea ar e
r ecommended ever y 3 months after chemoradi ati on tr eatment for 2
year s, and twi ce a year ther eafter. Ear l y detecti on of l ocal
r ecur r ence may enabl e l ess extensi ve sal vage sur gi cal pr ocedur es.
Di stant fai l ur es of epi der moi d cancer ar e r esponsi ve to radi ati on
therapy, and up to 30% of pati ents r espond to second-l i ne
chemotherapy. Ther efor e, chest radi ography, LF Ts, and pel vi c CT ar e
r ecommended ever y 6 to 12 months for 2 to 3 year s after i ni ti al
therapy. Pati ents wi th anal mar gi n cancer s shoul d have car eful ,
cl ose fol l ow-up, gi ven the i ndol ent natur e of these tumor s and the
benefi ts of fur ther l ocal therapy.
Anal Intraepithelial Neoplasia

Anal i ntraepi thel i al neopl asi a (AIN) i s a ter m used to descr i be
squamous i ntraepi thel i al l esi ons (SILs) of the anus. Thi s i s an
i ncr easi ngl y pr eval ent condi ti on associ ated wi th HPV i nfecti on and
condyl omata that can occur both exter nal l y on the per i anal ski n and
i nter nal l y wi thi n the anal canal . Dyspl asi a i n squamous
i ntraepi thel i al l esi ons may be l ow-grade (LSIL) or hi gh-grade
(HSIL), an i nter medi ate stage i n the mal i gnant transfor mati on to
SCC of the anus. Anal HSIL r epr esents cytopathol ogi cal and
hi stopathol ogi cal fi ndi ngs that have been r efer r ed to as AIN II/III,
sever e dyspl asi a, car ci noma i n si tu, or Bowen di sease. The pr esence
of HPV i nfecti on i s the pr i nci pal r i sk factor for anal neopl asi a.
Cofactor s i ncl ude anal -r ecepti ve i nter cour se and
i mmunocompr omi se. Paral l el i ng obser vati ons i n the cer vi x (cer vi cal
cancer and cer vi cal i ntraepi thel i al neopl asi a), i nfecti on by
oncogeni c strai ns of HPV ar e causal l y r el ated to the devel opment of
anal cancer and to the devel opment of the pr ecur sor l esi on, HSIL.
Under the mi cr oscope, cer vi cal SIL and anal SIL ar e vi r tual l y
i ndi sti ngui shabl e. The anatomi cal r egi on at r i sk i ncl udes the anal
transi ti on zone and the di stal r ectum extendi ng up to 8 cm pr oxi mal
to the dentate l i ne wher e i mmatur e squamous metapl asti c cel l s ar e
the most suscepti bl e to oncogeni c HPV, al though the nonkerati ni z i ng
and kerati ni z i ng squamous epi thel i um of the sur r oundi ng ti ssues
ar e al so suscepti bl e. Ther e i s al so
mor phol ogi c and hi stol ogi c si mi l ar i ty between cer vi cal and anal
cancer.
The popul ati ons at gr eatest r i sk for AIN ar e the same as for anal
cancer. Natural hi stor y studi es have demonstrated that i n HIVnegati ve MSM, the 4-year i nci dence of HSIL was 17% . It i s hi gher i n
HIV-posi ti ve men, wi th r ecepti ve anal i nter cour se, the pr esence of
condyl omata, mul ti pl i ci ty of HPV ser otype i nfecti ons, i njecti on dr ug
abuse, ci gar ette smoki ng, depr essed host i mmuni ty, and the
pr esence of cer vi cal , vul var, or peni l e neopl asi a.
Treatment
Pati ents wi th anal SIL often pr esent wi th mi nor compl ai nts r el ated
to anal condyl omata, hemor r hoi ds, or pr ur i tus ani . Physi cal exam
may r eveal anythi ng fr om typi cal condyl omatous l esi ons to nor mal appear i ng anal and r ectal mucosa. The per i anal ski n and the enti r e
sur gi cal anal canal , as defi ned by the AJCC and by the Wor l d Heal th
Or gani z ati on, extendi ng thr ough the l ength of the i nter nal anal
sphi ncter fr om the anal ver ge (24 cm i n women, up to 6 cm i n
men), shoul d be thor oughl y exami ned.
Pati ents wi th l ow vol ume di sease and no hi stor y of dyspl asi a may be
tr eated wi th topi cal agents i n the offi ce, r egar dl ess of r i sk factor s,
wi th sur vei l l ance anal Pap smear s. Pati ents wi th l ar ge vol ume
di sease ar e tr eated i n the operati ng r oom wi th a combi nati on of
exci si onal bi opsy or i nci si onal bi opsy and cauter y destr ucti on under
moni tor ed anestheti c car e wi th a standar d per i anal bl ock. Pati ents
wi th a hi stor y of dyspl asi a, ei ther fr om pr evi ous bi opsy or Pap
smear, may be mapped i n the operati ng r oom wi th the operati ng
mi cr oscope, aceti c aci d, and Lugol 's sol uti on or may be tr eated i n
the offi ce i f the l esi ons ar e r eadi l y vi sual i zed. HSIL demonstrates
var i ous character i sti c vascul ar patter ns al l owi ng other wi se occul t
pr emal i gnant di sease to be i denti fi ed. The ti ssues may subsequentl y
be pai nted sel ecti vel y wi th Lugol 's sol uti on, but the Lugol 's may
obscur e some of the aceti c aci d fi ndi ngs. The nonkerati ni z i ng hi ghgrade l esi ons of the anal canal do not r eadi l y take up Lugol 's
sol uti on and stai n ei ther mahogany or yel l ow. HSIL may be
destr oyed wi th el ectr ocauter y by super fi ci al l y pai nti ng the l esi on
and a smal l 2- to 10- mm r i m of ti ssue tr yi ng to avoi d i njur y that
extends deep i nto the submucosa i f a ti ssue di agnosi s has been
made. Thi s strategy i s safe and wel l tol erated, and has been shown
to eradi cate HSIL i n HIV-negati ve pati ents. In HIV-posi ti ve pati ents,
r ecur r ence i s hi gh and tr eatment may need to be r epeated;
however, wi th cl ose fol l ow-up, transfor mati on to i nvasi ve cancer can
be pr evented.
Bowen Disease
Bowen di sease i s an i ntraepi thel i al SCC (car ci noma i n si tu or
i ntraepi thel i al hi gh-grade dyspl asi a) that devel ops most commonl y
i n mi ddl e-age women and i s often di scover ed dur i ng hi stol ogi c
eval uati on of an anal speci men obtai ned for an unr el ated di agnosi s.
The l esi on i s rai sed, i r r egul ar, scal y, and pl aquel i ke, wi th
eczematoi d featur es. Hi stol ogi cal l y, l ar ge atypi cal hal oed cel l s
(Bowenoi d cel l s) ar e seen that stai n PAS negati ve. Al though i t has
pr evi ousl y been bel i eved to have an associ ati on wi th other i nvasi ve
car ci nomas, the evi dence for thi s i s weak. The r i sk of pr ogr essi on to
i nvasi ve cancer has been r epor ted to be appr oxi matel y
10% . Bowen di sease has tradi ti onal l y been tr eated wi th random
bi opsi es and wi de exci si on wi th fl ap r econstr ucti on. However, even i f
nor mal ti ssue i s sacr i fi ced to obtai n cl ear mar gi ns, the r ecur r ence
rate i s 23% , and the pati ent may sti l l be at r i sk for cancer
devel opment. Thi s aggr essi ve appr oach i s associ ated wi th
compl i cati ons such as anal stenosi s and fecal i nconti nence.
Bowen's di sease i s hi stol ogi cal l y and i mmunohi stochemi cal l y
i ndi sti ngui shabl e fr om anal HSIL and has al so been associ ated wi th
HPV i nfecti on. Ther e i s i ncr easi ng agr eement that Bowen di sease
and anal HSIL shoul d be tr eated i n a si mi l ar fashi on. Local
r ecur r ence may occur, but r e-exci si on pr ovi des excel l ent l ocal
contr ol . Other therapeuti c modal i ti es i ncl ude topi cal 5-F U cr eam,
topi cal i mi qui mod, photodynami c therapy, radi ati on therapy, l aser
therapy, and combi nati ons of these. The r epor ts ar e general l y smal l
ser i es wi th l i mi ted fol l ow-up, but ther e has been anecdotal success
wi th each appr oach, and the opti ons may be kept i n mi nd for
chal l engi ng cases.
Paget Disease
Paget di sease i s an i ntraepi thel i al adenocar ci noma that occur s
mostl y i n el der l y women. The l esi on (a wel l -demar cated, eczematoi d
pl aque) i s usual l y character i sti c; however, mor phol ogi c var i ati ons
can occur, maki ng the di agnosi s di ffi cul t by i nspecti on al one. The
di agnosi s i s made hi stol ogi cal l y by the pr esence of l ar ge, vacuol ated
Paget cel l s, whi ch stai n per i odi c aci d-Schi ff (PAS) posi ti ve (fr om
hi gh muci n content). Ther e i s some evi dence for the associ ati on of
per i anal Paget di sease wi th other i nvasi ve car ci nomas, but thi s
r el ati onshi p i s not as str ong as that seen wi th Paget di sease of the
br east. Invasi on can devel op i n these l esi ons, and the pr ognosi s i s
poor i n those cases. Per i anal Paget di sease shoul d be tr eated wi th
wi de l ocal exci si on.
Anal Melanoma
Pr i mar y mel anoma of the anus or r ectum i s a rar e tumor, accounti ng
for 0.4% to 1.6% of al l mel anomas and l ess than 1.0% of al l anal
canal tumor s. The overal l pr ognosi s for pati ents wi th anor ectal
mel anoma i s ver y poor. Several r epor ts i n the l i teratur e have shown
5-year sur vi val rates that ar e l ess than 25% and the medi an
sur vi val ti me i s about 15 months. Mucosal mel anoma i s fur ther
di scussed el sewher e i n thi s text. Thi s di scussi on focuses on anal
mel anoma.
The pr i mar y tumor may ar i se fr om the ski n of the anal ver ge or the
transi ti onal epi thel i um of the anal canal . Ingui nal nodal metastases
ar e common at pr esentati on. Pr ognosi s i s r el ated to tumor
thi ckness, as wi th cutaneous mel anomas.
Diagnosis
Pati ents most commonl y pr esent wi th r ectal bl eedi ng. The i nci dental
fi ndi ng of a mass on di gi tal exami nati on may al so l ead to a wor kup

that establ i shes the di agnosi s. Mel anoma may be an i nci dental
pathol ogi cal fi ndi ng after hemor r hoi dectomy. Physi cal exami nati on
shoul d i ncl ude eval uati on of the r ectal mass and
pal pati on of the i ngui nal nodes. Radi ographi c stagi ng shoul d be
per for med as for mel anomas el sewher e.
Treatment
Hi stor i cal l y, APR has been the tr eatment of choi ce, but hi gh fai l ur e
rates have questi oned the r ol e for thi s radi cal appr oach. Wi de l ocal
exci si on wi th at l east 2 cm of nor mal sur r oundi ng ti ssue and
senti nel l ymph node bi opsy of the i ngui nal l ymph nodes i s now
per for med whenever possi bl e, r eser vi ng APR for l ar ge bul ky tumor s
that cannot be l ocal l y exci sed. Therapeuti c i ngui nal node di ssecti on
i s i ndi cated for nodal di sease. Usi ng thi s appr oach wi th
hypofracti onated adjuvant radi ati on therapy (30 G y i n fi ve
fracti ons) to the pr i mar y si te and nodal beds, MDACC has r epor ted a
5-year actuar i al sur vi val of 31% , l ocal contr ol rate of 74% , and a
nodal contr ol rate of 84% i n 23 pati ents after a medi an fol l ow-up of
32 months.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 2 - He pa t o bilia ry C a nc e rs
12
Hepatobiliary Cancers
Eugene A . Choi
Steven E. Rodgers
Syed A . A hmad
Eddie K. A bdalla
Introduction
The appr oach to pati ents wi th l i ver and bi l i ar y tumor s i s compl ex.
Overal l assessment of comor bi di ty and speci fi c i ndi cati ons for
hepati c sur ger y of the l i ver depend on both tumor factor s and l i ver
factor s. Some tumor s devel op i n other wi se nor mal under l yi ng l i ver s,
whi l e other s ar i se i n l i ver s compr omi sed by bi l i ar y obstr ucti on or
under l yi ng l i ver di sease, such as steatosi s, fi br osi s, or ci r r hosi s.
The pr eoperati ve pr eparati on, operati ve appr oach, sur gi cal
techni ques, anti ci pated compl i cati ons, and outcome r el ate to both
the tumor and the l i ver factor s. Car eful attenti on to each of these
i ssues i s necessar y to opti mi ze outcome.
Advances i n hepatobi l i ar y sur ger y have come l ar gel y as a r esul t of
attenti on to these detai l s, and data suggest the outcome can be
i mpr oved by taki ng a mul ti di sci pl i nar y appr oach to the pati ent wi th
l i ver or bi l i ar y cancer s. In fact, both shor t- and l ong-ter m outcome
ar e si gni fi cantl y better i n center s of excel l ence, wher e sur geons
have speci al i zed trai ni ng and exper i ence i n hepatobi l i ar y sur ger y
and wor k as par t of a speci al i zed team of oncol ogi sts, radi ol ogi sts,
and gastr oenter ol ogi sts.
Thi s chapter outl i nes tr eatment appr oaches to the major
hepatobi l i ar y cancer s, addr esses i ssues of anatomy, and descr i bes
pr eoperati ve pr eparati on and the operati ve appr oach. For each
di sease type, the cur r ent l i teratur e i s r evi ewed to pr ovi de an
expl anati on of epi demi ol ogy, pathol ogy, cl i ni cal pr esentati on,
di agnosi s, stagi ng, and i ssues r egar di ng sur gi cal therapy.
Surgical Anatomy of the Liver

Hepati c anatomy i s hi ghl y var i abl e. Ten separate types of hepati c
ar ter i al anatomy have been defi ned, and numer ous por tal and
bi l i ar y segmental var i ati ons ar e i mpor tant to the hepati c sur geon. A
descr i pti on of the major ar ter i al var i ati ons i s beyond the scope of
thi s chapter, however an over vi ew of hepati c anatomy, whi ch i s
essenti al to the di scussi on of r esecti on opti ons for hepati c tumor s i s
pr ovi ded.
The por tal and ar ter i al vessel s i n the l i ver ar e the fi r st l evel of
compl exi ty i n the l i ver 's anatomy. Based on por tal segmentati on,
ei ght separate anatomi cal segments of the l i ver can be i denti fi ed,
and these ar e ter med the Coui naud segments of the l i ver. Thi s
pr edomi nantl y por tal segmentati on of the l i ver descr i bed by
Coui naud i n 1957 pr ovi des the sur geon wi th an anatomi cal appr oach
to the l i ver, such that any of the ei ght segments can be r esected
whi l e pr eser vi ng the vascul ar i nfl ow, venous outfl ow, and bi l i ar y
drai nage of the r emai ni ng segments.
The l eft and r i ght l i ver s ar e not symmetr i c. The r i ght l i ver i s
typi cal l y two-thi r ds of the total l i ver vol ume, and the l eft l i ver i s
about one-thi r d. The caudate or poster i or l i ver, whi ch i s a si ngl e
anatomi cal uni t, r epr esents about 1% the total l i ver vol ume
(segment 1). The r i ght l i ver can be di vi ded i nto the r i ght anter i or
and poster i or sector s, and the l eft l i ver di vi ded i nto the l ateral and
medi al sector s. The l eft l ateral l i ver i s subdi vi ded i nto segments II
and III, and the medi al l eft l i ver i s al so known as segment IV. The
r i ght anter i or l i ver i s subdi vi ded i nto segment V i nfer i or l y and
segment VIII super i or l y, and the r i ght poster i or l i ver i s subdi vi ded
i nto segment VI i nfer i or l y and segment VII super i or l y (F i g. 12.1).
F i gur e 12.1. Segmental l i ver anatomy as or i gi nal l y descr i bed by

Cl aude Coui naud, wi th the ter mi nol ogy that shoul d be used to
descr i be l i ver r esecti on accor di ng to the Br i sbane 2000
i nter nati onal consensus confer ence. (Adapted fr om Abdal l a EK,
Denys A, Cheval i er P, Nemr RA, Vauthey JN. Total and segmental
l i ver vol ume var i ati ons: i mpl i cati ons for l i ver sur ger y. Sur ger y
2004;135:405, wi th per mi ssi on.)
Thr ee major hepati c vei ns ar e typi cal l y found: the r i ght hepati c
vei n, whi ch typi cal l y drai ns the r i ght l i ver (segments VVIII); the
mi ddl e hepati c vei n, whi ch typi cal l y drai ns segment IV; and the l eft
hepati c vei n, whi ch typi cal l y drai ns segments II and III. The l eft
hepati c vei n cr osses the l eft l ateral l i ver transver sel y, between
segments II and III. The mi ddl e hepati c vei n defi nes the mai n pl ane,
or the di vi si on between the l eft and r i ght l i ver s, whi ch i s the pl ane
on whi ch r i ght or l eft hepatectomy i s under taken. The caudate l i ver,
because i t ar i ses embr yol ogi cal l y as a separate anatomi cal uni t fr om
the r emai ni ng l i ver, has i ts own venous drai nage, wi th shor t vei ns
drai ni ng di r ectl y i nto the vena cava, and hi ghl y var i abl e bi l i ar y and
por tal anatomy.
It i s essenti al that the sur geon under stand the many anatomi cal
var i ati ons of the l i ver that can be i denti fi ed on pr eoperati ve
i magi ng and i ntraoperati ve ul trasound (US). Sur gi cal techni ques
i ncl udi ng the G l i ssoni an appr oach or di ssecti on al ong the fi br ous
sheath that sur r ounds the por tal tr i adsmay enabl e the hepati c
sur geon to i denti fy i mpor tant el ements of the anatomy
i ntrahepati cal l y and ther eby mi ni mi ze the r i sk of i njur y to the
r emai ni ng l i ver after r esecti on of anatomi cal segments. Most l i ver
sur geons consi der i ntraoperati ve US essenti al for safe sur ger y
because i t per mi ts r eal -ti me i denti fi cati on of the i ntrahepati c
anatomy.
Terminology for Hepatic Resection

Ter mi nol ogy for hepati c r esecti on has changed over ti me. Di ffer ent
defi ni ti ons of the ter m l obe had been used i n Eur ope and the
Uni ted States, causi ng confusi on. Accor di ngl y, the Br i sbane 2000
Inter nati onal Confer ence was hel d to establ i sh a consensus on
ter mi nol ogy used for l i ver r esecti on. That r evi sed ter mi nol ogy i s
used thr oughout thi s chapter (F i g. 12.1).
The ter mi nol ogy for hepatectomy i s as fol l ows: (a) r esecti on of the
r i ght l i ver (or segments VVIII) i s ter med a r i ght hepatectomy or
r i ght hemi hepatectomy; (b) r esecti on of the l eft l i ver (or segments
IIIV) i s ter med a l eft hepatectomy or l eft hemi hepatectomy; (c)
r esecti on of the l eft l ateral l i ver (or segments II and III) i s ter med
a bi segmentectomy II + III or a l eft l ateral secti onectomy; and (d)
extended r i ght hepatectomy, or r i ght tr i secti onectomy, i s the
r esecti on of segments IV to VIII, wher eas extended l eft
hepatectomy, or l eft tr i secti onectomy, i s r esecti on of segments II to
V and VIII. El i mi nati on of the ter m l obe has enabl ed much cl ear er
communi cati on among physi ci ans wor l dwi de when di scussi ng and
wr i ti ng about hepati c r esecti on.
Predicting Liver Remnant Function

Liver Volume Determination
Li ver vol ume after major hepati c r esecti on has been cr i ti cal l y l i nked
to l i ver functi on. Al so, under l yi ng l i ver di sease wi l l affect l i ver
functi on so pati ents wi th nor mal under l yi ng l i ver ar e tr eated
di ffer entl y than pati ents wi th di seased under l yi ng l i ver. The
r eal i z ati on that l i ver vol ume al one does not pr edi ct functi on l eads
to two addi ti onal concl usi ons: Lar ge pati ents need l ar ge l i ver s and
smal l pati ents need smal l l i ver s, and pati ents wi th di seased l i ver s
need to have a l ar ger vol ume of l i ver pr eser ved than pati ents wi th
nor mal under l yi ng l i ver s. Car eful anal ysi s of outcome based on l i ver
r emnant vol ume strati fi ed by under l yi ng l i ver
di sease (or the absence of di sease) has l ed to r ecommendati ons
r egar di ng the safe l i mi ts of r esecti on. The l i ver r emnant to be l eft
after r esecti on i s ter med the futur e l i ver r emnant (F LR). For
pati ents wi th nor mal under l yi ng l i ver, compl i cati ons, extended
hospi tal stay, admi ssi on to the i ntensi ve car e uni t, and hepati c
i nsuffi ci ency ar e rar e when the standar di zed F LR i s >20% of the
total l i ver vol ume (TLV) as compar ed to when i t i s 20% . For
pati ents wi th mar ked under l yi ng l i ver di sease, a 40% l i ver r emnant
i s necessar y to avoi d chol estasi s, fl ui d r etenti on, and l i ver fai l ur e.
Pati ents wi th nor mal under l yi ng l i ver and a smal l r emnant have a
gr eater compl i cati on rate but rar el y di e of those compl i cati ons,
wher eas pati ents wi th ci r r hosi s and a smal l r emnant ar e at r i sk for
a cascade of compl i cati ons that may cul mi nate i n l i ver fai l ur e and
death.
When the l i ver r emnant i s nor mal or has onl y mi l d di sease, the
vol ume of l i ver r emnant can be measur ed di r ectl y and accuratel y
wi th thr ee-di mensi onal computed tomography (CT) vol umetr y.
However, CT vol umetr y i s fr equentl y not appr opr i ate for deter mi ni ng
the total functi onal l i ver vol ume when the goal i s to use thi s vol ume
to esti mate the functi onal i ty of the F LR after r esecti on. Inaccuracy
may ar i se because the l i ver to be r esected i s often di seased,
par ti cul ar l y i n pati ents wi th ci r r hosi s or bi l i ar y obstr ucti on; the
total l i ver si ze can be l ar ge, nor mal , or smal l , or when mul ti pl e or
l ar ge tumor s occupy a l ar ge vol ume of the l i ver to be r esected,
subtracti ng tumor vol umes fr om l i ver vol ume fur ther decr eases
accuracy of CT vol umetr y. The cal cul ated TLV, whi ch has been
der i ved fr om the cl ose associ ati on between pati ent si ze and l i ver
si ze (speci fi cal l y the associ ati on between body sur face ar ea [BSA]
and l i ver si ze), pr ovi des a standar di z i ng esti mate of the TLV. The
fol l owi ng for mul a i s used:
TLV (cm3 ) = -794.41 + 1267.28 BSA (squar e meter s)
Thus, the standar di zed F LR vol ume cal cul ati on uses the measur ed
F LR vol ume fr om CT vol umetr y as the numerator and the calculated
TLV as the denomi nator :
Standar di zed F LR = measur ed F LR vol ume/TLV

Cal cul ati ng the standar di zed TLV cor r ects the actual l i ver vol ume to
the i ndi vi dual pati ent's si ze and pr ovi des an i ndi vi dual i zed esti mate
of that pati ent's postr esecti on l i ver functi on. Thi s appr oach has
been val i dated and used at The Uni ver si ty of Texas M. D. Ander son
Cancer Center, wher e i t has enabl ed 127 consecuti ve extended
hepatectomi es wi th onl y a si ngl e mor tal i ty. F ur ther mor e, use of thi s
standar di zed appr oach to l i ver vol ume measur ement enabl es the
systemati c use of pr eoperati ve l i ver pr eparati on to i ncr ease the
l i ver r emnant vol ume pr i or to major r esecti on when i ndi cated based
on the cr i ter i a descr i bed pr evi ousl y.
Several other tests have been used to eval uate l i ver functi on,
i ncl udi ng the ur ea-ni tr ogen synthesi s rate, gal actose el i mi nati on
capaci ty, br omsul phal ei n and ami nopyr i ne br eath tests, and
i ndocyani ne gr een (ICG ) cl earance. ICG i s a dye that i s cl ear ed fr om
the ci r cul ati on by the l i ver, and i ts cl earance i s an i ndi cator of
hepatocyte functi on. ICG cl earance i s the most studi ed test used to
sel ect ci r r hoti c pati ents for hepati c r esecti on, al though
i t i s used mostl y i n Asi a. Makuuchi et al . advocated sel ecti on of
ci r r hoti c pati ents for minor r esecti on based on the pr esence or
absence of asci tes, strati fi cati on accor di ng to the total ser um
bi l i r ubi n l evel and ICG 15 val ue (i .e., the per centage of dye
cl earance i n 15 mi nutes). Pati ents wi th hi gh bi l i r ubi n l evel s and l ow
hepati c cl earance of ICG ar e consi der ed for l i mi ted r esecti on or
al ter nati ve l ocor egi onal abl ati ve tr eatments. These studi es ar e of
l i mi ted val ue i n sel ecti ng pati ents for major r esecti on because they
assess gl obal hepati c functi on. Standar di zed F LR vol ume r emai ns
our sol e appr oach at M. D. Ander son Cancer Center because i t i s a
val i dated appr oach to assessment of l i ver r emnant vol ume and
gui des tr eatment pl anni ng. The fol l owi ng secti on di scusses
strategi es to i ncr ease the vol ume and functi on of an i nadequate F LR
pr i or to major hepatectomy.
Portal Vein Embolization

Por tal vei n embol i z ati on (PVE) i s a pr eoperati ve pr ocedur e desi gned
to i ncr ease the safety of major l i ver r esecti ons. The por tal fl ow i s
di ver ted fr om the l i ver segments to be r esected to the l i ver that wi l l
r emai n (the F LR) because thi s di ver si on of fl ow l eads to i ncr eased
si ze and better functi on of the F LR befor e r esecti on. PVE was
r efi ned by Makuuchi after Ki noshi ta obser ved that embol i z ati on of
the por tal vei n to pr event tumor extensi on l ed to hyper tr ophy of the
contral ateral l i ver. Si nce then, PVE techni ques and i ndi cati ons have
been standar di zed to i ncr ease the safety of major hepatectomy i n
pati ents wi th nor mal and di seased l i ver s.
The i ndi cati ons for PVE ar e the same as those pr edi cti ng
postr esecti on l i ver functi on as descr i bed i n the pr evi ous secti on. In
pati ents wi th nor mal under l yi ng l i ver and a standar di zed F LR
vol ume 20% of the TLV, PVE i s i ndi cated to i ncr ease the vol ume
and functi on of the F LR. In pati ents wi th ci r r hoti c and fi br oti c l i ver s
and a standar di zed F LR vol ume 40% of the TLV, PVE i s al so
i ndi cated. For pati ents who have under gone extensi ve
chemotherapy, PVE shoul d be consi der ed when the standar di zed F LR
i s 30% .
Al though several di ffer ent appr oaches to embol i z ati on have been
pr oposed, we at M. D. Ander son Cancer Center use the per cutaneous
i psi l ateral appr oach to avoi d punctur i ng or other wi se i njur i ng the
l i ver r emnant. Then, usi ng smal l par ti cl es fol l owed by l ar ger coi l s,
the por tal branches suppl yi ng the enti r e tumor-bear i ng l i ver,
i ncl udi ng segment IV (i f thi s i s to be r esected), ar e occl uded. Thi s
pr ocedur e di ver ts por tal fl ow to the F LR. Studi es have shown that
hyper tr ophy-i nduci ng factor s ar e car r i ed i n the por tal vei n and not
the hepati c ar ter y, and so PVE l eads to F LR hyper tr ophy.
Hyper tr ophy occur s qui te rapi dl y, and the nor mal l i ver can be
r eassessed by vol umetr y wi thi n 3 or 4 weeks. Sur ger y i s under taken
when the tar get F LR vol ume i s r eached. In ci r r hoti cs and di abeti cs,
hyper tr ophy occur s mor e sl owl y; ther efor e, an i nter val of 5 or 6
weeks may be r equi r ed to achi eve the tar get vol ume. Numer ous
outcome studi es have shown that thi s hyper tr ophy cor r el ates wi th
an i mpr ovement i n hepati c functi on and r educes the r i sk of
chol estasi s, fl ui d r etenti on, and asci tes i n pati ents wi th nor mal
l i ver. It has al so been shown to r educe the r i sk of these pr obl ems,
as wel l as death due to hepati c fai l ur e,
i n ci r r hoti cs.
Attenti on to the l i ver r emnant, systemi c vol umetr y for major
r esecti on, and systemati c use of PVE based on car eful l y pr escr i bed
i ndi cati ons has enabl ed ver y safe extended hepati c r esecti on i n
pati ents wi th nor mal l i ver functi on and major hepatectomy i n
pati ents wi th under l yi ng l i ver di sease.
Primary Hepatocellular Carcinoma
Epidemiology
Wor l dwi de, hepatocel l ul ar car ci noma (HCC) i s the fi fth most
common mal i gnant neopl asm i n men and the ni nth most common i n
women, accounti ng for 500,000 to 1 mi l l i on cancer cases annual l y.
In the Uni ted States, HCC i s comparati vel y rar e, wi th an annual
i nci dence of fewer than 5 cases per 100,000 per sons, maki ng i t the
22nd most common type of cancer. However, the i nci dence of HCC i n
the Uni ted States i s r i si ng because of the i ncr easi ng pr eval ence of
hepati ti s B (HBV) and hepati ti s C (HCV) i nfecti on.
HCC occur s wi th gr eater fr equency i n r egi ons of the wor l d wher e
vi ral hepati ti s i s endemi c. Ther e i s, however, consi derabl e var i ati on
i n the pr eval ence of HCC, HBV, and HCV, dependi ng on the pati ent's
countr y of or i gi n. It i s esti mated that one-four th of pati ents wi th
HCC i n the Uni ted States have evi dence of HCV i nfecti on, and HBV
and HCV i nfecti ons together account for no mor e than 40% of HCC
cases. In contrast, i n many Easter n countr i es wher e both HBV and
HCV i nfecti ons ar e endemi c, the vast major i ty of HCC pati ents ar e
ser oposi ti ve for ei ther HBV or HCV. Even wi thi n Easter n countr i es,
however, ther e ar e geographi c var i ati ons. For exampl e, i n contrast
to Tai wan, Chi na, and Kor ea, wher e HBV i nfecti on rates ar e hi gh,
HCV and HBV+HCV i nfecti ons ar e pr edomi nant i n Japan. Pati ents
fr om the West (the Uni ted States and F rance) ar e mor e l i kel y than
pati ents fr om the East (Hong Kong and Japan) to have negati ve
hepati ti s ser ol ogy.
Several other r i sk factor s have been i mpl i cated i n the devel opment
of HCC. Al cohol -r el ated ci r r hosi s i s the l eadi ng cause of HCC i n the
Uni ted States, Canada, and Wester n Eur ope. Chemi cal s such as
ni tr i tes, hydr ocar bons, and pol ychl or i nated bi phenyl s have al so
been associ ated wi th HCC. Di etar y i ntake of afl atoxi ns i s hi gh i n
several countr i es wi th a hi gh i nci dence of HCC. The common
eti ol ogi c factor may be r ecur r ent chr oni c hepatocel l ul ar i njur y
and/or ci r r hosi s. HCC has al so been r epor ted i n associ ati on wi th
several metabol i c di sor der s, such as hemochr omatosi s, Wi l son
di sease, her edi tar y tyr osi nemi a, type I gl ycogen storage di sease,
fami l i al pol yposi s col i , al pha-1 anti tr ypsi n defi ci ency, and BuddChi ar i syndr ome. HCC i s mor e l i kel y to devel op i n men than i n
women. In hi gh-i nci dence ar eas, the mal e-to-femal e rati o i s
appr oxi matel y 8:1, and i n l ow-i nci dence ar eas, the rati o i s 4:1. HCC
devel ops ear l y i n l i fe i n the hi gh-i nci dence ar eas, wher eas i t occur s
pr edomi nantl y i n the el der l y i n l ow-i nci dence ar eas. Mor e i mpor tant
than the pati ent's age i s the chr oni ci ty of the i nfecti on or ci r r hosi s.
Pati ents wi th HCV i nfecti ons ar e often ol der and pr esent wi th acti ve
chr oni c hepati ti s

and l ar ger tumor s.
Pathology
The hi stol ogi cal var i ati ons of HCC ar e of l i ttl e i mpor tance i n
deter mi ni ng tr eatment and pr ognosi s, wi th two excepti ons:
fi br ol amel l ar car ci noma i s found i n younger pati ents wi thout
ci r r hosi s and car r i es a better pr ognosi s than standar d HCC, and
adenomatous hyper pl asi a i s a pr emal i gnant l esi on that can be cur ed
by r esecti on. HCC fr equentl y spr eads by l ocal extensi on to the
di aphragm and adjacent or gans and i nto the por tal and hepati c
vei ns. Metastati c spr ead occur s most often to the l ungs, bone,
adr enal gl ands, and brai n.
Pr esentati on depends on the stage of di sease. In countr i es wi th
systemati c scr eeni ng pr ograms, HCC may be detected at an ear l i er
stage. In the Uni ted States, wher e ther e i s no systemati c scr eeni ng
for HCC, pati ents usual l y pr esent at a l ate stage, often wi th upper
abdomi nal pai n or di scomfor t, a pal pabl e r i ght upper quadrant mass,
wei ght l oss, asci tes, or other sequel ae of por tal hyper tensi on.
Jaundi ce i s r el ati vel y uncommon but omi nous. The tr i ad of
abdomi nal pai n, wei ght l oss, and an abdomi nal mass i s the most
common cl i ni cal pr esentati on i n the Uni ted States. In fewer than
5% of cases, pati ents pr esent wi th tumor r uptur e. In Easter n
countr i es, i ncl udi ng Tai wan, Hong Kong, Japan, and Kor ea, HCC i s
often di agnosed by sur vei l l ance abdomi nal US, hel i cal CT scan,
magneti c r esonance i magi ng (MRI), or r outi ne scr eeni ng of bl ood for
featur es such as el evated ser um al pha-fetopr otei n (AF P) befor e
cl i ni cal symptoms ar e appar ent. Numer ous paraneopl asti c
compl i cati ons have been descr i bed, i ncl udi ng hypogl ycemi a,
hyper cal cemi a, er ythr ocytosi s, and hyper tr ophi c pul monar y
osteoar thr opathy. Pati ents wi th HCV i nfecti on ar e mor e often
scr eened and thus tend to pr esent wi th si gns and symptoms of
ci r r hosi s and ear l i er-stage HCC tumor s. Pati ents wi th HBV i nfecti on
or no ser ol ogi cal evi dence of hepati ti s i nfecti on tend to pr esent wi th
l ar ger tumor s and l ess ci r r hosi s.
Diagnosis
AF P i s i ncr eased i n 50% to 90% of al l pati ents wi th HCC, wi th l evel s
gr eater than 400 ng per mL usual l y found i n those wi th l ar ge or

rapi dl y gr owi ng tumor s. Despi te these general cor r el ati ons, AF P i s
nei ther sensi ti ve nor speci fi c for HCC. A pati ent wi th a smal l HCC
tumor may have mi ni mal or no el evati on of AF P. Mor eover, transi ent
i ncr eases i n AF P may be seen wi th i nfl ammator y hepati c di sease or
ci r r hosi s. Several studi es have r epor ted a cor r el ati on between AF P
el evati on, advanced tumor stage, and poor pati ent pr ognosi s, or an
associ ati on between hi ghl y el evated AF P and metastati c di sease;
AF P >200 ng per mL i n associ ati on wi th character i sti c i magi ng
fi ndi ngs i s near l y 100% sensi ti ve for HCC.
Several i magi ng modal i ti es can be used to di agnose HCC, i ncl udi ng
hel i cal (CT) scanni ng, per cutaneous US, and MRI. Both CT and MRI
per mi t dynami c contrast-enhanced i magi ng. Each i magi ng modal i ty
has advantages and di sadvantages. US i s an i nexpensi ve scr eeni ng
tool , but i ts sensi ti vi ty and speci fi ci ty ar e l ow, wi th an overal l fal senegati ve rate of mor e than 50% .
At M. D. Ander son Cancer Center, hel i cal thi n-sl i ce CT scanni ng i s
the pr efer r ed i magi ng techni que. These CT scans have the
advantage of speed when compar ed wi th MRI, and they effecti vel y
i mage the enti r e abdomen and the l i ver i n four phases of contrast
enhancement: pr econtrast, ear l y vascul ar or ar ter i al phases, a
por tal phase, and a del ayed phase. HCCs, hepati c adenomas, and
metastati c di sease demonstrate ar ter i al phase enhancement.
Enhancement dur i ng the por tal -domi nant phase r eveal s
hypovascul ar tumor s, such as metastati c adenocar ci noma or
chol angi ocar ci noma (CCA). Mul ti phasi c MRI i s used sel ecti vel y at
our i nsti tuti on to pr ovi de addi ti onal i nfor mati on concer ni ng the
beni gn or mal i gnant natur e of a hepati c l esi on or the anatomi cal
r el ati onshi p between a tumor and major vessel s. MRI has an
advantage over CT i n that i t does not r equi r e the use of contrast
agents for detecti ng l esi ons, al though HCC pr otocol s typi cal l y use
dynami c contrast enhancement. Many i nsti tuti ons pr efer MRI to CT,
but data that demonstrate super i or i ty of one modal i ty ar e l acki ng.
In some r egi ons, l i pi odol , an oi l y der i vati ve of the poppy seed, i s
combi ned wi th i odi ne contrast medi um; the mi xtur e i s r etai ned by
the tumor and has been used wi th CT scanni ng to eval uate smal l
HCCs.
Mor e i nvasi ve i magi ng techni ques ar e al so used i n the di agnosi s of
HCC, i ncl udi ng CT wi th ar ter i al por tography (CTAP), CT hepati c
ar ter i ography (CTHA), and angi ography. In CTAP, a contrast agent i s
i njected i nto the super i or mesenter i c ar ter y or the spl eni c ar ter y
pr i or to the scan. Del ayed i mages ar e obtai ned when the contrast
mater i al has enter ed the por tal venous system. Because i t i s not
wel l per fused by the por tal system, HCC appear s as a l ow-densi ty
ar ea agai nst the sur r oundi ng l i ver par enchyma. Angi ography of the
hepati c ar ter y i s per for med to fur ther del i neate aber rant bl ood
suppl y to the l i ver or, mor e i nfr equentl y, pr i or to the pl acement of a
hepati c ar ter y i nfusi on pump.
Di agnosti c l apar oscopy (DL), al though i nvasi ve, may have a r ol e i n
the wor kup for some pati ents wi th HCC. Pati ents most l i kel y to
benefi t fr om DL ar e those wi th l ar ge or r uptur ed tumor s, possi bl e
advanced ci r r hosi s, or i ndeter mi nate nodul es i n the F LR.
When the di agnosi s of HCC i s uncer tai n (e.g., when i magi ng fi ndi ngs
ar e noncharacter i sti c and AF P i s nor mal ), the hi stol ogi c di agnosi s of
HCC can be obtai ned by US-gui ded per cutaneous needl e bi opsy or
fi ne-needl e aspi rati on (F NA) bi opsy of the mass. Tumor seedi ng
al ong the bi opsy needl e track rar el y occur s when usi ng moder n
techni ques (<1% of cases). The r i sks of si gni fi cant bl eedi ng ar e l ow.
The r i sks associ ated wi th major r esecti on or transpl antati on for
beni gn di sease may be outwei ghed by the benefi t of F NA bi opsy i n
cases wher e the di agnosi s i s uncer tai n.
Staging
system for HCC i s shown i n Tabl e 12.1. Thi s system i s uni fi ed wi th
the Uni on Inter nati onal e Contr e l e Cancer (UICC) system and i s
der i ved fr om the anal ysi s by Vauthey et al ., of an i nter nati onal
gr oup of pati ents fr om the Uni ted States, F rance, and Japan who
under went compl ete r esecti on of HCC. Tumor si ze per se has no
effect on sur vi val i n pati ents who have sol i tar y tumor s wi thout
vascul ar i nvasi on. The new system r ecogni zes that the
pr ognosi s for T1 tumor s >10 cm i n l ar gest di ameter i s the same as

that for smal l er T1 tumor s (T1 = any si ze, wi thout vascul ar
i nvasi on). Tumor s havi ng evi dence of mi cr ovascul ar i nvasi on or
mul ti pl e tumor s l ess than 5 cm i n di ameter ar e desi gnated as T2
di sease. HCC wi th major vascul ar i nvasi on or wi th mul ti pl e tumor s,
wi th at l east one measur i ng 5 cm, ar e desi gnated T3. Most
i mpor tant, the pr esence of sever e fi br osi s of the under l yi ng l i ver
has a negati ve i mpact on overal l sur vi val , r egar dl ess of the T
cl assi fi cati on. For stage I di sease, the 5-year sur vi val rate i s 64%
when ther e i s no fi br osi s (F 0) and 49% when fi br osi s i s pr esent

(F 1). For stage II di sease, the 5-year sur vi val rate i s 46% for F 0
di sease and 30% for F 1 di sease. For stage IIIA di sease, the 5-year
sur vi val rate i s 17% for F 0 di sease and 9% for F 1 di sease. The
AJCC stagi ng manual r ecommends notati on of fi br osi s but has not
yet for mal l y i ncor porated the F cl assi fi cati on i nto the stagi ng
system.
Table 12.1. American Joint Commission on

Cancer staging system for primary liver
cancer
Primary tumor (T)
TX
Primary cannot be assessed
T0
T1
Solitary tumor without vascular

invasion
T2
Solitary tumor with vascular invasion or

multiple tumors none more than 5 cm
T3
Multiple tumors more than 5 cm or

tumor involving a major branch of the
portal or hepatic vein(s)
T4
Tumor(s) with direct invasion of

adjacent organs other than the
gallbladder or with perforation of
visceral peritoneum

NX

assessed
N0
N1

MX
M0
M1
Distant metastasis
Stage groupings
Stage
I
T1
N0
M0
Stage
II
T2
N0
M0
Stage
IIIA
T3
N0
M0
Stage
IIIB
T4
N0
M0
Stage
IIIC
Any T
N1
M0
Stage
IV
Any T
Any N
M1
Histological grade (G)

GX
Grade cannot be assessed
G1
Well differentiated
G2
Moderately differentiated
G3
G4
Undifferentiated
Fibrosis score (F)

F0
Fibrosis score 04 (no fibrosis to

moderate fibrosis)
F1
Fibrosis score 56 (severe fibrosis to

cirrhosis)

Fritzag, Balch EM, Haller DG, Marrow M,
editors. AJCC Cancer Staging Manual. 6th ed.
New York, NY: Springer-Verlag; 2002, with
permission.
The major i ty of pati ents anal yzed i n the i nter nati onal study by
Vauthey et al . had HCV-r el ated HCC rather than HBV-r el ated HCC;
thus, Poon et al . under took val i dati on of the stagi ng system wi th
HBV-i nfected pati ents fr om Hong Kong. Despi te the di ffer ent
cl i ni copathol ogi cal featur es of pati ents wi th HCV and HBV, Poon et
al . demonstrated that the new stagi ng system pr ovi des r el i abl e
pr ognosti c i nfor mati on for pati ents wi th hepati ti s B, and showed
that the new system i s si mpl er to use than the pr evi ous AJCC
stagi ng system. Appr opr i ate emphasi s i s pl aced on the most
i mpor tant pr ognosti c featur es: vascul ar i nvasi on wi thi n the tumor,
and fi br osi s of the nontumoral l i ver. Several other author s fr om
Tai wan and Eur ope have i ndependentl y val i dated the AJCC/UICC
system, confi r mi ng i ts pr ognosti c accuracy.
Patient Selection for Surgical Treatment

HCC typi cal l y occur s i n the backgr ound of ci r r hosi s. Thus, after
assessment of a pati ent's candi dacy for sur ger y based on overal l
heal th and comor bi di ty, assessment of l i ver functi on i s necessar y.
The most wi del y used cl assi fi cati on system for the assessment of
l i ver functi on i s the Chi l d-Pugh (someti mes cal l ed the Chi l d-PughTur cotte) system. The parameter s measur ed i n thi s cl assi fi cati on
system ar e the total bi l i r ubi n and al bumi n l evel s, pr esence or
absence of asci tes, pr esence or absence of encephal opathy, and
pr othr ombi n ti me/i nter nati onal nor mal i zed rati o; together, these
parameter s gi ve a r ough esti mate of the gr oss syntheti c and
detoxi fi cati on capaci ty of the l i ver. Numer ous studi es have val i dated
thi s system as an overal l pr edi ctor of sur vi val after sur ger y i n
ci r r hoti c pati ents (Tabl e 12.2). Pati ents wi th Chi l d-Pugh cl ass A
l i ver functi on general l y tol erate hepati c r esecti on. Pati ents wi th
cl ass B l i ver functi on may tol erate mi nor r esecti on, but general l y do
not tol erate major r esecti on. Pati ents wi th cl ass C l i ver functi on ar e
at si gni fi cant r i sk fr om anesthesi a and l apar otomy.
Several other cl i ni cal stagi ng systems have been devel oped to gui de
i ni ti al therapy for HCC. The Okuda stagi ng system, devel oped i n
Japan, i ncor porates tumor si ze, asci tes status, and al bumi n and
bi l i r ubi n l evel s, accounti ng for both l i ver functi on and tumor
extensi on. The Cancer of the Li ver Ital i an Pr ogram
(CLIP) gr oup der i ved a system fr om a r etr ospecti ve study of 435
pati ents di agnosed wi th HCC that i ncor porates the Chi l d-Pugh scor e,
data on tumor mor phol ogy and extensi on, pr esence or absence of
por tal vei n thr ombosi s, and ser um l evel of AF P. The Bar cel ona Cl i ni c
Li ver Cancer (BCLC) system uses a cl i ni cal stagi ng system based on
tumor pr ogr essi on and l i ver functi on. The CLIP and Okuda systems
may be useful to pr edi ct pr ognosi s i n pati ents who have advanced
tumor s and l i ver di sease but ar e not useful for tr eatment sel ecti on.
The BCLC system i s hi ghl y cr i ti ci zed and has not been wi del y
accepted because i t al l ocates pal l i ati ve tr eatment to pati ents who
ar e candi dates for curati ve r esecti on. The BCLC system i s general l y
consi der ed to be mor e of a tr eatment al gor i thm than a stagi ng
system.
Table 12.2. Child-Pugh classification of

hepatic functional reserve
Clinical or
1 Point
Laboratory Feature
2
3
Points Points
Encephalopathy
(grade)
0
(absent)
12
34
Ascites
Absent
Slight
Poorly
Bilirubin (mg/dL)
<2.0
2.0
3.0
>3.0
Albumin (g/dL)
>3.5
2.8
3.5
<2.8
International
normalized ratio
<1.7
1.7
2.2
>2.3
Each feature is assigned 1, 2, or 3 points.
Class A: 56 points; Class B: 79 points; Class

C: 1015 points.
For anatomi cal l y r esectabl e HCC wi thout extrahepati c metastases,
our appr oach to pati ent sel ecti on for major hepatectomy i s fi r st
based on cl i ni cal parameter s (per for mance status, Chi l d-Pugh
cl assi fi cati on) and degr ee of por tal hyper tensi on. We r equi r e a
pl atel et count 100,000 and excl ude pati ents wi th gastr i c or
esophageal var i ces. Next, systemati c deter mi nati on of the F LR
vol ume, as descr i bed pr evi ousl y, i s necessar y. PVE i s consi der ed
based on the pr evi ous cr i ter i a. We do not use ICG cl earance or
other tests of l i ver functi on i n thi s assessment.
Thi s appr oach enabl es r esecti on i n ci r r hoti cs wi th l ow i nci dences of
l i ver fai l ur e and death. In pati ents wi th nor mal l i ver s, thi s appr oach
enabl es extended hepatectomy wi th <1% mor tal i ty and ver y l ow
mor bi di ty. The systemati c eval uati on of pati ents usi ng standar di zed
vol umetr y i s the key to l ow mor bi di ty and mor tal i ty, despi te
extensi ve and aggr essi ve hepati c sur ger y i n our center.
Surgical Resection
The standar d tr eatment for HCC i s sur gi cal r esecti on or or thotopi c
l i ver transpl antati on (OLT). However, not al l pati ents wi th HCC ar e
candi dates for sur gi cal r esecti on; of those pr esenti ng wi th HCC,
onl y 10% and 30% wi l l be el i gi bl e for sur ger y, and of those pati ents
who under go expl orator y sur ger y, onl y 50% and
70% wi l l have a r esecti on wi th curati ve i ntent. Pati ents wi th
ci r r hosi s may be candi dates for l i mi ted sur gi cal r esecti on, OLT, or
l ocor egi onal abl ati ve tr eatment, dependi ng on the sever i ty of the
ci r r hosi s.
The onl y absol ute cr i ter i on that r ender s a tumor unr esectabl e i s the
pr esence of extrahepati c di sease (and even thi s excl usi on has
caveats i n hi ghl y sel ected cases). Other r el ati ve contrai ndi cati ons to
r esecti on ar e evi dence of sever e hepati c dysfuncti on, an i nadequate
F LR, and tumor i nvol vement of the por tal vei n or vena cava.
Pati ents wi th nor mal l i ver par enchyma ar e usual l y el i gi bl e for
extensi ve r esecti on. Pati ents wi th compensated ci r r hosi s may be
candi dates for mi nor or major hepatectomy i n sel ected cases.
Once the tumor has been deter mi ned to be r esectabl e, the next
deci si on i s the extent of l i ver r esecti on to be done. The extent of

sur ger y wi l l depend, i n par t, on the si ze of the mass, the number of
nodul es, the tumor 's pr oxi mi ty to vascul ar str uctur es, and as
di scussed pr evi ousl y, the sever i ty of any under l yi ng l i ver di sease.
For mer l y, a 1-cm sur gi cal mar gi n was bel i eved to be necessar y to
ensur e l ong-ter m sur vi val after r esecti on. However, Poon et al .
anal yzed outcome based on r esecti on mar gi ns i n 288 pati ents who
under went hepatectomy for HCC and found that r ecur r ence rates
wer e si mi l ar between gr oups wi th nar r ow (<1 cm) and wi de (1 cm)
mar gi ns; onl y pati ents wi th hi stol ogi cal l y posi ti ve mar gi ns or
satel l i tes separate fr om the mai n tumor had r el ati vel y hi gh
r ecur r ence rates. The author s noted that pati ents wi th mar gi ns
posi ti ve for HCC had a hi gher i nci dence of i ntratumoral
mi cr ovascul ar i nvasi on than other pati ents. In addi ti on, r ecur r ences
di d not necessar i l y occur at the mar gi n, but al so someti mes
appear ed i n the r emai ni ng l i ver, di stant fr om the mar gi n, r efl ecti ng
tumor bi ol ogy that was mor e l i kel y to l ead to a posi ti ve mar gi n.
The operati ve appr oach to the pati ent wi th a potenti al l y r esectabl e
HCC shoul d begi n wi th a thor ough sur gi cal expl orati on of the
abdomen, sear chi ng for evi dence of extrahepati c di sease. In
par ti cul ar, car e shoul d be taken to eval uate the per i por tal l ymph
nodes i n addi ti on to the nodes i n the hepatoduodenal l i gament. The
l i ver then shoul d be compl etel y mobi l i zed to al l ow ful l exami nati on
of the or gan. Intraoperati ve US shoul d be used to defi ne both the
si ze of the tumor and i ts r el ati onshi p to the major vascul ar and
bi l i ar y str uctur es. DL shoul d be consi der ed i n pati ents wi th r uptur ed
tumor s, i ndeter mi nate nodul es, or possi bl e extrahepati c di sease.
Anatomi cal r esecti ons ar e pr efer r ed over segmental r esecti ons,
when feasi bl e, based on the extent of under l yi ng l i ver di sease and
because of the tendency of HCC to spr ead al ong por tal tracts. In
addi ti on, por tal -or i ented r esecti ons have been shown to be
associ ated wi th l ower mor bi di ty, mor tal i ty, and bl ood l oss, as wel l as
hi gher sur vi val rates, than segmental r esecti ons. Regi mbeau et al .
demonstrated that the overal l 5-year sur vi val rate i n pati ents who
under went anatomi cal r esecti ons (54% ) exceeded that of those who
had segmental r esecti ons (35% ). Extended hepatectomy i s general l y
not feasi bl e i n pati ents wi th ci r r hosi s, but major hepatectomy can
be consi der ed when PVE i s used appr opr i atel y, as descr i bed
pr evi ousl y, fol l owi ng systemati c vol umetr y of the F LR.
A major patter n of r ecur r ence after hepati c r esecti on i s i ntrahepati c
fai l ur e wi th devel opment of new di sease. The concept of the fi el d of
cancer i z ati onthat i s, the tendency of the r emai ni ng l i ver to

generate new HCCspar ti al l y expl ai ns the 30% to 70% r ecur r ence
rate after hepati c r esecti on. Recur r ence r i sk and sur vi val var y,
based on two domi nant factor s and several other mi nor factor s. The
most potent pr edi ctor s of poor sur vi val and hi gh-r i sk r ecur r ence of
HCC ar e vascul ar i nvasi on i n the tumor and sever e fi br osi s i n the
under l yi ng l i ver. Other cor r el ates wi th poor outcome ar e absence of
a tumor capsul e and hi gh-grade or poor tumor di ffer enti ati on.
A r ecent study fr om our Inter nati onal Li ver Tumor Study G r oup
exami ned the r i sk factor s for r ecur r ence <1 year fr om r esecti on. We
i denti fi ed tumor si ze gr eater than 5 cm, mul ti pl e tumor s, and
hi stol ogy r eveal i ng mor e than fi ve mi toses per ten hi gh-power fi el ds
as bei ng associ ated wi th r i sk of ear l y death due to r ecur r ence. We
str ess that these ar e not excl usi on cr i ter i athat i s, the pr esence of
mul ti pl e or l ar ge tumor s that ar e r esectabl e shoul d not excl ude
pati ents fr om consi derati on for potenti al l y curati ve r esecti on.
Rather, these factor s hel p us move for war d i n i denti fyi ng pati ents
whose HCCs ar e l i kel y to r ecur and who mi ght benefi t fr om adjuvant
therapy, i f that i s devel oped for HCC.
Hepati ti s ser ol ogy has al so been pr oposed as a factor r el ated to the
r i sk of HCC, but i n another l ar ge study fr om our i nsti tuti on, we
demonstrated that hepati ti s ser ol ogy, per se, i s not a pr edi ctor of
thi s outcome. Anal ysi s of 446 pati ents i n our i nter nati onal database
who under went compl ete r esecti on for HCC demonstrated that
pati ents wi th HBV i nfecti on or no i nfecti on tended to have l ar ger
tumor s than pati ents wi th HCV or HBV+HCV i nfecti on. In addi ti on,
the ser ol ogy-negati ve and HBV-i nfected pati ents had a hi gher
i nci dence of vascul ar i nvasi on; i n contrast, they had l ower i nci dence
of sever e, under l yi ng l i ver fi br osi s, whi ch was pr edomi nant i n the
other two gr oups. However, the fi nal anal ysi s r eveal ed that status of
vascul ar i nvasi on and fi br osi s wer e equal l y pr edi cti ve of poor
outcome and that the other putati ve r i sk factor s wer e not
i ndependent; that i s, pati ents wi th HBV or no i nfecti on have l ar ger
tumor s wi th vascul ar i nvasi on but no fi br osi s, wher eas pati ents wi th
HCV i nfecti on who ar e scr eened r egul ar l y tend to have smal l er
tumor s and a l ower i nci dence of vascul ar i nvasi on but establ i shed
ci r r hosi s.
Major vascul ar i nvasi on, that i s, i nvasi on of a mai n por tal tr unk or
hepati c vei n, even extendi ng to the vena cava, pr esents a di ffi cul t
pr obl em. Sur vi val i n pati ents wi th thi s featur e has general l y been
poor ; however, sel ected pati ents can der i ve a si gni fi cant pal l i ati ve
benefi t fr om hepatectomy wi th extracti on of caval thr ombi or
hepatectomy i n the pr esence of segmental por tal vei n thr ombosi s.

Speci fi c i ndi cati ons for such extensi ve sur ger y ar e beyond the scope
of thi s chapter, but sel ected pati ents i n thi s gr oup can be tr eated
wi th major hepatectomy, whi ch can pr ovi de si gni fi cantl y better
sur vi val than other tr eatment opti ons.
In the event of r ecur r ence after r esecti on, sel ected pati ents can be
consi der ed for r epeat r esecti on, dependi ng on the patter n of
r ecur r ence. Both focal , i ntrahepati c, r ecur r ent tumor s and cer tai n
adr enal metastases can be r esected. Sol i tar y extrahepati c
metastases at si tes such as the l ung, di aphragm, and abdomi nal
wal l can al so be r esected. In al l these cases, medi an sur vi val may
be as hi gh as 50 months, compar ed wi th sur vi val on the or der of 10
months for those tr eated wi thout sur ger y.
Al though some cl assi fi cati on systems, such as the BCLC system, and
some gr oups i n the Uni ted States pr opose that pati ents wi th l ar ge
tumor s shoul d not be consi der ed for sur ger y, many author s
r ecogni ze that tumor si ze al one does not pr edi ct bi ol ogy. In fact,
many studi es have shown that pati ents wi th T1 tumor s >10 cm i n
di ameter have exactl y the same sur vi val patter n after r esecti on as
those wi th tumor s <3 cm. We r ecentl y anal yzed 300 pati ents
under goi ng r esecti on for tumor s >10 cm and found that, for the
enti r e gr oup, i ncl udi ng some pati ents wi th vascul ar i nvasi on, the 5year sur vi val was 27% and the 10-year sur vi val was 18% .
Per i operati ve mor tal i ty was 5% . Ther e wer e l ong-ter m (10 year s)
sur vi vor s among pati ents who had mor e than one tumor i n whi ch
the l ar gest exceeded 10 cm i n di ameter. As woul d be expected, the
best sur vi val was achi eved i n pati ents who had tumor s wi thout
vascul ar i nvasi on and who di d not have sever e fi br osi s. We al so
anal yzed the uti l i ty of a cl i ni cal scor i ng system to sel ect pati ents
wi th l ar ge HCCs for r esecti on, usi ng AF P, tumor number, and
pr esence or absence of major vascul ar i nvasi on and fi br osi s as the
factor s pl aced i nto the scor i ng system. Pati ents wi th no r i sk factor s
(hi gh AF P, mul ti pl e tumor s, major vascul ar i nvasi on or fi br osi s) had
a 5-year sur vi val rate of near l y 50% . Those wi th any r i sk factor had
a 5-year sur vi val rate i n the 20% range, but even i n the gr oup of
pati ents wi th thr ee r i sk factor s, ther e wer e 10-year sur vi vor s. AJCC
T cl assi fi cati on cl ear l y strati fi es sur vi val ; thi s has been val i dated i n
many studi es, i ncl udi ng that of Yamanaka et al ., who found that
r esecti on of T1 tumor s yi el ded a 5-year sur vi val rate as hi gh as
78% .
Orthotopic Liver Transplantation

Even i n the case of mar gi n-negati ve r esecti on of HCC, r ecur r ence
r emai ns a pr obl em. Most publ i shed ser i es r epor t a medi an sur vi val
of 30 to 40 months wi th a 5-year sur vi val rate of 30% to 40% , as
wel l as a hi gh i nci dence of r ecur r ence, rangi ng fr om 30% to 70% . It
has been suggested that the l i ver fi br osi s and necr osi s associ ated
wi th chr oni c, acti ve hepati ti s caused by HBV and HCV pr ovi des a
potenti al fi el d for fur ther HCC devel opment (a fi el d of
cancer i z ati on); i magi ng studi es of pati ents wi th chr oni c l i ver
di sease have l ed to the ear l y detecti on of smal l HCCs (<5 cm). For
these r easons, some have pr oposed that the onl y defi ni ti ve
tr eatment for HCC i s or thotopi c l i ver transpl antati on (OLT) to
r emove both the HCC tumor s and the damaged l i ver par enchyma.
Once l i ver transpl antati on was establ i shed as a safe tr eatment for
ci r r hosi s, i t began to be consi der ed as a tr eatment opti on for
unr esectabl e tumor s of the l i ver, but ear l y r ecur r ence was the r ul e.
The obser vati on that the outcome fol l owi ng transpl antati on for l i ver
fai l ur e i n pati ents found incidentally to have smal l HCC suggested
that better sel ecti on cr i ter i a mi ght r ei nser t l i ver transpl antati on
i nto the tr eatment strategy for HCC. These cr i ter i a wer e for mal i zed
after anal ysi s of a study by Maz z afer r o et al ., who eval uated
pati ents wi th ci r r hosi s and ei ther a si ngl e tumor 5 cm or thr ee
tumor s 3 cm i n maxi mum di ameter, who under went l i ver
transpl antati on. Sur vi val at 5 year s after transpl antati on
exceeded 60% , wi th di sease-fr ee sur vi val exceedi ng 50% . These
cr i ter i a, based on the Mi l an Meeti ng, wer e then adopted as the
cr i ter i a for appr opr i ate sel ecti on of pati ents for OLT for HCC,
al though the study was smal l (48 pati ents) and no tumor had
vascul ar i nvasi on.
Inter est exi sts i n expandi ng these cr i ter i a so OLT can be consi der ed
i n cases of l ar ger and mor e numer ous tumor s, al though bi ol ogi cal
sel ecti on cr i ter i a (e.g., tumor grade and AF P l evel ) woul d be mor e
attracti ve cr i ter i a for sel ecti on than the si mpl e mor phol ogi c cr i ter i a
of tumor si ze and number cur r entl y used. F ur ther mor e, the effect of
chr oni c i mmunosuppr essi on on the cour se of r ecur r ent cancer after
transpl antati on i s uncl ear.
Nonresectional Locoregional Therapies

For sel ected pati ents wi th HCC confi ned to the l i ver whose di sease
i s not amenabl e to sur gi cal r esecti on or OLT, l ocor egi onal abl ati ve
therapi es can be consi der ed. Al though these therapi es may al so be
used i n pati ents wi th r esectabl e HCC, thei r effi cacy has not been
establ i shed as equi val ent to r esecti on. A di scussi on of abl ati on
tr eatments fol l ows.
The advantages of abl ati on techni ques i ncl ude destr ucti on of tumor s
and pr eser vati on of a maxi mal vol ume of nontumor ous l i ver, and the
potenti al to combi ne abl ati on of smal l l esi ons wi th r esecti on of
l ar ger l esi ons. The major di sadvantages of any abl ati on techni que
ar e the l i mi ted abi l i ty to eval uate tr eatment mar gi ns and the need
to obtai n negati ve tr eatment mar gi ns i n thr ee di mensi ons. Al l
abl ati on techni ques have hi gher l ocal r ecur r ence rates than
r esecti on for vi r tual l y al l tumor s. Per cutaneous abl ati on i s
par ti cul ar l y attracti ve for tr eatment of pati ents wi th sever e
under l yi ng l i ver di sease, for tr eatment of pati ents wi th a
contrai ndi cati on to l apar otomy, or as a br i dge to mor e defi ni ti ve
therapy, such as OLT.
Percutaneous Ethanol Injection

Per cutaneous ethanol i njecti on (PEI) i s a tr eatment admi ni ster ed
under US gui dance thr ough a fi ne (22-gauge) needl e. Absol ute
ethanol (810 mL) i nduces cel l ul ar dehydrati on, necr osi s, and
vascul ar thr ombosi s, causi ng tumor cel l death. Outpati ent
tr eatments ar e r epeated once or twi ce a week, for up to 6 weeks.
PEI i s most effecti ve for tumor s <3 cm i n di ameter. Studi es have
demonstrated 100% necr osi s i n HCCs <2 cm i n di ameter. The
tr eatment-r el ated death rate has been r epor ted to be 0.09% to
0.1% and the compl i cati on rate 1.7% to 3.2% . PEI i s
contrai ndi cated i n pati ents wi th gr oss asci tes, coagul opathy, and
obstr ucti ve jaundi ce, as wel l as i n pati ents wi th l ar ge tumor s,
thr ombosi s i n the mai n por tal or hepati c vei n, and extrahepati c
metastasi s. Compl i cati ons that can occur wi th thi s method i ncl ude
mi nor adver se effects, such as pai n and fever, as wel l as
hemor r hage, l i ver abscess and fai l ur e, and chol angi ti s.
Several studi es have documented post-PEI sur vi val rates si mi l ar to
those obtai ned wi th hepati c r esecti on for extr emel y smal l tumor s i n
wel l -sel ected pati ents, but HCC r ecur r ence i n the l i ver i s fr equent,
wi th an i nci dence of 50% at 2 year s; the major i ty of r ecur r ences
ar e new l esi ons i n di stant segments of the l i ver. Randomi zed tr i al s
suggest PEI i s appr opr i ate for tumor s 2 cm i n
di ameter because i t has l ower rates of mor bi di ty but equi val ent
effi cacy when compar ed wi th other abl ati on techni ques, such as
radi ofr equency abl ati on (RFA).
Cryotherapy
Cr yotherapy i s no l onger commonl y used as an abl ati on techni que.
Ser i ous compl i cati ons that can occur wi th thi s method i ncl ude
i ntraoperati ve hemor r hage fr om the pr obe tract, bi l e duct fi stul a,
fr eez i ng i njur y to adjacent str uctur es, and r enal fai l ur e r el ated to
myogl obi nur i a. For these r easons, cr yotherapy has l ar gel y been
suppl anted by newer abl ati on techni ques.
Radiofrequency Ablation
RFA uses heat to destr oy tumor s. Usi ng US or CT gui dance, a needl e
el ectr ode wi th an uni nsul ated ti p i s i nser ted i nto the tumor. The
el ectr ode del i ver s a hi gh-fr equency al ter nati ng cur r ent, generati ng
rapi d vi brati on of i ons, whi ch l eads to fr i cti onal heat and,
ul ti matel y, coagul ati ve ti ssue necr osi s. RFA can be per for med
per cutaneousl y, l apar oscopi cal l y, or thr ough an open i nci si on and i s
most effecti ve i n tumor s <3 cm i n di ameter. Lar ger tumor s general l y
r equi r e several i nser ti ons of the el ectr ode.
RFA compl i cati ons ar e rar e but may i ncl ude pneumothorax, pl eural
effusi on, hemor r hage, subcapsul ar hematoma, hemobi l i a, bi l i ar y
str i ctur e, and l i ver abscess. The tr eatment-r el ated death rate has
been r epor ted to be 0% to 1% and the compl i cati on rate 0% to
12% . Ear l y tumor r ecur r ence after RFA tr eatment i s associ ated wi th
l ar ge tumor si ze, poor hi stol ogi cal di ffer enti ati on, advanced stage of
pr esentati on, el evated ser um AF P, and the pr esence of hepati ti s.
RFA may be mor e effecti ve i n pati ents wi th ci r r hosi s because the
fi br oti c l i ver per mi ts a baki ng effect by confi ni ng the heat to the
tumor. The safety and effi cacy of RFA for HCC i n ci r r hoti c pati ents
wer e l ar gel y establ i shed at the M. D. Ander son Cancer Center.
Several studi es have suggested that RFA may be effecti ve for
unr esectabl e tumor s. Two r epor ts have di r ectl y compar ed
per cutaneous RFA and sur ger y for tr eatment of HCC. Despi te havi ng
hi gher rates of l ocal r ecur r ence, pati ents tr eated wi th RFA had
overal l sur vi val and r ecur r ence-fr ee sur vi val rates si mi l ar to those
of pati ents under goi ng sur gi cal r esecti on. Hong et al . r epor ted a
ser i es of 148 pati ents who pr esented wi th sol i tar y smal l (<4 cm
di ameter ) HCCs and ei ther no evi dence of ci r r hosi s or Chi l d-Pugh
cl ass A hepati c functi on. The pati ents sel ected for RFA ei ther
r efused sur ger y or wer e pr edi cted to have i nsuffi ci ent postoperati ve
hepati c r eser ve to justi fy the hi gh operati ve r i sks, and wer e
si gni fi cantl y ol der than those i n the comparati ve r esecti on gr oup.
The overal l r ecur r ence rates for RFA and sur ger y wer e 41.8% and
54.8% , r especti vel y, but the rate of l ocal r ecur r ence (defi ned as
occur r i ng near the mar gi n of the abl ati on) was hi gher i n the RFA
gr oup (7.3% ) than i n the sur ger y gr oup (0.0% ). The rates of
r emote r ecur r ence (defi ned as di stant metastasi s or i ntrahepti c
metastasi s i n the hepati c par enchyma, but somewher e other than
the or i gi nal tumor si te) and of si mul taneous l ocal and r emote
r ecur r ence wer e si mi l ar between the two tr eatment gr oups. The 1and 3-year overal l sur vi val rates wer e 97.9% and 83.9% ,
r especti vel y, i n the sur ger y gr oup and 100% and 72.7% ,
r especti vel y, i n the RFA gr oup.
However, equi val ence of RFA to sur ger y has not been consi stentl y
suppor ted. Some studi es have demonstrated that pati ents tr eated
wi th sur gi cal r esecti on had si gni fi cantl y hi gher overal l and di seasefr ee sur vi val rates. F ur ther mor e, pati ents wi th si gni fi cant
under l yi ng l i ver dysfuncti on had si mi l ar sur vi val rates r egar dl ess of
tr eatment, suggesti ng RFA may be a sui tabl e al ter nati ve for
pati ents wi th pr ogr essi ve hepati c dysfuncti on i n l i ver s al r eady so
i mpai r ed as to pr ecl ude safe sur gi cal r esecti on; never thel ess,
sur gi cal r esecti on r emai ns the gol d standar d for HCC. Wi th the
cooperati on of two separate medi cal i nsti tuti ons, Vi var el l i et al .
r epor ted 158 pati ents who under went ei ther RFA or sur gi cal
r esecti on. The major i ty of pati ents i n the sur ger y gr oup had Chi l dPugh cl ass A l i ver functi on, wher eas most pati ents tr eated wi th RFA
had cl ass B functi on. The RFA gr oup di d have a few pati ents wi th
Chi l d-Pugh A l i ver functi on wi th a si ngl e potenti al l y r esectabl e
nodul e. F ur ther mor e, i n both the RFA and sur ger y gr oups, a
major i ty of pati ents had chr oni c hepati ti s caused by HBV, HCV, or
HCV+HBV i nfecti on. The overal l and di sease-fr ee sur vi val rates
wer e si gni fi cantl y hi gher for pati ents tr eated wi th r esecti on. Oneand 3-year rates of overal l sur vi val wer e 78% and 33% ,
r especti vel y, for sur gi cal pati ents and wer e 60% and 20% ,
r especti vel y, for RFA pati ents. Pati ents wi th Chi l d-Pugh cl ass A l i ver
functi on and wi th sol i tar y l esi ons, as wel l as l esi ons <3 cm i n
maxi mum di ameter, had si gni fi cantl y hi gher rates of sur vi val wi th
sur ger y (overal l 3-year sur vi val = 79% ) than wi th RFA (overal l 3year sur vi val = 50% ).
Ther e i s no consensus r egar di ng the effi cacy of RFA as a si ngl e
therapy for HCC, but the abl ati ve techni que i s general l y accepted as
the best tr eatment for smal l HCCs i n the pati ent whose tumor
cannot be r esected safel y or as a means of pr eventi ng tumor
gr owth/spr ead pr i or to OLT. For pati ents who have a tumor
r ecur r ence after tr eatment and who ar e not candi dates for
r esecti on, RFA i s pr obabl y the best sal vage techni que and may
enabl e l ong-ter m r emi ssi on. Abl ati on techni ques such as RFA cl ear l y
have an i mpor tant r ol e i n the tr eatment of a subset of pati ents wi th
HCC.
Chemotherapy
In general , systemi c chemotherapy has l i ttl e acti vi ty agai nst HCC.
Si ngl e-agent chemotherapy wi th 5-fl uor ouraci l (5-F U), doxor ubi ci n,
ci spl ati n, vi nbl asti ne, etoposi de, and mi toxantr one pr ovi des
r esponse rates of 15% to 20% , and the r esponses ar e usual l y shor t
l asti ng. Combi nati on chemotherapy does not seem to i mpr ove these
r esul ts. The most acti ve agent appear s to be doxor ubi ci n, wi th an
overal l r esponse rate pool ed fr om several tr i al s of 19% .
Cur r ent tr eatment r egi mens for unr esectabl e HCC combi ne
conventi onal chemotherapy (speci fi cal l y 5-F U) wi th
i mmunomodul ator y agents, such as al pha-i nter fer on. Pr ecl i ni cal and
cl i ni cal studi es have demonstrated that the two dr ugs have
syner gi sti c acti vi ty agai nst col or ectal cancer. Despi te i ts
consi derabl e toxi c effects, i ncl udi ng myel osuppr essi on, the
combi nati on of doxor ubi ci n, 5-F U, and al pha-i nter fer on (PIAF )
downstaged i ni ti al l y
unr esectabl e tumor s to a si ze amenabl e for r esecti on, and i ncr eased
the overal l medi an sur vi val rate i n an i mpor tant study conducted i n
Hong Kong. The same i nvesti gator s have r epor ted suffi ci ent tumor
r egr essi on for subsequent r esecti on, enabl i ng l ong-ter m sur vi val
after PIAF.
Other therapi es, i ncl udi ng hor monal l y acti ve (Tamoxi fen), vi tami nbased (r eti noi d), and mol ecul ar agents (angi ogenesi s i nhi bi tor s),
ar e under i nvesti gati on, but r esul ts so far ar e general l y
di sappoi nti ng.
Transcatheter Arterial Embolization and

Transarterial Chemoembolization
Transar ter i al chemoembol i z ati on (TACE) i s a combi nati on of i ntra-
ar ter i al l y i nfused chemotherapy and hepati c ar ter y occl usi on,

wher eas transcatheter ar ter i al embol i z ati on (TAE) omi ts the
chemotherapeuti c agent. Chemotherapeuti c agents may be ei ther
i nfused i nto the l i ver befor e embol i z ati on or i mpr egnated i n the
gel ati n sponges used for the embol i z ati on. Li pi odol al so has been
used i n conjuncti on wi th TACE because thi s agent wi l l r emai n
sel ecti vel y i n HCCs for an extended per i od, al l owi ng the del i ver y of
l ocal l y concentrated therapy.
Two randomi zed contr ol tr i al s have shown that TACE pr ovi des a
sur vi val advantage for pati ents wi th unr esectabl e HCC; thus, TACE
i s the standar d of car e for pati ents who ar e not candi dates for
r esecti on, transpl antati on, or abl ati on. F ur ther mor e, TACE can be
used i n combi nati on wi th abl ati on or r esecti on or as a br i dge to
transpl antati on.
Despi te the favorabl e r esul ts of TACE therapy, thi s tr eatment
modal i ty has l i mi tati ons. Mor bi di ty rates have been r epor ted to be
as hi gh as 23% , especi al l y among pati ents wi th HCCs >10 cm i n
di ameter. Mor eover, postembol i z ati on syndr ome, i ncl udi ng fever,
nausea, and pai n, i s common. Other si de effects and compl ai nts,
such as fatal hepati c necr osi s and l i ver fai l ur e, have rar el y been
r epor ted. TACE i s general l y contrai ndi cated i n pati ents wi th asci tes.
Lo et al . pr esented a randomi zed contr ol l ed tr i al of TACE and
Li pi odol for unr esectabl e HCC i n pati ents wi th compensated l i ver
fai l ur e and i n pati ents wi th advanced di sease (i ncl udi ng segmental
por tal i nvasi on). The chemotherapeuti c agent was an emul si on of
ci spl ati n i n Li pi odol and gel ati n-sponge par ti cl es, whi ch was i njected
thr ough the hepati c ar ter y. The chemoembol i z ati on gr oup (40
pati ents) r ecei ved a medi an of 4.5 cour ses per pati ent and showed
si gni fi cant tumor r esponse. For the chemoembol i z ati on gr oup, the
1-, 2-, and 3-year sur vi val rates wer e 57% , 31% , and 26% ,
r especti vel y, whi l e for the contr ol gr oup the rates wer e 32% , 11% ,
and 3% , r especti vel y (p = 0.005).
Another i nvesti gator fr om the BCLC gr oup per for med a randomi zed
tr i al compar i ng ei ther TAE or TACE wi th symptomati c tr eatment i n a
much mor e sel ected gr oup of pati ents, who had favorabl e
character i sti cs compar ed wi th those studi ed by Lo et al . The 112
nonsur gi cal candi dates wi th HCC and ci r r hosi s had Chi l d-Pugh cl ass
A or B l i ver functi onal r eser ve. The TACE gr oup r ecei ved
doxor ubi ci n combi ned wi th Li pi odol and gel foam. The tr i al was
stopped when data r evi ew demonstrated that chemoembol i z ati on
yi el ded sur vi val rates si gni fi cantl y hi gher
than those of conser vati ve tr eatment. One- and 2-year sur vi val
rates wer e, r especti vel y, 75% and 50% for the embol i z ati on gr oup,
82% and 63% for the chemoembol i z ati on gr oup, and 63% and 27%
for the contr ol gr oup. Si nce publ i cati on of these tr i al s, TACE has
secur ed a r ol e i n the tr eatment of sel ected pati ents wi th HCC.
Radiation Therapy
Exter nal -beam radi ati on therapy has l i mi ted uti l i ty i n the tr eatment
of HCC. The dose that can be safel y del i ver ed to the l i ver i s
appr oxi matel y 30 G y; hi gher doses cause radi ati on hepati ti s.
Radi ati on therapy can, however, pr ovi de pal l i ati ve, symptomati c
r el i ef among hi ghl y sel ected pati ents wi th HCC. Al ter nati vel y,
l ocal l y concentrated doses of radi ati on can be del i ver ed al ong wi th
i ntra-ar ter i al l y i nfused Li pi odol or anti fer r i ti n anti bodi es coupl ed to
radi oacti ve i odi ne. These therapi es ar e consi der ed i nvesti gati onal .
Multimodality Therapy
Combi nati ons of sur gi cal and nonsur gi cal therapi es ar e the state-ofthe-ar t for HCC. Some unr esectabl e tumor s can be r ender ed
r esectabl e by transar ter i al chemotherapy, por tal vei n embol i z ati on,
or systemi c chemotherapy. Var i ous chemotherapeuti c agents have
been studi ed i n the neoadjuvant setti ng, i ncl udi ng doxor ubi ci n, 5F U, mi tomyci n C, and ci spl ati n. F ur ther mor e, tumor r ecur r ence may
be pr evented by the admi ni strati on of adjuvant i ntra-ar ter i al
chemotherapy after sur gi cal r esecti on or PEI.
Strategi es i mpl ementi ng TACE and PVE have al l owed safe compl ete
r esecti on of HCCs i n pati ents wi th mar gi nal l i ver functi on. TACE
i nhi bi ts tumor pr ogr essi on because HCCs der i ve the major i ty of
thei r bl ood suppl y fr om the hepati c ar ter y. Subsequent PVE i nduces
hyper tr ophy of the contral ateral l i ver wi thout di ver ti ng bl ood
thr ough the tumor 's ar ter i al bl ood suppl y. Thi s combi ned tr eatment
modal i ty may be par ti cul ar l y i mpor tant for HCCs wi th vascul ar
i nvasi on of the por tal or major hepati c vei n.
Metastases to the Liver

Near l y al l mal i gnant tumor s can metastasi ze to and pr ol i ferate i n
the l i ver. Most metastases or i gi nate fr om gastr oi ntesti nal pr i mar y
tumor s, and of these, most ar e fr om the col on and r ectum. In
general , 5-year sur vi val i s rar e among pati ents who under go
r esecti on for noncol or ectal metastases to the l i ver. The excepti ons
ar e sel ected pati ents wi th, i n par ti cul ar, neur oendocr i ne tumor s,
Wi l m's tumor, and to a l esser extent, r enal cel l car ci noma; 5-year
sur vi val rates of 40% to >70% have been r epor ted after r esecti on
of thei r metastases. Hepati c r esecti on may pr ovi de excel l ent
pal l i ati on of the hor mone syndr ome i n sel ected pati ents wi th
hor mone-secr eti ng neur oendocr i ne tumor s. G i ven that the vast
major i ty of l i ver metastases that ar e consi der ed for r esecti on ar e
fr om col or ectal pr i mar y tumor s, the r emai nder of thi s di scussi on i s
concer ned wi th thei r management.

Col or ectal cancer r epr esents the thi r d most common type of cancer
for both men and women i n the Uni ted States, wi th an
esti mated i nci dence of 150,000 cases per year. Appr oxi matel y 85%
of the pati ents wi l l have mal i gnanci es that ar e amenabl e to sur gi cal
cur e, but hal f of the r esected cancer s wi l l r ecur wi thi n 5 year s. Onl y
20% of these r ecur r ences wi l l be sol el y or pr edomi nantl y i n the
l i ver, and fewer sti l l wi l l be amenabl e to sur gi cal r esecti on a second
ti me. It has been esti mated that 15,000 to 20,000 pati ents per year
ar e potenti al candi dates for r esecti on of thei r l i ver metastases.
Clinical Presentation and Diagnosis

Symptoms or cl i ni cal si gns suggesti ng metastati c di sease i n the
l i ver usual l y ar e l ate occur r ences. Consequentl y, fi ndi ngs such as
asci tes, jaundi ce, r i ght upper quadrant pai n, and i ncr eases i n ser um
l evel s of factor s associ ated wi th l i ver functi on ar e associ ated wi th a
poor pr ognosi s. In the vast major i ty of pati ents, metastases to the
l i ver ar e found dur i ng r outi ne postoperati ve car ci noembr yoni c
anti gen (CEA) scr eeni ng or radi ol ogi c i magi ng after r esecti on of a
col or ectal pr i mar y tumor. Pati ents wi th i ncr easi ng CEA l evel s shoul d
under go thor ough di agnosti c eval uati on, i ncl udi ng chest radi ography
and contrast-enhanced CT scan of the abdomen and pel vi s. A sl owl y
i ncr easi ng CEA l evel usual l y i ndi cates l ocal or r egi onal r ecur r ence,
wher eas a rapi dl y i ncr easi ng CEA l evel suggests hepati c metastases.
Overal l , 75% to 90% of pati ents wi th hepati c col or ectal cancer
metastases have an i ncr eased CEA l evel . In addi ti on, col onoscopy
shoul d be per for med to excl ude a l ocal r ecur r ence or metachr onous
col on or r ectal pr i mar y tumor as the sour ce of the i ncr easi ng CEA
val ue.
Determining Resectability
Because i ndi cati ons for hepati c r esecti on have been extended to
i ncl ude sel ected metastases fr om col or ectal cancer, her e, too, the
F LR defi nes r esectabi l i ty. When al l hepati c di sease can be exti r pated
wi th a negati ve mar gi n, l eavi ng an adequate F LR (20% of the
standar di zed TLV) wi th adequate vascul ar i nfl ow, hepati c venous
outfl ow, and bi l i ar y drai nage, metastases fr om col or ectal cancer
shoul d be deemed r esectabl e. Speci fi c r ecommendati ons wi th r egar d
to r esponse to chemotherapy ar e di ffi cul t to make, al though
pati ents wi th mul ti pl e metastases that conti nue gr owi ng dur i ng
chemotherapy shoul d pr obabl y be excl uded fr om candi dacy for
hepati c r esecti on; thi s same r ul e may not be appl i cabl e to pati ents
wi th sol i tar y l esi ons. Si mi l ar l y, r esponsi veness to chemotherapy
shoul d not be a cr i ter i on for deter mi ni ng r esectabi l i ty. Cl i ni cal
cr i ter i a such as CEA l evel , number of tumor s, si ze of tumor s, and
l ocati on of the pr i mar y tumor, al though pr ognosti c, cannot be used
to excl ude pati ents fr om r esecti on and a potenti al cur e.
In cases of bi l ateral di sease, mul ti stage appr oaches to sur ger y
shoul d be consi der ed. At the fi r st stage, wedge or l i mi ted r esecti on
cl ear s the pl anned F LR, pr eser vi ng the major por ti on of the
par enchyma i n pr eparati on for r esecti on of the r emai ni ng l i ver. At
the second stage, major hepatectomy or extended hepatectomy
r emoves al l r emai ni ng di sease. Resecti on of domi nant l esi ons and
RFA of r esi dual di sease may be consi der ed, but thi s appr oach yi el ds
poor sur vi val compar ed wi th staged r esecti on. Staged r esecti on
r equi r es a cer tai n l evel of excel l ence, an i ntegrated
mul ti di sci pl i nar y appr oach to di sease management, and usual l y,
i nter val PVE to i ncr ease the vol ume and functi on of the F LR after
the fi r st-stage r esecti on. Hi gh tumor number, l ar ge tumor si ze,
pr esence of l i mi ted extrahepati c di sease, and extensi ve r esecti on
ar e no l onger bar r i er s to r esecti on. Systemi c chemotherapy can
r educe the si ze and vol ume of tumor s such that al l tumor si tes can
be r esected safel y and pr ovi de l ong-ter m sur vi val . Hi ghl y sel ected
pati ents wi th extrahepati c di seasewhether l i mi ted per i toneal
car ci nomatosi s, mi ni mal hi l ar l ymphadenopathy, or metastati c
di sease to the l ungcan under go r esecti on wi th acceptabl e sur vi val .
F i nal l y, the r ul e that a 1-cm mar gi n i s necessar y to ensur e l ongter m sur vi val has been shatter ed. Anal ysi s of near l y 500 pati ents i n
a mul ti -i nsti tuti onal database showed that the patter n and
pr obabi l i ty of di sease r ecur r ence and the rates of di sease-fr ee and
overal l sur vi val wer e i denti cal i n pati ents wi th 1-mm and 1-cm
r esecti on mar gi ns. Thus, deter mi ni ng whether metastases fr om
col or ectal cancer ar e r esectabl e r equi r es a mul ti di sci pl i nar y
appr oach and the par ti ci pati on of an exper i enced hepati c sur geon;
other wi se, pati ents who have metastases that woul d other wi se be
consi der ed r esectabl e wi l l be r el egated to noncurati ve therapy, such
as systemi c chemotherapy. A 1-cm mar gi n r emai ns the goal , but
cl ose mar gi n-negati ve r esecti on i s al so safe.
Evaluation of Operative Risk

Most pati ents wi th col or ectal l i ver metastases (CRLM) have a nor mal
under l yi ng l i ver, al though some wi l l have i njur y due to pr i or
therapy or mor e i mpor tant pati ent factor s (e.g., obesi ty and
di abetes, whi ch ar e associ ated wi th steatosi s). Al though some
studi es suggest that hepati c r esecti on i n pati ents wi th steatosi s i s
associ ated wi th i ncr eased operati ve r i sk, bl ood l oss, and
compl i cati ons, we have not found an i ncr ease i n operati ve or
postoperati ve compl i cati ons r el ated to chemotherapy. Most agr ee
that mor tal i ty i s equi val ent to that for r esecti on i n pati ents wi thout
si gni fi cant steatosi s.
Pati ents who r equi r e extended hepatectomy shoul d under go
systemati c vol umetr y as descr i bed pr evi ousl y and i f the F LR vol ume
i s <20% of the standar di zed TLV, they shoul d under go PVE of the
enti r e tumor-bear i ng l i ver befor e r esecti on. Some i nvesti gator s
have pr oposed that a l ar ger r emnant (e.g., 30% of the TLV) i s
necessar y for pati ents who have r ecei ved i ntensi ve chemotherapy;
however, thi s gr oup has not been studi ed systemati cal l y.
Par ti cul ar to pati ents wi th metastases i s the concer n that tumor
gr owth may be i nci ted by the embol i z ati on. We have shown that
compl ete embol i z ati on of the tumor-bear i ng l i ver i s not associ ated
wi th changes i n tumor si ze that affect r esectabi l i ty; thus, we str ess
the i mpor tance of compl ete embol i z ati on of the l i ver to be r esected
and compl ete hepati c r esecti on when thi s appr oach i s used.
Other Methods of Preoperative Staging

Hi gh-qual i ty i magi ng i s cr i ti cal to assessment of CRLM r esectabi l i ty.
Al though many modal i ti es have been pr oposed, i ncl udi ng MRI and
posi tr on emi ssi on tomography (PET) scanni ng, we use CT scanni ng
al most excl usi vel y at our i nsti tuti on; our publ i shed
sur vi val rates ar e equal to the best r epor ted for r esecti on of
metastases fr om col or ectal cancer, val i dati ng thi s appr oach. CT not
onl y per mi ts assessment of extrahepati c str uctur es, but al so
accuratel y pr ovi des for l i ver vol umetr y, accurate l ocal i z ati on of the
tumor s wi thi n the l i ver, and accurate l esi on detecti on. Mul ti phase,
thi n-cut, spi ral , hepati c CT i s our modal i ty of choi ce, and the
i nfor mati on thus gai ned has been super i or to that affor ded by MRI
and other appr oaches, r esul ti ng i n our hi gh rates of sur vi val .
DL has a l i mi ted r ol e i n stagi ng of CRLM; mai nl y because i magi ng i s
sensi ti ve, ful l expl orati on by means of DL i s often l i mi ted due to
pr i or sur ger y, and addi ti onal fi ndi ngs at DL may change the
operati ve appr oach, but typi cal l y do not l ead to abandonment of
r esecti on.
Car eful pr el apar otomy stagi ng must i ncl ude col onoscopy to r ul e out
l ocal r ecur r ence, pl ai n radi ography of the chest, and CT of the chest
when i ndi cated by the radi ographi c fi ndi ngs.
Al though [1 8 F ]fl uor o-2-deoxy-D-gl ucose PET has been pr oposed by
Fer nandez et al . as necessar y for stagi ng, no study (i ncl udi ng that
by Fer nandez et al ., whi ch di d not use hi gh-qual i ty CT) has shown
that PET i mpr oves outcome when hi gh-qual i ty cr oss-secti onal
i magi ng i s used. However, fal se-negati ve PET i s the r ul e after
chemotherapy, l i mi ti ng the uti l i ty of thi s techni que al one. PET i s
l i kel y to i mpr ove detecti on of extrahepati c di sease, but has not yet
become the standar d of car e.
Surgical Therapy
At expl orator y l apar otomy, a car eful sear ch for extrahepati c di sease
shoul d be under taken, and detecti on of enl ar ged por tal and cel i ac
l ymph nodes may pr ompt bi opsy when necessar y. The col on shoul d
be exami ned for any l ocal r ecur r ence of the pr i mar y tumor. The
l i ver i s exami ned by vi sual i nspecti on and pal pati on, and then by
i ntraoperati ve US. US wi l l hel p defi ne the r el ati onshi p of the
tumor (s) to the por tal vei ns, hepati c vei ns, and vena cava. In
addi ti on, i t can i denti fy smal l l esi ons that wer e not pal pabl e or
demonstrabl e on pr eoperati ve i magi ng studi es. Suspi ci ous ar eas can
be sampl ed by F NA under US gui dance. The type of r esecti on to be
per for med wi l l depend on what i s needed to r emove al l di sease and
obtai n mi cr oscopi cal l y di sease-negati ve mar gi ns. Anatomi cal or i ented r esecti on i s favor ed over wedge r esecti on because i t i s
associ ated wi th l ess bl ood l oss and l ower l i kel i hood of posi ti ve
mar gi ns; thi s techni que i s often mandator y for pati ents wi th
mul ti pl e l esi ons. However, i t shoul d be r ecogni zed that ther e i s no
oncol ogi c i ndi cati on for whi ch anatomi cal r esecti on i s pr efer r ed to
wedge r esecti on, as l ong as the r esecti on mar gi n i s negati ve for
di sease.
Survival After Resection of Colorectal Liver

Metastases
Moder n r epor ts on ser i es of pati ents under goi ng hepati c r esecti on
for CRLM r eveal that the new, gol d standar d 5-year sur vi val rate i s
53% to 58% . The 5-year sur vi val rates have i mpr oved fr om ear l i er
r epor ted rates of 25% to 40% , despi te the expansi on of cr i ter i a,
i ncl udi ng r esecti on of mor e and l ar ger tumor s and bi l obar tumor s,
r esecti on of synchr onous CRLM, and r esecti on wi th CRLM i n the
pr esence of l i mi ted extrahepati c di sease. In sel ect cases, i t may be
possi bl e to r esect synchr onous l i ver metastases
at the same ti me as the pr i mar y tumor. The compl exi ty of the
operati on necessar y to r emove the pr i mar y tumor and the extent of
hepati c r esecti on that mi ght be r equi r ed for the pr i mar y tumor wi l l
affect deci si on maki ng because the r i sk of adver se events fr om
hepati c r esecti on i ncr eases when the pr ocedur e i s associ ated wi th
extrahepati c sur ger y. Ear l i er studi es demonstrated by uni var i ate
anal ysi s that synchr onous metastases wer e a pr edi ctor of poor
pr ognosi s. Sol i tar y, smal l , per i pheral l y l ocated l esi ons i n a heal thy,
hemodynami cal l y stabl e pati ent can be exci sed adequatel y by
nonanatomi cal r esecti on or segmentectomy. Lesi ons that ar e l ar ger
or that wi l l r equi r e a major hepati c r esecti on ar e best appr oached
dur i ng a second operati on, after fur ther eval uati on and stagi ng. A
del ay of weeks or months between sur ger i es has not been shown to
negati vel y affect sur vi val . At the ti me of the i ni ti al operati on, a
thor ough expl orati on shoul d be conducted to r ul e out the pr esence
of extrahepati c metastases.
Prognostic Factors After Resection

Several moder n studi es have hi ghl i ghted the i mpr ovement i n
sur vi val over ti me wi th the use of i mpr oved operati ve techni ques,
anesthesi a, pati ent sel ecti on, i magi ng, and pr obabl y chemotherapy.
F i gueras et al ., who deemed al l CRLMs r esectabl e i n pati ents who
had an adequate F LR, r egar dl ess of tumor si ze or number, and who
i ncl uded pati ents wi th r esectabl e extrahepati c di sease, r epor ted a
5-year sur vi val rate of 53% . Choti et al . r epor ted on a ser i es of
pati ents tr eated between 1984 and 1992 and compar ed the outcome
wi th that of pati ents tr eated at the same i nsti tuti on between 1993
and 1999. They demonstrated a si gni fi cant i ncr ease i n the rate of 5year overal l sur vi val , whi ch was 31% i n the ear l y gr oup and 58% i n
the l ater gr oup, despi te r educti ons i n the hospi tal i z ati on durati on
and the rate of per i operati ve bl ood transfusi on and si mi l ar rates of
mor bi di ty and mor tal i ty. It i s notewor thy that PET scanni ng was not
r outi nel y used i n thi s study; <10% of the pati ents under went PET
scanni ng, al though mor e pati ents r ecei ved pr e- or postoperati ve
chemotherapy.
We subsequentl y publ i shed a r epor t on the l ar gest moder n ser i es of
pati ents who under went r esecti on of CRLMs. Most pati ents r equi r ed
a major r esecti on (64% under went a hemi hepatectomy or extended
hepatectomy), and near l y one-four th of the pati ents r equi r ed a
pr ocedur e i n addi ti on to the hepati c r esecti on. Sur vi val i n our
ser i es was 58% , i denti cal to that seen i n the Choti et al . ser i es.
Fer nandez et al . used PET rather than hi gh-qual i ty CT, and the
outcome for the 100 pati ents i n thei r ser i es was si mi l ar, wi th
sur vi val of 58% at 5 year s. Thus, despi te an expansi on i n the
i ndi cati ons for r esecti on, cl ear l y a new gol d standar d of 58% 5-year
sur vi val can be achi eved because thi s rate has been val i dated i n
several ser i es fr om di ffer ent i nsti tuti ons ar ound the wor l d.
Despi te the pr ogr essi ve i mpr ovement i n sur vi val after r esecti on of
CRLM, most pati ents (50% 70% ) wi l l have a tumor r ecur r ence after
hepati c r esecti on. Several i mpor tant studi es have outl i ned the key
pr ognosti c factor s.
The fi r st i s fr om Scheel e et al ., who anal yzed 654 pati ents tr eated
between 1960 and 1998. Thi s i s an i mpor tant paper because none of
the pati ents r ecei ved chemotherapy. The 5-, 10-, and
20-year sur vi val rates wer e 39% , 28% , and 24% , r especti vel y. It i s
i mpor tant to note that i n thi s ser i es, pati ents wi th onl y one tumor
had the same sur vi val rate as pati ents wi th thr ee or mor e tumor s
despi te the absence of chemotherapy. Scheel e et al . emphasi zed the
i mpor tance of mar gi n-negati ve (R0) r esecti on i n thi s r egar d.
The second and most wi del y quoted study to outl i ne pr ognosti c
factor s i s fr om Fong et al ., who eval uated a ser i es of 1,001
consecuti ve pati ents who under went hepati c r esecti on for metastati c
col or ectal cancer at the Memor i al Sl oan-Ketter i ng Cancer Center.
Seven i ndependent factor s wer e associ ated wi th poor outcome,
i ncl udi ng di sease at the sur gi cal mar gi n, pr esence of extrahepati c
di sease, metastati c di sease i n the l ymph nodes of the pr i mar y
l esi on, a shor t di sease-fr ee i nter val fr om r esecti on of the pr i mar y

tumor to detecti on of metastases, the number of hepati c tumor s,
hepati c tumor di ameter >5 cm, and the el evati on of the CEA l evel .
These factor s contr i bute to outcome i n di ffer ent degr ees, and
scor i ng of these factor s i s hel pful i n pr edi cti ng pr ognosi s after
r esecti on, but not i n sel ecti ng pati ents for sur ger y.
A r ecent study fr om the M. D. Ander son Cancer Center cl ar i fi ed the
i mpor tance of a mar gi n-negati ve r esecti on by exami ni ng the si te of
r ecur r ence after r esecti on for CRLM based on sur gi cal mar gi n status
i n a mul ti -i nsti tuti onal database. Pati ents wi th sur gi cal mar gi ns
posi ti ve for tumor cel l s had an overal l r ecur r ence rate of 52% ,
compar ed wi th 39% for pati ents wi th negati ve mar gi ns. Mar gi n
wi dth (whether > or <1 cm) di d not affect r ecur r ence fr equency,
l ocati on, or overal l sur vi val . The overal l r ecur r ence rate for al l 557
pati ents was 40% . The major i ty of pati ents who had r ecur r ences
devel oped them at an extrahepati c si te (66% ), whether al one
(30% ) or wi th si mul taneous i ntrahepati c r ecur r ence (36% ). Onl y
3.8% of pati ents had a r ecur r ence at the sur gi cal mar gi n. The
r ecur r ence rates wer e si mi l ar i n pati ents wi th negati ve mar gi ns of 1
and 4 mm (39% ), 5 and 9 mm (41% ), and 1 cm (39% ). Thi s mul ti i nsti tuti onal study confi r med the pr evi ousl y publ i shed 58% 5-year
sur vi val rate after r esecti on of CRLM.
Pathobi ol ogi cal factor s, such as pr ol i ferati on-associ ated pr otei n (Ki 67) and tel omerase (hTERT), have been shown to be i ndependent
and mor e potent pr edi ctor s of sur vi val after r esecti on than the
pr evi ousl y menti oned cl i ni cal factor s. F i nal l y, the use of
chemotherapy i n conjuncti on wi th sur ger y, and the use of mor e
effecti ve chemotherapy, wi l l undoubtedl y al ter the effects of cl i ni cal
factor s on outcome, as i ndi cated by the steadi l y i mpr ovi ng l ongter m sur vi val rates that have been achi eved despi te the expandi ng
i ndi cati ons for r esecti on of CRLMs.
Ablative Therapy
RFA i s used wi del y as a tr eatment for CRLM. Unfor tunatel y, i ts use
was wi despr ead befor e tr ue i ndi cati ons for abl ati on wer e defi ned.
Ini ti al , wel l -desi gned studi es pr oved the safety, excel l ent si de
effects pr ofi l e, and effi cacy of RFA for CRLM. Ini ti al studi es fr om our
i nsti tuti on and l ater fr om Eur ope and the Cl evel and Cl i ni c suggested
a 78% 1-year sur vi val rate coul d be attai ned by RFA, wi th 3-year
sur vi val at 46% . Unfor tunatel y, >12% of pati ents had di sease
r ecur r ence at 1 year. We wer e pr ompted to r e-exami ne RFA as a
tr eatment for CRLM and found that,
al though RFA pr ovi des a modest sur vi val benefi t over chemotherapy
al one for CRLM at 4 year s (22% vs. 7% ), the outcome after RFA i s
vastl y i nfer i or to that after r esecti on i n ter ms of both overal l and
di sease-fr ee sur vi val , whether si ngl e or mul ti pl e tumor s ar e tr eated
and r egar dl ess of tumor si ze. F ur ther mor e, the overal l r ecur r ence
rate after RFA (84% ) i n our study was much gr eater than that after
r esecti on (52% ); i ntrahepati c-onl y r ecur r ence was four ti mes
hi gher wi th RFA (44% ) than wi th r esecti on (11% ), and the
fr equency of tr ue l ocal r ecur r ences at the RFA si te (9% ) was 4.5
ti mes that of mar gi n r ecur r ences after r esecti on (2% ). Al though we
abl ated onl y unr esectabl e tumor s, these data str ongl y suggest RFA
i s i nfer i or to r esecti on as a tr eatment for CRLM.
Subsequent studi es have suppor ted our fi ndi ngs. In 2003, Li vraghi
et al . r epor ted on per cutaneous RFA of potenti al l y r esectabl e
CRLMs. Despi te the fact that the tr eatment was done at a center of
excel l ence, and despi te the i nvesti gator s exper i ence wi th RFA, they
r epor ted a 40% tr eatment fai l ur e rate and a 70% r ecur r ence rate i n
the 88 tr eated pati ents. Thi s r esul t can be contrasted wi th the 10%
or l ess rate of r ecur r ence i n the case of posi ti ve-mar gi n r esecti on,
and the 50% or l ess r ecur r ence rate among pati ents who under go
hepati c r esecti on wi th much mor e aggr essi ve tumor s, l ar ger tumor s,
mor e l esi ons, and even pati ents wi th extrahepati c di sease,
suggesti ng that RFA i s not equi val ent to r esecti on i n pati ents wi th
potenti al l y r esectabl e l esi ons.
The next i mpor tant study compar ed RFA wi th r esecti on i n pati ents
wi th sol i tar y CRLMs, and was r epor ted by Oshowo et al . i n 2003.
They, too, showed that RFA i s i nfer i or to r esecti on as a tr eatment
modal i ty for the gr oup of pati ents wi th pr obabl y the best pr ognosi s
that i s, those wi th sol i tar y l esi ons. Al though these i nvesti gator s
cl ai med that the RFA outcome was equi val ent to that of r esecti on,
they r epor ted onl y a 55% 3-year sur vi val rate for pati ents wi th
sol i tar y metastases after r esecti on (compar ed wi th 53% wi th RFA),
whi ch i s i nfer i or to the sur vi val rate achi eved by r esecti on i n
vi r tual l y ever y other ser i es, i ncl udi ng our own (whi ch yi el ded a 5year sur vi val rate >60% ).
RFA may be used as an adjunct to r esecti on, as pr oposed by El i as et
al . and fur ther anal yzed by our gr oup. Resecti on of domi nant
l esi ons may be suppl emented wi th RFA of smal l , r esi dual tumor s i n
the F LR. Unfor tunatel y, our ser i es r eveal s that thi s appr oach i s no
mor e effecti ve than RFA al one, and 5-year sur vi val wi l l be <20% .
F ur ther mor e, mor tal i ty rates ar e hi gher wi th thi s appr oach (2.3% )
than wi th extended hepatectomy (0.8% i n our ser i es). F i nal l y,

several studi es exami ni ng two-stage appr oaches to r esecti on wi th
PVE have demonstrated sur vi val rates of 40% at 5 year s, agai n
pr ovi ng the super i or i ty of compl ete r esecti on over abl ati on of CRLM.
Abl ati on may be used to tr eat di sease that i s unr esectabl e because
the pati ent i s not a candi date for l apar otomy (because of
comor bi di ty) or because r emoval of the tumor-bear i ng l i ver wi th a
negati ve mar gi n woul d l eave an i nsuffi ci ent F LR, par ti cul ar l y i n
pati ents wi th under l yi ng l i ver di sease. An al ter nati ve to RFA i n
some pati ents i s staged hepati c r esecti on and por tal vei n
embol i z ati on. RFA may al so have a r ol e i n tr eatment of the i l l pl aced
r ecur r ence after major hepatectomy when r epeat r esecti on i s not
safe.
The potenti al for abl ati on may be l i mi ted by a tumor 's pr oxi mi ty to
the confl uence of the bi l e ducts because ther mal i njur y to the bi l e
ducts can l ead to bi l oma and bi l e fi stul a; a 1-cm di stance i s
r equi r ed. F ur ther mor e, the effect of ther mal damage on the F LR can
be mor e si gni fi cant than that i denti fi ed at the ti me of tr eatment;
abl ati on at the ti me of r esecti on must be per for med wi th car e.
RFA i s safe. Cur l ey et al . r epor ted a tr eatment-r el ated mor tal i ty
rate of 0.5% and an ear l y (<30 days) tr eatment-r el ated
compl i cati on rate of 7.1% . The l ate (>30 days) compl i cati on rate
was 2.4% . The two most common ear l y compl i cati ons wer e
symptomati c pl eural effusi on and per i hepati c and RFA l esi on
abscesses. Late compl i cati ons wer e bi l omas i n the RFA l esi on or
bi l i ar y fi stul as. Open or l apar oscopi c RFA i s contrai ndi cated for
l esi ons wi thi n 2 cm of the bi l i ar y confl uence, i n the pr esence of
bi l i oenter i c anastomosi s, and near cr i ti cal por tal str uctur es i n the
l i ver r emnant after r esecti on or at the ti me of combi ned r esecti on
and abl ati on. Cl ose pr oxi mi ty to bowel or the di aphragm i s a
r el ati ve contrai ndi cati on. Mul l en et al . r epor ted successful RFA
usi ng a transthoraci c appr oach for a postr esecti on r ecur r ence
adjacent to the di aphragm. Contrai ndi cati ons for per cutaneous RFA
i ncl ude not onl y those for the open/l apar oscopi c appr oach, but al so
i nabi l i ty to adequatel y i mage or access the l esi on per cutaneousl y.
Per cutaneous RFA i s associ ated wi th tr eatment fai l ur e and,
consequentl y, a hi gher r ecur r ence rate.
Thus, as for assessment of the r esectabi l i ty of CRLM, assessment for
RFA of CRLM shoul d be made joi ntl y by a mul ti di sci pl i nar y team and
a hepati c sur geon wi th consi derabl e exper i ence i n thi s deci si on

scenar i o.
Chemotherapy
Recent advances i n chemotherapy for col or ectal cancer have
dramati cal l y changed the outl ook for pati ents wi th stage IV di sease.
The for mer standar d was a combi nati on of 5-F U and l eucovor i n (LV),
whi ch pr ovi ded r esponse rates fr om 12% to 40% and medi an
sur vi val of 10 to 17 months. Two new dr ugs that have shown
pr omi se ar e i r i notecan (CPT-11) and oxal i pl ati n. Var i ous
combi nati on therapi es usi ng these agents (5-F U or LV, wi th or
wi thout oxal i pl ati n, F OLF OX [5-F U, LV, fol i ni c aci d, and oxal i pl ati n],
and F OLF IRI [5-F U, LV, fol i ni c aci d, and i r i notecan]) have yi el ded
overal l r esponse rates >50% and medi an sur vi val ti mes >20 months
i n the general popul ati on of pati ents wi th stage IV di sease.
Of gr eat i nter est i s the potenti al for r ender i ng unr esectabl e tumor s
r esectabl e wi th chemotherapy. G i acchetti et al ., and subsequentl y
Adam et al ., showed that about 13% of pati ents who pr esent wi th
unr esectabl e CRLM, wi th or wi thout extrahepati c di sease, can
under go r esecti on after chemotherapy. Adam has shown a 33% rate
of overal l sur vi val and a 22% rate of di sease-fr ee sur vi val after
r esecti on i n pati ents wi th pr evi ousl y unr esectabl e di sease tr eated
usi ng thi s appr oach. New bi ol ogi cal agents that tar get angi ogenesi s
have been appr oved for use and general l y i ncr ease r esponse rates
fr om standar d chemotherapy by about 10% .
It i s hoped that these agents wi l l be abl e to downstage di sease and
ther eby per mi t r esecti on i n a gr eater pr opor ti on of pati ents who
pr esent wi th unr esectabl e di sease. Chemotherapy can be
hepatotoxi c; thi s pr obl em i s onl y now bei ng r ecogni zed and studi ed
i n r el ati on to subsequent r esecti on and compl i cati ons.
Regional Chemotherapy
Al though pati ents wi th CRLM have systemi c di sease, the
appr oxi mate 50% i ntrahepati c r el apse rate l ed to i nvesti gati on of
l i ver-di r ected chemotherapy, al one or as an adjuvant to r esecti on.
Al though 5-F U i s the favor ed dr ug for use i n systemi c
chemotherapy, i ts fi r st-pass cl earance by the l i ver i s l ow.
Consequentl y, the r el ati ve i ncr ease i n hepati c exposur e to the dr ug
by hepati c ar ter i al i nfusi on (HAI) i s esti mated to be onl y fi ve- to
tenfol d. A r el ated pyr i mi di ne antagoni st, fl oxur i di ne
(fl uor odeoxyur i di ne [F UDR]), has a much hi gher extracti on on the

fi r st pass thr ough the l i ver. The esti mated i ncr ease i n the l i ver 's
exposur e to thi s dr ug when del i ver ed by HAI i s 100- to 400-fol d,
maki ng i t i deal for thi s pur pose.
The best r epor ted r esponse rates usi ng HAI chemotherapy ar e 50%
to 62% i n studi es that date fr om the l ate 1980s. Two r ecent
Eur opean tr i al s usi ng 5-F U i n pati ents wi th unr esectabl e l i ver
di sease fai l ed to demonstrate an i mpr ovement i n sur vi val and had a
hi gh compl i cati on rate. HAI therapy for unr esectabl e di sease has
fai l ed to keep pace wi th i mpr ovi ng systemi c chemotherapy i ncl udi ng
the emer gence of new agents such as i r i notecan and oxal i pl ati n that
can yi el d hi gh r esponse rates (54% 56% ) and medi an sur vi val of
22 months wi th acceptabl e toxi ci ty. The addi ti on of bi ol ogi cal agents
(i ncl udi ng bevaci z umab and cetuxi mab) has i ncr eased r esponse
rates by 10% and i ncr eased medi an sur vi val to 25 to 27 months.
Use of the new chemotherapeuti c and bi ol ogi cal dr ugs has made i t
possi bl e to downstage unr esectabl e tumor s to the poi nt wher e
sur gi cal r esecti on i s possi bl e. HAI therapy al one enabl es onl y 2% to
3% of pati ents wi th unr esectabl e CRLM to downstage such that
r esecti on i s possi bl e; the rate i s si gni fi cantl y l ower than that
obtai ned usi ng systemi c chemotherapy. Mor eover, HAI chemotherapy
makes the assessment of l i ver functi on and hepatectomy di ffi cul t,
and may r esul t i n ar ter i al thr ombosi s, an associ ated compl i cati on
that can el i mi nate hepatectomy as a vi abl e opti on or i ncr ease the
pr obabi l i ty of postr esecti on l i ver fai l ur e. After HAI therapy, l i ver
i magi ng under esti mates the si ze and number of l esi ons,
compl i cati ng fur ther management. HAI chemotherapy can cause
thr ombosi s of the hepati c ar ter y and can make sur gi cal r esecti on of
the l i ver mor e di ffi cul t techni cal l y. Other compl i cati ons of the
therapy i ncl ude gastr i ti s (25% of cases), ul cer (9% ), di ar r hea (5% ),
bi l i ar y scl er osi s (11% ), and death due to hepati c fai l ur e (2% 3% ).
At our i nsti tuti on, we have al l but abandoned HAI therapy i n any
for m for CRLM.
HAI chemotherapy has al so been pr oposed as an adjuvant to l i ver
r esecti on, but pr ospecti ve randomi zed studi es of thi s appr oach
showed no sur vi val advantage. F ur ther mor e, the tr eatment fai l ed i n
the major i ty of pati ents, wi th extrahepati c di sease as a component
of r ecur r ence. Thi s l ocor egi onal strategy fai l s to addr ess occul t
metastases, whi ch ar e suppl i ed by the por tal vei n,
and di stant extrahepati c di sease, whi ch occur s i n the major i ty of
pati ents wi th CRLM.
Cancer of the Extrahepatic Bile Duct

Cancer of the extrahepati c bi l e duct (CCA) i s extr emel y rar e,
compr i si ng 2% of al l cancer s i n the Uni ted States. In 2004, 3,000
new cases of CCA wer e di agnosed i n the Uni ted States. In most
r epor ted ser i es, mal es and femal es have near l y equal i nci dence
(wi th the mal e:femal e i nci dence rati o at 1.21.5:1), and pati ents
wer e 60 year s ol d. The i nci dence of CCA i s 1 case per 100,000
peopl e i n the Uni ted States, 5.5 cases to per 100,000 i n Japan, and
7 cases per 100,000 i n Israel . Peopl e of Asi an descent ar e affected
al most twi ce as often as whi tes and bl acks, pr obabl y because of
endemi c chr oni c parasi ti c i nfestati on.
The eti ol ogy of CCA i s unknown. Several di seases ar e associ ated
wi th an i ncr eased r i sk of such tumor sscl er osi ng chol angi ti s,
ul cerati ve col i ti s, and chol edochal cysts or Car ol i di sease (a
congeni tal di sease character i zed by mul ti pl e i ntrahepati c bi l i ar y
cysts). Exposur e to Thor otrast and chr oni c typhoi d car r i er status
has al so been shown to i ncr ease r i sk. No str ong evi dence i mpl i cates
gal l stones or parasi ti c i nfecti on wi th Ophisthor chis viver r ini or
Clonor chis sinensis i n CCA car ci nogenesi s, but ther e i s an i ncr eased
r i sk of CCA i n pati ents who have parasi ti c i nfestati on or
hepatol i thi asi s. The common cancer-causi ng factor i n these
condi ti ons i s uncl ear, al though chr oni c i nfl ammati on of the bi l e duct
pr obabl y pl ays a r ol e.
Adenocar ci noma i s the most common hi stol ogi cal type of bi l i ar y
cancer ; mor phol ogi cal l y, CCA can be cl assi fi ed as papi l l ar y (<5% of
cases), nodul ar (20% ), or scl er osi ng (70% ). Most papi l l ar y tumor s
ar e wel l di ffer enti ated and pr esent wi th mul ti pl e l esi ons wi thi n the
duct. Vi r tual l y al l l ong-ter m sur vi vor s have papi l l ar y-type CCA.
Conver sel y, most scl er osi ng-type CCAs ar e poor l y di ffer enti ated,
and thi s type i s often associ ated wi th a poor pr ognosi s. A tumor
ar i si ng at the confl uence of the r i ght and l eft hepati c ducts i s
ter med Kl atski n's tumor, fol l owi ng the descr i pti on of 13 such l esi ons
by Kl atski n i n 1965.
CCAs ar e sl ow gr owi ng and most often spr ead by l ocal i ntrabi l i ar y
ductal extensi on, per i toneal metastasi s, or i ntrahepati c metastasi s.
Metastasi s to r egi onal l ymph nodes occur s l ess fr equentl y (30%
50% of cases), and per i neural extensi on occur s as wel l . Di stant

metastases ar e pr esent i n appr oxi matel y 25% to 30% of pati ents at
the ti me of di agnosi s, but hematogenous spr ead i s rar e. Lesi ons of
the pr oxi mal and mi ddl e thi r ds of the extrahepati c bi l e duct can
compr ess, constr i ct, or i nvade the under l yi ng por tal vei n or hepati c
ar ter y. In addi ti on, pr oxi mal tumor s can i nvade the l i ver
par enchyma. Hi l ar CCAs wi l l i nvol ve the par enchyma of the caudate
l obe i n as many as 36% of pati ents; thei r appearance at thi s si te
usual l y occur s by means of bi l i ar y extensi on thr ough the shor t
caudate ducts that drai n to the confl uence, al though they may
emanate fr om a tumor l ocated near the bi l i ar y confl uence.
Intrahepatic Cholangiocarcinoma
Intrahepati c CCA i s a di ffer ent enti ty than hi l ar CCA, and for ms of
i ntrahepati c CCA can be gr ouped accor di ng to thei r gr owth patter ns.
These cancer s can be mass-for mi ng (MF ), per i ductal -i nfi l trati ng
(PI), or can gr ow wi thi n the duct l umens (i ntraductal gr owth). The
MF type pr esents as a r ound mass wi thi n the l i ver par enchyma and
can r ecur i n the r emnant l i ver after hepati c r esecti on. The PI type
of i ntrahepati c CCA gr ows l ongi tudi nal l y al ong the bi l e duct, often
causi ng an obstr ucti on or str i ctur e. Several pathol ogi cal fi ndi ngs
ar e i mpor tant i n pr edi cti ng the outcome of pati ents wi th CCA;
poor er outcome i s associ ated wi th tumor i nfi l trati on of the bi l e duct
ser osa, l ymph node metastases, and vascul ar and per i neural
i nvasi on. Intrahepati c CCAs have a hi gher pr opensi ty to metastasi ze
to l ymph nodes than hi l ar CCAs.
The most common pr esenti ng symptoms i n pati ents wi th hi l ar CCA
ar e obstr ucti ve jaundi ce (whi ch occur s i n 90% of pati ents) and
i tchi ng. Rar el y, a ver y pr oxi mal tumor may bl ock a segmental or
l obar bi l e duct wi thout causi ng jaundi ce. Other symptoms that may
occur ar e wei ght l oss (29% of cases), vague abdomi nal pai n (20% ),
fati gue, and nausea. A pati ent may al so pr esent wi th chol angi ti s
and sepsi s r esul ti ng fr om bacter i al contami nati on of the obstr ucted
bi l e. In the case of mi ddl e or di stal duct obstr ucti on, a di stended
gal l bl adder may be pal pabl e on abdomi nal exam; conver sel y hi l ar
CCA i s typi cal l y associ ated wi th a nondi stended gal l bl adder. In
addi ti on to havi ng el evated ser um total bi l i r ubi n, pati ents wi th CCA
wi l l pr esent wi th el evated al kal i ne phosphatase, gammagl utamyl transferase, and possi bl y el evated tumor mar ker s
(car bohydrate anti gen 19-9 [CA19-9] and CEA).
Diagnosis
The fi r st radi ol ogi c test that shoul d be per for med when extrahepati c
bi l e duct obstr ucti on i s suspected i s US, whi ch can pr ovi de
i nfor mati on about the l evel and natur e of an obstr ucti ng l esi on. US
can al so gi ve i nfor mati on r egar di ng the mor phol ogy of the l esi ons,
possi bl e di l ati on of extrahepati c and i ntrahepati c bi l e ducts, por tal
vei n and hepati c ar ter y obstr ucti on, and the pr esence of gal l stones
and gal l bl adder di l ati on.
F ur ther i magi ng i s necessar y to del i neate the cr oss-secti onal and
l ongi tudi nal (i ntrabi l i ar y) extent of the tumor. Some center s use a
combi nati on of MRI and col or or spectral Doppl er US. At M. D.
Ander son, mul ti phase hel i cal thi n-cut CT scanni ng i s used i n
combi nati on wi th pr er efer ral endoscopi c r etr ograde
chol angi opancr eatography (ERCP). Hel i cal CT scanni ng has an
overal l accuracy of 76% to 100% , and MRI has an overal l accuracy
of 89% for stagi ng CCA. We pr efer CT because pati ents usual l y
pr esent to us after ERCP; al so, the CT per mi ts assessment of
vascul ar encasement, cr oss-secti onal assessment of tumor extent,
and accurate del i neati on of the tumor 's bi l i ar y extent i n a si ngl e
study.
CT i s as sensi ti ve as US i n demonstrati ng bi l i ar y di l ati on, but i n
addi ti on CT can gi ve i nfor mati on about the l ocal , r egi onal , and
di stant extent of the di sease. CT al so gi ves i nfor mati on about the
r el ati onshi p between the tumor and sur r oundi ng str uctur es
(i ncl udi ng the hepati c ar ter y and por tal vei n and hepati c l obar
atr ophy), and may be used i n the sear ch for metastati c spr ead. If
di stant di sease i s demonstrated on CT, pal l i ati ve per cutaneous or
endoscopi c stent pl acement can be per for med dur i ng
chol angi ography.
In the absence of di stant di sease, the actual l ocati on of the tumor
and i ts pr oxi mal and di stal extent must be defi ned befor e any
i nter venti on i s pl anned. Thi s i nfor mati on can be obtai ned usi ng
ERCP, magneti c r esonance chol angi opancr eatography (MRCP), or
per cutaneous transhepati c chol angi ography (PTC). To eval uate
l esi ons i n the di stal bi l e duct, ERCP i s super i or to the other
techni ques because i t i mages both the bi l e and the pancr eati c ducts.
MRCP can al so i mage the bi l e duct and pr ovi des i nfor mati on about
sur r oundi ng vascul ar str uctur es. MRCP usual l y has an advantage
over ERCP because i t i s noni nvasi ve. Both ERCP and MRCP
over esti mate the extent of bi l e duct i nvol vement i n about 40% of
cases. Both i magi ng modal i ti es may fai l to defi ne the extent of
i ntrabi l i ar y tumor pr oxi mal l y. If the poi nt of obstr ucti on i s bel i eved
to be pr oxi mal to the per i hi l ar r egi on, PTC i s the pr efer r ed method
for defi ni ng the bi l i ar y tract. PTC al so al l ows br ush bi opsi es of the
tumor, exter nal drai nage of obstr ucted bi l i ar y ducts, and pal l i ati ve
stent pl acement when i ndi cated. The wor kup for a suspected CCA
rar el y r equi r es vi sceral angi ography or por tography to assess
vascul ar i nvol vement because of the hi gh qual i ty of moder n CT and
MRI, wi th or wi thout thr ee-di mensi onal r econstr ucti on.
Despi te i mpr oved pr el apar otomy i magi ng, 25% to 40% of pati ents
ar e found to have unr esectabl e di sease at the ti me of sur ger y. DL i s
consi der ed i n most pati ents wi th l ar ge or extensi ve hi l ar tumor s
because of the fr equency of metastases i n the per i toneal cavi ty and
because i ts use i n sel ected cases r esul ts i n fewer nontherapeuti c
l apar otomi es and shor ter hospi tal stays.
For r esectabl e CCA, obtai ni ng ti ssue to confi r m the di agnosi s of bi l e
duct cancer i s not essenti al and may be di ffi cul t. In most i nstances,
the deci si on to operate i s based on the pr eoperati ve radi ol ogi c
fi ndi ngs, not hi stol ogi c confi r mati on. The sensi ti vi ty of br ush
bi opsi es i s poor (wel l bel ow 50% ), al though newer techni ques such
as fl uor escence i n si tu hybr i di z ati on assay and endoscopi c USgui ded F NA of the bi l e duct may i mpr ove di agnosti c accuracy.
Tr eatment i s gui ded by anatomi cal fi ndi ngs (e.g., bi l i ar y obstr ucti on,
enhanci ng hi l ar mass, vascul ar encasement, l i ver atr ophy).
Staging and Anatomical Classification

The cur r ent AJCC stagi ng system for CCA i s shown i n Tabl e 12.3.
The anatomi cal cl assi fi cati on of CCA i s subdi vi ded by the si te of
or i gi n: i ntrahepati c (6% ), di stal extrahepati c (27% ), or per i hi l ar
(67% ). Extrahepati c CCA i s typi cal l y cl assi fi ed accor di ng to the
Bi smuth-Cor l ette cl assi fi cati on, whi ch descr i bes the common
patter ns of hi l ar CCA wi thi n the bi l i ar y tr ee, defi nes the sur gi cal
strategy, and pr ovi des the l anguage used to descr i be such tumor s
(F i g. 12.2). Type I tumor s obstr uct the bi l i ar y confl uence but do not
touch the r oof of the bi l i ar y confl uence. Type II tumor s ar e si mi l ar
to type I tumor s but do touch the r oof. Type III l esi ons extend
thr ough the i ntrahepati c bi l e ducts to i nvol ve second-or der
ducts to the r i ght (type IIIa) or l eft (type IIIb) onl y, spar i ng
contral ateral ducts. Type IV tumor s extend to second-or der ducts on

both the r i ght and the l eft. Tr eatment i s defi ned by l ocati on due to
the fact that the l i ver drai ned by al l i nvol ved ducts must be
r esected for cur e.

Cancer staging system for cancer of the
extrahepatic bile duct
Primary tumor (T)
TX
T0
Tis
Carcinoma in situ
T1
Tumor confined to bile duct

histologically
T2
Tumor invades beyond the wall of the

bile duct
T3
Tumor invades the liver, gallbladder,

pancreas, and/or unilateral branches of
the portal vein (right or left) or hepatic
artery (right or left)
Tumor invades any of the following:
main portal vein or its branches
bilaterally, common hepatic artery, or
T4
other adjacent structures, such as the

colon, stomach, duodenum, or
abdominal wall

NX

assessed
N0
N1

MX
M0
M1
Distant metastasis
Stage groupings
Stage
0
Tis
N0
M0
Stage
IA
T1
N0
M0
Stage
IB
T2
N0
M0
Stage
IIA
T3
N0
M0
Stage
IIB
T1T3
N1
M0
Stage
III
T4
Any N
M0
Stage
IV
Any T
Any N
M1

permission.
Resectability Criteria
The defi ni ti ve therapy for al l extrahepati c bi l e duct car ci nomas i s
compl ete r esecti on. Overal l r esectabi l i ty rates range fr om 10% to
85% , dependi ng on whether di stal cancer s ar e pr esent. Lesi ons of
the l ower thi r d of the bi l e duct have the best rates of r esectabi l i ty
by pancr eati coduodenectomy (consi der ed i n Chapter 13); mi ddl ethi r d obstr ucti ons of the bi l e duct ar e al most al ways due to
gal l bl adder cancer, whi ch i s consi der ed separatel y. Hi l ar CCAs and
Kl atski n's tumor s ar e techni cal l y mor e chal l engi ng to r esect, gi vi ng
them the l owest rate of r esectabi l i ty among bi l e duct tumor s.
Standar d cr i ter i a used to deter mi ne r esectabi l i ty r el ate to the
bi l i ar y extent and vascul ar encasement by the tumor. Invol vement
of secondar y bi l e ducts necessi tates hepati c r esecti on on the si de
i nvol ved. Vascul ar i nvol vement of the por tal vei n or hepati c ar ter y
necessi tates hepati c r esecti on of the anatomi cal si de i nvol ved as

wel l . Thus, i f secondar y bi l i ar y extensi on and vascul ar encasement
occur uni l ateral l y, these tumor s can be r esected al ong wi th the
hepati c r esecti on. If secondar y bi l e ducts ar e i nvol ved on one si de
and vascul ar encasement occur s on the opposi te si de, compl ete
r esecti on i s not possi bl e. Lymph node i nvol vement outsi de the
hepati c pedi cl e (N2) and di stant metastases al so
pr ecl ude r esecti on. Intrahepati c CCAs ar e tr eated by hepati c
r esecti on wi th tumor-fr ee mar gi ns.
F i gur e 12.2. Cl assi fi cati on of extrahepati c bi l e duct tumor s

accor di ng to the Bi smuth-Cor l ette system, whi ch descr i bes the
common patter ns of hi l ar CCA wi thi n the bi l i ar y tr ee. The fi gur e
di spl ays the sur gi cal strategy for each tumor type and pr ovi des
the l anguage used to descr i be such tumor s. Types I, II, and IIIa
ar e tr eated by extended r i ght hepatectomy, wher eas type IIIb i s
tr eated by l eft or extended l eft hepatectomy.
Sur gi cal tr eatment of hi l ar CCA i s subject to several contr over si es,

whi ch ar e descr i bed br i efl y: bi l i ar y drai nage, extent of hepati c and
caudate r esecti ons, and por tal vei n r esecti on. Other factor s i n
sel ecti ng pati ents for r esecti on, such as pati ent per for mance status,
ar e common between thi s di sease and any other s, and assessment
of the F LR vol ume i s a mandator y par t of CCA tr eatment because
most pati ents r equi r e major or extended hepatectomy wi th r esecti on
of the extrahepati c bi l e duct. Thi s i s not contr over si al .
Studi es fr om our own i nsti tuti on, as wel l as that of the l ar gest
ser i es of pati ents i n the wor l d (fr om Nagi no and Ni mura i n Japan),
show that F LR vol ume must be consi der ed and PVE used to i ncr ease
the F LR vol ume pr i or to extended hepatectomy for hi l ar CCA.
Because the confl uence of the bi l e ducts si ts at the base of segment
IV, thi s segment must usual l y be r esected, r egar dl ess of whether
the tumor i s central , to the l eft, or to the r i ght. Hepati c r esecti on i s
usual l y to the r i ght, to i ncl ude extended r i ght hepatectomy, because
97% of the var i ati ons i n bi l i ar y anatomy that have been descr i bed
i ncl ude a l ong l eft hepati c duct. Thus, hi l ar di sease extendi ng even
sl i ghtl y to the l eft or si gni fi cantl y to the r i ght can be cl ear ed by
means of extended r i ght hepatectomy, taki ng advantage of thi s l ong
l eft duct. Cl ear l y, di sease to the l eft r equi r es a l eft hepatectomy,
whi ch necessar i l y i ncl udes r esecti on of segment IV or extended l eft
hepatectomy. Based on these pr i nci pl es, we next di scuss the four
contr over si al i ssues and pr ovi de our r ecommendati ons, whi ch attend
cl osel y to the pr i nci pl es of pr eoperati ve pr eparati on of the pati ent
and l i ver for sur ger y.
Biliary Drainage
The need for pr eoperati ve bi l i ar y drai nage has been debated at
l ength i n the l i teratur e, but most consi der r esol uti on of jaundi ce as
a cr i ti cal el ement i n pr epar i ng the pati ent and l i ver for major
hepatectomy. Pr i or studi es eval uati ng stent pl acement and i ts
associ ated mor bi di ty and mor tal i ty, i ncl udi ng si x randomi zed studi es
(conducted dur i ng 19851994), r epor ted onl y a si ngl e pati ent who
subsequentl y under went hepatectomy. Mor eover, onl y one
r etr ospecti ve r evi ew demonstrated that stent pl acement was
associ ated wi th an i ncr ease i n i nfecti ous compl i cati ons. At M. D.
Ander son, r outi ne pl acement of pr eoperati ve bi l i ar y drai nage
catheter s i s done for several r easons. The effect of
hyper bi l i r ubi nemi a i s wel l known: It i mpai r s l i ver r egenerati on and
r educes r esi stance to systemi c i nfecti on. Hepati c r esecti on i n a
jaundi ced pati ent i s associ ated wi th i ncr eased rates of mor tal i ty
(36% vs. 16% for those wi th bi l i r ubi n <2 mg per dL) and
compl i cati ons (50% vs. 15% ). Camer on et al . advocated r outi ne
pr eoperati ve pl acement of bi l i ar y drai nage catheter s to faci l i tate
i denti fi cati on and di ssecti on of the bi l e duct dur i ng sur ger y and to
ai d the i ntraoperati ve pl acement of l ar ger, softer Si l asti c
transhepati c stents. In a Japanese ser i es of 160 pati ents wi th hi l ar
CCA, per cutaneous i ntrahepati c bi l i ar y drai nage was per for med i n
50 of the 52 pati ents who under went combi ned l i ver and por tal vei n
r esecti on wi thout compl i cati ons. At the M. D. Ander son Cancer
Center, we uni ver sal l y drai n the F LR, but drai n the l i ver to be
r esected onl y i f necessar y to r esol ve jaundi ce, and do not l eave
transanastomoti c bi l i ar y drai ns.
Extent of Hepatic Resection

In ter ms of outcome for sur gi cal tr eatment of hi l ar CCA, pati ents i n
center s wher e major hepati c r esecti on i s per for med (rather than
duct exci si on) have the best pr ognosi s. Resecti on of hi l ar CCA
shoul d be per for med onl y when negati ve sur gi cal mar gi ns (R0) can
be achi eved. The necessi ty of r esecti ng the caudate l obe (segment
I) en bl oc wi th the bi l e duct i s al so a poi nt of contr over sy.
Pathol ogi cal exami nati on of r esected speci mens demonstrates di r ect
i nvasi on of tumor i nto the l i ver par enchyma or bi l e ducts of the
caudate l obe i n as many as 35% of pati ents. In addi ti on, the
caudate l obe i s often the si te of tumor r ecur r ence fol l owi ng bi l e
duct r esecti on. Some sur geons bel i eve the caudate l obe shoul d be
r emoved onl y i f i t has been i nvaded by the tumor, noti ng that
sur vi val data for those who had caudate r esecti on ar e si mi l ar to
data for those wi th si mi l ar CCA who di d not under go thi s pr ocedur e.
Jar nagi n et al . r epor ted a ser i es of 80 pati ents who under went
r esecti on for CCA; the operati ve mor tal i ty and 5-year sur vi val rates
wer e 10% and 27% , r especti vel y. However, the 5-year sur vi val after
r esecti on i ncl udi ng hepatectomy (28% wi th caudate r esecti on) was
37% vs. 0% after r esecti on of the bi l e duct wi thout hepatectomy.
Ebata et al . l ater r epor ted a ser i es of 160 pati ents, al l of whom
under went hepati c r esecti on wi th caudate r esecti on and r epor ted a
si mi l ar operati ve mor tal i ty (10% ) and 5-year sur vi val (37% ),
despi te the need for por tal r esecti on i n 52/160 pati ents. At our
i nsti tuti on, we r esect the l i ver i ncl udi ng segment IV, the caudate
pr ocess, and paracaval caudate l obe i n al l cases; Spi egel 's l obe i s
r esected when the domi nant Spi egel 's duct drai ns to the tumor ous
duct.
Lesi ons of the l ower thi r d of the bi l e duct do not r equi r e hepati c
r esecti on, but rather pancr eati coduodenectomy (Whi ppl e
pr ocedur e). The pr oxi mal bi l e duct shoul d be r esected to the poi nt
that the sur gi cal mar gi n i s negati ve for tumor. Occasi onal l y, thi s
may r equi r e r emoval of most of the extrahepati c bi l i ar y tract wi th a
hi gh hepati cojejunostomy. The operati ve appr oach for
pancr eati coduodenectomy at M. D. Ander son i s outl i ned i n Chapter
13.
Lesi ons of the mi ddl e thi r d of the bi l e duct (ter med type 0 tumor s
by Akeeb and Pi tt) ar e exceedi ngl y rar e. Because of these tumor s
pr oxi mi ty to the hepati c ar ter y and the por tal vei n, these str uctur es
ar e typi cal l y i nvaded. When a type 0 tumor i s deemed r esectabl e, i t
i s best tr eated by ei ther hi l ar r esecti on or
pancr eati coduodenectomy. Cl i ni cal l y, most mi dduct obstr ucti ons ar e
due to gal l bl adder cancer.
Li mi ted r egi onal l ymphadenectomy i s general l y i ndi cated for hi l ar
CCAs dur i ng extrahepati c bi l e duct r esecti on so stagi ng and
strati fi cati on for postoperati ve therapy and pr ognosi s can be done.
Portal Vein Resection

Ther e ar e two general appr oaches to por tal vei n (PV) i nvasi on when
consi der i ng r esecti on of hi l ar CCA. Al though some woul d
consi der por tal i nvasi on a contrai ndi cati on to r esecti on, l ong-ter m
sur vi val can be achi eved by compl ete r esecti on, even i ncl udi ng PV
r esecti on (PVR).
Neuhaus et al . i n G er many pr oposed a systemati c appr oach to PVR,
the no touch techni que. It i nvol ves PVR i n al l cases of hi l ar CCA.
Anal ysi s of these data r eveal s the tendency to per for m por tal vei n
r esecti on and anastomosi s. Al though a better 5-year sur vi val rate
was attai ned wi th PV r esecti on (65% ) than wi thout (0% ), most
pati ents wi th PVR under went r i ght-si ded mar gi n-negati ve r esecti on
(whi ch, as descr i bed pr evi ousl y, enabl es a tumor-negati ve mar gi n
because of the l ong l eft duct). F ur ther mor e, the operati ve mor tal i ty
rate was 17% , per haps unacceptabl y hi gh. A second appr oach was
pr oposed by Ni mura et al . and updated by thei r gr oup i n a r epor t
fr om Ebata et al . Thi s gr oup r ecommended eval uati ng por tal
adher ence to the r egi on of the tumor at sur ger y. They val i dated
thei r sel ecti ve PVR appr oach (used i n 52/160 pati ents) by
demonstrati ng that 69% of those who under went PVR had
mi cr oscopi c evi dence of tumor i nvasi on i n the r esected PV. Those i n
thi s ser i es who di d not under go PVR had a better 5-year sur vi val
rate (37% ) than those who di d (10% ), whi ch r efl ects the di ffer ent
bi ol ogi es i n these cases and suppor ts a sel ecti ve appr oach.

At the M. D. Ander son Cancer Center, the sur gi cal appr oach to
pr oxi mal bi l e duct tumor s depends on thei r l ocati on r el ati ve to the
confl uence of the r i ght and l eft hepati c bi l e ducts and on thei r
pr oxi mal extensi on. Lesi ons i n thi s r egi on ar e assessed accor di ng to
the cl assi fi cati on descr i bed by Bi smuth and Cor l ette. Intrahepati c
CCAs ar e managed wi th hepati c r esecti on. Resectabl e l esi ons of the
l ower thi r d of the bi l e duct ar e tr eated wi th a
pancr eati coduodenectomy. Lesi ons of the mi ddl e thi r d (type 0) ar e
managed by pancr eati coduodenectomy or hepatectomy, dependi ng
on thei r l ocati on wi thi n the mi dduct. Type I, II, and IIIa CCAs ar e
tr eated wi th an extended r i ght hepatectomy, al ong wi th r esecti on of
the caudate pr ocess and paracaval caudate. The Spei gel l obe i s
r esected i f the duct i s i nvol ved. Type IIIb CCAs ar e tr eated wi th a
l eft or extended l eft hepatectomy, al ong wi th r esecti on of the enti r e
caudate l i ver. The PV i s r esected and r econstr ucted when the vei n i s
i nseparabl e fr om the tumor and when r esecti on of the vei n wi l l
enabl e a mar gi n-negati ve r esecti on. Routi ne PVR i s not per for med
at our i nsti tuti on.
Type IV l esi ons ar e general l y not consi der ed to be r esectabl e.
Several studi es have r epor ted OLT as a tr eatment opti on for CCA as
a par t of a mul ti modal i ty pr otocol -based appr oach. The r esul ts have
been consi stentl y di sappoi nti ng, wi th hi gh tumor r ecur r ence rates
and l ow overal l sur vi val (5-year sur vi val rate of 23% ).
The sequence of open l apar otomy for stagi ng, i ntensi ve
chemoradi ati on, and then OLT i s bei ng i nvesti gated pr i mar i l y at the
Mayo Cl i ni c (Rochester, MN). The medi an fol l ow-up after OLT was 42
months, and the 5-year actuar i al sur vi val rate was 87% i n the
hi ghl y sel ected pati ents tr eated usi ng thi s i nvesti gati onal appr oach.
Despi te aggr essi ve sur gi cal management, most pati ents wi th bi l e
duct car ci noma wi l l succumb to thei r tumor s. Sur vi val after
r esecti on of di stal bi l e duct tumor s has general l y been better than
that after r esecti on of hi l ar CCAs. Repor ted 5-year sur vi val rates
range fr om 9% to 18% for pr oxi mal CCAs and 20% to 30% for
di stal l esi ons. Medi an sur vi val i s 18 to 30 months for pati ents
wi thout hi l ar i nvol vement but onl y 12 to 24 months i n pati ents wi th
hi l ar i nvol vement. Factor s that ar e pr edi cti ve of l ong-ter m sur vi val
after hepati c r esecti on for CCA ar e T1 tumor stage, N0 l ymph node
stage, nonmass-for mi ng hi stol ogy, and R0 r esecti on. Vascul ar
i nvasi on, N2 l ymph node metastases, and l obar atr ophy ar e
associ ated wi th an adver se outcome. Lymph node metastases ar e

found i n 3% to 53% of pati ents; no data suppor t extended
l ymphadenectomy.
The opti mal pal l i ati on for pati ents wi th unr esectabl e tumor s i s
uncl ear. If the tumor has been deemed unr esectabl e befor e
expl orati on, the bi l e duct can be drai ned ei ther per cutaneousl y or
endoscopi cal l y. The use of metal l i c i n-dwel l i ng stents, whi ch ar e
mor e durabl e than tradi ti onal stents, has made thi s opti on mor e
appeal i ng. If the tumor has been found to be unr esectabl e at
expl orati on, the duct can be i ntubated wi th ei ther transhepati c
Si l asti c stents or a T-tube after di l ati on of the l esi on. Operati ve
bi l i ar y bypass, wi th or wi thout pal l i ati ve tumor r esecti on, i s not
general l y r ecommended. Unr esectabl e l esi ons at the bi l e duct
confl uence, especi al l y Bi smuth type III and IV l esi ons, can be
par ti cul ar l y di ffi cul t to pal l i ate and usual l y r equi r e per cutaneous
stenti ng, al though the goal of tubefr ee pal l i ati on may be achi eved
by endoscopi c or per cutaneous methods.
Chemotherapy
No chemotherapeuti c agents ar e cl ear l y effecti ve agai nst CCA.
Si ngl e-agent tr i al s usi ng 5-F U have demonstrated r esponse rates
l ess than 15% . Other agents, such as doxor ubi ci n, mi tomyci n C, and
ci spl ati n, used al one or i n combi nati on wi th 5-F U, have been no
mor e successful . Newer agents, par ti cul ar l y gemci tabi ne and
oxal i pl ati n, ar e showi ng some pr omi se, par ti cul ar l y i n combi nati on.
Toxi ci ty r emai ns a pr obl em i n pati ents wi th bi l i ar y obstr ucti on and
stents.
Radiation Therapy
Several studi es have i nvesti gated the r ol e of adjuvant radi ati on
therapy after bi l e duct r esecti on. Two separate studi es fr om The
Johns Hopki ns Uni ver si ty found no benefi t fr om adjuvant radi ati on
therapy. Kamada et al ., however, showed radi ati on to be benefi ci al
i n pati ents wi th sur gi cal mar gi ns hi stol ogi cal l y posi ti ve for di sease.
At M. D. Ander son, postoperati ve chemoradi ati on i s gi ven r outi nel y
to pati ents wi th r esected bi l e duct cancer s. If pathol ogi cal anal ysi s
r eveal s posi ti ve mar gi ns or nodes, or per i toneal i nvasi on, pati ents
r ecei ve a conti nuous i nfusi on of 5-F U concomi tantl y wi th 54 G y of
radi ati on to the tumor bed. Al though pati ent number s ar e smal l and
fol l ow-up durati on i s shor t, i ni ti al r esul ts suggest l onger sur vi val i n
tr eated pati ents than i n untr eated, hi stor i cal contr ol s. Radi ati on
therapy has al so been found to be effecti ve i n the pal l i ati on of

unr esectabl e bi l e duct cancer s. Doses of 40 to 60 G y have r esul ted
i n a medi an sur vi val of 12 months, as wel l as r educed symptoms,
pr obabl y because of i mpr oved stent patency. Pal l i ati ve
photodynami c bi l e duct therapy i s al so emer gi ng.
Gallbladder Cancer
Al though car ci noma of the gal l bl adder i s rar e, i t was the most
common mal i gnant neopl asm among the esti mated 6,950 cases of
bi l i ar y tract cancer di agnosed i n the Uni ted States i n 2004 and i s
the si xth most common cancer of the gastr oi ntesti nal tract. The
tumor has been r epor ted i n al l age gr oups, but occur s most often i n
pati ents i n thei r fi fti es and si xti es. Ther e i s a str i ki ng di ffer ence i n
i nci dence of the tumor between the gender s: femal es ar e affected
thr ee to four ti mes as often as mal es. Exami nati on of the
Sur vei l l ance, Epi demi ol ogy, and End Resul ts database r eveal s an
i nci dence of 1.2 cases per 100,000 peopl e per year i n the Uni ted
States.
The exact eti ol ogy of car ci noma of the gal l bl adder i s not known;
however, i t has been associ ated wi th several condi ti ons.
Chol el i thi asi s i s pr esent i n 75% and 92% of gal l bl adder car ci noma
cases. Pati ents wi th l ar ger stones (>3 cm i n di ameter ) have a ten
ti mes gr eater r i sk of cancer than pati ents wi th smal l stones (<1
cm). In addi ti on, gal l bl adder car ci noma can be found i n 1% to 2% of
al l chol ecystectomy speci mens, a rate several ti mes hi gher than
that r epor ted i n autopsy studi es. Chr oni c chol ecysti ti s, i ncl udi ng
cases i n whi ch the gal l bl adder i s cal ci fi ed (por cel ai n gal l bl adder ),
i s not associ ated wi th an i ncr eased r i sk of cancer, as was once
bel i eved. Towfi gh et al . eval uated the pathol ogy sl i des of 10,741
gal l bl adder speci mens for evi dence of cal ci fi cati on and gal l bl adder
car ci noma. Among the speci mens r evi ewed, none had gal l bl adder
car ci noma.
The i nci dence of gal l bl adder cancer i s hi gher i n cer tai n ethni c
gr oups, such as Al askan and Amer i can nati ves, mi r r or i ng the
i nci dence of chol el i thi asi s. Other factor s l i nked to gal l bl adder
car ci noma i ncl ude chol ecystoenter i c fi stul as, anomal ous
pancr eati cobi l i ar y juncti on, exposur e to chemi cal car ci nogen
exposur e, i nfl ammator y bowel di sease, femal e gender, fami l i al
pr edi sposi ti on, chr oni c sal monel l a car r i er status, and Mi r i z z i
syndr ome.
Adenocar ci noma of the gal l bl adder i s a sl ow-gr owi ng tumor that
ar i ses fr om the fundus i n 60% of cases. On gr oss exami nati on, the
gal l bl adder appear s fi r m wi th thi ckened wal l s. The papi l l ar y
adenocar ci noma subtype character i sti cal l y gr ows i ntral umi nal l y and
spr eads i ntraductal l y. It i s a l ess aggr essi ve tumor that,
consequentl y, car r i es a better pr ognosi s when compar ed wi th other
hi stol ogi cal subtypes. Adenosquamous cancer i s ver y rar e and i s
tr eated l i ke adenocar ci noma.
G al l bl adder car ci noma spr eads by metastasi s to the l ymph nodes
and di r ect i nvasi on of the adjacent l i ver. It can spr ead to the
per i toneal cavi ty after bi l e spi l l age, and cel l s may be i mpl anted i n
bi opsy tracts or at l apar oscopi c por t si tes. Lymph node metastases
ar e found i n 56% of T2 gal l bl adder car ci nomas and per i toneal
di sease has been found i n 79% of pati ents wi th T4 gal l bl adder
car ci noma. The cysti c duct node, at the confl uence of the cysti c and
hepati c ducts, i s the usual i ni ti al si te of r egi onal l ymphati c spr ead.
Invasi on of the l i ver, ei ther by di r ect extensi on
or vi a drai ni ng vei ns that empty i nto segments IV and V, i s seen i n
>50% of pati ents. The most common si te of di stant extra-abdomi nal
metastasi s i s the l ung.
In most ser i es, abdomi nal pai n i s the most common pr esenti ng
symptom. Nausea, vomi ti ng, wei ght l oss, and jaundi ce ar e other
fr equent symptoms. On physi cal exami nati on, pati ents may have
r i ght upper quadrant pai n wi th hepatomegal y or a pal pabl e,
di stended gal l bl adder. Laborator y r esul ts ar e unr emar kabl e unl ess
the pati ent has devel oped obstr ucti ve jaundi ce. The tumor mar ker s
CEA and CA19-9 may be el evated i n pati ents wi th gal l bl adder
car ci noma but ar e nei ther sensi ti ve nor speci fi c for the di sease.
Diagnosis
No l aborator y or radi ol ogi c tests have shown consi stent sensi ti vi ty
i n the di agnosi s of gal l bl adder car ci noma. F ur ther mor e, the pauci ty
of cl i ni cal si gns and symptoms makes pr eoperati ve di agnosi s of thi s
cancer di ffi cul t. The di sease i s usual l y di agnosed ei ther i nci dental l y
after chol ecystectomy or at an advanced stage, when pr esenti ng

wi th a mass, jaundi ce, asci tes, or per i toneal di sease. A cor r ect
pr eoperati ve di agnosi s of gal l bl adder car ci noma i s made i n fewer
than 10% of cases i n most ser i es. In the Roswel l Par k exper i ence,
none of the 71 cases wer e di agnosed cor r ectl y pr eoperati vel y. The
most common pr eoperati ve di agnoses ar e acute or chr oni c
chol ecysti ti s and mal i gnanci es of the bi l e duct or pancr eas. Jaundi ce
wi th a mi dl eft bi l e duct str i ctur e (type 0) i s al most al ways r el ated to
gal l bl adder cancer.
In the case of gal l bl adder car ci noma, US may demonstrate an
abnor mal l y thi ckened gal l bl adder wal l or the pr esence of a mass.
Addi ti onal i magi ng by contrast-enhanced CT or MRI wi l l hel p
deter mi ne r esectabi l i ty and pr ovi de i nfor mati on about the l ocal
extent of di sease, i ncl udi ng por tal vascul ar i nvasi on, the pr esence
of l ymphadenopathy, and di stant metastases.
Staging
Numer ous stagi ng systems have been descr i bed for gal l bl adder
car ci noma. The or i gi nal stagi ng system, as descr i bed by Nevi n, i s
based on the depth of i nvasi on and the spr ead of tumor. The AJCC
stagi ng system for gal l bl adder car ci noma was r evi sed r ecentl y
(Tabl e 12.4). The most si gni fi cant change i n the AJCC stagi ng
system i s that ther e i s no l onger a di sti ncti on between T3 and T4
tumor s based on the depth of l i ver i nvasi on; i nstead, T3 tumor s ar e
defi ned as those that di r ectl y i nvade the l i ver and/or other adjacent
or gans and T4 tumor s as those that i nvade the por tal vei n or
hepati c ar ter y.
Lapar oscopy has a cl ear r ol e i n pr el apar otomy stagi ng of gal l bl adder
car ci noma because DL compl ements hi gh-qual i ty i magi ng i n
detecti on of per i toneal di sease, whi ch i s common wi th thi s cancer.
G al l bl adder car ci noma al so spr eads l ocal l y, metastasi z i ng to the
l ocor egi onal (N1) and di stant parapancr eati c/per i aor ti c l ymph
nodes, often encasi ng the por tal vei n and hepati c ar ter y pr ecl udi ng
sur gi cal r esecti on. Two studi es demonstrated that DL coul d pr event
nontherapeuti c l apar otomy i n 33% to 55% of
pati ents wi th metastati c di sease. Lapar oscopy was mor e accurate

than CT i n detecti ng per i toneal di sease i n pati ents wi th l ocal l y
advanced tumor s, suggesti ng that pati ents wi th T3 and T4 l esi ons
may benefi t fr om DL pr i or to sur ger y.

Cancer staging system for gallbladder
carcinoma
Primary tumor (T)
TX
T0
Tis
Carcinoma in situ
T1
Tumor invades lamina propria or muscle

layer
T1a
Tumor invades lamina propria
T1b
Tumor invades muscle layer
T2
Tumor invades perimuscular connective

tissue; no extension beyond serosa or
into liver
T3
Tumor perforates the serosa (visceral

peritoneum) and/or directly invades the
liver and/or one other adjacent organ
or structure, such as the stomach,
duodenum, colon or pancreas,
omentum, or extrahepatic bile ducts
T4
Tumor invades main portal vein or

hepatic artery or invades multiple
extrahepatic organs or structures

NX

assessed
N0
N1

MX
M0
M1
Distant metastasis
Stage groupings
Stage
0
Tis
N0
M0
Stage
IA
T1
N0
M0
Stage
IB
T2
N0
M0
Stage
IIA
T3
N0
M0
Stage
IIB
T1T3
N1
M0
Stage
III
T4
Any N
M0
Stage
IV
Any T
Any N
M1

permission.
Surgical Therapy
Standar d featur es that make a gal l bl adder tumor unr esectabl e
i ncl ude (a) the pr esence of di stant hematogenous or l ymphati c
metastases; (b) the pr esence of per i toneal i mpl ants; and (c)
i nvasi on of tumor i nto major vascul ar str uctur es such as the cel i ac
or super i or mesenter i c ar ter i es, vena cava, or aor ta. G al l bl adder
car ci noma i n si tu (Ti s) and car ci noma l i mi ted to the mucosa (T1)
can be tr eated adequatel y wi th a chol ecystectomy al one, pr ovi ded
that the cysti c duct mar gi n i s negati ve for di sease. Thi s appr oach
can gi ve 5-year sur vi val rates as hi gh as 100% . When car ci noma i s
suspected befor e sur ger y, open chol ecystectomy wi th
hepatoduodenal l ymphadenectomy i s advocated because the exact T
cl assi fi cati on cannot be deter mi ned at the ti me of sur ger y and
because bi l e spi l l age i s a si gni fi cant r i sk factor for per i toneal or
wound r ecur r ence. Lymphadenectomy i s per for med pr i mar i l y for
stagi ng pur poses but may al so i mpr ove l ocal contr ol of di sease.
Sur gi cal tr eatment for T2 tumor s i s somewhat contr over si al .

Because the i nci dence of l ymph node spr ead i n the case of T2
tumor s i s 56% , opti mal sur gi cal tr eatment for these pati ents woul d
consi st of at l east an extended chol ecystectomy that i ncl udes
r esecti on of the gal l bl adder en bl oc al ong wi th the por tal l ymph
nodes. Addi ti on of a wedge r esecti on of the gal l bl adder bed (wedge
r esecti on of segments IVb and V) i s contr over si al . Several r ecent
studi es eval uati ng extended r esecti on for T2 tumor s demonstrated
si gni fi cant i mpr ovements i n 5-year sur vi val rates (61% 100% )
compar ed wi th si mpl e chol ecystectomy (19% 45% ). Radi cal second
operati ons for T2 tumor s ar e al so associ ated wi th i mpr oved 5-year
sur vi val rates (61% 75% ). In contrast, other studi es have r epor ted
si mi l ar sur vi val rates after chol ecystectomy when compar ed wi th
mor e radi cal operati ons for T2 l esi ons. At the M. D. Ander son
Cancer Center, we r ecommend extended chol ecystectomy that
i ncl udes a r esecti on of the gal l bl adder en bl oc al ong wi th the por tal
l ymph nodes, and wedge or anatomi cal r esecti on of the gal l bl adder
bed (segments IVb and V) for T2 tumor s.
Local l y advanced tumor s (T3 and T4) often pr esent wi th l ymph node
metastases (75% of cases) and per i toneal metastases (79% ) and
ar e often associ ated wi th l ong-ter m (>5 year ) sur vi val rates i n the
range of 0% to 5% . However, r ecent studi es have r epor ted 5-year
sur vi val rates of 21% to 44% for ser i es of pati ents wi th T3 and T4
tumor s who under went radi cal r esecti on. The extent of hepati c
r esecti on i s deter mi ned by the extent of tumor i nvasi on i nto the
gal l bl adder fossa and i nvol vement of the r i ght por tal tr i ad. To
achi eve a tumor-fr ee mar gi n, a r i ght hepatectomy, extended r i ght
hepatectomy, or pancr eati coduodenectomy may be necessar y.
Pancr eati coduodenectomy has been pr oposed to opti mi ze l ymph
node cl earance, but i t i s general l y not war ranted unl ess the tumor
extends i nto the head of the pancr eas. Other studi es have r epor ted
r outi ne r esecti on of the extrahepati c bi l e duct and per i chol edochal
and hi l ar l ymph nodes, as wel l as en
bl oc r esecti on of gr ossl y i nvol ved adjacent str uctur es to achi eve R0
r esecti ons because ther e i s a hi gh i nci dence of occul t, mi cr oscopi c
i nvasi on of the hepatoduodenal l i gament i n cases of advanced
gal l bl adder car ci noma. Tumor s i nvol vi ng the hepati c ar ter y or por tal
vei n have been exti r pated wi th en bl oc vascul ar r esecti on and
subsequent r econstr ucti on, but such an extensi ve pr ocedur e i s not
consi der ed to be standar d therapy because of the associ ated hi gh
mor bi di ty and mor tal i ty rates. The most si gni fi cant negati ve
pr ognosti c factor i n gal l bl adder car ci noma i s l ymph node
i nvol vement, and vascul ar i nvasi on has al so been r epor ted as

i ndi cati ve of poor pr ognosi s. We r ecommend r outi ne r esecti on of the
extrahepati c bi l e duct and por tal l ymph nodes.
Nonoperative Therapy
The use of si ngl e and mul ti pl e chemotherapeuti c agents, ei ther as
pr i mar y or adjuvant therapy, has been di sappoi nti ng. The r esponse
rate of l ocal l y advanced gal l bl adder cancer to 5-F U r egi mens i s
appr oxi matel y 12% . 5-F U combi ned wi th doxor ubi ci n has pr oduced
r esponse rates of 30% to 40% . HAI chemotherapy pr oduces
r esponse rates of 50% to 60% i n pati ents wi th unr esectabl e
di sease. These r esponses ar e shor t l i ved, however, and most
pati ents di e of pr ogr essi ve di sease wi thi n 12 months; thus, HAI i s
not r ecommended.
Radi ati on therapy has shown some pr omi se i n the postoperati ve
adjuvant setti ng, al though most ser i es have been smal l .
Intraoperati ve radi ati on therapy has al so been used wi th some
success. Exter nal -beam radi ati on therapy at a dose of 45 G y can
r educe the tumor si ze i n 20% to 70% of cases and r el i eves jaundi ce
i n up to 80% of pati ents. At M. D. Ander son, pati ents wi th
gal l bl adder cancer ar e tr eated postoperati vel y wi th a combi nati on of
conti nuous-i nfusi on chemotherapy and exter nal -beam radi ati on
therapy i n an appr oach si mi l ar to that used i n pati ents wi th CCA.
Conclusion
Many advances have been made i n the sur gi cal tr eatment of
di seases of the l i ver. Advances i n i magi ng, pati ent sel ecti on, and
pati ent pr eparati on for major hepatectomy have transl ated i nto
l onger and better sur vi val of pati ents who under go sur ger y. In
par ti cul ar, car eful attenti on to vol ume measur ement pr i or to major
r esecti on i n pati ents wi th l i ver di sease and extended r esecti on i n
pati ents wi th nor mal l i ver, usi ng such techni ques as PVE, have
enabl ed much l ower mor bi di ty and ver y l ow mor tal i ty for l i ver
sur ger y. For HCC, the spectr um of tr eatments r efl ects the spectr um
of the di sease and/or under l yi ng l i ver di sease compl ex. Tr eatments
range wi del y, i ncl udi ng OLT, hepati c r esecti on, tumor abl ati on, and
transar ter i al embol i z ati on. For thi s di sease, systemi c therapy has a
r el ati vel y smal l r ol e i n a hi ghl y sel ected gr oup of pati ents.
For pati ents wi th CRLM, cr i ter i a for r esecti on ar e expandi ng rapi dl y,
to i ncl ude l ar ger, mul ti pl e, and bi l ateral tumor s. Despi te these
expanded i ndi cati ons, sur vi val i s i mpr ovi ng. F ur ther mor e, rapi dl y
evol vi ng effecti ve chemotherapy i s expandi ng the popul ati on of

pati ents el i gi bl e for defi ni ti ve sur gi cal tr eatment.
These benefi ts fr om adjuvant therapy have, unfor tunatel y, not
extended to pati ents wi th bi l i ar y tract cancer. Al though a smal l
gr oup of pati ents wi th hi l ar CCA and gal l bl adder car ci noma benefi t
fr om major hepati c r esecti on, most pati ents pr esent wi th
unr esectabl e di sease and l i mi ted tr eatment opti ons, despi te
therapeuti c advances i n other ar eas.
In summar y, the mul ti di sci pl i nar y appr oach to pati ents wi th l i ver
tumor s r equi r es the i nvol vement of speci al i sts i n hepatobi l i ar y
sur ger y; sur gi cal , medi cal , and radi ati on oncol ogy;
gastr oenter ol ogy; and radi ol ogy to enabl e opti mal tr eatment today
and advancement of tr eatment i n the futur e.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 3 - Pa nc re a t ic Ade no c a rc ino m a
13
Pancreatic Adenocarcinoma
Rosa F. Hw ang
A na M. Grau
Francis R. Spitz
Michael Bouvet
George M. Fuhrman
David H. Berger
Epidemiology
Pancr eati c cancer i s the ei ghth most common mal i gnancy and the
fi fth l eadi ng cause of adul t cancer death i n the Uni ted States. Onl y
1% to 4% of al l pati ents di agnosed wi th pancr eati c cancer can
expect to sur vi ve for 5 year s. In the year 2000, 28,300 new cases
of adenocar ci noma of the pancr eas wer e di agnosed i n the Uni ted
States, and 28,200 pati ents di ed of thi s aggr essi ve mal i gnancy.
Thus, i nci dence rates ar e vi r tual l y i denti cal to mor tal i ty rates. The
i nci dence of pancr eati c cancer i n the Uni ted States steadi l y
i ncr eased for several decades but has l evel ed off si nce the mi d1980s as a r esul t of a steady decl i ne i n the rate for whi te men. In
contrast, rates for whi te women, bl ack men, and bl ack women have
not decr eased and may have i ncr eased sl i ghtl y, br i ngi ng the mal eto-femal e rati o to 1.3:1.0. The r i sk of devel opi ng pancr eati c cancer
i ncr eases shar pl y after age 50, and most pati ents ar e between 65
and 80 year s ol d at di agnosi s.
The eti ol ogy of pancr eati c adenocar ci noma i s uncer tai n.
Epi demi ol ogi c studi es r epor ted that ci gar ette smoki ng i ncr eases the
r i sk of devel opi ng pancr eati c cancer two- to thr eefol d. The r i sk of
pancr eati c cancer i ncr eases as the amount and durati on of smoki ng
i ncr ease. The excess r i sk of devel opi ng pancr eati c cancer per si sts
for at l east 10 year s after smoki ng cessati on. Coffee, al cohol ,
or gani c sol vents, and petr ol eum pr oducts have been l i nked
epi demi ol ogi cal l y to pancr eati c cancer. However, the data ar e
confl i cti ng, and none of these agents ar e concl usi vel y causal .
Di abetes mel l i tus has been i mpl i cated as both an ear l y
mani festati on of pancr eati c car ci noma and a pr edi sposi ng factor.
Recent studi es have shown that pancr eati c cancer occur s mor e
fr equentl y i n pati ents wi th l ong-standi ng di abetes, whi ch may
i ncr ease the r i sk of pancr eati c cancer by twofol d. Repor ts have
val i dated the epi demi ol ogi c associ ati on between chr oni c pancr eati ti s
and pancr eati c cancer, but the magni tude of the r i sk of pancr eati c
cancer attr i butabl e to pancr eati ti s r emai ns contr over si al . Al l types
of chr oni c pancr eati ti s ar e associ ated wi th an el evated r i sk of
pancr eati c cancer. Indi vi dual s wi th a hi stor y of i di opathi c or
al cohol i c pancr eati ti s have a 15-fol d i ncr eased r i sk. Tr opi cal
pancr eati ti s, whi ch occur s i n souther n Indi a and Afr i ca and has no
known eti ol ogy, i s associ ated wi th a hi gh r i sk of pancr eati c cancer.
Her edi tar y pancr eati ti s has been attr i buted to a ger m-l i ne defect on
chr omosome 7q35 that i s i nher i ted i n an autosomal domi nant
patter n wi th 80% penetrance. These pati ents devel op chr oni c
pancr eati ti s at a young age and have a l i feti me r i sk of pancr eati c
cancer of appr oxi matel y 30% to 40% . Appr oxi matel y 5% to 10% of
pancr eati c cancer cases have been associ ated wi th a fami l i al
pr edi sposi ti on.
The most common i nher i ted gene that has been l i nked to pancr eati c
cancer i s the BRCA2 tumor suppr essor gene, whi ch has al so been
i mpl i cated i n fami l i al br east cancer. G er m-l i ne BRCA2 mutati ons
may be found i n about 12% to 20% of pati ents wi th her edi tar y
pancr eati c adenocar ci noma. It i s l i kel y that r i sk factor s such as
fami l i al pr edi sposi ti on and smoki ng may i nteract to r esul t i n ear l y
onset of pancr eati c cancer.
Table 13.1. Presenting signs and symptoms

of patients with carcinoma of the head of
the pancreas
Sign or Symptom
Percentage of
Patients
Weight loss
90
Pain
75
Malnutrition
75
Jaundice
70
Anorexia
60
Pruritus
40
Courvoisier's sign
33
Diabetes mellitus
15
Ascites
Gastric outlet
obstruction
The pr esenti ng si gns and symptoms of pati ents wi th pancr eati c
cancer ar e shown i n Tabl e 13.1. The most common pr esenti ng
symptoms ar e wei ght l oss, pai n, and jaundi ce. Pai n i s i ni ti al l y of l ow
i ntensi ty, i s vi sceral i n or i gi n, and i s poor l y l ocal i zed to the upper
abdomen. Thi s pai n may mi mi c pepti c ul cer di sease. Sever e pai n
l ocal i zed to the l ower thoraci c or upper l umbar ar ea i s mor e
character i sti c of advanced di sease due to i nvasi on of the cel i ac and
super i or mesenter i c pl exus.
Anor exi a and wei ght l oss ar e common i n pancr eati c cancer pati ents.
Wei ght l oss r esul ts fr om mal absor pti on and decr eased cal or i c
i ntake. The sudden onset of di abetes mel l i tus i n nonobese adul ts
ol der than 40 year s war rants eval uati on for pancr eati c cancer.
Pai nl ess jaundi ce as the sol e pr esenti ng symptom i s mor e fr equentl y
seen wi th ampul l ar y or di stal bi l e duct tumor s, but can be pr esent
wi th adenocar ci noma of the head or unci nate pr ocess of the
pancr eas. Smal l tumor s of the pancr eati c head may obstr uct the
i ntrapancr eati c por ti on of the bi l e duct and cause the pati ent to
seek medi cal attenti on when the tumor i s sti l l l ocal i zed and
potenti al l y r esectabl e. In the absence of extrahepati c bi l i ar y
obstr ucti on, few pati ents pr esent wi th potenti al l y r esectabl e
di sease. Cour voi si er 's si gn, a pal pabl e gal l bl adder at pr esentati on,
i s seen i n l ess than one-thi r d of pati ents.
Natural History
Pancr eati c cancer spr eads ear l y to r egi onal l ymph nodes, and
mi cr oscopi c i nvol vement of the l i ver i s fr equentl y pr esent at
di agnosi s. Pati ents who under go sur gi cal r esecti on for l ocal i zed
adenocar ci noma of the pancr eati c head have a medi an sur vi val of
13 to 20 months. Sur vi val and l ocal contr ol ar e i mpr oved wi th
ei ther pr eoperati ve or postoperati ve chemoradi ati on. Wi th i mpr oved
l ocor egi onal contr ol , the l i ver has become the most fr equent si te of
r ecur r ence for these pati ents. Pati ents wi th l ocal l y advanced di sease
and pati ents wi th metastati c di sease have medi an sur vi val s of 6 to
10 and 3 to 6 months, r especti vel y. Ther efor e, i mpr ovements i n
systemi c or r egi onal therapy di r ected to the l i ver and the
devel opment of scr eeni ng strategi es for ear l i er di agnosi s wi l l be
necessar y to change the natural hi stor y of thi s di sease.
Preoperative Evaluation
Radiologic Studies
An al gor i thm for the cur r ent di agnosti c and therapeuti c
management of pancr eati c adenocar ci noma at the M. D. Ander son
Cancer Center i s pr esented i n F i gur e 13.1. When pancr eati c cancer
i s suspected, radi ol ogi c confi r mati on shoul d be attempted. Several
l ar ge r evi ews of pancr eati c cancer noted del ays of mor e than 2
months fr om the onset of symptoms to di agnosi s i n most pati ents.
Mul ti detector thi n-secti on computed tomography (CT) scanni ng
usi ng a pancr eas-speci fi c pr otocol i s the test of choi ce to eval uate
the extent of di sease and to assess tumor r esectabi l i ty. Usi ng thi s
technol ogy, hi gh-r esol uti on i mages can be di spl ayed to pr ovi de
detai l ed i nfor mati on r egar di ng the pr i mar y tumor, l ocor egi onal
extensi on, l ymph node i nvol vement, and vascul ar i nvasi on. In
addi ti on, these i mages can be conver ted i nto thr ee-di mensi onal
r econstr ucti ons. Local tumor r esectabi l i ty i s most accuratel y
assessed befor e sur ger y. Lapar otomy shoul d be therapeuti c, not
di agnosti c. At M. D. Ander son, we use objecti ve and r epr oduci bl e
radi ol ogi c cr i ter i a to operate onl y on pati ents wi th potenti al l y
r esectabl e di sease. Resectabi l i ty i s defi ned as the absence of
extrapancr eati c di sease; the absence of di r ect tumor extensi on to
the super i or mesenter i c ar ter y (SMA) and cel i ac axi s, as defi ned by
the pr esence of a fat pl ane between the l ow-densi ty tumor and
these ar ter i al str uctur es; and a patent super i or mesenter i c-por tal
vei n confl uence. The accuracy of thi s for m of radi ographi c stagi ng i s
suppor ted by pr evi ous wor k at M. D. Ander son and val i dated by a
hi gh r esectabi l i ty rate (94 of 118, 80% ) and l ow rate of mi cr oscopi c
r etr oper i toneal mar gi n posi ti vi ty (17% ). The accuracy of CT i n
pr edi cti ng unr esectabi l i ty and the i naccuracy of i ntraoperati ve
assessment of r esectabi l i ty ar e both wel l establ i shed. F ur ther mor e,
hi gh-r esol uti on pancr eas pr otocol CT scans ar e usual l y abl e to
demonstrate aber rant ar ter i al anatomy pr i or to sur gi cal expl orati on.
The use of standar di zed, objecti ve radi ol ogi c cr i ter i a for
pr eoperati ve tumor stagi ng al l ows physi ci ans to devel op detai l ed
tr eatment pl ans for thei r pati ents, avoi d unnecessar y l apar otomy i n
pati ents wi th l ocal l y advanced or metastati c di sease, and i mpr ove
rates of r esectabi l i ty at l apar otomy. Ther efor e, we r ecommend a
system for cl i ni cal (radi ol ogi c) stagi ng as i l l ustrated i n Tabl e 13.2.
F i gur e 13.1. Al gor i thm for the management of pancr eati c

car ci noma. CT, computed tomography; CXR, chest x-ray; US,
ul trasound; F NA, fi ne-needl e aspi rati on; EUS, endoscopi c
ul trasound; EUS-F NA, endoscopi c ul trasound wi th fi ne-needl e
aspi rati on; ERCP, endoscopi c r etr ograde
chol angi opancr eatography; PET, posi tr on emi ssi on tomography.
Table 13.2. Clinical/radiologic staging of

pancreatic cancer
Stage Clinical/Radiologic Criteria
Resectable (T1T3, NX, M0)

No encasement of the celiac axis or
SMA
Patent SMPV confluence
No extrapancreatic disease
II
Locally advanced (T4, NX1, M0)

Arterial encasement (celiac axis or
SMA) or venous occlusion (SMV or
portal vein)
No extrapancreatic disease
III
Metastatic (T1T4, NX1, M1) (liver,

peritoneum, lungs)
SMA, superior mesenteric artery; SMPV,

superior mesenteric-portal vein; SMV, superior
mesenteric vein.
Other i magi ng modal i ti es such as posi tr on emi ssi on tomography
(PET) usi ng 18F -fl uor odexogl ucose (F DG ) and magneti c r esonance
i magi ng (MRI) ar e used l ess fr equentl y for the management of
pancr eati c cancer. F DG PET takes advantage of the i ncr eased
gl ucose uti l i z ati on of mal i gnant cel l s to detect car ci nomas; however,
i nfl ammator y condi ti ons such as pancr eati ti s al so accumul ate F DG
and can r esul t i n fal se-posi ti ve PET i mages. Mor eover, el evated
ser um gl ucose can l ower the sensi ti vi ty of F DG PET due to
competi ti ve i nhi bi ti on and decr eased F DG uptake i n tumor s. In
several studi es, the sensi ti vi ty of F DG PET i n hyper gl ycemi c pati ents
was l ower than i n eugl ycemi c pati ents, and i t has been suggested
that the standar di zed uptake val ue be adjusted to account for ser um
gl ucose l evel for mor e accurate i nter pr etati on of F DG PET i mages.
MRI wi th i ntravenous gadol i ni um i s useful for pati ents wi th a
contrai ndi cati on to CT contrast agents, and thr ee-di mensi onal
i mages can be constr ucted for noni nvasi ve i magi ng of the bi l i ar y
tr ee (magneti c r esonance chol angi opancr eatography).
American Joint Committee on Cancer Staging

System
system for pancr eati c cancer i s l i sted i n Tabl e 13.3. In the si xth
edi ti on of the AJCC Staging Manual, ther e ar e two mai n changes
fr om the pr evi ous edi ti on. The T cl assi fi cati on i s modi fi ed to

di sti ngui sh between potenti al l y r esectabl e (T3) and l ocal l y advanced
(T4) pr i mar y pancr eati c tumor s. In addi ti on, the gr oupi ng of the
stages i s changed such that stage III character i zes unr esectabl e,
l ocal l y advanced pancr eati c cancer, whi l e stage IV i s r eser ved for
pati ents wi th metastati c di sease. The AJCC stagi ng
system pr ovi des onl y one system for both cl i ni cal (radi ographi c) and
pathol ogi cal stagi ng. Pathol ogi cal stagi ng can be appl i ed onl y to
pati ents who under go pancr eatectomy; i n al l other pati ents, onl y
cl i ni cal stagi ng, based on radi ographi c exami nati ons, can be
per for med. Wi thout sur ger y, the hi stol ogi c status of the r egi onal
l ymph nodes cannot be deter mi ned. Opti mal assessment of a
pancr eati coduodenectomy speci men shoul d i ncl ude hi stol ogi c
eval uati on of at l east ten r egi onal l ymph nodes, whi ch i ncl ude
per i pancr eati c nodes al ong the hepati c ar ter y, cel i ac axi s, and
spl eni c and pyl or i c r egi ons. In addi ti on, tr eatment and pr ognosi s ar e
based on whether the tumor i s potenti al l y r esectabl e, l ocal l y
advanced, or metastati c, defi ni ti ons that may not di r ectl y cor r el ate
wi th TNM status.

Cancer staging of pancreatic cancer
Primary tumor (T)
Tis
Carcinoma in situ
T1
Tumor limited to the pancreas 2 cm in

greatest dimension
T2
Tumor limited to the pancreas >2 cm in

greatest dimension
Tumor extends beyond the pancreas
T3
T4
but without involvement of the celiac

axis or the superior mesenteric artery
Tumor involves the celiac axis or the
superior mesenteric artery
(unresectable primary tumor)

N0
N1
Distant metastasis
M0
M1
Distant metastasis
Stage grouping
Stage
IA
T1
N0
M0
Stage
IB
T2
N0
M0
Stage
IIA
T3
N0
M0
T1T3
N1
M0
Stage
IIB
Stage
III
T4
Any N
M0
Stage
IV
Any T
Any N
M1
Endoscopy
Endoscopi c ul trasound wi th fi ne-needl e aspi rati on bi opsy (EUS-F NA)
has emer ged as a hel pful di agnosti c tool that has pr oven to be safe
and accurate. Pr etr eatment confi r mati on of mal i gnancy i s
mandator y i n pati ents wi th l ocal l y advanced or metastati c di sease
pr i or to chemotherapy or exter nal -beam radi ati on therapy (EBRT)
and befor e i ni ti ati on of neoadjuvant therapy i n pati ents wi th
r esectabl e pancr eati c cancer. In our exper i ence, EUS-F NA has a
speci fi ci ty and posi ti ve pr edi cti ve val ue of 100% , whi l e
sensi ti vi ty and negati ve pr edi cti ve val ues ar e 90% and 38% ,
r especti vel y. In addi ti on to pati ents wi th l ar ge tumor s, EUS-F NA i s
successful i n most pati ents wi th smal l , r esectabl e tumor s, al l owi ng
for the del i ver y of pr otocol -based neoadjuvant therapy. Negati ve
r esul ts wi th EUS-F NA shoul d not be i nter pr eted as defi ni ti ve pr oof
that a mal i gnancy does not exi st.
Al though pr etr eatment pancr eati c fi ne-needl e aspi rati on (F NA)
bi opsy i s fr equentl y per for med, physi ci ans shoul d be cauti oned
about the use of i ntraoperati ve pancr eati c bi opsy. In pati ents wi th
r esectabl e di sease, ther e i s no i ndi cati on for r outi ne i ntraoperati ve
pancr eati c bi opsy and the use of pr eoperati ve EUS-F NA shoul d be
l i mi ted to those pati ents r ecei vi ng pr eoperati ve chemoradi ati on for
whom cytol ogi c confi r mati on of mal i gnancy i s needed. Unl i ke F NA,
sur gi cal mani pul ati on and i ntraoperati ve l ar ge-needl e bi opsy dur i ng
sur ger y i ncr eases the r i sk of per i toneal di ssemi nati on of tumor
cel l s. Havi ng under gone a pr evi ous l apar otomy wi th tumor bi opsy
pr i or to defi ni ti ve pancr eati coduodenectomy i s the onl y factor
associ ated wi th an i ncr eased r i sk of l ocor egi onal tumor r ecur r ence.
F ur ther mor e, i ntraoperati ve pancr eati c bi opsy has been associ ated
wi th si gni fi cant compl i cati ons, such as pancr eati ti s, pancr eati c
fi stul a, and hemor r hage.

Endoscopi c r etr ograde chol angi opancr eatography (ERCP) i s used to
di ffer enti ate chol edochol i thi asi s and chr oni c pancr eati ti s fr om
mal i gnant obstr ucti on of the di stal common bi l e duct when CT does
not see a mass. To pr event chol angi ti s i n pati ents who under go
di agnosti c ERCP because of extrahepati c bi l i ar y obstr ucti on,
endoscopi c stents ar e r outi nel y pl aced. Endoscopi c stents ar e al so
pl aced i n pati ents wi th el evated bi l i r ubi n l evel s who ar e enr ol l ed i n
pr eoperati ve chemoradi ati on pr otocol s. At our i nsti tuti on,
expandabl e metal l i c stents have demonstrated a super i or patency
rate wi th fewer epi sodes of chol angi ti s and no di ffer ence i n i ntra- or
postoperati ve compl i cati ons compar ed wi th pl asti c bi l i ar y stents.
Laparoscopy
Lapar oscopy has been advocated for the i denti fi cati on of potenti al
extrapancr eati c di sease i n pati ents wi th radi ol ogi c evi dence of
l ocal i zed di sease. Recent i nvesti gati ons suggest that extrapancr eati c
di sease not vi si bl e by CT i s uncommon, bei ng found i n onl y 4% to
15% of pati ents wi th pancr eati c tumor s consi der ed r esectabl e
fol l owi ng hi gh-qual i ty CT. Lapar oscopy befor e l apar otomy (dur i ng a
si ngl e anesthesi a i nducti on) i s a r easonabl e appr oach i n pati ents
wi th bi opsy-pr oven or suspected potenti al l y r esectabl e pancr eati c
cancer i n whom a deci si on has been made to pr oceed wi th
pancr eati coduodenectomy. However, data ar e not avai l abl e to
suppor t the cost effecti veness of r outi nel y usi ng l apar oscopy as a
stagi ng pr ocedur e under a separate anesthesi a i nducti on pr i or to
tr eatment pl anni ng.
Tumor Markers
Cur r entl y, the gol d standar d ser ol ogi c mar ker for pancr eati c cancer
i s CA19-9. Or i gi nal l y descr i bed as a mar ker for col on cancer, the
CA19-9 anti gen i s a si al yl ated l acto-N-fucopentaose II r el ated to the
Lewi s a bl ood gr oup anti gen. The sensi ti vi ty and speci fi ci ty
of CA19-9 i n the di agnosi s of pancr eati c cancer has been r epor ted
to be as hi gh as 90% and 98% , r especti vel y. A si gni fi cant l i mi tati on
of the use of CA19-9 as a mar ker for pancr eati c cancer i s i ts
el evati on i n the setti ng of beni gn, as wel l as mal i gnant, bi l i ar y
obstr ucti on. Bi l i ar y decompr essi on usual l y r esul ts i n a decr ease i n
CA19-9 l evel s cor r espondi ng to a fal l i n ser um bi l i r ubi n. To i mpr ove
the useful ness of CA19-9 for the jaundi ced pati ent, some
i nvesti gator s have pr oposed usi ng an adjusted CA19-9 by di vi di ng

the ser um CA19-9 by the total bi l i r ubi n when the bi l i r ubi n i s
gr eater than 2.0 mg per dL. The uti l i ty of CA19-9 i s al so l i mi ted i n
the 5% to 15% of the popul ati on that i s Lewi sa b negati ve who l ack
the enz yme speci fi ed by the Le gene i nvol ved i n the synthesi s of
CA19-9. In these i ndi vi dual s, CA19-9 wi l l be fal sel y l ow even wi th
an extensi ve pancr eati c tumor bur den.
CA19-9 i s commonl y used not onl y to di agnose pancr eati c cancer,
but i t may al so hel p i denti fy pati ents wi th r esectabl e tumor s.
Vi r tual l y al l pati ents wi th a CA19-9 gr eater than 200 U per mL wi l l
have a pancr eati c mal i gnancy, and when CA19-9 i s gr eater than 300
U per mL, r esecti on i s rar el y possi bl e. Ser um CA19-9 i s an
i ndependent pr edi ctor of r ecur r ence and sur vi val after r esecti on and
has r ecentl y been shown to cor r el ate wi th r esponse to therapy.
Pathology
Appr oxi matel y 90% of pancr eati c exocr i ne tumor s ar i se fr om the
pancr eati c ductul es, and 80% of these tumor s ar e adenocar ci nomas.
Pancr eati c adenocar ci nomas ar i se i n the head of the gl and i n 60%
to 70% of cases. The r est of the tumor s ar e l ocated i n the body or
tai l , or di ffusel y thr oughout the pancr eas.
In gr oss hi stol ogi c exami nati on, pancr eati c adenocar ci noma i s fi r m
and whi te wi th poor l y defi ned mar gi ns. An associ ated sur r oundi ng
ar ea of pancr eati ti s i s often pr esent and can make pathol ogi cal
di agnosi s di ffi cul t. An i ntense desmopl asti c r eacti on i s i denti fi abl e
on both gr oss and mi cr oscopi c exami nati on. Hi stol ogi c i denti fi cati on
of muci n pr oducti on i s hel pful i n di agnosi ng an adenocar ci noma.
Per i neural i nvasi on can be i denti fi ed i n most speci mens. The degr ee
of di ffer enti ati on r epor ted on mi cr oscopi c exami nati on i s based on
the degr ee of for mati on of tubul ar gl andul ar str uctur es.
Surgical Treatment
Sur gi cal r esecti on of car ci noma of the pancr eati c head r emai ns the
onl y potenti al l y curati ve tr eatment modal i ty. F i ve sur gi cal
techni ques ar e used to r esect pancr eati c cancer : (a) the standar d
pancr eati coduodenectomy, modi fi ed fr om Whi ppl e's i ni ti al
descr i pti on i n 1935; (b) pyl or us-pr eser vi ng
pancr eati coduodenectomy; (c) total pancr eatectomy; (d) r egi onal
pancr eatectomy; and (e) the M. D. Ander son extended r esecti on.
Thor ough abdomi nal expl orati on shoul d pr ecede r esecti on. Ther e i s
no r ol e for r esecti on of adenocar ci noma i n the pr esence of
metastati c di sease. Expl orati on shoul d i ncl ude i ntraoperati ve

i nspecti on and pal pati on of the l i ver, per i toneal sur faces, paraaor ti c l ymphati cs, and r oot of the mesenter y to defi ne the tumor 's
extent.
F i gur e 13.2. Si x sur gi cal steps of pancr eati coduodenectomy

(cl ockwi se r esecti on). SMV, super i or mesenter i c vei n; SMA,
super i or mesenter i c ar ter y. (F r om Tyl er DS, Evans DB.
Reoperati ve pancr eati coduodenectomy. Ann Sur g 1994;219:214 ,
r epr i nted wi th per mi ssi on.)
The sur gi cal r esecti on i s di vi ded i nto the fol l owi ng si x cl ear l y
defi ned steps (F i g. 13.2):
1. A Cattel l -Braasch maneuver i s per for med by mobi l i z i ng the r i ght
col on and i nci si ng the vi sceral per i toneum to the l i gament of
Tr ei tz . When compl ete, thi s maneuver al l ows cephal ad r etracti on
of the r i ght col on and smal l bowel , exposi ng the thi r d and four th
por ti ons of the duodenum. Mobi l i z ati on of the r etr oper i toneal
attachments of the mesenter y i s of par ti cul ar i mpor tance i n
pati ents who r equi r e venous r esecti on and r econstr ucti on. The
omental bur sa i s enter ed by taki ng the gr eater omentum fr om
the transver se col on. The mi ddl e col i c vei n i s i denti fi ed, l i gated,
and di vi ded befor e i ts juncti on wi th the SMV. Routi ne di vi si on of
the mi ddl e col i c vei n al l ows gr eater exposur e of the
i nfrapancr eati c SMV and pr events i atr ogeni c tracti on i njur y
dur i ng di ssecti on of the mi ddl e col i c vei n-SMV juncti on.
2. The Kocher maneuver i s begun at the juncti on of the ur eter and
r i ght gonadal vei n. The r i ght gonadal vei n i s l i gated and di vi ded,
and al l fi br ofatty and l ymphati c ti ssue over l yi ng the medi al

aspect of the r i ght ki dney and i nfer i or vena cava i s r emoved
wi th the tumor speci men. The gonadal vei n i s agai n l i gated at i ts
entrance i nto the i nfer i or vena cava. The Kocher maneuver i s
conti nued to the l eft l ateral edge of the aor ta, wi th car eful
i denti fi cati on of the l eft r enal vei n.
3. The por tal di ssecti on i s i ni ti ated, exposi ng the common hepati c
ar ter y pr oxi mal and di stal to the gastr oduodenal ar ter y. The
gastr oduodenal ar ter y i s then l i gated and di vi ded. Two l ar ge
l ymph nodes ar e commonl y encounter ed dur i ng por tal di ssecti on:
one al ong the i nfer i or bor der of the common hepati c ar ter y, and
one behi nd the por tal vei n seen after transecti on of the common
bi l e duct. Removal of these l ymph nodes (en bl oc wi th the
speci men) i s necessar y to mobi l i ze
the hepati c ar ter y and por tal vei n. However, they rar el y contai n
metastati c di sease. Lymph node metastases fr om pancr eati c
cancer ar e commonl y smal l and ar e al most al ways found by the
pathol ogi st rather than the sur geon. The gal l bl adder i s di ssected
out of the l i ver bed and the common hepati c duct transected just
cephal ad to i ts juncti on wi th the cysti c duct. The anter i or wal l of
the por tal vei n i s easi l y exposed fol l owi ng di vi si on of the
common hepati c duct and medi al r etracti on of the common
hepati c ar ter y. Thi s connecti ve ti ssue anter i or to the por tal vei n
i s di vi ded i n a caudal di r ecti on to the juncti on of the por tal vei n
and the neck of the pancr eas. A constant venous tr i butar y, the
poster i or pancr eati c duodenal vei n, can be l ocated at the
supral ateral aspect of the por tal vei n. Bl eedi ng caused by
tracti on i njur y to thi s venous tr i butar y may be di ffi cul t to
contr ol at the ti me of the operati on. The por tal di ssecti on i s
made mor e di ffi cul t i n the pr esence of anomal ous hepati c ar ter y
ci r cul ati on. Rar el y, the hepati c ar ter y (di stal to the or i gi n of the
gastr oduodenal ar ter y) cour ses poster i or to the por tal vei n.
Mor e commonl y, an accessor y or r epl aced r i ght hepati c ar ter y
ar i ses fr om the pr oxi mal SMA and l i es poster i or and l ateral to
the por tal vei n. The common hepati c ar ter y may ar i se fr om the
SMA (type IX hepati c ar ter i al anatomy). Fatal hepati c necr osi s
can r esul t i f thi s i s unr ecogni zed and the vessel i s sacr i fi ced.
Identi fi cati on of aber rant ar ter i al anatomy i s general l y not
di ffi cul t, except i n r eoperati ve por tal di ssecti ons.
4. The stomach i s transected at the l evel of the thi r d or four th
transver se vei n on the l esser cur vatur e and at the confl uence of
the gastr oepi pl oi c vei ns on the gr eater cur vatur e. The omentum
i s di vi ded at the l evel of the gr eater cur vatur e transecti on.
5. The jejunum i s transected appr oxi matel y 10 cm di stal to the
l i gament of Tr ei tz , and i ts mesenter y i s sequenti al l y l i gated and
di vi ded. The duodenal mesenter y i s si mi l ar l y di vi ded to the l evel
of the aor ta; the duodenum and jejunum ar e then r efl ected
beneath the mesenter i c vessel s.
6. After tracti on sutur es ar e pl aced on the super i or and i nfer i or
bor der s of the pancr eas, the pancr eas i s transected usi ng
el ectr ocauter y at the l evel of the por tal vei n. If ther e i s
evi dence of tumor adher ence to the por tal vei n or SMV, the
pancr eas can be di vi ded at a mor e di stal l ocati on i n pr eparati on
for segmental venous r esecti on. The speci men i s separated fr om
the SMV by l i gati ng and di vi di ng the smal l venous tr i butar i es to
the unci nate pr ocess and the pancr eati c head. Compl ete r emoval
of the unci nate pr ocess combi ned wi th medi al r etracti on of the
super i or mesenter i c-por tal vei n confl uence faci l i tates exposur e
of the SMA, whi ch i s then di ssected to i ts or i gi n at the aor ta.
Total exposur e of the SMA avoi ds i atr ogeni c i njur y and ensur es
di r ect l i gati on of the i nfer i or pancr eati coduodenal ar ter y.
Reconstr ucti on pr oceeds i n the counter cl ockwi se di r ecti on, and
agai n i n a stepwi se and or der l y fashi on (F i g. 13.3).
7. The pancr eati c r emnant i s mobi l i zed fr om the r etr oper i toneum
and spl eni c vei n for a di stance of 2 to 3 cm. Fai l ur e to
adequatel y mobi l i ze the pancr eati c r emnant r esul ts
i n poor sutur e pl acement at the pancr eati cojejunal anastomosi s.
The transected jejunum i s br ought thr ough a smal l i nci si on i n
the transver se mesocol on to the r i ght or l eft of the mi ddl e col i c
vessel s. A two-l ayer, end-to-si de, duct-to-mucosa
pancr eati cojejunostomy i s per for med over a smal l Si l asti c stent.
Fol l owi ng compl eti on of the poster i or r ow of 3-0 ser omuscul ar
sutur es, a smal l , ful l -thi ckness openi ng i n the bowel i s made.
The anastomosi s between the pancr eati c duct and smal l bowel
mucosa i s compl eted wi th 4-0 or 5-0 monofi l ament sutur es. Each
sti tch i ncor porates a gener ous bi te of pancr eati c duct and a ful l thi ckness bi te of jejunum. The poster i or knots ar e ti ed on the
i nsi de, and the l ateral and anter i or knots ar e ti ed on the
outsi de. Pr i or to the anter i or sutur es bei ng ti ed, the stent i s
pl aced acr oss the anastomosi s so i t extends i nto the pancr eati c
duct and i nto the smal l bowel for a di stance of appr oxi matel y 2
to 3 cm. The anastomosi s i s compl eted wi th a pl acement of an
anter i or r ow of 3-0 ser omuscul ar sutur es. When the pancr eati c
duct i s not di l ated and/or the pancr eati c substance i s soft (not
fi br oti c), a two-l ayer anastomosi s that i nvagi nates the cut end of
the pancr eas i nto the jejunum i s r ecommended. The outer
poster i or r ow of 3-0 sutur es i s pl aced as outl i ned ear l i er. The
bowel i s then opened to a l ength equi val ent to the transver se
di ameter of the pancr eati c r emnant. Usi ng a r unni ng, doubl ear med, 4-0 nonabsor babl e monofi l ament sutur e, the pancr eati c
r emnant i s sewn to the jejunum. The anastomosi s i s compl eted
wi th pl acement of an anter i or r ow of 3-0 ser omuscul ar sutur es.
F i gur e 13.3. Four sur gi cal steps of counter cl ockwi se

r econstr ucti on fol l owi ng standar d pancr eati coduodenectomy.
(F r om Tyl er DS, Evans DB. Reoperati ve
pancr eati coduodenectomy. Ann Sur g 1994;219:214 , r epr i nted
wi th per mi ssi on.)
8. A si ngl e-l ayer bi l i ar y anastomosi s i s per for med usi ng

i nter r upted, 4-0 absor babl e monofi l ament sutur es. It i s
i mpor tant to al i gn the jejunum wi th the bi l e duct to avoi d
tensi on on the pancr eati c and bi l i ar y anastomosi s. A stent i s
rar el y used i n the constr ucti on of the hepati cojejunostomy.
9. An anti col i c, end-to-si de gastr ojejunostomy i s constr ucted i n two
l ayer s. Star ti ng fr om the gr eater cur vatur e, 6 to
8 cm of gastr i c stapl e l i ne i s r emoved. A poster i or r ow of si l k
sutur es i s fol l owed by a r unni ng, monofi l ament, ful l -thi ckness
i nner l ayer ; the anter i or r ow of si l k sutur es compl etes the
anastomosi s. The di stance between the bi l i ar y and gastr i c
anastomosi s shoul d al l ow the jejunum to assume i ts anti col i c
posi ti on (for the gastr ojejunostomy) wi thout tensi on. Ther e i s no

har m i n maki ng a l ong (2535 cm) affer ent l i mb.
10. Feedi ng jejunostomy tubes may be pl aced usi ng the Wi tzel

techni que, and cl osed sucti on drai ns ar e onl y used i f ther e i s a
speci fi c i ndi cati on for drai nage.
Traver so and Longmi r e i ntr oduced the concept of pyl or us-pr eser vi ng
pancr eati coduodenectomy i n 1978, i n an attempt to el i mi nate the
postgastr ectomy syndr omes seen after antr ectomy. Thi s operati on
techni cal l y di ffer s fr om a standar d Whi ppl e pr ocedur e onl y i n the
pr eser vati on of the bl ood suppl y to the pr oxi mal duodenum. Thi s
can be accompl i shed by car eful l y pr eser vi ng the r i ght gastr oepi pl oi c
ar cade after l i gati on of the r i ght gastr oepi pl oi c ar ter y and vei n
cl ose to thei r or i gi n. The r i ght gastr i c ar ter y can be spar ed i n some
cases to pr ovi de addi ti onal bl ood suppl y to the duodenum. The most
si gni fi cant mor bi di ty of pyl or us pr eser vati on i s transi ent gastr i c
stasi s. Operati ve ti me and bl ood l oss ar e sl i ghtl y r educed compar ed
wi th those of cl assi c pancr eati coduodenectomy. Pyl or us pr eser vati on
shoul d not be per for med i n pati ents wi th bul ky tumor s or tumor s
i nvol vi ng the fi r st and second por ti on of the duodenum.
Some author s have advocated r outi ne total pancr eatectomy as
defi ni ti ve therapy for adenocar ci noma of the head of the pancr eas.
They ci te the possi bl e mul ti centr i c natur e of pancr eati c cancer and
the avoi dance of a pancr eati c anastomosi s as justi fi cati on for thi s
appr oach. However, the i nci dence of pathol ogi cal documentati on of
mul ti centr i ci ty of pancr eati c adenocar ci noma i s l ess than 10% and
does not justi fy the addi ti onal operati ve mor bi di ty and l i fel ong
i nsul i n dependence that r esul ts fr om total pancr eatectomy. The
si gni fi cant operati ve mor bi di ty and mor tal i ty fr om
pancr eati coduodenectomy i s hi stor i cal l y attr i buted to
pancr eati cojejunal anastomoti c l eak. However, anastomoti c
compl i cati ons ar e rar e at i nsti tuti ons exper i enced wi th thi s
operati on. Al so, mor e effecti ve management of pancr eati c
anastomoti c l eakage wi th hyperal i mentati on, per cutaneous
drai nage, and somatostati n anal og has r educed the magni tude of
thi s pr obl em. Total pancr eatectomy i s onl y i ndi cated i f ther e i s
tumor at the pancr eati c mar gi n on ser i al fr ozen secti ons or i f the
pancr eas i s not sui tabl e for an anastomosi s.
Regi onal pancr eatectomy i ncl udes extensi ve r etr oper i toneal and
hepatoduodenal l ymph node di ssecti on and sl eeve r esecti on of the
SMV-por tal venous confl uence. Super i or mesenter i c and hepati c
ar ter i al r esecti ons have al so been i ncl uded by pr oponents of thi s

mor e radi cal appr oach. The potenti al oncol ogi c advantages of
r egi onal pancr eatectomy ar e offset by i ts i ncr eased mor bi di ty and
mor tal i ty.
Venous r esecti on shoul d be consi der ed when the l esi on has been
deemed r esectabl e, the pancr eati c neck i s di vi ded, and, whi l e
di ssecti ng the unci nate pr ocess fr om the SMV, the tumor i s found
to be adher ent to the poster i or-l ateral por ti on of the vei n. Vei n
r esecti on i s pr eferabl e to shavi ng the tumor fr om the por tal super i or mesenter i c venous confl uence. In addi ti on, venous
r esecti on for any tumor i nvol vi ng the SMV-por tal venous confl uence
shoul d be per for med as l ong as the vei n has been demonstrated to
be patent by pr eoperati ve CT. An i nter posi ti on i nter nal jugul ar vei n
graft i s our pr efer r ed method of r econstr ucti on. Unl i ke other r ecent
r epor ts, data fr om our i nsti tuti on suggest that r esecti on of the SMV
at pancr eati coduodenectomy can be per for med safel y, i s not
associ ated wi th r etr oper i toneal mar gi n posi ti vi ty (when hi gh-qual i ty
pr eoperati ve i magi ng i s per for med), and does not negati vel y
i nfl uence pati ent sur vi val . In a r evi ew of 141 pati ents at our
i nsti tuti on who under went pancr eati coduodenectomy wi th major
vascul ar r esecti on, a R0 r esecti on was possi bl e i n 78% . Vascul ar
r esecti on was consi der ed onl y when ther e was i sol ated tumor
i nvol vement of the SMV or por tal vei n wi thout extensi on to the
cel i ac axi s or SMA. The medi an sur vi val of 110 pati ents wi th
pancr eati c adenocar ci noma who under went vascul ar r esecti on was
23 months.
Intraoperati ve deci si on maki ng i n the sur gi cal tr eatment of
pancr eati c cancer can chal l enge the most exper i enced sur geon. The
mor bi di ty and mor tal i ty associ ated wi th pancr eati coduodenectomy
ar e gr eater than those seen wi th many other pr ocedur es and shoul d
be per for med onl y by exper i enced sur geons. Thi s concl usi on was
suppor ted by Li eber man et al . i n 1995, who r epor ted the exper i ence
wi th pancr eati coduodenectomy i n New Yor k State fr om 1984 to
1991. Mor e than 75% of pati ents who under went
pancr eati coduodenectomy had thei r operati ons per for med at
hospi tal s that r epor ted l ess than seven of these operati ons per year.
For pati ents who r ecei ved thei r sur gi cal car e at those hospi tal s,
mean per i operati ve hospi tal stay was mor e than 1 month, and the
r i sk-adjusted per i operati ve mor tal i ty was 12% to 19% . Pati ents and
thei r fami l i es must be i nfor med pr eoperati vel y of the r equi r ed
compl ex postoperati ve car e and potenti al compl i cati ons of
pancr eati coduodenectomy. Thi s i s most cr i ti cal when ther e i s no

pr eoperati ve hi stol ogi c confi r mati on of the di agnosi s. Neopl asms of
the pancr eati c head can obstr uct the pancr eati c duct, r esul ti ng i n
pancr eati ti s, whi ch makes defi ni ti ve hi stol ogi c di agnosi s di ffi cul t. An
i ntraoperati ve transduodenal bi opsy speci men that r eveal s
i nfl ammati on does not excl ude the possi bi l i ty of mal i gnancy.
Because of thi s, many exper i enced pancr eati c sur geons do not
r outi nel y per for m i ntraoperati ve bi opsi es i f mal i gnancy i s suspected.
In our i nsti tuti on, we do not r outi nel y per for m i ntraoperati ve
bi opsi es i n pati ents wi th radi ographi c (CT or ERCP) studi es
consi stent wi th mal i gnancy. Occasi onal l y, a sur geon suspects that a
mal i gnancy exi sts but cannot establ i sh radi ol ogi c or hi stol ogi c
confi r mati on. Ever y l ar ge ser i es of pancr eati c r esecti ons i ncl udes a
few pati ents r esected for beni gn di sease. The potenti al mor bi di ty of
an unnecessar y pancr eati c r esecti on i s pr efer r ed to l eavi ng a
potenti al l y curabl e l esi on i n si tu. Repeated bi opsi es to obtai n
hi stol ogi c confi r mati on of mal i gnancy ar e i nadvi sabl e because of the
r i sk of pancr eati c fi stul a, pancr eati ti s, and hemor r hage. Pati ents
shoul d be awar e of the potenti al need to per for m a r esecti on
wi thout hi stol ogi c confi r mati on of mal i gnancy.
Results of Surgery
Aggr essi ve sur gi cal r esecti on of pancr eati c head tumor s has come
under i ntense scr uti ny, al though, pr esentl y,
pancr eati coduodenectomy r emai ns the onl y pr ocedur e capabl e of
cur i ng adenocar ci noma of the pancr eati c head. Postoperati ve
mor bi di ty rates that wer e gr eater than 50% i n the l ate 1960s ar e
now l ess than 25% i n the most r ecentl y r epor ted ser i es.
Postoperati ve mor tal i ty rates have al so decr eased, fr om a hi gh of
mor e than 20% to as l ow as 3% i n the most r ecent r evi ews.
The pr esence of fever after postoperati ve day 3 or 4 shoul d pr ompt
car eful eval uati on. Potenti al sour ces of fever i ncl ude those common
to al l abdomi nal sur ger i es and i ntra-abdomi nal abscess as a r esul t
of pancr eati cojejunostomy l eak. G astr i c and bi l i ar y anastomoses
rar el y l eak. The study of choi ce i s CT scan of the abdomen, wi th CTgui ded drai nage of any l ocal i zed fl ui d col l ecti on.
Pancr eati cojejunostomy anastomoti c l eaks general l y cl ose when
adequatel y drai ned. The use of octr eoti de i n thi s setti ng shoul d be
i ndi vi dual i zed. Postoperati ve gastr oi ntesti nal or drai n tract bl eedi ng
shoul d pr ompt i mmedi ate angi ography to eval uate for ar ter i al enter i c fi stul a. The most common cause i s pancr eati cojejunostomy
l eak fol l owed by a heral d bl eed due to r uptur e of the l i gated

gastr oduodenal ar ter y stump. Thi s i s a rar e compl i cati on and shoul d
be managed by embol i z ati on at the ti me of di agnosti c angi ography.
Despi te the i mpr ovement i n mor bi di ty and mor tal i ty, ther e has been
l i ttl e change i n l ong-ter m pati ent sur vi val . The 5-year sur vi val rate
fol l owi ng curati ve pancr eati coduodenectomy for car ci noma of the
pancr eati c head r emai ns l ess than 25% , wi th a medi an sur vi val of
20 to 25 months.
Body and tai l tumor s ar e often consi der ed to have a poor er
pr ognosi s than l esi ons of the pancr eati c head because the for mer
fr equentl y go undetected unti l they ar e l ocal l y advanced or
metastati c. At our i nsti tuti on, these l esi ons account for onl y 2% of
the pancr eatectomi es per for med. However, a Mayo Cl i ni c r epor t
suggested that the few pati ents wi th body or tai l l esi ons amenabl e
to r esecti on for cur e have l ong-ter m sur vi val rates si mi l ar to those
pati ents who have under gone compl ete r esecti on of the mor e
common car ci noma of the pancr eati c head.
Adjuvant Therapy
Because the 5-year sur vi val rate of pati ents wi th r esected
pancr eati c cancer i s poor, i t i s i mperati ve to exami ne the potenti al
benefi t of adjuvant therapy for thi s di sease. Autopsy ser i es have
i ndi cated that 85% of pati ents wi l l exper i ence r ecur r ences i n the
fi el d of r esecti on. F ur ther mor e, appr oxi matel y 70% of pati ents wi l l
devel op metastasi s to the l i ver. Ther efor e, adjuvant therapy must
addr ess the possi bi l i ti es of di stant di sease (chemotherapy) and
l ocor egi onal r ecur r ence (radi ati on therapy). The i ni ti al studi es
exami ni ng adjuvant therapy of pancr eati c cancer wer e based on
r esul ts fr om studi es on pati ents wi th advanced di sease.
Most wi del y used chemotherapeuti c agents have l i mi ted acti vi ty
agai nst pancr eati c cancer. 5-F l uor ouraci l (5-F U) i s the onl y acti ve
agent, and i ts effect i s mar gi nal . Most studi es r epor t an overal l
r esponse rate of 15% to 28% i n pati ents wi th advanced
di sease. Studi es of 5-F U have al so demonstrated the abi l i ty of thi s
agent to act as a radi ati on sensi ti zer. G emci tabi ne, a deoxycyti di ne
anal og capabl e of i nhi bi ti ng DNA r epl i cati on and r epai r, has
demonstrated acti vi ty agai nst pancr eati c cancer. In a randomi zed
tr i al of pati ents wi th advanced di sease, pati ents tr eated wi th
gemci tabi ne exper i enced a modest but stati sti cal l y si gni fi cant
i mpr oved r esponse rate and medi an sur vi val and an i mpr oved
qual i ty of l i fe compar ed wi th pati ents tr eated wi th 5-F U.

Combi ned 5-F U and radi ati on therapy have been r epor ted to
si gni fi cantl y i ncr ease sur vi val i n pati ents wi th l ocal l y advanced
di sease. In a study by the G astr oi ntesti nal Tumor Study G r oup
(G ITSG ), pati ents wi th unr esectabl e pancr eati c cancer wer e
randomi zed to r ecei ve hi gh-dose postoperati ve radi ati on therapy
(60 G y) al one, hi gh-dose postoperati ve radi ati on therapy (60 G y)
pl us concomi tant 5-F U, or standar d-dose postoperati ve radi ati on
therapy (40 G y) and 5-F U. Pati ents r ecei vi ng 5-F U and radi ati on
therapy exper i enced a si gni fi cant sur vi val advantage compar ed wi th
pati ents who r ecei ved radi ati on therapy al one. The hi gher dose of
radi ati on therapy di d not confer an addi ti onal sur vi val advantage.
The combi nati on of postoperati ve EBRT and concomi tant 5-F U as
adjuvant therapy after r esecti on was al so i nvesti gated by the
G ITSG . Pati ents wer e randomi zed to r ecei ve sur ger y al one or
sur ger y fol l owed by radi ati on therapy (40 G y del i ver ed i n two 20-G y
cour ses) and 5-F U (500 mg per m2 by i ntravenous bol us del i ver ed
dai l y for the i ni ti al 3 days of each radi ati on therapy cour se and then
weekl y for 2 year s). Medi an sur vi val was 20 months i n the gr oup
that r ecei ved adjuvant therapy; thi s was si gni fi cantl y l onger than
the 11-month medi an sur vi val seen i n pati ents tr eated wi th sur ger y
al one.
Unl i ke sur ger y for adenocar ci noma of the esophagus, stomach, or
col or ectum, pancr eati coduodenectomy r equi r es compl ete
r econstr ucti on of the upper gastr oi ntesti nal tract, i ncl udi ng
r eanastomosi s of the pancr eas, bi l e duct, and stomach. The
magni tude of the operati on and i ts associ ated mor bi di ty may r esul t
i n a l engthy r ecover y, pr eventi ng the ti mel y del i ver y of
postoperati ve therapy. In most l ar ge ser i es, appr oxi matel y 25% of
pati ents who under go pancr eati coduodenectomy do not r ecei ve
postoperati ve chemoradi ati on because of pr ol onged r ecover y.
The r i sk of del ayi ng adjuvant therapy, combi ned wi th smal l
pr el i mi nar y exper i ences of successful pancr eati c r esecti on fol l owi ng
EBRT, pr ompted many i nsti tuti ons to i ni ti ate studi es of
chemoradi ati on befor e pancr eati coduodenectomy for pati ents wi th
potenti al l y r esectabl e or l ocal l y advanced adenocar ci noma of the
pancr eas. The pr eoperati ve use of chemoradi ati on i s suppor ted by
the fol l owi ng consi derati ons:
1. Radi ati on therapy i s mor e effecti ve on wel l -oxygenated tumor s
that have not been devascul ar i zed by sur ger y.
2. Per i toneal spr ead of tumor cel l s as a r esul t of sur ger y may be
pr evented by pr eoperati ve chemoradi ati on.
3. The hi gh fr equency of posi ti ve-mar gi n r esecti ons r ecentl y
r epor ted suppor ts the concer n that the r etr oper i toneal mar gi n of
exci si on, even when negati ve, may be onl y a few
mi l l i meter s. Sur ger y al one may ther efor e be i nadequate for l ocal
tumor contr ol .
4. Pati ents wi th di ssemi nated di sease evi dent on r estagi ng studi es
after chemoradi ati on wi l l not be subjected to l apar otomy and
ther efor e wi l l be spar ed the associ ated mor bi di ty and r i sk of
tr eatment-r el ated mor tal i ty. Repeat stagi ng CT after
chemoradi ati on r eveal s l i ver metastases i n appr oxi matel y 25%
of pati ents. It i s pr obabl e that the l i ver metastases wer e al r eady
pr esent subcl i ni cal l y at di agnosi s, and i f these pati ents had
under gone pancr eati coduodenectomy, then they woul d have had
a major sur gi cal pr ocedur e onl y to have l i ver metastases found
soon after sur ger y.
5. Because radi ati on therapy and chemotherapy ar e gi ven fi r st,
l ong postoperati ve r ecover y wi l l have no effect on the del i ver y
of al l components of the mul ti modal i ty tr eatment, a fr equent
pr obl em i n postoperati ve adjuvant therapy studi es.
The standar d-fracti onati on pr eoperati ve chemoradi ati on r egi men at
M. D. Ander son was del i ver ed over 5.5 weeks to a total dose of 50.4
G y (1.8 G y per fracti on) concur r entl y wi th conti nuous-i nfusi on 5-F U
at a dosage of 300 mg/m2 /day, 5 days per week, thr ough a central
venous catheter. To avoi d the gastr oi ntesti nal toxi ci ty seen wi th thi s
standar d 5.5-week pr ogram, a rapi d-fracti onati on pr ogram of
chemoradi ati on was desi gned. Rapi d-fracti onati on chemoradi ati on i s
del i ver ed over 2 weeks to a total dose of 30 G y (3 G y per fracti on)
for 5 days per week. 5-F U i s gi ven concur r entl y by conti nuous
i nfusi on at a dosage of 300 mg/m2 /day, 5 days per week. Thi s
pr ogram i s based on the pr i nci pl e that the total radi ati on dose
r equi r ed to obtai n a gi ven bi ol ogi cal effect decr eases as the dose
per fracti on i ncr eases. Restagi ng wi th chest radi ography and
abdomi nal CT i s per for med 4 weeks after chemoradi ati on. Pati ents
wi th l ocal i zed di sease on r estagi ng under go
pancr eati coduodenectomy wi th el ectr on-beam i ntraoperati ve
radi ati on therapy (EB-IORT). In our r ecentl y publ i shed ser i es,
pati ents wi th radi ographi cal l y r esectabl e l ocal i zed adenocar ci noma
of the pancr eati c head wer e enter ed onto thi s pr eoperati ve pr otocol .
Thi r ty-fi ve pati ents r ecei ved thi s tr eatment, 27 had sur ger y, and 20
(74% ) under went successful pancr eati coduodenectomy. Local tumor
contr ol and pati ent sur vi val wer e equal to the r esul ts r epor ted wi th
standar d-fracti onati on (5.5-week) chemoradi ati on: Locor egi onal
r ecur r ence devel oped i n onl y 2 (10% ) of the 20 pati ents who
under went r esecti on, and the medi an sur vi val ti me for al l 20
pati ents was 25 months. Thi s pr otocol had mi ni mal toxi ci ty,
maxi mi zed the pr opor ti on of pati ents who r ecei ved al l components
of therapy, was si gni fi cantl y shor ter than standar d therapy, and
avoi ded pancr eati coduodenectomy on pati ents wi th metastati c
di sease on r estagi ng.
The r ol e of pr eoperati ve rapi d-fracti onati on EBRT and concomi tant
gemci tabi ne for pati ents wi th r esectabl e adenocar ci noma of the
pancr eati c head i s cur r entl y bei ng eval uated. A dose of 400 mg per
m 2 of gemci tabi ne i s admi ni ster ed weekl y for 7 weeks. A total
radi ati on dose of 30 G y i n 10 fracti ons over 2 weeks (Monday to
F r i day) i s gi ven begi nni ng 4 days after the fi r st dose of
gemci tabi ne. Pancr eati coduodenectomy i s per for med 4 weeks after
compl eti on of therapy i f r estagi ng CT demonstrates
r esectabl e di sease. So far, 69 pati ents have been enter ed i n thi s
study, and 65 have compl eted pr eoperati ve therapy. F i fty pati ents
have had sur ger y, and 42 had r esecti on. No tr eatment-r el ated
mor tal i ty has been obser ved. Tabl e 13.4 summar i zes the most
r ecent publ i shed r epor ts of adjuvant and neoadjuvant therapy for
pancr eati c cancer.
Table 13.4. Recent chemoradiation therapy st

of patients with resectable pancreatic canc
Author
(year)
Med
No. of
EBRT
Chemotherapy Surv
Patients (Gy)
(mo
Postoperative
Kalser
(1985)
21
40
5-FU
Surgery
alone
22
GITSG
(1987)
30
40
5-FU
Yeo
(1997)
120
40
57.6
5-FU
19
Surgery
alone
53
13
Klinkenbijl
(1999)
60
40
5-FU
17
Surgery
alone
54
12
132
30
50.4
5-FU,
paclitaxel or
gemcitabine
Preoperative
Breslin
(2000)
EBRT, external beam radiation therapy; 5-FU, 5fluorouracil; GITSG, Gastrointestinal Tumor Study
Group.
One potenti al bar r i er to neoadjuvant therapy for pancr eati c cancer

i s the need for stent pl acement for bi l i ar y decompr essi on. At the M.
D. Ander son Cancer Center, the rates of bi l i ar y stent-r el ated
compl i cati ons and mor tal i ty wer e eval uated i n 300 pati ents
under goi ng pr eoperati ve chemoradi ati on therapy, 207 of whom
r ecei ved stents. On mul ti var i ate anal ysi s, stent pl acement was
associ ated onl y wi th an i ncr eased rate of wound i nfecti on after
pancr eati coduodenectomy. Stents di d not r esul t i n pr ohi bi ti ve
mor bi di ty dur i ng pr eoperati ve chemoradi ati on therapy.
Investi gator s fr om our i nsti tuti on studi ed a r egi men of pr eoperati ve
EBRT (50.4 G y i n 28 fracti ons or 30 G y i n 10 fracti ons) and
concomi tant pr otracted-i nfusi on 5-F U (300 mg/m2 /day), fol l owed by
pancr eati coduodenectomy and EB-IORT (1020 G y) to the r esecti on
bed. EB-IORT was del i ver ed wi th mi ni mal mor bi di ty after
pr eoperati ve chemoradi ati on and pancr eati coduodenectomy. The
medi an sur vi val durati on i n our most r ecent r epor t was 25 months.
Di sease r ecur r ed i n 70% of the pati ents at a medi an fol l ow-up of 37
months; 86% of the r ecur r ences wer e di stant, and onl y 14% wer e
l ocor egi onal . The r esul ts of these studi es i ndi cated that EB-IORT
can be safel y combi ned wi th pancr eati coduodenectomy and cur r ent
chemoradi ati on r egi mens. Al though EB-IORT appear s to i mpr ove
l ocal contr ol , mar ked i mpr ovements i n sur vi val have not been
demonstrated. At pr esent, the use of EB-IORT
shoul d be l i mi ted to i nvesti gati onal pr otocol s. EB-IORT for l ocal l y
advanced unr esectabl e tumor s has been r epor ted to r educe
symptoms fr om advanced di sease and to pr ol ong sur vi val . A
Nati onal Cancer Insti tute contr ol l ed pr ospecti ve tr i al of adjuvant
radi ati on therapy for pancr eati c cancer exami ned the benefi t of EBIORT (20 G y) i n addi ti on to EBRT (50 G y) after r esecti on. Al though
EB-IORT di d not have an i mpact on overal l sur vi val i n thi s smal l
study, pati ents who r ecei ved EB-IORT exper i enced pr ol onged
di sease-fr ee sur vi val and i mpr oved l ocal contr ol .
Surveillance
Pati ents shoul d be seen at 3 to 4 months after potenti al l y curati ve
r esecti on of pancr eati c adenocar ci noma or ear l i er i f symptoms
devel op. Fol l ow-up vi si ts shoul d i ncl ude a thor ough hi stor y, chest
radi ograph, and abdomi nal CT.
Ther e have been numer ous attempts to i denti fy a tumor mar ker for
pancr eati c cancer. The most fr equentl y measur ed anti gens ar e
car ci noembr yoni c anti gen, CA19-9, and pancr eati c-oncofetal
anti gen. Some encouragi ng r esul ts have been r epor ted wi th use of
CA19-9 to pr edi ct r ecur r ence fol l owi ng r esecti on of pancr eati c
adenocar ci noma.
Postoperati vel y, al l pati ents r ecei ve some for m of enteral nutr i ti onal
suppl ementati on vi a a jejunostomy tube for at l east 6 weeks.
Nutr i ti onal status, i ncl udi ng ser um al bumi n l evel , di etar y hi stor y,
and general body habi tus, shoul d be car eful l y assessed at each
cl i ni c vi si t. Pati ents must al so be eval uated for si gns of
mal absor pti on r esul ti ng fr om pancr eati c enz yme i nsuffi ci ency. Thi s
i s r eadi l y tr eatabl e wi th pancr eati c enz yme r epl acement.
Palliation
Pati ents wi th unr esectabl e or r ecur r ent pancr eati c cancer fr equentl y
r equi r e pal l i ati ve tr eatment for bi l i ar y obstr ucti on, gastr i c outl et
obstr ucti on, and pai n. Hi stor i cal l y, pal l i ati on for these pati ents was
under taken at l apar otomy after a tumor was deemed unr esectabl e.
Operati ve bi l i ar y bypass, gastr i c bypass, and spl anchni cectomy ar e
effecti ve methods of pal l i ati on. However, wi th cur r ent i mpr oved
di agnosti c techni ques, unr esectabi l i ty shoul d be deter mi ned befor e
l apar otomy. Bi l i ar y di ver si on can then be achi eved ei ther
endoscopi cal l y or per cutaneousl y. G astr i c outl et obstr ucti on occur s
i n onl y 10% to 15% of pati ents and i s often a pr eter mi nal event,
and so does not mandate sur gi cal cor r ecti on. CT-gui ded al cohol
spl anchni cectomy i s an effecti ve opti on for the pal l i ati on of pai n i n
the occasi onal pati ent unr esponsi ve to nar coti cs. Ther efor e, the
sur geon can avoi d l apar otomy i n most pati ents who have a l i mi ted
l i fe expectancy.
Biliary Obstruction
Jaundi ce i s a common pr esenti ng symptom i n pati ents who have
car ci noma of the head of the pancr eas. Pr ol onged bi l i ar y obstr ucti on
l eads to coagul opathy, hepati c dysfuncti on, mal absor pti on, and
al ter ed bi l e sal t metabol i sm. Pati ents often compl ai n of sever e,
di sabl i ng pr ur i tus. Rel i ef of bi l i ar y obstr ucti on si gni fi cantl y pal l i ates
these pr obl ems and i mpr oves overal l pati ent wel l -bei ng. It i s hel pful
to gr oup pati ents wi th pancr eati c cancer i nto four
separate categor i es when consi der i ng operati ve ver sus nonoperati ve
bi l i ar y decompr essi on:
1. Pati ents i n poor heal th who woul d not tol erate l apar otomy and
ar e cl ear l y best ser ved by nonoperati ve pal l i ati ve measur es
2. Pati ents wi th concomi tant gastr i c outl et obstr ucti on who r equi r e
l apar otomy for pal l i ati on of that symptom and for whom the
benefi t of avoi di ng the compl i cati ons of a stent or transhepati c
drai n war rants the l i mi ted addi ti onal mor bi di ty of a sur gi cal
bi l i ar y bypass
3. Pati ents under goi ng operati on for r esecti on but who ar e found to
have unsuspected unr esectabl e di sease; these pati ents ar e al so
best ser ved by an operati ve bi l i ar y bypass
4. Pati ents who have unr esectabl e pancr eati c cancer on di agnosti c
eval uati on and ar e an acceptabl e medi cal r i sk for l apar otomy;
these pati ents ar e candi dates for operati ve or nonoperati ve
management, dependi ng on the judgment of the sur geon and the
exper ti se of the avai l abl e endoscopi st or i nvasi ve radi ol ogi st (At
M. D. Ander son, these pati ents ar e tr eated successful l y wi th
nonoperati ve pal l i ati ve measur es.)
Sur gi cal bi l i ar y di ver si on can be accompl i shed by ei ther
chol edochoenter i c or chol ecystenter i c bypass. Constr ucti ng a Roux
l i mb r equi r es an addi ti onal anastomosi s and l onger operati ve ti me
than maki ng a si mpl e l oop of smal l bowel for bi l i ar y bypass. Roux
r econstr ucti on i s necessar y when an unr esectabl e tumor pr events a
l oop fr om r eachi ng the r i ght upper quadrant wi thout tensi on. Most
author i ti es advocate ei ther l oop chol edochojejunostomy or
chol ecystojejunostomy for sur gi cal pal l i ati on of mal i gnant bi l i ar y
obstr ucti on. Chol ecystojejunostomy has the advantage of bei ng
si mpl e to per for m; however, ther e i s the possi bi l i ty of r ecur r ent
bi l i ar y obstr ucti on after thi s pr ocedur e. The advantage of
chol edochojejunostomy i s that i t pr ovi des a mor e pr oxi mal bi l i ar y
anastomosi s and ther efor e obstr ucti on by pr ogr essi ve extensi on of
the tumor i s l ess l i kel y. The hi gh operati ve mor tal i ty and shor t
medi an sur vi val associ ated wi th each pr ocedur e ar e due to the
aggr essi ve natur e of the mal i gnancy rather than to the techni que
used. The choi ce of sur gi cal opti on ul ti matel y depends on l ocal
tumor consi derati ons and the sur geon's exper i ence.
Nonoperati ve pal l i ati ve bi l i ar y decompr essi on can be accompl i shed
endoscopi cal l y or per cutaneousl y. Exper i enced endoscopi sts r epor t a
success rate of gr eater than 90% . In randomi zed studi es compar i ng
endoscopi c bi l i ar y decompr essi on wi th conventi onal sur gi cal bypass,
the pr ocedur es have r esul ted i n i denti cal sur vi val ti mes and r el i ef of
jaundi ce. Total hospi tal stay i s al so si mi l ar for the two pr ocedur es
because of the need for occasi onal r eadmi ssi ons to change stents
after endoscopi c decompr essi on. Per cutaneous transhepati c bi l i ar y
drai nage has pr ovi ded successful pal l i ati on i n 80% to 90% of
pati ents. Exter nal catheter s ar e bei ng r epl aced by newer i ndwel l i ng
endopr ostheses, whi ch ar e associ ated wi th a l ower rate of i nfecti ous
compl i cati ons. Al though endoscopi c bi l i ar y decompr essi on i s the
pr efer r ed method of
nonoperati ve pal l i ati on, the choi ce of techni que depends on the
exper ti se avai l abl e.
We use a sel ecti ve appr oach to bi l i ar y decompr essi on. Outpati ent
endoscopi c stenti ng i s per for med i n al l pati ents who ar e not
candi dates for pancr eati coduodenectomy. In pati ents wi th a l i fe
expectancy of 3 to 5 months (i .e., those wi th poor per for mance
status or l i ver or per i toneal metastases), an 11.5F pol yethyl ene
stent i s pl aced. In pati ents wi th a l i fe expectancy of 6 to 12 months
(i .e., those wi th l ocal l y advanced, nonmetastati c di sease), a sel fexpandi ng metal stent i s pr efer r ed. However, pati ents i n whom ear l y
stent occl usi on or mi grati on devel ops or who by cl i ni cal cr i ter i a
appear to do poor l y wi th endoscopi c bi l i ar y decompr essi on ar e
qui ckl y r efer r ed for operati ve bi l i ar y bypass. A mul ti di sci pl i nar y
appr oach to these pati ents i s cr i ti cal the medi cal oncol ogi st,
gastr oenter ol ogi st, and sur geon must communi cate and avoi d over l y
dogmati c appr oaches to pal l i ati ve car e.
Gastric Outlet Obstruction

Pati ents wi th pancr eati c cancer rar el y pr esent wi th duodenal
obstr ucti on. F ur ther mor e, l ess than 15% of pati ents wi l l r equi r e
operati ve cor r ecti on of gastr i c outl et obstr ucti on befor e death.
Cl ear l y, pati ents wi th unr esectabl e di sease and gastr i c outl et
obstr ucti on r equi r e a gastr ojejunostomy for pal l i ati on. Ther e i s
contr over sy about whether al l pati ents under goi ng pal l i ati ve
l apar otomy shoul d under go pr ophyl acti c gastr oenter ostomy.
Compl i cati ons r esul ti ng fr om the l onger sur ger y and the addi ti onal
anastomosi s ar e mi ni mal . However, the i nci dence of subsequent
duodenal obstr ucti on i n asymptomati c pati ents who under go onl y
bi l i ar y bypass i s l ow. In addi ti on, gastr i c outl et obstr ucti on often
occur s shor tl y befor e death and does not r equi r e tr eatment. In
general , we do not per for m pr ophyl acti c sur ger y i n pati ents wi th
pancr eati c cancer.
If a pati ent i s found to have unr esectabl e di sease dur i ng sur ger y for
pl anned pancr eati coduodenectomy, gastr ojejunostomy i s consi der ed
when cl i ni cal symptoms or anatomi cal fi ndi ngs suggest i mpendi ng
obstr ucti on. However, i n pati ents wi th l ocal l y advanced or l i mi ted
metastati c di sease wi th good per for mance status, pr ospecti ve
randomi zed data woul d suppor t the cr eati on of a gastr ojejunostomy.
Noninvasive Pancreatic Lesions

Several types of noni nvasi ve l esi ons of the pancr eas have been
character i zed that can be pr ecur sor s to i nvasi ve adenocar ci noma of
the pancr eas. These l esi ons i ncl ude pancr eati c i ntraepi thel i al
neopl asi a (PanINs), i ntraductal papi l l ar y muci nous neopl asms
(IPMNs), and muci nous cysti c neopl asms. Onl y r ecentl y have these
l esi ons been cl ear l y defi ned by an i nter nati onal l y accepted set of
di agnosti c cr i ter i a. A mor e thor ough under standi ng of the mol ecul ar
natur e of these l esi ons may pr ovi de a means of ear l y di agnosi s and
mor e effecti ve tr eatment.
Pancreatic Intraepithelial Neoplasia

PanINs ar e character i zed as mi cr oscopi c pancr eati c duct l esi ons
wi thout i nvasi on thr ough the basement membrane. The grade of
PanIN l esi ons ranges fr om 1 thr ough 3, based on factor s such
as the pr esence of a papi l l ar y component, nucl ear abnor mal i ty,
pr esence of mi toses, and necr osi s. The PanIN-1 l esi ons ar e often
i nci dental fi ndi ngs and can be i denti fi ed i n 40% of i ndi vi dual s
wi thout pancr eati c car ci noma. However, PanIN-3 l esi ons ar e found
i n 30% to 50% of i ndi vi dual s wi th i nvasi ve pancr eati c ductal
adenocar ci noma, suggesti ng that hi gh-grade PanIN l esi ons ar e
pr ecur sor s of i nvasi ve car ci noma. A ser i es of mol ecul ar aber rati ons
have been i denti fi ed wi th PanIN l esi ons to for m a model for the
devel opment and pr ogr essi on of pancr eati c cancer.
Intraductal Papillary Mucinous Neoplasm

IPMNs ar e i ntraductal neopl asms ar i si ng i n the mai n pancr eati c
duct, pancr eati c si de branches, or both, wi th cysti c for mati on and
var i abl e degr ees of muci n secr eti on. The cur r ent Wor l d Heal th
Or gani z ati on gradi ng system cl assi fi es IPMNs as adenomas,
bor der l i ne tumor s, or i ntraductal papi l l ar y muci nous car ci noma
based on the degr ee of dyspl asi a, nucl ear abnor mal i ty, and other
pathol ogi cal featur es. Al though IPMNs and PanINs shar e many
pathol ogi cal character i sti cs, most IPMNs ar e cl i ni cal l y detectabl e,
wher eas PanINs ar e often i nci dental fi ndi ngs detected
mi cr oscopi cal l y. IPMN l esi ons ar e usual l y gr eater than 1 cm i n
di ameter and can be typi cal l y i denti fi ed radi ographi cal l y by
pancr eati c ductal di l atati on. F ur ther mor e, IPMNs often pr oduce
l ar ge amounts of muci n that can be vi sual i zed endoscopi cal l y.
IPMNs, par ti cul ar l y those ar i si ng fr om the mai n pancr eati c duct, can
be associ ated wi th i nvasi ve car ci noma. When IPMN i s associ ated
wi th an i nvasi ve car ci noma, the pr ognosi s i s si gni fi cantl y wor se
than IPMN wi th i nvasi ve car ci noma.
Cystic Neoplasms
Cysti c neopl asms of the pancr eas account for appr oxi matel y 1% of
al l pancr eati c cancer s and 10% of al l pancr eati c cysti c l esi ons.
These tumor s ar e typi cal l y l ar ge, ar e l ocated i n the di stal pancr eas,
and affect women thr ee ti mes mor e fr equentl y than men. The
di agnosi s of a cysti c neopl asm or IPMN must be consi der ed i n
pati ents wi th radi ographi c evi dence of a pancr eati c cyst and no pr i or
symptoms or hi stor y of pancr eati ti s. Muci nous cysti c neopl asms
shoul d be di sti ngui shed fr om IPMNs by the pr esence of ovar i an-type
str oma and the absence of ductal i nvol vement.
Cysti c neopl asms wi th a cuboi dal epi thel i al l i ni ng (ser ous
cystadenoma) have no mal i gnant potenti al . When a col umnar
epi thel i al l i ni ng i s pr esent i n the cyst wal l , the l esi on i s frankl y
mal i gnant (muci nous cystadenocar ci noma) or pr emal i gnant
(muci nous cysti c neopl asm).
It i s often i mpossi bl e to di sti ngui sh mal i gnant fr om beni gn cysti c
neopl asms pr eoperati vel y or i ntraoperati vel y because the epi thel i al
l i ni ng i s often i ncompl ete. Ther efor e, al l cysti c neopl asms shoul d be
r esected for potenti al cur e. Pati ents wi th mal i gnant cysti c
neopl asms who under go compl ete r esecti on have a 40% to 60% 5year sur vi val rate. Tabl e 13.5 offer s cl i ni cal and l aborator y tool s to
hel p di ffer enti ate i nfl ammator y pseudocysts fr om neopl asti c cysti c
l esi ons of the pancr eas.
Table 13.5. Differentiation of inflammatory p

from cystic neoplasms of the pancre
Patient History,
CT and FNA
Findings
Mucinous
Serous
In
Neoplasm
Cystadenoma Ps
(Adenoma
or
Carcinoma)
History of
pancreatitis,
alcohol abuse,
complicated
biliary disease
No
No
Ye
CT
Small
number
(6) of
large cysts
(>2 cm)
Many small
cysts
Cyst fluid
analysis/cytology
Positive for
mucin;
malignant
(if
carcinoma)
No mucin;
positive for
glycogen
Cyst fluid CEA

(ng/mL)
Usually
>500;
highly
variable
<5
>
el
u
Cyst fluid
amylase (U/mL)
50%
>2,000;
variable
<5,000
>
CT, computed tomography; FNA, fine-needle aspira

carcinoembryonic antigen.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 4 - Pa nc re a t ic Endo c rine Tum o rs a nd M ult iple Endo c rine
Ne o pla s ia
14
Pancreatic Endocrine Tumors and
Multiple Endocrine Neoplasia
Jeffrey T. Lenert
Richard J. Bold
Jeffrey J. Sussman
Douglas S. Tyler
Pancreatic Endocrine Tumors

Pancr eati c endocr i ne tumor s ar e r el ati vel y rar e, wi th appr oxi matel y
fi ve cl i ni cal l y r ecogni zed cases occur r i ng per one mi l l i on peopl e
annual l y. However, some ser i es of car eful l y per for med, unsel ected
autopsi es have demonstrated an i nci dence as hi gh as 0.5% to 1.5% .
Many of these tumor s ar e functi onal and pati ents pr esent wi th
symptoms attr i butabl e to excess hor mone pr oducti on and secr eti on.
The tumor s tend to ar i se i n the i sl et cel l s of the pancr eas but can
al so be l ocated i n the smal l bowel , especi al l y the duodenum, and i n
other i ntraabdomi nal si tes. Al though the i sl et cel l s have l ong been
thought to be of neural cr est or i gi n because of metabol i c
character i sti cs shar ed wi th other cel l s of neur oectoder mal or i gi n,
speci fi cal l y the ami ne pr ecur sor uptake and decar boxyl ati on (APUD)
cel l s, mor e r ecent studi es suggest they may be of endoder mal or i gi n
(e.g., pancr eati c ductal epi thel i um).
Isl et cel l tumor s ar e usual l y di vi ded i nto functi oni ng and
nonfuncti oni ng tumor s. Mor e than 75% of the i sl et cel l tumor s
di agnosed cl i ni cal l y ar e functi oni ng and fr equentl y pr oduce, and
often secr ete, mor e than one hor mone. The tumor s ar e categor i zed
by the major hor mone pr oduci ng the cl i ni cal syndr ome. The
hor mones may i ncl ude gastr i n, i nsul i n, gl ucagon, somatostati n,
neur otensi n, pancr eati c pol ypepti de (PP), vasoacti ve i ntesti nal
pol ypepti de (VIP), gr owth hor mone-r el easi ng factor (G RF ), and

adr enocor ti cotr opi c hor mone (ACTH). The tumor s ar e consi der ed
entopi c, or or thoendocr i ne, i f they pr oduce hor mones or pepti des
usual l y found wi thi n the pancr eas (e.g., i nsul i nomas, gl ucagonomas,
somatostati nomas, and PPomas) or ectopi c (paraendocr i ne) i f the
hor mones or pepti des ar e not nati ve to the nor mal pancr eas (e.g.,
gastr i nomas, VIPomas, G RFomas, neur otensi nomas, and ACTHoma).
An over vi ew of the character i sti cs of pancr eati c endocr i ne tumor s i s
shown i n Tabl e 14.1.
The di agnosi s of pancr eati c endocr i ne tumor s i s usual l y made by the
r ecogni ti on of the cl i ni cal syndr ome caused by excess hor mone
secr eti on. The speci fi c hor mone excess al so al l ows assessment of a
pati ent's r esponse to therapy and pr ovi des a mechani sm for
obser vi ng the l ong-ter m status of the di sease. However, PPomas and
nonfuncti oni ng i sl et cel l tumor s do not secr ete cl i ni cal l y appar ent
hor mones and hence ar e di agnosed as a r esul t of mass-effect
symptoms or as an i nci dental fi ndi ng on computed tomography (CT)
scans of the abdomen for unr el ated r easons. Unl i ke i n pati ents wi th
functi oni ng neur oendocr i ne tumor s, r esponse to tr eatment and
l ong-ter m fol l ow-up of pati ents wi th
nonfuncti oni ng tumor s i s not ai ded by measur ement of hor mones

speci fi c to the tumor i n questi on; however, mor e general tumor
mar ker s can be used. F uncti oni ng and nonfuncti oni ng pancr eati c
neur oendocr i ne tumor s secr ete several tumor mar ker s, i ncl udi ng
chr omograni ns, PP, and subuni ts of human chor i oni c gonadotr opi n.
Chr omograni n A (CgA) i n par ti cul ar may be a useful mar ker to
suppl ement speci fi c mar ker s i n functi oni ng tumor s and may be
useful by i tsel f or wi th other general mar ker s when tumor s ar e
nonfuncti oni ng. Hi stol ogi c di agnosi s of the i sl et cel l tumor can be
obtai ned wi th CT-gui ded fi ne-needl e aspi rati on, al though thi s i s
often not r equi r ed, gi ven the syndr ome of pancr eati c hor monal
excess and a l ocal i z i ng study. (See Tabl e 14.2 for the di str i buti on of
these tumor s wi thi n the pancr eas.)
Table 14.1. Characteristics of pancre

Hormone
Pancreatic Clin
Tumor Name
Secreted
Cell Type
Syn
Gastrinoma
Gastrin
D or D
variant
Pep
diar
Hyp
neu
sym
adr
exc
sym
Wat
diar
ach
hyp
Insulinoma
Insulin
VIPoma
Vasoactive
intestinal
peptide
Glucagonoma
Glucagon
Hyp
der
(ne
mig
ery
cac
thro
Ppoma
Pancreatic
polypeptide
PP
Non
or
Hyp
Ste
Gal
Somatostatinoma
Somatostatin
GRFoma
Growth hormonereleasing factor
ACTHoma
Adrenocorticotropic
hormone
PTHrp-oma
Parathyroid hormonerelated protein
Nonfunctioning
None
Non
GERD, gastroesophageal reflux disease; MEN 1, mu
Table 14.2. Anatomic distribution of pancrea

tumors within the pancreas (head, body, and
the extrapancreatic tissue, including the
Tumor
Head Body Tail Extrapancr

(%) (%) (%)
Gastrinoma
30
12
14
Insulinoma
25
41
33
Glucagonoma
23
37
40
PP-secreting
tumor
52
14
14
Somatostatinoma
62
12
Adapted from Howard TJ, Stabile BE, Zinner MJ, et

distribution of pancreatic endocrine tumors. Am J S
1990;159:258.
a More recent series show that two-thirds are extrap
In general , pancr eati c endocr i ne tumor s ar e mor e i ndol ent than
ductal adenocar ci noma and car r y a better pr ognosi s; even pati ents
wi th hepati c metastasi s may have a mean sur vi val ti me of 5 year s.
Gastrinoma: Zollinger-Ellison Syndrome

In 1955, Zol l i nger and El l i son descr i bed a syndr ome character i zed
by the tr i ad of sever e, atypi cal pepti c ul cerati on; gastr i c
hyper secr eti on and hyperaci di ty; and a non-i nsul i npr oduci ng i sl et
cel l tumor of the pancr eas. They theor i zed that a humoral factor
ar i si ng fr om the tumor was r esponsi bl e for the syndr ome. Several
year s l ater, the hor mone gastr i n was di scover ed and found to be the
under l yi ng cause of the pepti c hyperaci di ty, and the ter m Zol l i ngerEl l i son syndr ome (ZES) was appl i ed to the cl i ni cal compl ex.
Epidemiology
At l east 0.1% of pati ents wi th duodenal ul cer di sease and
appr oxi matel y 2% of pati ents wi th r ecur r ent ul cer s after
appr opr i ate medi cal therapy ar e found to have a gastr i noma,
maki ng i t the most common functi oni ng mal i gnant pancr eati c
endocr i ne tumor. Appr oxi matel y 75% of gastr i nomas occur
sporadi cal l y; the r emai ni ng 25% ar e associ ated wi th the mul ti pl e
endocr i ne neopl asi a type 1 syndr ome (MEN 1). The mean age at
onset of
symptoms i s 50 year s, and appr oxi matel y 60% of those di agnosed
wi th ZES ar e men. G astr i nomas that occur as par t of MEN 1 ar e
mor e often beni gn, mul ti centr i c, and extrapancr eati c and occur at
an ear l i er age than sporadi c gastr i nomas. In mor e than hal f of the
pati ents wi th MEN 1 syndr ome, the pancr eati c tumor s ar e
gastr i nomas.
Hi gh l evel s of gastr i n sti mul ate the par i etal cel l s wi thi n the stomach
to secr ete excess aci d i n an unr egul ated state. Thi s l eads to sever e
ul cer di athesi s and i njur y to the smal l bowel mucosa wel l past the
l i gament of Tr ei tz , r esul ti ng i n var yi ng degr ees of mal absor pti on.
Pr ofuse water y di ar r hea occur s i n up to 50% of pati ents because of
the combi nati on of aci d hyper secr eti on and smal l bowel mucosal
i njur y. In addi ti on to secr eti ng gastr i n, the major i ty of gastr i nomas
secr ete at l east one other pepti de hor mone, such as i nsul i n, PP,
gl ucagon, or even ACTH.
The cl i ni cal mani festati ons of gastr i nomas ar e al most i nvar i abl y due
to hyper gastr i nemi a. Ni nety per cent of pati ents have endoscopi cal l y
documented ul cerati ons of the upper gastr oi ntesti nal (G I) tract.
Most of these ul cer s ar e accompani ed by abdomi nal pai n, whi ch i s
the most fr equent si ngl e symptom. Bl eedi ng occur s i n 30% to 50%
of pati ents and per forati on i n 5% to 10% . Secr etor y di ar r hea i s the
onl y cl i ni cal mani festati on of the syndr ome i n 20% of pati ents,
al though di ar r hea and pai n i n combi nati on i s mor e fr equent than
ei ther symptom al one. Symptoms of gastr oesophageal r efl ux di sease
ar e al so bei ng r ecogni zed mor e often i n associ ati on wi th ZES. The
syndr ome i s often i ni ti al l y mi sdi agnosed due to the fr equency of
typi cal pepti c ul cer di sease (PUD) and a br oad di ffer enti al di agnosi s.
The mean durati on of symptoms befor e di agnosi s i s often several
year s. Cl i ni cal si tuati ons i n whi ch ZES shoul d be suspected and the
di ffer enti al di agnoses ar e l i sted i n Tabl es 14.3 and 14.4.
Table 14.3. Clinical situations warranting

further evaluation for gastrinoma
Recurrent peptic ulcers after appropriate
medical or surgical therapy
Failure of peptic ulcer to heal on appropriate
medical therapy, including treatment for H.
pylori if present
Multiple UGI ulcers or ulcers in atypical
locations
Family history of PUD
Persistent diarrhea without clear etiology
Peptic ulcer in the absence of H. pylori
Personal or family history of MEN 1 tumors or
endocrinopathies
Prominent gastric rugae with PUD
PUD resulting in complication (bleeding,
perforation, obstruction)
GERD, gastroesophageal reflux disease; MEN 1,
multiple endocrine neoplasia type 1; PUD,
peptic ulcer disease; UGI, upper
gastrointestinal.
Table 14.4. Differential diagnosis of

hypergastrinemia and gastric
hypersecretion
H. pylori infection
Gastric outlet obstruction
Antral G-cell hyperfunction/hyperplasia
Chronic renal failure
Retained gastric antrum syndrome
Short bowel syndrome
Zollinger-Ellison syndrome
Adapted from Jensen RT. Zollinger-Ellison
syndrome. In: Doherty GM, Skgseid B, eds.
Surgical endocrinology. Philadelphia: Lippincott

Williams & Wilkins, 2001.
Biochemical Diagnosis
The di agnosi s of gastr i noma r equi r es confi r mati on wi th l aborator y
studi es. A fasti ng ser um gastr i n measur ement shoul d be the fi r st
test obtai ned and i s i ncr eased i n gr eater than 90% of pati ents wi th
gastr i noma (nor mal i s 100200 pg/mL). A l evel gr eater than 1,000
pg/mL i s usual l y di agnosti c of a gastr i noma and i s seen i n
appr oxi matel y 30% of pati ents. Most pati ents wi th gastr i nomas have
mor e moderate el evati on of fasti ng gastr i n l evel s (i n the 2001,000
pg/mL range). In addi ti on to hyper gastr i nemi a, gastr i c aci d
hyper secr eti on i s r equi r ed for the di agnosi s of gastr i noma because
hyper gastr i nemi a i s a nor mal physi ol ogi c r esponse to achl or hydr i a
or hypochl or hydr i a. Documentati on of a gastr i c pH l ess than 2.5
r ul es out thi s physi ol ogi c r esponse as the cause of
hyper gastr i nemi a. One thi r d of pati ents wi th gastr i noma wi l l have
ser um gastr i n l evel s gr eater than 1,000 pg/mL and a gastr i c pH l ess
than 2.5, whi ch confi r ms the di agnosi s. In the r emai ni ng two thi r ds,
measur ement of gastr i c aci d output i s r equi r ed. Typi cal l y, pati ents
wi th gastr i nomas have a basal aci d output of mor e than 15
mEq/hour or gr eater than 5 mEq/hour i f they have had a pr evi ous
ul cer operati on ai med at r educi ng gastr i c aci d secr eti on. A basal
aci d output/maxi mal aci d output rati o gr eater than 0.6 al so hel ps
suppor t the di agnosi s of gastr i noma.
Pr ovocati ve testi ng usi ng the secr eti n sti mul ati on test hel ps confi r m
the di agnosi s i n pati ents wi th mor e moderate hyper gastr i nemi a
(2001,000 pg/mL) and gastr i c aci d hyper secr eti on. After an
over ni ght fast, the pati ent i s gi ven 2 uni ts of secr eti n per ki l ogram
of body wei ght i ntravenousl y. Ser um gastr i n l evel s ar e measur ed at
15 and 2 mi nutes befor e secr eti n i njecti on and 0, 2, 5, 10, and 20
mi nutes fol l owi ng i njecti on. A paradoxi cal i ncr ease i n the ser um
concentrati on of gastr i n by mor e than 200 pg/mL over basel i ne
l evel s i s di agnosti c of gastr i noma. Pati ents wi th ei ther antral G -cel l
hyper pl asi a or hyper tr ophy do not r espond to secr eti n i njecti on,
al though they do have postprandi al gastr i n el evati on.
Tumor Localization
Tumor l ocal i z ati on has become i ncr easi ngl y i mpor tant i n r ecent
year s wi th the demonstrati on that r esecti on of gastr i nomas

i s associ ated wi th an excel l ent pr ognosi s and i s fr equentl y curati ve.
Hi stor i cal l y, numer ous tests have been used to l ocal i ze gastr i nomas
pr eoperati vel y, often wi thout a wel l -desi gned strategy. Thi s
appr oach has used any, and fr equentl y many, of the fol l owi ng
modal i ti es: CT scans, magneti c r esonance i magi ng (MRI),
transabdomi nal ul trasound, sel ecti ve vi sceral angi ography, sel ecti ve
venous sampl i ng of por tal venous tr i butar i es, i ntraar ter i al secr eti n
wi th hepati c venous sampl i ng for gastr i n, and conventi onal upper
endoscopy. Two newer di agnosti c methodssomatostati n r eceptor
sci nti graphy (SRS) and endoscopi c ul trasonography (EUS)ar e now
compl ementi ng, and often r epl aci ng, the mor e tradi ti onal
l ocal i z ati on techni ques. SRS, whi ch takes advantage of the pr esence
of hi gh-affi ni ty somatostati n r eceptor s on the major i ty of pancr eati c
endocr i ne tumor s, has been shown to have a sensi ti vi ty and
speci fi ci ty as hi gh as 90% and 80% , r especti vel y, equal to or
gr eater than those for al l other conventi onal l ocal i z i ng techni ques
combi ned (CT, MRI, US, angi ography). The one r el ati ve weakness of
SRS i s i n detecti ng smal l duodenal gastr i nomas: i t has been
r epor ted to mi ss up to one thi r d of such l esi ons ul ti matel y i denti fi ed
sur gi cal l y. Because mor e than hal f of al l l esi ons i n r ecent sur gi cal
ser i es have been duodenal gastr i nomas, EUS has shown pr omi se i n
compl ementi ng the i nfor mati on gai ned by SRS. Endoscopi c
ul trasound can l ocal i ze up to hal f of duodenal l esi ons as wel l as
most pancr eati c gastr i nomas. The combi nati on of SRS and EUS
shoul d al l ow pr eoperati ve l ocal i z ati on of most extrahepati c
gastr i nomas. When both of these studi es ar e negati ve, an
i ntraar ter i al secr eti n i njecti on wi th hepati c venous sampl i ng for
gastr i n i s r ecommended by some because of i ts hi gh sensi ti vi ty
(appr oxi matel y 89% ) and abi l i ty to detect l esi ons i ndependent of
si ze, a drawback wi th SRS and EUS. CT and MRI can be used to
addr ess speci fi c questi ons, i f necessar y (e.g., extent of l i ver
metastases).
The i ntr oducti on of SRS and EUS has cl ear l y i mpr oved pr eoperati ve
l ocal i z ati on; sti l l , up to one thi r d of pati ents at exper i enced
i nsti tuti ons wi l l under go expl orati on when pr eoperati ve i magi ng i s
negati ve. Al though somewhat contr over si al , sur gi cal expl orati on i s
war ranted i n pati ents wi th sporadi c gastr i noma wi thout di ffuse l i ver
metastases, even wi thout successful pr eoperati ve l ocal i z ati on. Thi s
scenar i o under scor es the need for a car eful operati ve strategy to
ensur e i denti fi cati on of the l esi ons to be r esected.
Because most gastr i nomas ar e found i n the gastr i noma tr i angl e (an
anatomi c ar ea bounded by the juncti on of the body and neck of the
pancr eas medi al l y, the juncti on of the second and thi r d por ti on of
the duodenum i nfer i or l y, and the juncti on of the cysti c duct and
common bi l e duct super i or l y), the operati ve focus i s on thi s r egi on.
However, one must r emember that pr i mar y gastr i nomas can be
found i n numer ous si tes, i ncl udi ng the l ymph nodes, stomach,
jejunum, mesenter y, l i ver, ovar y, and ki dney. The combi ned use of
an extensi ve Kocher maneuver for bi manual pal pati on of the
pancr eati c head and i ntraoperati ve ul trasonography detects vi r tual l y
al l i ntrapancr eati c l esi ons. Detecti on of duodenal l esi ons r equi r es
mor e effor t. Intraoperati ve endoscopy wi th duodenal
transi l l umi nati on wi l l i ncr ease the duodenal gastr i noma
detecti on rate above that of pal pati on and i ntraoperati ve
ul trasound, but the keysome woul d advocate mandator y
maneuver i s duodenotomy wi th car eful pal pati on of the duodenal
wal l . The use of these i ntraoperati ve techni ques has r esul ted i n the
abi l i ty to i denti fy near l y al l gastr i nomas (i ncl udi ng fai r l y smal l
tumor s, <5 mm) and essenti al l y el i mi nated the nonpr oducti ve
l apar otomy. A fi nal i ntraoperati ve techni que usi ng the gamma pr obe
and radi ol abel ed octr eoti de to detect mi cr oscopi c and other wi se
undetected abdomi nal neur oendocr i ne tumor s i s cur r entl y bei ng
eval uated.
Treatment
Once the di agnosi s of gastr i noma i s suspected, the fi r st step i s to
contr ol the gastr i c aci d hyper secr eti on and i ts end-or gan effects.
After i ni ti ati on of appr opr i ate medi cal therapy, defi ni ti ve di agnosi s
and eval uati on may pr oceed. Total gastr ectomy war rants onl y a
hi stor i cal note and i s rar el y i ndi cated because effecti ve medi cal
tr eatment i s now r eadi l y avai l abl e. Hi stor i cal l y, total gastr ectomy
ser ved as the onl y modal i ty to el i mi nate the potenti al l y l ethal
sequel ae of gastr i c hyper secr eti on. H2 -bl ocker s i ni ti al l y contr ol aci d
secr eti on i n most pati ents wi th gastr i nomas, but over ti me most of
these i ndi vi dual s r equi r e i ncr easi ng dosages. In addi ti on, up to 65%
of pati ents, dependi ng on the ser i es, wi l l fai l to r espond to thi s for m
of medi cal therapy. On the other hand, omeprazol e, a gastr i c pr oton
pump i nhi bi tor, i s associ ated wi th a consi derabl y l ower fai l ur e rate
(0% 7.5% ) and a mor e conveni ent dosi ng schedul e. Omeprazol e, or
one of the newer pr oton pump i nhi bi tor s (e.g., l ansoprazol e,
pantoprazol e), i s cur r entl y the dr ug of fi r st choi ce. Long-ter m use
may l ead to dr ug-i nduced achl or hydr i a or hypochl or hydr i a wi th

r esul tant vi tami n B12 defi ci ency. Si mi l ar l y, the questi on of
i ncr eased i nci dence of gastr i c car ci noi dspar ti cul ar l y i n pati ents
wi th MEN 1has yet to be r esol ved sati sfactor i l y. The somatostati n
anal ogue, octr eoti de acetate, or the l onger-acti ng l antr eoti de, may
al so be useful for symptomati c r el i ef by decr easi ng the r el ease of
gastr i n and other pepti de hor mones fr om gastr i nomas and di r ectl y
i nhi bi ti ng gastr i c par i etal cel l s.
In a pati ent wi th a sporadi c gastr i noma, sur gi cal expl orati on wi th
attempted curati ve r esecti on shoul d fol l ow l ocal i z ati on studi es
r egar dl ess of whether the tumor i s i denti fi ed pr eoperati vel y.
Because as many as 10% to 40% of tumor s may not be l ocal i zed
befor e sur ger y, a standar di zed appr oach to expl orati on shoul d be
under taken. The expl orati on shoul d be done thr ough a bi l ateral
subcostal i nci si on and the abdomen compl etel y expl or ed for
evi dence of metastasi s, especi al l y the r egi onal l ymph nodes and the
l i ver, because up to 50% of gastr i nomas ar e mal i gnant wi th
demonstrabl e di sease at expl orati on. A compl ete mobi l i z ati on of the
pancr eas i s essenti al to al l ow i nspecti on and pal pati on of the gl and.
Any suspi ci ous l ymph node or mass shoul d be eval uated by fr ozensecti on exami nati on, as i t i s uncl ear whether sur gi cal r esecti on i n
the pr esence of metastasi s pr ol ongs sur vi val or al l evi ates medi cal
management of gastr i c hyper secr eti on. Some gr oups do r ecommend
aggr essi ve debul ki ng of al l tumor deposi ts i f they ar e unr esectabl e
because sur vi val may be i mpr oved and medi cal
management of the aci d di sease may be better contr ol l ed.
Intraoperati ve ul trasound may hel p i denti fy i ntrapancr eati c l esi ons,
whi l e i ntraoperati ve endoscopy wi th transi l l umi nati on of the
duodenal wal l may hel p to i denti fy duodenal gastr i nomas. If no
tumor i s i denti fi ed, a l ongi tudi nal duodenotomy shoul d be made i n
the second por ti on of the duodenum. Car eful bi manual exami nati on
of the bowel wal l , al ong wi th i ts ever si on, hel ps i denti fy duodenal
gastr i nomas, whi ch ar e fr equentl y l ocated submucosal l y wi th
decr easi ng fr equency fr om the pr oxi mal to the di stal duodenum.
When the tumor i s smal l (<2 cm), duodenal gastr i nomas can be
r esected wi th a smal l mar gi n of nor mal ti ssue, wher eas pancr eati c
gastr i nomas shoul d be enucl eated, i f possi bl e, par ti cul ar l y i n the
head of the pancr eas. Lar ger tumor s often r equi r e pancr eati c
r esecti on, ei ther di stal pancr eatectomy or
pancr eati coduodenectomy, par ti cul ar l y wi th tumor s that ar e cl ear l y
i nvasi ve or abut cr i ti cal ductal or vascul ar str uctur es.
Despi te extensi ve pr eoperati ve l ocal i z i ng studi es and car eful

sur gi cal expl orati on, the tumor of some pati ents cannot be
i denti fi ed even at l apar otomy. Bl i nd pancr eati c head r esecti on i s
contr over si al , especi al l y gi ven the di chotomous natur e of
gastr i noma wher eby 75% of tumor s pur sue a fai r l y nonaggr essi ve
cour se. Pati ents wi th ZES i n whom no tumor i s found have an
excel l ent pr ognosi s, wi th 5- and 10-year sur vi val rates of mor e than
94% and 87% , r especti vel y. If gastr i c hyper secr eti on r emai ns
pr obl emati c despi te maxi mal medi cal management, consi derati on
may be gi ven to per for mi ng a hi ghl y sel ecti ve vagotomy. Total
gastr ectomy shoul d be consi der ed i n pati ents who have had pr evi ous
l i fe-thr eateni ng compl i cati ons fr om thei r ul cer di sease despi te
appr opr i ate medi cal management.
Medi cal management of ZES i n pati ents wi th MEN 1 can be mor e
di ffi cul t because of decr eased sensi ti vi ty to anti secr etor y dr ugs,
especi al l y H2 -bl ocker s. Parathyr oi dectomy and contr ol of
hyper cal cemi a can i ncr ease the potency of both pr oton pump
i nhi bi tor s and H2 -bl ocker s. The r ol e of sur ger y i n pati ents wi th ZES
and MEN 1 i s contr over si al . Resecti on of gastr i nomas i n pati ents
wi th MEN 1 rar el y r esul ts i n nor mal ser um gastr i n l evel s, suggesti ng
that the pr obabi l i ty of cur i ng these pati ents wi th sur ger y i s
extr emel y l ow. However, pati ents wi th MEN 1 tend to exper i ence the
l ess aggr essi ve di sease pr ocess and have a consi derabl y l ong
sur vi val ti me even wi thout compl ete sur gi cal r esecti on. As a r esul t,
many author i ti es have r ecommended that pati ents wi th MEN 1 and
gastr i nomas do not under go expl orati on. Other gr oups thi nk that
r esecti on of l ocal i zed, l ar ger (>2.53 cm) tumor s may hel p r educe
the r i sk of di stant metastati c di sease and pr esumabl y al ter the
natural hi stor y of the di sease; ther efor e, they r ecommend that
pati ents wi th MEN 1 under go expl orati on. Mor e extensi ve r esecti ons
ar e general l y di scouraged because of the mor e favorabl e natural
hi stor y, i n addi ti on to the pr obl emati c pr esence of mul ti pl e,
synchr onous, nonfuncti oni ng pancr eati c endocr i ne tumor s, the
pr ognosti c effect of whi ch i s uncl ear.
Metastatic Disease
Now that medi cal tr eatment of gastr i c aci d hyper secr eti on i n ZES i s
so effecti ve, pati ents rar el y di e fr om compl i cati ons r el ated to PUD.
As a r esul t, they l i ve l onger, onl y to di e fr om metastati c
di sease. G i ven the pr opensi ty of mal i gnant gastr i nomas to
metastasi ze to the l i ver, i t i s not sur pr i si ng that pati ents ul ti matel y
di e of l i ver fai l ur e. When feasi bl e (appr oxi matel y 15% of the ti me),
cytor educti ve hepati c r esecti on can pl ay a si gni fi cant r ol e i n
pal l i ati on of metastati c gastr i noma, often i mpr ovi ng symptoms and
extendi ng l i fe expectancy. When debul ki ng pr ocedur es ar e not
practi cal , nonsur gi cal therapy i s often tar geted di r ectl y at the l i ver
i n the for m of per i pheral hepati c ar ter y embol i z ati on or
chemoembol i z ati on and, i n ver y sel ected cases, hepati c
transpl antati on. Hepati c ar ter y embol i z ati on wi th or wi thout
chemotherapeuti c or radi otherapeuti c agents takes advantage of the
hyper vascul ar mor phol ogy of pancr eati c endocr i ne tumor s der i ved
pr efer enti al l y fr om the hepati c ar ter y. The natur e of systemi c
therapy i s to tr eat the enti r e body at r i sk for metastases and any
cur r entl y mani fest l esi ons. Systemi c strategi es i ncl ude tradi ti onal
chemotherapy, i nter fer on-al pha, and somatostati n anal ogues used
wi th and wi thout radi oi sotopes (e.g., 9 0 yttr i um). The l ar ger ser i es of
gastr i noma pati ents r epor t a 50% to 90% i nci dence of metastati c
di sease. Chemotherapy rar el y r esul ts i n cur e, al though some
r egi mens have r easonabl e rates of r esponse. The most pr omi si ng
r egi men appear s to be a combi nati on of str eptozoci n and 5fl uor ouraci l , wi th or wi thout doxor ubi ci n; thi s combi nati on gi ves
r esponse rates of 50% to 70% . Impor tantl y, al though many
gastr i nomas may not decr ease demonstrabl y i n vol ume, pati ents
may have a symptomati cal l y si gni fi cant bi ochemi cal r esponse. The
somatostati n anal ogues appear effecti ve i n contr ol l i ng symptoms of
gastr i nomas but show a di sappoi nti ng objecti ve tumor r esponse rate
of 10% to 20% . Inter fer on-al pha has al so been studi ed al one and i n
combi nati on wi th chemotherapy and somatostati n therapy. It al so
may r esul t i n bi ochemi cal r esponse, wi th fewer pati ents r eal i z i ng a
r educti on i n tumor vol ume. G eneral l y, tradi ti onal chemotherapy i s
consi der ed fi r st-l i ne nonsur gi cal therapy.
When to i ni ti ate therapy for metastati c di sease r emai ns a
contr over si al topi c. Metastati c gastr i noma appear s to fol l ow at l east
thr ee di sti nct cl i ni cal cour ses. In pati ents wi th rapi dl y pr ogr essi ng
symptomati c di sease, ther e woul d be l i ttl e di sagr eement r egar di ng
the need to i ni ti ate potenti al l y toxi c therapy. However, i n pati ents
wi th sl owl y pr ogr essi ng, or even stabl e di sease wi th easi l y
contr ol l ed symptoms, the deci si on becomes l ess cl ear. Ul ti matel y,
the deci si on must be i ndi vi dual i zed to maxi mi ze the qual i ty of the
pati ent's r emai ni ng l i fe.
Insulinoma
Epidemiology
In most ser i es, i nsul i nomas ar e the most common i sl et cel l tumor s
of the pancr eas, wi th a r epor ted i nci dence esti mated between l ess
than one and four cases per 1 mi l l i on peopl e per year. These tumor s
occur sl i ghtl y mor e often i n women than i n men. The average
pati ent age at pr esentati on i s between 40 and 50 year s. These
tumor s ar e al most al ways beni gn and over whel mi ngl y smal l (<2
cm), sol i tar y l esi ons wi thi n the pancr eas unl ess associ ated wi th MEN
1, when they tend to occur i n a mul ti centr i c fashi on.
Table 14.5. Symptoms associated with an

insulinoma and their respective frequency
Symptoms
Frequency (%)
Neuroglycopenic symptoms
Visual disturbances
59
Confusion
51
Altered consciousness
38
Weakness
32
Seizures
23
Symptoms related to hypoglycemic

catecholamine release
Sweating
43
Tremulousness
23
Tachycardia
23
The or i gi nal di agnosti c cr i ter i a for an i nsul i noma ar e known as
Whi ppl e's tr i ad and wer e pr oposed by Whi ppl e, who i ni ti al l y
descr i bed the syndr ome. Thi s tr i ad consi sts of symptoms of
hypogl ycemi a at fasti ng, documentati on of bl ood gl ucose l evel s l ess
than 50 mg/dL, and r el i ef of symptoms fol l owi ng admi ni strati on of
gl ucose. However, Whi ppl e's tr i ad has pr oven not to be ver y
speci fi c, under scor i ng the i mpor tance of cl i ni cal suspi ci on and
car eful , systemati c eval uati on. The cl i ni cal symptoms of i nsul i nomas
ar e due to the hypogl ycemi a i nduced by excess i nsul i n secr eti on and
ar e commonl y character i zed as ei ther neur ogl ycopeni c or autonomi c
adr ener gi c. No tr ul y hypogl ycemi c di sor der pr esents wi th
excl usi vel y excess adr ener gi c symptoms. Many pati ents l ear n to
r ecogni ze thei r speci fi c symptom onset and thus avoi d them by
fr equent meal s or snacks. Thi s i s r efl ected i n the often l ong
durati on of symptoms befor e di agnosi s, fr equentl y measur ed i n
months i f not year s. A l i st of the common symptoms and thei r
fr equency i s shown i n Tabl e 14.5. Hunger, nausea, wei ght gai n, and
vomi ti ng ar e al so r epor ted occasi onal l y.
Biochemical Diagnosis
The measur ement of nor mal ser um gl ucose concentrati on
documented dur i ng character i sti c symptoms el i mi nates the di agnosi s
of i nsul i noma. The most r el i abl e method of di agnosi ng an
i nsul i noma i s the pr ovocati ve 72-hour super vi sed fast. Bl ood
gl ucose and i nsul i n l evel s ar e measur ed ever y 4 to 6 hour s dur i ng
the fast unti l ser um gl ucose l evel s decr ease bel ow 60 mg/dL, at
whi ch ti me the fr equency i s i ncr eased to ever y 1 to 2 hour s. Ei ghty
per cent of pati ents wi th i nsul i noma become symptomati c wi thi n 24
hour s of star ti ng the fast, and al most al l ar e symptomati c i f the fast
i s conti nued for 72 hour s. The pr esence of hypogl ycemi a wi th
concur r ent el evati on of ser um i nsul i n concentrati ons hi gher than 6
U/mL (l ack of appr opr i ate suppr essi on) and an i nsul i n to gl ucose
rati o of mor e than 0.3 confi r m the di agnosi s. One l ar ge ser i es
found, however, that 19% of pati ents wi th exci sed i nsul i nomas had
i nsul i n to gl ucose rati os l ess than 0.3, poi nti ng out the potenti al
di agnosti c weakness of the rati o. Measur ement of the beta cel l
pr oducts C-pepti de and pr oi nsul i n i s i mpor tant because both ar e
usual l y i ncr eased i n pati ents wi th i nsul i noma. In fact, the hal f-l i fe
of C-pepti de i s r oughl y twi ce that of i nsul i n; ther efor e measurabl e
C-pepti de i n a hypogl ycemi c pati ent i s i ndi cati ve of an endogenous
i nsul i n sour ce. Pati ents who sur r epti ti ousl y admi ni ster i nsul i n to
themsel ves usual l y have l ow l evel s of C-pepti de and pr oi nsul i n,
because commer ci al i nsul i n does not contai n the i nsul i n pr ecur sor
or i ts cl eavage fragments. Pati ents taki ng oral hypogl ycemi c agents
have nor mal or el evated l evel s of C-pepti de and pr oi nsul i n, so
di ffer enti ati on fr om an i nsul i noma i s made by measur ement of
pl asma l evel s of sul fonyl ur eas. Occasi onal l y, anci l l ar y tests such as
the C-pepti de suppr essi on test and the tol butami de test may pr ovi de
evi dence to suppor t the di agnosi s of i nsul i noma i n equi vocal cases.
Tumor Localization
Most i nsul i nomas ar e smal l (<2 cm i n di ameter ), and onl y
appr oxi matel y 10% of i nsul i nomas ar e mul ti centr i c. Ther e ar e no
hi stol ogi c cr i ter i a of mal i gnancy for i nsul i nomas; ther efor e, the
di agnosi s of a mal i gnant tumor i s based on the demonstrati on of
metastati c di sease, whi ch i s noted i n 10% of cases. As wi th
gastr i nomas, al l of the di ffer ent modal i ti es noted have al so been
used i n an attempt to pr eoperati vel y l ocal i ze i nsul i nomas. Hi stor i cal
exper i ence has demonstrated that, as wi th gastr i nomas, no si ngl e
techni que i s consi stentl y r el i abl e i n l ocal i z i ng i nsul i nomas shor t of
expl orati on. Dynami c CT scanni ng i s often the fi r st l ocal i z i ng study
per for med, because i t can detect appr oxi matel y two thi r ds of the
pr i mar y tumor s and most metastati c l esi ons. When no tumor i s seen
wi th the CT scan, vi sceral angi ography wi th di gi tal subtracti on
techni ques i s successful i n vi sual i z i ng l esi ons appr oxi matel y 60% to
90% of the ti me, al though over the past decade the sensi ti vi ty of
thi s study has fal l en consi derabl y i n several r epor ts. Sel ecti ve
por tal venous sampl i ng i s r eser ved mai nl y for pati ents whose
tumor s cannot be vi sual i zed wi th CT or angi ography. Por tal venous
sampl i ng i s abl e to defi ne the general ar ea of the tumor i n 90% of
pati ents overal l and i n appr oxi matel y 75% of pati ents i n whom
other l ocal i z i ng tests ar e negati ve. The per fect study does not exi st
and thus the deci si on of whi ch techni que(s) wi l l be used shoul d
r evol ve ar ound i nsti tuti onal exper ti se and expected yi el d, the r i sk
to the pati ent, and the cost of the total eval uati on r el ati ve to i ts
expected yi el d. In some exper i enced hands, pr eoperati ve
l ocal i z ati on i s l i mi ted to transabdomi nal ul trasound.
Newer modal i ti es ar e encouragi ng but conti nue to under go
defi ni ti ve eval uati on. Endoscopi c ul trasound has shown pr omi se, as
i t has wi th i ntrapancr eati c gastr i nomas, al though i ts success
becomes mor e l i mi ted when eval uati ng mor e di stal pancr eati c
l esi ons. Lesi ons i n the head of the pancr eas can be vi sual i zed up to
95% of the ti me, whi l e those i n the body and tai l wer e vi sual i zed i n
78% and 60% , r especti vel y, i n one ser i es. Unfor tunatel y,
i nsul i nomas often (30% 90% of cases) do not possess appr opr i ate
somatostati n r eceptor s, l i mi ti ng the benefi t of SRS i n i nsul i nomas
as compar ed wi th other pancr eati c endocr i ne tumor s.
Regar dl ess of pr eoperati ve i magi ng, i ntraoperati ve ul trasound has
been uni for ml y hel pful i n l ocati ng l esi ons not i denti fi ed befor e
expl orati on or by manual pal pati on al one and for r ul i ng out or
i denti fyi ng mul ti pl e tumor s.
Treatment
At expl orati on, r eddi sh-pur pl e or whi te tumor s may be vi si bl e on
the sur face of the gl and; however, the pancr eas must be compl etel y
mobi l i zed as descr i bed pr evi ousl y for i ntrapancr eati c gastr i nomas.
Smal l i nsul i nomas l ocated away fr om the mai n pancr eati c duct can
be enucl eated. Smal l l esi ons i n pr oxi mi ty to the mai n pancr eati c
duct can al so be enucl eated, and such a pr ocedur e i s ai ded by
i ntraoperati ve ul trasound gui dance to avoi d i njur y to the duct.
Di stal pancr eatectomy i s r ecommended for smal l l esi ons near the
pancr eati c duct to mi ni mi ze the r i sk of a pancr eati c fi stul a. Lar ge
l esi ons i n the head of the pancr eas may r equi r e
pancr eati coduodenectomy, wher eas those i n the body and tai l can
be tr eated wi th a di stal pancr eatectomy. Resecti on i s al so pr efer r ed
when si gns of mal i gnancy ar e pr esent (e.g., har d tumor s, pucker i ng
of adjacent ti ssue, i nfi l trati on, or tumor s causi ng di stal ductal
obstr ucti on). Intraoperati ve ul trasound can hel p i denti fy tumor s
that coul d not be l ocal i zed pr eoperati vel y usi ng standar d i magi ng
techni ques. Insul i nomas ar e i denti fi ed appr oxi matel y 95% of the
ti me at i ni ti al expl orati on. As wi th gastr i nomas, bl i nd r esecti on of
the pancr eas i s not r ecommended when no tumor i s i denti fi ed.
G i ven the fai r l y uni for m di str i buti on of i nsul i nomas thr oughout the
pancr eas, the l ogi c behi nd bl i nd r esecti on i s uncl ear, al though
ther e ar e those that woul d consi der a r egi onal i z i ng transhepati c
por tal venous sampl i ng study adequate l ocal i z ati on, par ti cul ar l y
after an i ni ti al fai l ed expl orati on and i nadequate contr ol of
symptoms by appr opr i ate medi cal therapy. If no tumor i s i denti fi ed
at expl orati on, then pancr eati c bi opsy to r ul e out beta cel l
hyper pl asi a and adul t nesi di obl astosi s i s advi sabl e. Beta cel l
hyper pl asi a or adul t nesi di obl astosi s can general l y be successful l y
tr eated by subtotal pancr eatectomy.
Metastatic Disease
Pati ents wi th successful r esecti on of i nsul i nomas can expect an
other wi se nor mal l i fe expectancy. However, i n those pati ents whose
tumor s ar e not found at expl orati on, ar e unsui tabl e for operati ve
expl orati on, or have metastati c di sease, symptoms can often be
managed phar macol ogi cal l y wi th di azoxi de, verapami l , phenytoi n,
pr opranol ol , or octr eoti de. Nonethel ess, pati ents wi th metastati c
di sease shoul d be consi der ed for r esecti on of the pr i mar y tumor and
accessi bl e metastati c l esi ons. Medi an di sease-fr ee sur vi val i s
appr oxi matel y 5 year s i n pati ents wi th mal i gnant i nsul i noma who
under go curati ve r esecti on. Appr oxi matel y 65% of pati ents wi th
mal i gnant tumor s wi l l have r ecur r ences at a mean of about 2.8
year s. Al though the chances for cur e after r esecti on ar e l ow i n
pati ents wi th mal i gnant i nsul i noma, 10-year sur vi val rates ar e 29% .
Tumor debul ki ng may i mpr ove contr ol of hypogl ycemi c symptoms,
but i s r ecommended onl y i f gr eater than 90% of di sease can be
r esected.
Pal l i ati on can be achi eved wi th medi cal therapy as wel l as sur ger y.
Di azoxi de can contr ol the endocr i ne symptoms of
i nsul i nomas i n 50% to 70% of pati ents by i nhi bi ti ng the r el ease of
i nsul i n fr om i sl et cel l s di r ectl y and by enhanci ng gl ycogenol ysi s
i ndi r ectl y. Octr eoti de contr ol s symptoms i n 40% to 60% of pati ents;
however, i ts effect may be unpr edi ctabl e i n i ndi vi dual pati ents wi th
tumor s havi ng atypi cal beta granul es or none at al l . Of the
chemotherapeuti c agents used for pati ents wi th metastati c di sease,
str eptozoci n, 5-fl uor ouraci l , and doxor ubi ci n have shown the best
r esponse rates.
Vasoactive Intestinal Polypeptidoma

Epidemiology
Al though not a nor mal pr oduct of pancr eati c i sl et cel l s, VIP can be
secr eted by i sl et cel l tumor s. The syndr ome of excessi ve VIP

secr eti on i s associ ated wi th water y di ar r hea, hypokal emi a, and
ei ther hypochl or hydr i a or achl or hydr i a. F i r st descr i bed i n
associ ati on wi th i sl et cel l tumor s i n 1958, the syndr ome has many
names, i ncl udi ng Ver ner-Mor r i son syndr ome, pancr eati c chol era,
and WDHA (water y di ar r hea, hypokal emi a, and achl or hydr i a).
Subsequentl y, i t has been r eal i zed that 80% to 90% of so-cal l ed
VIPomas ar e l ocated i n the pancr eas, most often the body and tai l
(75% ). Extrapancr eati c tumor s ar e often l ocated i n the chest and
r etr oper i toneum (l ung, esophagus, adr enal medul l a [as
gangl i obl astomas, neur obl astomas, and gangl i oneur omas], and
al ong the autonomi c ner vous system). Ten per cent of cases ar e due
to i sl et cel l hyper pl asi a. To date, appr oxi matel y 200 wel l documented cases of VIPoma have been descr i bed, and i n most
cases the tumor i s mal i gnant. An i nter esti ng bi modal di str i buti on i s
noted, wi th younger pati ents (<10 year s ol d) havi ng l ess aggr essi ve
and extrapancr eati c tumor s.
Clinical Presentation/Tumor Localization

Pati ents usual l y pr esent wi th excessi ve secr etor y di ar r hea, often
gr eater than 3 L/day that i s aggravated by oral food i ntake and
per si sts despi te fasti ng. The pati ents become hypokal emi c secondar y
to fecal potassi um l oss and aci doti c fr om l oss of fecal bi car bonate.
The pr esence of a VIPoma i s confi r med by demonstrati ng an
i ncr eased fasti ng ser um VIP l evel (>200 pg/mL) i n the setti ng of
secr etor y di ar r hea wi th the pr esence of a mass. Ther e ar e no
pr ovocati ve or i nhi bi tor y confi r mator y studi es. Pancr eati c VIPomas
ar e usual l y sol i tar y, ar e gr eater than 3 cm i n di ameter, and most
often ar e l ocated i n the tai l of the pancr eas. Di ar r hea i s such a
nonspeci fi c symptom that the eval uati on shoul d focus on el i mi nati ng
mor e common causes (i .e., i nfecti ous, i nfl ammator y, mechani cal ,
even gastr i noma) befor e pr oceedi ng to ser um VIP l evel s or
l ocal i z ati on studi es. Typi cal l y, pr eoperati ve l ocal i z ati on i s easi l y
achi eved by abdomi nal and chest CT scans or by SRS. Mesenter i c
ar ter i ography and hepati c por tal venous sampl i ng (HPVS) may be
useful i f the tumor l ocati on i s sti l l i n questi on.
Treatment
Sur gi cal exci si on r emai ns the onl y effecti ve method of cur e.
Pr eoperati ve pr eparati on shoul d i ncl ude adequate r ehydrati on and
cor r ecti on of el ectr ol yte i mbal ances. The fi r st-l i ne therapy for
contr ol of the di ar r hea i s the use of l ong-acti ng somatostati n
anal ogues. However, admi ni strati on of ster oi ds, nonster oi dal

anti i nfl ammator y dr ugs, or phenothi az i nes may al so be hel pful . At
expl orati on, most tumor s ar e l ocated i n the di stal pancr eas and ar e
amenabl e to a compl ete r esecti on by a di stal pancr eatectomy. A
car eful eval uati on of both adr enal gl ands i s mandator y i f no tumor
i s found i n the pancr eas. Appr oxi matel y 50% of the ti me, metastati c
di sease i s found outsi de the pancr eas at expl orati on. If curati ve
r esecti on i s not possi bl e, sur gi cal debul ki ng i s often i ndi cated to
hel p pal l i ate symptoms.
Long-ter m sur vi val i s r el ati vel y poor at appr oxi matel y 15% .
Str eptozoci n and i nter fer on ar e cur r entl y the most acti ve
chemotherapeuti c agents for advanced di sease, and these ar e
general l y bel i eved to be mor e effecti ve agai nst VIPomas than
agai nst other pancr eati c endocr i ne tumor s. Octr eoti de and other
somatostati n anal ogues ar e useful for symptomati c r el i ef fr om
di ar r hea i n pati ents wi th metastati c di sease and have been shown
by some i nvesti gator s to have some effect on tumor gr owth.
Glucagonoma
G l ucagonomas ar i se fr om the A cel l s i n the pancr eati c i sl ets of
Langer hans. The syndr ome caused by thi s tumor i s due to excess
secr eti on of gl ucagon. In contrast to other pancr eati c endocr i ne
tumor s, gl ucagonomas ar e fr equentl y fai r l y l ar ge at di agnosi s (>5
cm) and ar e rar el y found outsi de the pancr eas. Appr oxi matel y 70%
of these tumor s ar e mal i gnant.
Clinical Presentation/Diagnosis
The most common and usual l y i ni ti al symptom i n pati ents wi th
gl ucagonoma i s mi l d gl ucose i ntol erance (occur r i ng i n >90% of
pati ents) that rar el y r equi r es i nsul i n admi ni strati on. The most
str i ki ng and character i sti c featur e i s a sever e der mati ti s cal l ed
necr ol yti c mi grator y er ythema, seen i n appr oxi matel y 70% of
pati ents. The ski n rash i s most often l ocated on the l ower abdomen,
per i neum, per i oral ar ea, or feet. Other symptoms i ncl ude a
catabol i c state, hypoami noaci demi a, stomati ti s, anemi a
(nor mochr omi c/nor mocyti c), wei ght l oss, gl ossi ti s, depr essi on, and
venous thr ombosi s.
The di agnosi s i s confi r med by documenti ng the pr esence of an
i ncr eased fasti ng ser um gl ucagon l evel ; l evel s gr eater than 1,000
pg/mL (nor mal , 0150 pg/mL) ar e vi r tual l y di agnosti c. Other
condi ti ons may cause hyper gl ucagonemi a (e.g., hepati c

i nsuffi ci ency, sever e str ess, bacter emi a, and star vati on), but ser um
gl ucagon l evel s rar el y exceed 500 pg/mL. In addi ti on, the di agnosi s
can be confi r med by the character i sti c fi ndi ngs on bi opsy of the ski n
rash.
Tumor Localization
CT scanni ng i s the fi r st l ocal i z ati on study. Most tumor s ar e l ar ge at
the ti me of di agnosi s, rangi ng fr om 5 to 10 cm, and occur most
often i n the body and tai l of the pancr eas. As wi th the other
pancr eati c endocr i ne tumor s, SRS l ocal i zes gl ucagonomas ver y
r el i abl y. G i ven the l ar ge si ze of these l esi ons, addi ti onal l ocal i z ati on
studi es ar e rar el y needed, al though angi ography and por tal
venous sampl i ng may be r equi r ed for gl ucagonomas that ar e
di ffi cul t to i denti fy.
Treatment
Sur gi cal expl orati on shoul d be under taken i n any pati ent whose
tumor i s thought to be r esectabl e. Pr eoperati ve pr eparati on of
pati ents to r ever se catabol i sm shoul d i ncl ude the use of
somatostati n anal ogues and r epl eni shment of ami no aci dshel pi ng
to amel i orate the catabol i c state and often l eadi ng to r esol uti on of
the associ ated der mati ti s. Si xty-ei ght per cent of pati ents wi l l have
metastati c di sease di agnosed by pr eoperati ve studi es or at the ti me
of expl orati on. Pati ents who ar e symptomati c due to metastati c
di sease fr equentl y benefi t fr om sur gi cal r esecti on. Pati ents wi th
wi del y metastati c di sease i n whom sur gi cal debul ki ng i s i mpossi bl e
can often benefi t fr om medi cal therapy. Octr eoti de has been
successful i n contr ol l i ng the di abetes and der mati ti s i n 60% to 90%
of pati ents. Dacar baz i ne and str eptozoci n have been successful l y
used to tr eat some unr esectabl e or r ecur r ent gl ucagonomas.
Al though gl ucagonomas ar e rar el y cur ed, l ong-ter m sur vi val of up
to 50% at 5 year s i s r epor ted due to the fr equent r esectabi l i ty and
sl ow-gr owi ng natur e of the l esi ons.
Somatostatinoma
Somatostati nomas ar i se fr om the D cel l s of the i sl ets of Langer hans
and ar e among the rar est endocr i ne neopl asms, wi th an esti mated
year l y i nci dence of one i n 40 mi l l i on. G eneral l y mi l d hyper gl ycemi a,
chol el i thi asi s, steator r hea, and di ar r hea mar k the somatostati noma
syndr ome associ ated wi th these tumor s. Thi s cl assi c syndr ome i s
seen i n pati ents wi th pancr eati c tumor s, whi l e i t i s typi cal l y absent
i n those wi th duodenal somatostati nomas. Al though duodenal
tumor s ar e not often associ ated wi th the cl assi c somatostati noma
syndr ome, they have been noted r etr ospecti vel y to be often
associ ated wi th neur ofi br omatosi s. Thi s has r esul ted i n the pr oposal
of a new MEN syndr ome and shoul d cause the cl i ni ci an to be awar e
of the possi bi l i ty of concur r ent pheochr omocytoma.
Ear l y detecti on i s di ffi cul t because symptoms ar e fr equentl y mi l d
and nonspeci fi c. Di agnosi s i s often ser endi pi tous dur i ng
chol ecystectomy, expl orator y l apar otomy, or radi ol ogi c or
endoscopi c eval uati on of nonspeci fi c abdomi nal symptoms.
Confi r mati on of di agnosti c suspi ci on can be achi eved by
demonstrati on of ser um somatostati n l evel s 50-fol d hi gher than
nor mal . Pr ovocati ve testi ng i s not r outi nel y avai l abl e, al though
tol butami de has been r epor ted to cause an i ncr ease i n ser um l evel s
i n pati ents wi th somatostati nomas and not i n contr ol s. Most of these
l esi ons ar e l ar ge and sol i tar y and l ocated i n the head of the
pancr eas, and they ar e easi l y l ocal i zed by CT scan or ul trasound
(duodenal l esi ons ar e usual l y smal l er but can be confi r med by
esophagogastr oduodenoscopy or radi ography). Up to 90% of the
l esi ons ar e mal i gnant, and metastati c di sease i s found i n most
cases. In the absence of di stant metastati c di sease, r esecti on i s the
tr eatment of choi ce; debul ki ng, when possi bl e, can offer
symptomati c r el i ef. Pati ents under goi ng sur ger y for attempted
r esecti on shoul d al so have a chol ecystectomy per for med because of
the hi gh
i nci dence of chol el i thi asi s. Medi cal therapy has pr oven
di sappoi nti ng, wi th 13% 5-year sur vi val and onl y 48% 1-year
sur vi val r epor ted.
Miscellaneous Functioning Tumors

Many i sl et cel l tumor s pr evi ousl y thought to be nonfuncti oni ng have
been found to secr ete PP. Because thi s substance can now be
measur ed, these tumor s ar e r efer r ed to as PPomas. (Inter esti ngl y,
28% 70% of al l functi oni ng pancr eati c endocr i ne tumor s al so
secr ete PP, the most l i kel y bei ng VIPomas and l east l i kel y
i nsul i nomas.) When an i ncr eased l evel of PP (>300 pmol /L) i s
detected i n conjuncti on wi th a pancr eati c mass, the di agnosi s of
PPoma i s made by excl udi ng the possi bi l i ty of other functi oni ng i sl et
cel l tumor s. The excess secr eti on of PP i s not associ ated wi th any
cl ear l y defi ned cl i ni cal syndr ome; thus these tumor s ar e usual l y
l ar ge at di agnosi s, pr esenti ng wi th symptoms r el ated to l ocal
gr owth. Nonspeci fi c symptoms such as di ar r hea and wei ght l oss may
be pr esent, however, possi bl y due to the i nhi bi tor y natur e of PP on
pancr eati c secr eti on and gal l bl adder contracti on. Sur gi cal exci si on
i s the tr eatment of choi ce for r esectabl e tumor s, whi ch can usual l y
be easi l y l ocal i zed by CT scan. PPomas ar e usual l y l ocated i n the
head of the pancr eas and ar e al most al ways mal i gnant, though often
sl ow-gr owi ng. Si xty per cent ar e metastati c at the ti me of di agnosi s.
As wi th other pancr eati c endocr i ne tumor s, str eptozoci n i s the
chemotherapy of choi ce; however, because of the absence of
hor monal l y r el ated symptoms, no speci fi c r ol e for somatostati n
anal ogues has been i denti fi ed. The 5-year overal l sur vi val rate i s
44% .
G r owth hor moner el easi ng factor (G RF ) i s another hor mone that
has r ecentl y been i denti fi ed as a tumor pr oduct. Refer r ed to as
G RFomas, tumor s that secr ete G RF ar e l ocated i n the pancr eas 30%
of the ti me, the l ung 55% of the ti me, and the i ntesti ne 15% of the
ti me. Appr oxi matel y 30% of these l esi ons ar e mal i gnant. Pati ents
usual l y pr esent wi th acr omegal y, but these tumor s al so may secr ete
other pr oducts. In addi ti on to G RFomas, 40% of pati ents have ZES,
and 40% have Cushi ng's syndr ome. Al though octr eoti de can
si gni fi cantl y suppr ess the l evel s of ci r cul ati ng gr owth hor mone i n
thi s syndr ome, sur gi cal exci si on, i f possi bl e, i s the tr eatment of
choi ce.
Other uncommon i sl et cel l tumor s i ncl ude those that secr ete
neur otensi n, ACTH, or a parathyr oi d hor monel i ke pepti de.
Carcinoid
The cl assi c car ci noi d tumor of the pancr eas i s extr emel y rar e,
al though anecdotal cases have been r epor ted. Pancr eati c car ci noi ds
ar e gr ouped wi th for egut car ci noi ds, and pati ents wi th these tumor s
may have nor mal ser um l evel s of ser otoni n (may be i ncr eased or
tumor stai n for 5-hydr oxytr yptami ne) but commonl y have el evated
ur i nar y l evel s of 5-hydr oxyi ndol aceti c aci d. F ur ther mor e, the typi cal
car ci noi d syndr ome i s mor e common than i n other for egut
car ci noi ds. Pancr eati c car ci noi ds general l y ar e l ar ger than mi dgut,
hi ndgut, or other for egut car ci noi ds and ther efor e pati ents often
pr esent wi th mass-effect symptoms such as epi gastr i c pai n, wei ght
l oss, or jaundi ce fr om common bi l e duct compr essi on. Local i z ati on
has tradi ti onal l y been by CT scan
because most of these tumor s ar e several centi meter s i n di ameter

at the ti me of di agnosi s, al though octr eoti de scanni ng has shown
pr omi se as a method to di agnose the di sease and fol l ow these
pati ents after r esecti on. G eneral l y, car ci noi d tumor s gr ow sl owl y
and i nvade adjacent or gans l ate i n the cour se of the di sease,
maki ng r esecti on possi bl e i n most pati ents. Unfor tunatel y, at l east
70% of pati ents have di stant metastases at the ti me of di agnosi s,
mi ni mi z i ng the l i kel i hood of l ong-ter m sur vi val . However, i n the
absence of di stant metastases, compl ete r esecti on of the pr i mar y
tumor offer s an excel l ent possi bi l i ty of l ong-ter m sur vi val .
Nonfunctioning Tumors
Recent ser i es r epor t that 35% to 50% of pancr eati c i sl et tumor s ar e
nonfuncti oni ng, that i s, they do not secr ete detectabl e l evel s of
functi onal hor mones. Instead of a wel l -defi ned cl i ni cal syndr ome,
the pr esentati on of these tumor s i s si mi l ar to that of pancr eati c
ductal adenocar ci noma. Si nce many nonfuncti oni ng pancr eati c
tumor s stai n for one or many known hor mones or pr ecur sor
hor mones, several hypotheses have been pr oposed to account for
the l ack of mani fest symptoms. F i r st, the hor mones secr eted i n
excess may not pr oduce si gns or symptoms. Second, a cl i ni cal l y
acti ve hor mone may be secr eted i n cl i ni cal l y i r r el evant amounts.
F i nal l y, the secr eted hor mone pr oduct may actual l y be ei ther a
pr ecur sor hor mone or one that has yet to be i denti fi ed. Common
symptoms i ncl ude abdomi nal pai n, wei ght l oss, and jaundi ce. Most
of these tumor s ar e found i n the head of the pancr eas, and most ar e
mal i gnant.
Di agnosi s can be made by CT-gui ded fi ne-needl e aspi rati on as wel l
as by the character i sti c hyper vascul ar appearance on ar ter i ography.
However, conventi onal CT scans may have featur es character i sti c of
pancr eati c i sl et cel l tumor s i n contrast to adenocar ci noma of the
pancr eas. These featur es i ncl ude a hi gh degr ee of enhancement,
cysti c degenerati on, and cal ci fi cati on. Addi ti onal l y, endocr i ne
tumor s ar e l ess l i kel y to encase vascul ar str uctur es or obstr uct the
pancr eati c duct. Fol l owi ng l ocal i z ati on studi es, operati ve expl orati on
for attempted curati ve r esecti on i s often i ndi cated.
The pr ognosi s for pati ents wi th nonfuncti oni ng i sl et cel l tumor s i s
si gni fi cantl y better than that for pati ents wi th pancr eati c ductal
adenocar ci noma, wi th the overal l medi an sur vi val rate i n the for mer
gr oup r epor ted at over 3 year s. In pati ents wi th l ocal i zed and
compl etel y r esected di sease, however, medi an overal l sur vi val i s as
l ong as 7 year s. Even when l ocal i zed di sease i s unr esectabl e, the
pr ognosi s can r emai n fai r l y good, wi th a medi an sur vi val of over 5
year s. Chemotherapy wi th str eptozoci n and 5-fl uor ouraci l has shown
some favorabl e r esul ts and shoul d be consi der ed ear l y i n the cour se
of the di sease because medi an sur vi val for unr esectabl e metastati c
di sease i s l ess than 2 year s.

Ther e ar e cur r entl y thr ee wel l -defi ned MEN syndr omes (MEN 1, MEN
2A, and MEN 2B), character i zed by a fami l i al pr edi sposi ti on to the
devel opment of tumor s (often mul ti pl e) i n var i ous endocr i ne gl ands.
Recogni ti on of the i ndi vi dual components of
each syndr ome may be synchr onous but mor e often i s over a l ong
per i od of fol l ow-up. Typi cal l y, not al l of the cl i ni cal mani festati ons
of the cl assi c syndr omes ar e expr essed. A descr i pti ve over vi ew of
the thr ee syndr omes i s gi ven i n Tabl e 14.6. Recentl y, speci fi c
geneti c mutati ons have been i denti fi ed as the l i kel y causal event
r esul ti ng i n the cl i ni cal phenotypes associ ated wi th the devel opment
of the MEN syndr omes.
Table 14.6. Features of multiple endocrine

neoplasia syndromes and the associated tum
(approximate incidence of tumor with each
syndrome)
Acronym
Genetic
mutation
MEN 1
MEN 2A
MEN 2B
Werner's
syndrome
Sipple's
syndrome
None
Chromosome
11q13
RET protooncogene
chromosome
10q11.2
RET proto
oncogene
chromoso
10q11.2
Tumors
Parathyroid
(90%)
MTC (100%)
MTC (100
Pancreas
(80%)
Pheo (20%
50%)
Pheo (20%
50%)
Pituitary
adenoma
(55%)
Parathyroid
(20%35%)
Neuromas
(~100%)
Adrenal
adenomas
(30%)
Cutaneous
lichen
amyloidosis
Skeletal
deformiti
Hirschprung's
disease
Megacolo
Thyroid
nodules
(10%)
Enlarged peripheral nerve
MEN, multiple endocrine neoplasia; MTC, medullary

thyroid carcinoma; Pheo, pheochromocytoma.
MEN 1 was mapped by l i nkage anal ysi s to the l ong ar m of
chr omosome 11 (11q13). In 1997, posi ti onal cl oni ng i denti fi ed the
speci fi c gene. The MEN 1 gene encodes a 610-ami no aci d pr otei n
desi gnated menin. Meni n i s pr i nci pal l y a nucl ear pr otei n known to
r epr ess JUN-Dmedi ated RNA transcr i pti on, suppor ti ng the
hypothesi s that MEN 1 i s caused by a tumor-suppr essor gene.
Conver sel y, the gene r esponsi bl e for MEN 2 i s a pr oto-oncogene. It
i s l ocated on chr omosome sub-band 10q11.2 and i s known as the
RET pr oto-oncogene. Thi s gene encodes the pr otei n RET (r ear ranged
dur i ng transfecti on), whi ch i s a r eceptor tyr osi ne ki nase.
Men 1
MEN 1, al so known as Wer mer 's syndr ome, has hi stor i cal l y been
character i zed by the devel opment of mul ti gl and parathyr oi d
hyper pl asi a, pancr eati c i sl et cel l tumor s, and pi tui tar y tumor s.
Pati ents wi th MEN 1 al so have a hi gh i nci dence of for egut car ci noi d
tumor s, adr enocor ti cal tumor s, and thyr oi d adenomas and
car ci nomas. In addi ti on to endocr i ne gl and abnor mal i ti es, pati ents
wi th MEN 1 often have subtl e ski n l esi ons, i ncl udi ng l i pomas, faci al
angi ofi br omas, and ski n col l agenomas. MEN 1 i s found i n
appr oxi matel y one of ever y 30,000 i n the general popul ati on.
Var i ous combi nati ons of tumor s devel op, wi th 94% penetrance by
age 50 year s. The i nher i tance patter n i s autosomal domi nant,
al though the mechani sm of tumor i genesi s at the cel l ul ar l evel i s
r ecessi ve. A par ti cul ar i ndi vi dual i nher i ts a ger ml i ne mutati on to
one al l el e at 11q13 (most often encodi ng tr uncated, i nacti ve
pr otei n); a subsequent somati c mutati on to the other al l el e at the
MEN 1 l ocus r esul ts i n l oss of heter oz ygosi ty and eventual
phenotypi c expr essi on. The cl i ni cal mani festati ons var y and ar e
general l y appar ent by the thi r d or four th decade, al though wi th
car eful scr eeni ng most known car r i er s show evi dence of
tumor i genesi s by thei r mi d-twenti es.
Hyperparathyroidism
Hyper parathyr oi di sm i s the most common endocr i ne abnor mal i ty
seen i n MEN 1 and i s usual l y the fi r st to devel op (i n 60% 90% of
affected pati ents). Al most al l hyper parathyr oi di sm devel ops
secondar y to asymmetr i c, four-gl and hyper pl asi a. The cl i ni cal
pr esentati on i s si mi l ar to that seen i n sporadi c hyper parathyr oi di sm,
wi th most pati ents bei ng asymptomati c. Measur ement of ser um
cal ci um, phosphate, and i ntact-PTH l evel s l eads to the di agnosi s.
Incr eased ser um cal ci um i n the face of i nappr opr i atel y el evated
i ntact-PTH and an el evated 24-hour ur i nar y cal ci um col l ecti on
confi r m the di agnosi s of hyper parathyr oi di sm. As wi th sporadi c
hyper parathyr oi di sm, tr eatment i s sur gi cal exci si on. Pr e-exci si on
i magi ng i s of l i ttl e val ue pr i or to i ni ti al expl orati on because of the
mul ti -gl and natur e of the pathophysi ol ogy of MEN 1. In r ecur r ent or
per si stent hyper parathyr oi di sm, however, noni nvasi ve i magi ng and
often i nvasi ve modal i ti es (e.g., angi ography and venous sampl i ng)
may ai d i n gui di ng successful r e-expl orati on. The fr equency of
synchr onous thyr oi d neopl asms (15% ) di ctates that a car eful
eval uati on of the thyr oi d gl and be par t of any neck expl orati on i n
pati ents wi th MEN 1.
Ther e conti nues to be contr over sy over the appr opr i ate sur gi cal
pr ocedur e for hyper parathyr oi di sm i n the setti ng of MEN 1. Many
sur geons per for m a thr ee-and-one-hal f gl and parathyr oi dectomy,
whi l e other s advocate total parathyr oi dectomy wi th
autotranspl antati on. Ther e i s consi derabl e over l ap i n the r epor ted
i nci dence of r ecur r ent or per si stent hyper parathyr oi di sm, as wel l as
per manent hypoparathyr oi di sm wi th ei ther techni que. Theor eti cal l y,
total parathyr oi dectomy mi ni mi zes the l i kel i hood of r ecur r ent or
per si stent di sease, al though addi ng to the potenti al r i sk of
per manent hypoparathyr oi di sm. Our pr efer r ed techni que i s to
per for m a four-gl and exci si on wi th autotranspl antati on of pi eces of
the l east hyper pl asti c gl and i nto the brachi oradi al i s muscl e of the
non-domi nant for ear m. G raft-dependent hyper parathyr oi di sm may
devel op i n up to 50% of pati ents and can be effecti vel y managed by
r emovi ng several pi eces of parathyr oi d ti ssue fr om the for ear m
under l ocal anesthesi a, pr ecl udi ng the need for neck r e-expl orati on
and i ts attendant i ncr eased r i sk of r ecur r ent
ner ve par esi s/paral ysi s and per manent hypoparathyr oi di sm. Ei ther
pr ocedur e shoul d i ncl ude cer vi cal thymectomy because MEN 1 i s
associ ated wi th an i ncr eased i nci dence of supranumer y parathyr oi d
gl ands, whi ch ar e often l ocated wi thi n the thymus, i n up to 20% of
pati ents. In general , hyper parathyr oi di sm associ ated wi th MEN 2A i s
much easi er to contr ol and i s associ ated wi th a l ess fr equent
r ecur r ence rate after sur ger y than i s MEN 1. Hyper parathyr oi di sm
shoul d be addr essed befor e therapy for pancr eati c i sl et cel l tumor s
because contr ol of cal ci um-dependent hor mone r el ease fr om these
tumor s may be i mpr oved.
Pancreatic Tumors
The second most common neopl asms associ ated wi th MEN 1 ar e the
pancr eati c i sl et cel l tumor s, whi ch occur i n appr oxi matel y 60% of
pati ents wi th MEN 1. The cl i ni cal syndr ome associ ated wi th these
tumor s r esul ts fr om the speci fi c hor mone secr eted by each. The
most common i sl et cel l tumor s ar e gastr i nomas, fol l owed by
i nsul i nomas. Rar el y, gl ucagonomas, VIPomas, and somatostati nomas
ar e found. MEN 1associ ated pancr eati c endocr i ne tumor s ar e
mul ti focal and may be l ocated outsi de the pancr eas, as i s typi cal
wi th gastr i nomas. It i s i mpor tant to r ecogni ze that any par ti cul ar
radi ographi cal l y demonstrabl e pancr eati c mass may not be
speci fi cal l y r esponsi bl e for a cl i ni cal l y appar ent syndr ome. However,
the r i sk of mal i gnancy r emai ns even, and often especi al l y, for
cl i ni cal l y si l ent pancr eati c masses. Detai l s of the tr eatment of these
tumor s have been di scussed pr evi ousl y. One must keep i n mi nd that
al though bi ochemi cal cur e i s often not a r eal i sti c goal , pr eventi on of
the l ethal consequences of mal i gnant transfor mati on and metastati c
di sease may be possi bl e by aggr essi ve sur gi cal i nter venti on.
Thompson et al . (1988) have advocated a strategy wi th thi s i n mi nd,
i ncl udi ng the fol l owi ng: di stal pancr eatectomy at the l evel of the
super i or mesenter i c vei n, r egar dl ess of tumor l ocati on i n the
pancr eas or duodenum; duodenotomy even wi thout pal pabl e
duodenal l esi ons when faced wi th el evated ser um gastr i n and a
posi ti ve secr eti n-sti mul ati on test; per i pancr eati c l ymph node
di ssecti on for duodenal or pancr eati c neur oendocr i ne masses
gr eater than 3 cm; and enucl eati on of pancr eati c head or unci nate
pr ocess tumor s i denti fi ed by pal pati on or i ntraoperati ve ul trasound.
Thi s aggr essi ve appr oach r emai ns contr over si al .
Pituitary Neoplasms
Pi tui tar y neopl asms occur i n 30% to 50% of pati ents wi th MEN 1;
beni gn pr ol acti n-pr oduci ng adenomas ar e most common. Symptoms
may be r el ated di r ectl y to tumor mass effect (i .e., headache,
di pl opi a, and hypopi tui ti sm) or be r el ated to speci fi c hor mone
over pr oducti on. Excess pr ol acti n causes gal actor r hea and
amenor r hea i n women and i mpotence i n men. Tumor s may al so
pr oduce gr owth hor mone (30% ) or ACTH (>10% ), l eadi ng to
acr omegal y or Cushi ng's di sease, r especti vel y. Br omocr i pti ne, a
dopami ne agoni st, can be used to tr eat pr ol acti nomas medi cal l y.
Transsphenoi dal hypophysectomy i s r eser ved for pati ents who do not
r espond to br omocr i pti ne and who have nonpr ol acti n-secr eti ng
tumor s. Al l pati ents wi th MEN 1 shoul d be obser ved per i odi cal l y
wi th measur ement of ser um pr ol acti n and gr owth hor mone l evel s.
Men 2
MEN 2 consi sts of thr ee subtypes, each i nher i ted i n an autosomal
domi nant patter n wi th 100% penetrance but var i abl e expr essi on; al l
ar e mar ked by the pr esence of medul l ar y thyr oi d car ci noma (MTC).
MEN 2A and MEN 2B ar e defi ned by the pr esence of MTC and
pheochr omocytoma. Addi ti onal l y, i n MEN 2A (90% of al l cases MEN
2), hyper parathyr oi di sm often devel ops secondar y to four-gl and
hyper pl asi a. Pati ents wi th MEN 2B (5% of cases of MEN 2) al most

i nvar i abl y have character i sti c faci es and mar fanoi d habi tus. MEN 2B
i s al so mar ked by the pr esence of mul ti pl e neur omas on the l i ps,
tongue, and oral mucosa. In addi ti on, pati ents wi th MEN 2B have a
hi gh i nci dence of skel etal abnor mal i ti es as wel l as di ffuse
gangl i oneur omatosi s of the G I tract, whi ch can l ead to a number of
G I moti l i ty pr obl ems, most fr equentl y i nvol vi ng the col on.
Megacol on, associ ated wi th sever e consti pati on, i s the most common
G I mani festati on. Fami l i al MTC i s bel i eved to be the most i ndol ent
of the thr ee subtypes and i s character i zed by the absence of
consi stent phenotypi c mani festati ons i n addi ti on to MTC.
Medullary Thyroid Carcinoma

MTC compr i ses appr oxi matel y 5% to 10% of al l thyr oi d
mal i gnanci es. The vast major i tyappr oxi matel y 80% of these
tumor s occur sporadi cal l y; the r emai ni ng 20% ar e fami l i al . MTC can
occur i n the fami l i al setti ng wi thout any other associ ated
syndr omes. Some featur es of sporadi c and fami l i al MTC ar e shown i n
Tabl e 14.7. In the setti ng of MEN 2, MTC i s usual l y the fi r st
endocr i ne abnor mal i ty to occur. MTC ar i ses fr om the parafol l i cul ar
or C cel l s of the thyr oi d gl and and as a r esul t can secr ete not onl y
cal ci toni n but al so a var i ety of other hor monal l y acti ve substances,
such as ser otoni n, ACTH, pr ostagl andi ns, mel ani n, and
car ci noembr yoni c anti gen.
MTC i s often detected by geneti c or bi ochemi cal scr eeni ng when i t i s
cl i ni cal l y occul t. Most i ndex cases, or pati ents who ar e not i denti fi ed
by scr eeni ng, pr esent wi th a pal pabl e neck mass. Appr oxi matel y
30% of the pati ents wi th MTC pr esent wi th water y di ar r hea, usual l y
secondar y to the sti mul ator y effect of hi gh pl asma cal ci toni n l evel s
on i ntesti nal fl ui d and el ectr ol yte secr eti on. Symptoms such as
hoar seness, dysphagi a, and r espi rator y di ffi cul ty may be r el ated to
l ocal l y advanced di sease. Pr esenti ng symptoms may al so be
secondar y to
metastati c di sease, whi ch i s most commonl y seen i n the l ungs, l i ver,
and bones.
Table 14.7. Comparison of features of
sporadic versus familial medullary thyroid

carcinoma
Feature
Sporadic
Familial
Proportion of cases
80%
20%
Age at onset
4060 yr
1030 yr
Location
Unilateral
Bilateral
Diagnosis
Hi stor i cal l y, demonstrati ng el evated cal ci toni n l evel s usi ng
pr ovocati ve testi ng i n at-r i sk i ndi vi dual s has made the di agnosi s of
MTC. Thi s strategy r equi r ed mul ti pl e tests over many year s to
establ i sh a di agnosi s of MTC, and thus MEN 2. Because of the
autosomal -domi nant patter n of i nher i tance, 50% of at-r i sk pati ents
usi ng thi s strategy woul d under go consi derabl e i nconveni ence, be
subjected to undue anxi ety, and be exposed to some degr ee of r i sk
fr om pr ovocati ve testi ng. The appl i cati on of geneti c scr eeni ng for
the RET pr oto-oncogene has al l owed ear l i er and mor e r el i abl e
di agnosi s of MEN 2 whi l e obvi ati ng l ong-ter m bi ochemi cal scr eeni ng
i n those pati ents l acki ng the RET gene. Thus, ear l y scr eeni ng for
the RET gene i s the pr efer r ed method of di agnosi s i n at-r i sk
pati ents. The appr opr i ate ti mi ng of scr eeni ng i s sti l l a topi c of
debate, but i t i s general l y accepted that chi l dr en of pati ents wi th
MEN 2B shoul d be scr eened i n i nfancy. Metastati c MTC has been
r epor ted i n i nfants l ess than 1 year ol d and war rants ear l y and
aggr essi ve tr eatment. Affected chi l dr en of pati ents wi th MEN 2A
may have a mor e i ndol ent di sease cour se, but chi l dhood MTC can
devel op and shoul d be scr eened for by age 5 to 6 year s.
Other wi se, when pati ents pr esent wi th a pal pabl e mass, fi ne-needl e
aspi rati on bi opsy shoul d be per for med. Hi stol ogi cal l y, MTC
fr equentl y shows sheets of uni for ml y r ound or pol ygonal cel l s
separated by fi br ovascul ar str oma. Immunohi stochemi cal stai ni ng
for cal ci toni n i n the tumor cel l s i s the most r el i abl e way to confi r m
the di agnosi s. Laborator y measur ements for ser um cal ci toni n ar e
al so i mpor tant as a basel i ne measur ement and ar e usual l y mar kedl y

i ncr eased. Pati ents wi th cl i ni cal l y occul t tumor s, however, may have
nor mal or mi ni mal l y el evated ser um cal ci toni n l evel s.
Pr ovocati ve tests sti l l can be useful for fol l ow-up of pati ents
pr evi ousl y tr eated for MTC. G eneral l y, pati ents wi th MTC wi l l have a
demonstrabl e i ncr ease i n ser um cal ci toni n l evel ; however, up to
30% of pati ents may have nor mal l evel s. By usi ng pentagastr i n
(wi th or wi thout cal ci um i nfusi on) as a cal ci toni n secr etagogue, the
di agnosi s of r ecur r ence can be made.
Treatment
Once the di agnosi s of MTC i s made, the pr esence of
pheochr omocytoma shoul d be excl uded befor e defi ni ti ve sur gi cal
tr eatment or i nter venti on. Si mi l ar l y, hyper parathyr oi di sm shoul d be
di agnosed, i f pr esent, befor e sur ger y. If a pheochr omocytoma i s
found, i t shoul d be tr eated fi r st (see Chapter 15). If
hyper parathyr oi di sm i s di agnosed, i t can be tr eated at the ti me of
neck expl orati on for the MTC. Impor tant poi nts to keep i n mi nd wi th
r egar d to tr eatment of MTC ar e i ts aggr essi ve natur e r el ati ve to
wel l -di ffer enti ated thyr oi d cancer, i ts i nabi l i ty to concentrate
radi oacti ve i odi ne, the i neffecti veness of radi ati on and
chemotherapy, i ts fr equent mul ti centr i ci ty, and the hi gh pr obabi l i ty
of nodal metastases.
Wi th the above poi nts i n mi nd, the appr opr i ate tr eatment for MTC i s
total thyr oi dectomy and central neck di ssecti on (l evel s VI and VII).
In pati ents wi th MEN 2 syndr omes, MTC i s fr equentl y mul ti centr i c
and bi l ateral and metastasi zes ear l y to the cer vi cal l ymph nodes.
The central neck di ssecti on, whi ch r emoves the
l ymphati c ti ssue between the jugul ar vei ns l ateral l y, the hyoi d bone
super i or l y, and the i nnomi nate vessel s i nfer i or l y, hel ps eradi cate
mi cr oscopi c metastati c di sease. Some author s ar gue that i n pati ents
wi th pal pabl e pr i mar y tumor s, the hi gh fr equency of mi cr oscopi c
di sease i n the l ymph nodes bi l ateral l y war rants bi l ateral functi onal
neck di ssecti ons i n addi ti on to central nodal di ssecti on.
Intraoperati ve nodal eval uati on i s bel i eved to be an i nadequate
pr edi ctor of nodal i nvol vement. Other s contend that onl y pati ents
wi th pal pabl e l ymphadenopathy shoul d under go a concomi tant
functi onal neck di ssecti on on the si de of the enl ar ged pathol ogi c
nodes.
Intraoperati ve management of the parathyr oi d gl ands i s an
i mpor tant consi derati on dur i ng operati on for MTC and i s

contr over si al as wel l . Some sur geons ar e content to i denti fy the
gl ands and l eave them i n si tu, whi l e other s advocate four-gl and
r esecti on wi th autotranspl antati on i nto the non-domi nant for ear m
(MEN 2A [possi bi l i ty or pr esence of hyper parathyr oi di sm]) or the
ster nocl ei domastoi d muscl e (MEN 2B and sporadi c MTC).
Pati ents can be fol l owed postoperati vel y wi th pr ovocati ve testi ng to
i denti fy r esi dual or r ecur r ent MTC. Overal l , the pr ognosi s of MTC i s
good, wi th 10-year sur vi val rates of 60% to 80% r epor ted for
pati ents wi th MEN 2A. Pati ents wi th MEN 2B usual l y pr esent wi th
mor e advanced di sease (i .e., extrathyr oi dal extensi on or
macr oscopi c nodal metastasi s), and l ong-ter m sur vi val i s l ess
common. In general , the cour se of the MTC deter mi nes the
pr ognosi s for pati ents wi th MEN 2. The average l i fe expectancy for
thi s gr oup of pati ents i s mor e than 50 year s.
Metastatic Disease
Contr over sy exi sts over the appr opr i ate tr eatment of pati ents wi th
sti mul ated el evati ons of pl asma cal ci toni n l evel s i n the
postoperati ve per i od. Such a fi ndi ng i mpl i es the pr esence of
r esi dual di sease i n the neck or medi asti num or undetected
metastati c di sease. Some cl i ni ci ans pr efer to si mpl y fol l ow these
pati ents wi th obser vati on because of the r el ati vel y sl ow rate of
pr ogr essi on of MTC, whi l e the chances for cur e wi th r epeat neck
expl orati on ar e l ow and the r i sks of expl orati on ar e i ncr eased.
Other s r ecommend a r epeat neck expl orati on after sel ecti ve
catheter i z ati on of the neck vei ns and deter mi nati on of sti mul ated
pl asma cal ci toni n l evel s. In exper i enced hands, and wi th car eful
pati ent sel ecti on to excl ude the pr esence of di stant metastases
(often i ncl udi ng l apar oscopi c l i ver eval uati on), a 30% to 40%
nor mal i z ati on of pl asma cal ci toni n l evel s by pr ovocati ve testi ng can
be achi eved after r epeat expl orati on. Radi ati on therapy may be
useful when sur gi cal opti ons ar e exhausted for r esi dual or r ecur r ent
di sease i n the neck, but such tr eatment i s general l y i neffecti ve.
Li kewi se, chemotherapy i s general l y i neffecti ve i n tr eati ng
metastati c di sease; however, doxor ubi ci n, al one or i n combi nati on,
may r esul t i n a par ti al r esponse. Because of the i ndol ent natur e of
the tumor, many physi ci ans do not tr eat metastati c di sease
aggr essi vel y.
Pheochromocytoma
Usual l y, pheochr omocytoma associ ated wi th MEN 2 appear s between

the ages of 10 and 30 year s and i s di agnosed concur r entl y wi th, or
shor tl y after, MTC. The pheochr omocytomas associ ated
wi th MEN 2 ar e usual l y bi l ateral (60% 80% of the ti me), l i mi ted to
the adr enal medul l a, and al most al ways beni gn. The adr enal gl and
appear s to become hyper pl asti c befor e the pheochr omocytoma
devel ops. F ur ther di scussi on of pheochr omocytoma can be found i n
the chapter on adr enal tumor s (Chapter 15).
The wor kup and management of pheochr omocytoma ar e di scussed i n
mor e detai l i n Chapter 15. MEN 2 i s typi cal l y di agnosed by
catechol ami ne scr eeni ng (ur i nar y epi nephr i ne, nor epi nephr i ne, and
total metanephr i nes) befor e the onset of character i sti c symptoms. A
cr oss-secti onal i magi ng study (CT or MRI) that demonstrates a
uni l ateral adr enal mass or bi l ateral adr enal masses i s general l y
adequate for pr eoperati ve l ocal i z ati on i n most cases. When cr osssecti onal i magi ng or catechol ami ne scr eeni ng i s equi vocal 1 3 1 I
metai odobenz yl guani di ne (MIBG ) scanni ng and addi ti onal l ocal i z i ng
studi es can hel p confi r m the di agnosi s. MIBG sci nti graphy i s al so
useful to fur ther el i mi nate the possi bi l i ty of bi l ateral
pheochr omocytomas.
Because many year s (10 or mor e) can separate the appearance of
pheochr omocytomas i n the opposi te adr enal gl and i n pati ents wi th
MEN 2, i f a subsequent tumor devel ops at al l , some contr over sy
exi sts about the opti mal sur gi cal pr ocedur e for pati ents who ar e
i ni ti al l y found to have a uni l ateral pheochr omocytoma. Al though
some sur geons r ecommend bi l ateral adr enal ectomy i n pati ents wi th
MEN 2 because bi l ateral tumor s wi l l devel op i n up to 80% of these
pati ents, a mor e conser vati ve appr oach i s fol l owed by most to avoi d
as l ong as possi bl e the need for l i feti me gl ucocor ti coi d and
mi neral ocor ti coi d r epl acement. Thi s appr oach i nvol ves uni l ateral
adr enal ectomy and exami nati on of the contral ateral adr enal gl and
at the ti me of expl orati on. If no abnor mal i ty i s found, the
unaffected adr enal gl and i s l eft i ntact and the pati ent i s obser ved
cl osel y for evi dence of a contral ateral tumor, whi ch devel ops i n
appr oxi matel y 50% of pati ents after 10 year s of fol l ow-up. In the
event of bi l ateral pheochr omocytoma, cor ti cal -spar i ng
adr enal ectomy has been demonstrated to be an effecti ve al ter nati ve
to bi l ateral adr enal ectomy, avoi di ng chr oni c ster oi d r epl acement and
the r i sk of Addi soni an cr i si s. Long-ter m fol l ow-up i s i ndi cated i n al l
pati ents wi th MEN syndr omes for the r ecur r ence of any endocr i ne
l esi on.
Al though l apar oscopi c adr enal ectomy has become i ncr easi ngl y
popul ar for beni gn adr enal l esi ons, the r ol e of l apar oscopy i n the
sur gi cal tr eatment of pheochr omocytoma has yet to be ful l y defi ned.
Several gr oups have demonstrated the safety of l apar oscopi c
adr enal ectomy, al though pati ents wi th pheochr omocytoma may
exper i ence si gni fi cant hyper tensi ve cr i ses dur i ng l apar oscopy, even
i n the face of adequate pr eoperati ve medi cal tr eatment. Thi s i ssue
i s fur ther di scussed i n the chapter on adr enal tumor s (Chapter 15).
Hyperparathyroidism
Hyper parathyr oi di sm i s the thi r d and most var i abl e component of
the MEN 2A syndr ome. Most often, pati ents ar e asymptomati c and
the di agnosi s i s made on r outi ne fol l ow-up l aborator y tests.
Occasi onal l y, pati ents pr esent wi th ki dney stones. In pati ents wi th
MEN 2, a wor kup for hyper parathyr oi di sm shoul d be under taken
befor e neck expl orati on for MTC. In the vast major i ty
of cases, the hyper parathyr oi di sm i s secondar y to hyper pl asi a or
mul ti pl e gl and di sease. As pr evi ousl y di scussed, many sur geons
pr efer total parathyr oi dectomy wi th autotranspl antati on at the ti me
of thyr oi dectomy whether or not concur r ent hyper parathyr oi di sm
exi sts. However, sur geons who pr efer a sel ecti ve appr oach may
choose not to per for m a parathyr oi dectomy i f, at the ti me of
expl orati on, the cal ci um l evel s ar e nor mal and the parathyr oi d
gl ands appear nor mal . If the cal ci um and ser um PTH l evel s ar e
el evated, or i f the gl ands appear gr ossl y abnor mal or ar e
hyper pl asti c on bi opsy, a total parathyr oi dectomy shoul d be
per for med.
Appr oxi matel y one-hal f of the most nor mal -appear i ng parathyr oi d
gl and shoul d be transpl anted i nto the for ear m. If nor mal
parathyr oi d ti ssue becomes devascul ar i zed dur i ng total
thyr oi dectomy for MTC i n a pati ent wi th MEN 2, parathyr oi d
autotranspl antati on shoul d al so be per for med. Pati ents wi th MEN 2A
shoul d have the autotranspl ant per for med i nto the brachi oradi al i s
muscl e of the for ear m, because the gl and coul d become hyper pl asti c
i n the futur e and thi s pl acement faci l i tates l ater r emoval . In
pati ents wi th MEN 2B, because hyper parathyr oi di sm rar el y devel ops,
the devascul ar i zed parathyr oi d gl ands can be transpl anted i nto the
ster nocl ei domastoi d muscl e i n the neck.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 5 - Adre na l Tum o rs
15
Adrenal Tumors
Ricardo J. Gonzalez
Jeffrey E. Lee
The di agnosi s and tr eatment of adr enal tumor s have under gone a
si gni fi cant transfor mati on wi th advances i n di agnosti c i magi ng and
mi ni mal l y i nvasi ve appr oaches to sur gi cal r esecti on. However,
tr eatment of the pati ent wi th an adr enal mass sti l l r equi r es a
thor ough under standi ng of adr enal endocr i ne physi ol ogy and sound
cl i ni cal judgment. Appr opr i ate bi ochemi cal eval uati on and
radi ographi c assessment of an i denti fi ed adr enal mass ar e cr uci al
befor e sur gi cal i nter venti on. Common nonfuncti onal adr enal
adenomas or i nci dental omas must be di ffer enti ated fr om
functi oni ng adr enal tumor s (cor ti sol -pr oduci ng adenomas,
al doster onomas, and pheochr omocytomas), the occasi onal
metastasi s to the adr enal gl and, and the rar e adr enocor ti cal
car ci noma.
Aldosteronoma
Pr i mar y hyperal doster oni sm (Conn syndr ome) i s a cl i ni cal syndr ome
that r esul ts fr om hyper secr eti on of al doster one. Thi s condi ti on i s
caused by bi l ateral adr enal hyper pl asi a i n appr oxi matel y 40% of
cases and by an adr enal adenoma i n appr oxi matel y 60% of cases.
Other rar e causes of pr i mar y al doster oni sm i ncl ude gl ucocor ti coi dsuppr essi bl e hyperal doster oni sm, adr enocor ti cal car ci noma, and
al doster one-secr eti ng ovar i an tumor s. Pr i mar y hyperal doster oni sm
i s r esponsi bl e for appr oxi matel y 0.5% to 2.0% of al l cases of
hyper tensi on and r epr esents 5% to 10% of sur gi cal l y cor r ectabl e
cases of hyper tensi on.
Clinical Manifestations
The mai n di ffi cul ty i n di agnosi ng pr i mar y hyperal doster oni sm i s that
the symptoms ar e usual l y mi l d and nonspeci fi c. The most common
symptoms ar e headache, fati gue, pol ydi psi a, pol yur i a, and noctur i a.
Hyper tensi on i s al most al ways pr esent but i s fr equentl y mi l d, wi th
di astol i c bl ood pr essur es l ess than 120 mm Hg i n mor e than 70% of
cases.
Diagnosis
Ini ti al l aborator y fi ndi ngs that suppor t a di agnosi s of pr i mar y
hyperal doster oni sm i ncl ude hyper tensi on and spontaneous
hypokal emi a. Befor e fur ther bi ochemi cal testi ng, di ur eti cs shoul d be
di sconti nued for at l east 2 to 4 weeks. A pl asma al doster one/pl asma
r eni n rati o gr eater than 30 (ng/dL:ng/mL/h), al ong wi th a pl asma
al doster one l evel gr eater than 20 ng per dL, i s sensi ti ve and
speci fi c i n the scr eeni ng and di agnosi s of pr i mar y
hyperal doster oni sm. The pl asma r eni n l evel i s typi cal l y ver y l ow i n
pati ents wi th pr i mar y hyperal doster oni sm, and a pl asma
al doster onepl asma r eni n acti vi ty rati o of gr eater than 30
(ng/dL:ng/mL/h), al ong wi th a pl asma al doster one concentrati on
l ess than 20 ng per dL, have been shown to be ver y sensi ti ve and
speci fi c for the di agnosi s of pr i mar y hyperal doster oni sm.
Confi r mati on of hyperal doster oni sm can be obtai ned usi ng the
sal i ne suppr essi on test or the 3-day sodi um l oadi ng test. In the
sal i ne suppr essi on test, 2 L of nor mal sal i ne i s i nfused
i ntravenousl y over 4 hour s and pl asma al doster one i s measur ed.
Confi r mati on of hyperal doster oni sm i s obtai ned when the pl asma
al doster one l evel i s gr eater than 10 ng per dL. In the 3-day sodi um
l oadi ng test (100 mmol NaCl per day), a 24-hour ur i ne col l ecti on i s
obtai ned on the thi r d day of the test to measur e al doster one,
sodi um, and potassi um, and ser um i s obtai ned to measur e sodi um
and potassi um. Confi r mati on of hyperal doster oni sm i s obtai ned
when the ur i nar y al doster one i s gr eater than 14 g per 24 hour s. In
the l atter test, i t i s i mpor tant to demonstrate adequate sal t l oadi ng;
ther efor e, ur i nar y sodi um shoul d be gr eater than 200 mEq per 24
hour s.
Once the di agnosi s of hyperal doster oni sm i s establ i shed, i t i s
cr i ti cal to di ffer enti ate uni l ateral adr enal adenoma (60% of cases)
fr om bi l ateral hyper pl asi a of the zona gl omer ul osa (i di opathi c
hyperal doster oni sm; 40% of cases). In pati ents wi th an
al doster one-pr oduci ng adenoma, uni l ateral adr enal ectomy cor r ects
the hypokal emi a and decr eases the bl ood pr essur e i n 70% of
sur gi cal l y tr eated pati ents. However, sur ger y i s of l i ttl e val ue i n
pati ents wi th i di opathi c hyperal doster oni sm. Pati ents wi th a
uni l ateral adenoma usual l y have mor e sever e hyper tensi on, hi gher
pl asma al doster one l evel s, and ther efor e mor e pr ofound
hypokal emi a; however, these fi ndi ngs cannot accuratel y
di ffer enti ate pati ents wi th uni l ateral adenoma fr om those wi th
i di opathi c hyperal doster oni sm. Computed tomography (CT) and
magneti c r esonance i magi ng (MRI) can hel p confi r m the pr esence of
a uni l ateral adr enal nodul e, whi l e i odochol ester ol (NP-59) i magi ng
and sel ecti ve venous sampl i ng for al doster one deter mi nati ons can
l ocal i ze the hyper functi oni ng adr enal ti ssue to the r i ght or l eft si de.
The hi gh fr equency of nonfuncti oni ng adenomas i n the nor mal
popul ati on (2% 8% ) means that the fi ndi ng of a smal l adr enal mass
on CT or MRI i s not necessar i l y di agnosti c of a uni l ateral
al doster one-pr oduci ng adenoma. Because sel ecti ve venous sampl i ng
i s i nvasi ve and cannul ati on of the r i ght adr enal vei n i s often
di ffi cul t and occasi onal l y r esul ts i n adr enal vei n thr ombosi s wi th
adr enal i nfar cti on, we now often combi ne adr enal i magi ng (CT or
MRI) wi th i odochol ester ol i magi ng to confi r m the pr esence of a
uni l ateral functi oni ng adr enal mass. Our cur r ent appr oach to the
eval uati on of pati ents suspected of havi ng pr i mar y
hyperal doster oni sm i s shown i n F i gur e 15.1.
Treatment
The tr eatment of pr i mar y hyperal doster oni sm depends on the cause.
Bi l ateral adr enal hyper pl asi a i s best managed medi cal l y usi ng the
al doster one antagoni st spi r onol actone. Most pati ents can achi eve
adequate contr ol of thei r bl ood pr essur e wi th thi s medi cati on al one
or i n conjuncti on wi th other anti hyper tensi ves. When an
al doster one-pr oduci ng adenoma i s di agnosed, the appr opr i ate
therapy r emai ns sur gi cal r esecti on. Pr eoperati vel y, pati ents shoul d
be pl aced on spi r onol actone and gi ven potassi um suppl ementati on
to hel p nor mal i ze fl ui d and el ectr ol yte bal ance over a 3- to 4-week
per i od.
F i gur e 15.1. Al gor i thm for the eval uati on of the pati ent wi th
suspected pr i mar y hyperal doster oni sm. CT, computed
tomography; MRI, magneti c r esonance i magi ng.
Al though sur gi cal r esecti on can be per for med ei ther thr ough an
open or a l apar oscopi c appr oach because near l y al l pati ents wi th
al doster onomas have r el ati vel y smal l tumor s, they ar e usual l y
excel l ent candi dates for a l apar oscopi c appr oach, and l apar oscopi c
adr enal ectomy has become the standar d sur gi cal appr oach for
pati ents wi th al doster one-pr oduci ng adenomas due to i ts l ower
mor bi di ty, fewer postoperati ve compl i cati ons, and equal r esul ts i n
cur e rates compar ed wi th open adr enal ectomy. As noted pr evi ousl y,
the ear l y r esul ts fr om sur gi cal r esecti on of an al doster onepr oduci ng adenoma ar e good, and the l ong-ter m cur e rate i s
appr oxi matel y 70% . Near l y al l pati ents wi l l have r esol uti on of
hypokal emi a wi th adr enal ectomy, whi l e 30% wi l l r equi r e conti nued
management wi th anti hyper tensi ve medi cati ons.
Appr oxi matel y 2% or l ess of adr enocor ti cal car ci nomas cause
i sol ated hyperal doster oni sm. In the ver y rar e si tuati on of a pati ent
pr esenti ng wi th hyperal doster oni sm and a l ar ge adr enal mass, an
open anter i or appr oach shoul d be taken to faci l i tate compl ete
r esecti on.
Table 15.1. Causes of Cushing syndrome

Exogenous steroids
Cushing disease (due to pituitary adenoma)
Adrenal tumors
Adrenal cortical adenoma
Adrenal cortical carcinoma
Primary adrenal cortical hyperplasia
Ectopic adrenocorticotropin syndrome
Ectopic corticotropin-releasing factor syndrome
Cortisol-Producing Adrenal Adenoma

Cushi ng syndr ome i s the ter m used to r efer to the state of
hyper cor ti sol i sm that can r esul t fr om a number of di ffer ent
pathol ogi cal pr ocesses (Tabl e 15.1). Cor ti sol r egul ati on i nvol ves
feedback l oops thr ough the pi tui tar y gl and and hypothal amus. The
most common cause of Cushi ng syndr ome i s exogenous ster oi d
admi ni strati on. After excl usi on of pati ents taki ng exogenous
ster oi ds, appr oxi matel y 70% of the r emai ni ng cases of
hyper cor ti sol i sm ar e secondar y to hyper secr eti on of
adr enocor ti cotr opi c hor mone (ACTH) fr om the pi tui tar y gl and, a
condi ti on known as Cushi ng di sease. Most of the ti me, a smal l
pi tui tar y adenoma i s found to be the cause. Ectopi c secr eti on of
ACTH, r efer r ed to as ectopi c ACTH syndr ome, i s the cause of
appr oxi matel y 15% of cases of Cushi ng syndr ome. Ectopi c ACTH
syndr ome i s usual l y caused by mal i gnant tumor s, wi th car ci noma of
the l ung, car ci noma of the pancr eas, car ci noi d tumor s, and
mal i gnant thymoma accounti ng for 80% of such cases. Ectopi c
secr eti on of cor ti cotr opi n-r el easi ng factor i s exceedi ngl y rar e but
has been r epor ted i n a few cases.
Hyper secr eti on of cor ti sol fr om the adr enal gl ands accounts for
appr oxi matel y 10% to 20% of cases of Cushi ng syndr ome. The
under l yi ng cause i s an adr enal adenoma 50% to 60% of the ti me

and an adr enocor ti cal car ci noma 20% to 25% of the ti me. Bi l ateral
adr enal hyper pl asi a accounts for the r emai ni ng 20% to 30% of
cases.
Wei ght gai n i s the most common featur e of hyper cor ti sol i sm and
occur s pr edomi nantl y i n the tr uncal ar ea. Centr i petal obesi ty
combi ned wi th muscl e wasti ng i n the extr emi ti es, fat deposi ti on i n
the head and neck r egi on (moon faci es), and dor sal kyphosi s
(buffal o hump) gi ves the pati ent a character i sti c habi tus.
Abdomi nal str i ae, hyper tensi on, and hyper gl ycemi a ar e thr ee other
common fi ndi ngs.
Diagnosis
The eval uati on for Cushi ng syndr ome shoul d be ai med at
establ i shi ng the di agnosi s fi r st and then deter mi ni ng the eti ol ogy.
To establ i sh the di agnosi s, a state of hyper cor ti sol i sm must be
documented. The adul t adr enal gl ands secr ete on average 10 to 30
mg of cor ti sol each day. The secr eti on fol l ows a di ur nal var i ati on
cor ti sol l evel s tend to be hi gh ear l y i n the mor ni ng and
l ow i n the eveni ng. The most sensi ti ve i ni ti al scr eeni ng test for
hyper cor ti sol i sm i n pati ents wi th an adr enal mass i s an over ni ght 1mg dexamethasone suppr essi on test. Documentati on of l ack of
cor ti sol suppr essi on fol l owi ng 1 mg of dexamethasone shoul d be
fol l owed by measur ement of 24-hour ur i nar y fr ee cor ti sol ; the
nor mal l evel i s general l y bel ow 80 g per day. In addi ti on, to
deter mi ne the eti ol ogy of an el evated cor ti sol l evel , pl asma ACTH
l evel s must be checked. ACTH secr eti on al so fol l ows a di ur nal
var i ati on, pr ecedi ng that of cor ti sol by 1 to 2 hour s. Suppr essed
l evel s of ACTH ar e seen i n pati ents wi th adr enal adenomas,
adr enocor ti cal car ci nomas, or autonomousl y functi oni ng adr enal
hyper pl asi a. In such cases, autonomous secr eti on of cor ti sol by the
pathol ogi cal pr ocess wi thi n the adr enal gl and i nhi bi ts pi tui tar y ACTH
r el ease. Pati ents wi th Cushi ng di sease (i .e., a pi tui tar y adenoma
secr eti ng ACTH) usual l y have pl asma ACTH l evel s that ar e el evated
or wi thi n the upper l i mi ts of nor mal . When ther e i s an ectopi c
sour ce of ACTH secr eti on, for exampl e, a metastati c tumor pr ocess,
the pl asma ACTH l evel i s usual l y mar kedl y i ncr eased.
The most sensi ti ve method for detecti ng hyper cor ti sol i sm i s the
over ni ght l ow-dose dexamethasone suppr essi on test. One mi l l i gram

of dexamethasone i s taken oral l y at 11:00 p.m.; nor mal i ndi vi dual s
have a cor ti sol l evel l ess than 5 mg per dL at 8:00 a.m. the
fol l owi ng mor ni ng. Fai l ur e to suppr ess the 8:00 a.m. cor ti sol l evel
to l ess than 5 mg per dL i s consi stent wi th hyper cor ti sol i sm;
however, al though thi s test has a fal se-negati ve rate of onl y 3% ,
the fal se-posi ti ve rate i s 30% . Ther efor e, al though a nor mal
over ni ght dexamethasone suppr essi on test excl udes cl i ni cal l y
si gni fi cant hyper cor ti sol i sm, an abnor mal test r esul t r equi r es
fur ther i nvesti gati on. Twenty-four-hour ur i ne col l ecti on for ur i nar y
fr ee (unmetabol i zed) cor ti sol i s somewhat l ess sensi ti ve than
over ni ght dexamethasone suppr essi on but mor e speci fi c. Sal i var y
cor ti sol can al so be used as a scr eeni ng test for the pr esence of
hyper cor ti sol i sm.
To confi r m the pr esence of Cushi ng syndr ome fol l owi ng abnor mal
scr eeni ng test r esul ts, l ow-dose and hi gh-dose dexamethasone
suppr essi on tests can be per for med. However, these tests ar e
usual l y unnecessar y i n pati ents wi th a uni l ateral adr enal mass wi th
hyper cor ti sol i sm i denti fi ed by the over ni ght 1-mg dexamethasone
suppr essi on test and confi r med by 24-hour ur i ne col l ecti on.
Li kewi se, al though the metyrapone test i s occasi onal l y used to
di ffer enti ate between the var i ous eti ol ogi es of Cushi ng syndr ome,
thi s test i s rar el y hel pful i n pati ents wi th hyper cor ti sol i sm and an
adr enal mass.
Al l pati ents wi th an i nci dental l y i denti fi ed adr enal mass shoul d
under go an eval uati on to excl ude Cushi ng syndr ome. Ini ti al
scr eeni ng i nvol ves the 1-mg over ni ght dexamethasone suppr essi on
test. Pati ents wi th suppr essed cor ti sol l evel s do not have Cushi ng
syndr ome and do not r equi r e fur ther eval uati on for thi s condi ti on.
Pati ents wi thout suppr essed cor ti sol l evel s shoul d under go a 24hour ur i ne col l ecti on for measur ement of fr ee cor ti sol l evel . In
sel ected cases of pati ents wi th hyper cor ti sol i sm and equi vocal
abdomi nal cr oss-secti onal i magi ng studi es, i magi ng of the adr enal
gl ands wi th radi ol abel ed i odochol ester ol can hel p di sti ngui sh
pr i mar y adr enal hyper pl asi a (whi ch shoul d
demonstrate bi l ateral uptake) fr om a cor ti sol -secr eti ng adenoma
(whi ch suppr esses the contral ateral gl and and thus l i mi ts uptake to
onl y the si de contai ni ng the adenoma).
Treatment
The appr opr i ate management of Cushi ng syndr ome depends on the
under l yi ng eti ol ogy. Pati ents wi th Cushi ng di sease shoul d under go
transsphenoi dal hypophysectomy of the pi tui tar y adenoma when i t
i s bel i eved to be r esectabl e. Bi l ateral adr enal ectomy i s rar el y
i ndi cated for pati ents wi th Cushi ng syndr ome and shoul d be
r eser ved for those pati ents who fai l to r espond to standar d
management, i ncl udi ng medi cal therapy and transsphenoi dal
hypophysectomy, and who exper i ence end or gan i njur y fr om the
consequences of over t hyper cor ti sol i sm. If bi l ateral adr enal ectomy
i s per for med, pati ents r equi r e not onl y per i operati ve ster oi d
coverage (Tabl es 15.2 and 15.3), but al so l i fel ong r epl acement of
both gl ucocor ti coi ds and mi neral ocor ti coi ds. Pati ents wi th
autonomousl y functi oni ng bi l ateral adr enal hyper pl asi a usual l y
r equi r e bi l ateral adr enal ectomy. Pati ents wi th ectopi c ACTH
syndr ome shoul d have the under l yi ng mal i gnant condi ti on i denti fi ed
and tr eated. Bi l ateral adr enal ectomy i n thi s setti ng shoul d be
r eser ved for the smal l gr oup of pati ents whose pr i mar y tumor i s
unr esectabl e and whose symptoms of cor ti sol excess cannot be
contr ol l ed medi cal l y. Bi l ateral adr enal ectomy can be per for med
l apar oscopi cal l y, vi a a poster i or appr oach, or vi a l apar otomy; our
cur r ent pr efer r ed appr oach to the major i ty of these pati ents i s vi a a
poster i or appr oach.
Pati ents wi th a cor ti sol -pr oduci ng neopl asm of the adr enal gl and,
whether adenoma or car ci noma, shoul d under go r esecti on of the
i nvol ved si de. Al though al most al l adenomas can be r esected,
adr enocor ti cal car ci nomas that secr ete cor ti sol ar e r esectabl e i n
onl y 25% to 35% of pati ents. Chemotherapy has been di sappoi nti ng
i n pati ents wi th unr esectabl e or metastati c adr enocor ti cal
car ci noma. Symptoms r el ated to hyper cor ti sol i sm i n
pati ents wi th metastati c or unr esectabl e functi oni ng tumor s can
someti mes be mi ni mi zed wi th var i ous agents, i ncl udi ng mi totane,
ami nogl utethi mi de, metyrapone, or ketoconazol e.
Table 15.2. Recommendations for perio

glucocorticoid coverage
Surgical
Examples
Hydrocortis
Equivale
Stress
(mg)
Minor
Inguinal herniorrhaphy
25
Moderate
Open cholecystectomy
Lower-extremity
revascularization
Segmental colon
resection
Total joint replacement
Abdominal hysterectomy
Major
Pancreaticoduodenectomy
Esophagogastrectomy
Total proctocolectomy
Cardiac surgery with
cardiopulmonary bypass
5075
100150
Table 15.3. Comparison of steroid prepa
Steroid
Halflife
(h)
Cortisol
8
12
Cortisone
Glucocorticoid
Miner
Activity
Activi
(Relative to
to
Cortisol)
1
0.8
12
Prednisone
12
36
Prednisolone
12
36
Methylprednisolone
12
36
Triamcinolone
12
36
Betamethasone
36
72
25
Dexamethasone
36
72
3040
Pheochromocytoma
Pheochr omocytomas r epr esent a potenti al l y curabl e for m of
endocr i ne hyper tensi on that, i f undetected, pl aces pati ents at hi gh
r i sk for mor bi di ty and mor tal i ty, par ti cul ar l y dur i ng sur ger y and
pr egnancy. In l ar ge ser i es of hyper tensi ve pati ents, l ess than 0.1%
of pati ents ar e found to have pheochr omocytomas. These
neur oectoder mal tumor s ar i se fr om the chr omaffi n cel l s of the
adr enal medul l a. Appr oxi matel y 10% of pheochr omocytomas ar e
bi l ateral , wi th some pati ents pr esenti ng wi th mul ti pl e tumor s. Ten
per cent of pheochr omocytomas can be found i n extra-adr enal si tes,
wher e they ar e mor e appr opr i atel y cal l ed paragangl i omas because
of thei r cl ose associ ati on wi th gangl i a of the sympatheti c ner vous
system. The most common extra-adr enal si tes i ncl ude the or gan of
Zucker kandl (l ocated between the i nfer i or mesenter i c ar ter y and
the aor ti c bi fur cati on), the ur i nar y bl adder, the thorax, and the
r enal hi l um.
Hi stol ogi c evi dence of mal i gnancy i n pheochr omocytomas can be
demonstrated appr oxi matel y 10% of the ti me; mal i gnancy i s mor e
commonl y seen wi th extra-adr enal l esi ons than wi th those ar i si ng i n
the adr enal gl ands. Documenti ng mal i gnancy can be di ffi cul t
because i nvasi on of adjacent or gans or metastati c di sease must be
pr esent. F ur ther mor e, both beni gn and mal i gnant l esi ons may show
tumor penetrati on of the gl and's capsul e, i nvasi on of vei ns drai ni ng
the gl and, cel l ul ar pl eomor phi sm, mi toses, and atypi cal nucl ei .
Fami l i al pheochr omocytomas have been esti mated to account for
appr oxi matel y 10% of cases; however, r ecent data suggest that up
to 25% of unsel ected cases of appar entl y sporadi c
pheochr omocytomas ar e i n fact her edi tar y. Her edi tar y
pheochr omocytomas ar e al most al ways beni gn. The fami l i al
syndr omes associ ated wi th pheochr omocytomas i ncl ude mul ti pl e
endocr i ne neopl asi a
(MEN) types IIA and IIB, i n whi ch bi l ateral tumor s ar e common, as
wel l as the neur oectoder mal dyspl asi as consi sti ng of
neur ofi br omatosi s, tuber ous scl er osi s, Stur ge-Weber syndr ome, and
von Hi ppel -Li ndau di sease. The r i sk for i nher i ted
pheochr omocytomas i s ver y l ow i n neur ofi br omatosi s type 1 (<1% )
and MEN 1 syndr ome (<1% ). Pheochr omocytoma can al so occur i n
her edi tar y paragangl i oma syndr ome (mutati ons i n SDHD, SDHB, and
SDHC genes). Her edi tar y paragangl i oma syndr ome pr edi sposes to
both extra-adr enal and adr enal paragangl i omas. Pati ents wi th
fami l i al pheochr omocytoma syndr omes r equi r e fol l ow-up and
per i odi c scr eeni ng for pheochr omocytoma, especi al l y befor e any
pl anned sur gi cal pr ocedur e.
The cl i ni cal mani festati ons of pheochr omocytoma can be var i ed and
at ti mes qui te dramati c. Hyper tensi on, sustai ned or par oxysmal , i s
the most common cl i ni cal pr esentati on. Par oxysmal el evati ons i n
bl ood pr essur e can var y mar kedl y i n fr equency and durati on, and
can be i ni ti ated by var i ous events, i ncl udi ng heavy physi cal exer ti on
and eati ng foods hi gh i n tyrami ne (e.g., chocol ate, cheese, r ed
wi ne). Other common symptoms i ncl ude excessi ve sweati ng,
pal pi tati ons, tr emul ousness, anxi ety, and chest pai n. Mor e than hal f
of pati ents wi th pheochr omocytomas have i mpai r ed gl ucose
tol erance, and may have symptoms of di abetes mel l i tus, i ncl udi ng
pol ydi psi a or pol yur i a. These si gns and symptoms ar e secondar y to
the excess catechol ami ne secr eti on by the tumor s, and r esol ve wi th
tumor r esecti on. Pati ents wi th functi oni ng tumor s ar e rar el y
asymptomati c; an excepti on i s pati ents wi th her edi tar y
pheochr omocytomas. Nonfuncti oni ng pheochr omocytomas ar e rar e;
extra-adr enal paragangl i omas, however, may be nonfuncti oni ng.
Diagnosis
The di agnosi s of pheochr omocytoma i s made by documenti ng the
excess secr eti on of catechol ami nes. Pl asma fr ee metanephr i ne
deter mi nati on i s a ver y sensi ti ve scr een for the pr esence of
catechol ami ne el evati on and i s mor e conveni ent than ti med ur i ne
col l ecti on. Twenty-four-hour ur i ne col l ecti on for fr ee catechol ami ne
l evel s (dopami ne, epi nephr i ne, and nor epi nephr i ne) and thei r
metabol i tes (nor metanephr i ne, metanephr i ne, vani l l yl mandel i c aci d)
shoul d be used to confi r m suspected catechol ami ne el evati on
i denti fi ed by pl asma scr een. Incr eased l evel s of catechol ami nes or
thei r metabol i tes ar e seen i n mor e than 90% of pati ents wi th
pheochr omocytoma. The adr enal gl ands and the or gan of
Zucker kandl pr oduce the enz yme phenyl ethanol ami ne-N-methyl transferase, whi ch conver ts nor epi nephr i ne to epi nephr i ne.
Pheochr omocytomas that ar i se el sewher e do not contai n thi s
enz yme and thus do not pr oduce much, i f any, epi nephr i ne. As a
r esul t, extra-adr enal pheochr omocytomas secr ete pr edomi nantl y
dopami ne and nor epi nephr i ne.
Once the di agnosi s of pheochr omocytoma i s made, l ocal i z ati on
studi es can be car r i ed out. A r evi ew of pr eoperati ve i magi ng i n a
l ar ge ser i es of hi stol ogi cal l y confi r med pheochr omocytomas found
that MRI was the most sensi ti ve modal i ty (98% ), fol l owed by CT
scans (89% ) and 1 3 1 I-metai odobenz yl guani di ne (MIBG ) scanni ng
(81% ). Our exper i ence i ndi cates that hi gh-qual i ty spi ral CT scans
can depi ct up to 95% of adr enal masses l ar ger than 6 to 8 mm and
i s usual l y the i ni ti al i magi ng study. MRI may be useful i n sel ected
cases because the T2-wei ghted i mages can i denti fy chr omaffi n
ti ssue; the T2-wei ghted adr enal mass-to-l i ver rati o of
pheochr omocytomas or paragangl i omas i s usual l y mor e than thr ee.
Thi s rati o i s hi gher than that of adr enal cor ti cal adenomas, adr enal
cor ti cal car ci nomas, or metastases to the adr enal gl and. Thus, the
MRI may pr ovi de potenti al l y useful functi onal or bi ochemi cal
i nfor mati on. MIBG i magi ng i s another pr ocedur e that i s hel pful i n
l ocal i z i ng extra-adr enal , metastati c, or bi l ateral

pheochr omocytomas. Thi s radi ol abel ed ami ne i s sel ecti vel y pi cked
up by chr omaffi n ti ssue and can i denti fy the major i ty of
pheochr omocytomas, r egar dl ess of thei r l ocati on. Ther efor e, MIBG
scanni ng i s useful i n pati ents wi th bi ochemi cal evi dence of
pheochr omocytoma whose tumor s cannot be l ocal i zed by CT or MRI
and i n the fol l ow-up eval uati on of pati ents wi th suspected or
documented r ecur r ent or metastati c di sease. Usi ng these
techni ques, i t i s rar e to have a pati ent whose pheochr omocytoma
cannot be l ocal i zed pr eoperati vel y.
Treatment
After di agnosi s and l ocal i z ati on of the pheochr omocytoma, car eful
pr eoperati ve pr eparati on i s r equi r ed to pr event a car di ovascul ar
cr i si s dur i ng sur ger y caused by excess catechol ami ne secr eti on. The
mai n focus of the pr eoperati ve pr eparati on i s adequate al phaadr ener gi c bl ockade and compl ete r estorati on of fl ui d and
el ectr ol yte bal ance. Phenoxybenz ami ne i s the al pha-adr ener gi c
bl ocki ng agent of choi ce and i s usual l y begun at a dose of 10 mg
twi ce a day. The dosage i s gradual l y i ncr eased over a 1- to 3-week
per i od unti l adequate bl ockade i s r eached. The total dosage used
shoul d not exceed 1 mg per kg per day. Beta bl ockade fol l owi ng
al pha bl ockade may hel p pr event tachycar di a and other
ar r hythmi as. Beta bl ockade shoul d not be i nsti tuted unl ess al pha
bl ockade has been establ i shed; other wi se, the beta-bl ocker wi l l
i nhi bi t epi nephr i ne-i nduced vasodi l ati on, l eadi ng to mor e si gni fi cant
hyper tensi on and l eft hear t strai n. In addi ti on to r equi r i ng
phar macol ogi c pr eparati on, pati ents wi th pheochr omocytoma r equi r e
cor r ecti on of fl ui d vol ume depl eti on and any concur r ent el ectr ol yte
i mbal ances.
The per i operati ve management of pati ents wi th pheochr omocytoma
can be di ffi cul t. Rar el y i s al pha-adr ener gi c bl ockade compl ete. The
anesthesi ol ogi st shoul d be pr epar ed to tr eat a hyper tensi ve cr i si s
wi th sodi um ni tr opr ussi de, and tachyar r hythmi as wi th ei ther a betabl ocker or anti ar r hythmi cs. If pr eoperati ve i magi ng suggests a
modestl y si zed, beni gn-appear i ng uni l ateral pheochr omocytoma wi th
a radi ographi cal l y nor mal contral ateral gl and, we cur r entl y pr efer a
uni l ateral l apar oscopi c appr oach. A l apar oscopi c appr oach i s al so
appr opr i ate for pati ents wi th MEN II or von Hi ppel -Li ndau di sease
wi th a smal l , uni l ateral pheochr omocytoma; for pati ents wi th MEN II
or von Hi ppel -Li ndau di sease wi th bi l ateral di sease, a bi l ateral
l apar oscopi c appr oach may al so be appr opr i ate. Cor ti cal -spar i ng
adr enal ectomy, ei ther open or l apar oscopi c, has been per for med
successful l y i n pati ents wi th MEN II or von Hi ppel -Li ndau di sease
wi th bi l ateral
pheochr omocytomas, avoi di ng chr oni c ster oi d hor mone r epl acement
and the r i sk of Addi soni an cr i si s i n most pati ents. Whatever the
operati ve appr oach, the sur geon shoul d mani pul ate the tumor as
l i ttl e as possi bl e, and l i gate the tumor 's venous outfl ow vi a the
adr enal vei n as ear l y i n the pr ocedur e as possi bl e.
Postoperati vel y, pati ents shoul d be moni tor ed car eful l y for 24 hour s
so they can be obser ved for ar r hythmi as, as wel l as hypotensi on
secondar y to compensator y vasodi l ati on. Occasi onal l y, hyper tensi on
r emai ns a pr obl em postoperati vel y, especi al l y i n those pati ents who
had sustai ned hyper tensi on pr eoperati vel y. Fol l owi ng sur gi cal
tr eatment for pheochr omocytoma, al l pati ents shoul d under go
year l y eval uati on to i ncl ude pl asma fr ee metanephr i ne l evel or
ti med ur i ne col l ecti on for catechol ami ne deter mi nati on to excl ude
r ecur r ence.
The most common si tes of metastases fr om mal i gnant
pheochr omocytoma ar e bone, l i ver, and l ungs, and l ess commonl y,
r egi onal l ymph nodes. Pati ents wi th known or suspected mal i gnant
pheochr omocytoma shoul d be staged wi th standar d i magi ng studi es
and MIBG scanni ng. Therapy shoul d be i ndi vi dual i zed based on
extent of di sease. Pal l i ati ve therapy may i ncl ude tr eatment wi th
al pha-methyl tyr osi ne, as wel l as - and -bl ockade. Resecti on of
mal i gnant pheochr omocytoma, i ncl udi ng r esecti on of metastases,
may be consi der ed i n good r i sk i ndi vi dual s i f the metastases ar e
l i mi ted i n extent. The most commonl y used chemotherapy r egi mens
for pheochr omocytoma ar e hi gh-dose str eptozoci n and a
combi nati on of cycl ophosphami de, vi ncr i sti ne, and dacar baz i ne. The
overal l r esponse rates wi th these r egi mens ar e appr oxi matel y 50% .
Radi ati on therapy has been effecti ve onl y for bony metastases.
Ther e has been some i nter est i n tr eati ng metastati c l esi ons wi th
therapeuti c doses of 1 3 1 I-MIBG . Unfor tunatel y, a hi gh per centage of
metastati c pheochr omocytomas do not take up 1 3 1 I-MIBG ; ther efor e,
the r esponse rate, as mani fested by a r educti on i n ur i nar y
catechol ami nes, i s onl y appr oxi matel y 50% . Objecti ve r esponses as
deter mi ned by i magi ng studi es ar e seen even l ess fr equentl y. The 5year sur vi val rate for pati ents wi th mal i gnant pheochr omocytoma i s
appr oxi matel y 43% , as compar ed wi th a 97% 5-year sur vi val rate
for beni gn l esi ons.
Adrenal Cortical Carcinoma

Adr enal cor ti cal car ci noma i s a rar e mal i gnancy, wi th appr oxi matel y
150 to 200 new cases r epor ted each year i n the Uni ted States.
Ther e i s a bi modal age di str i buti on, wi th i nci dence peaki ng i n young
chi l dr en and then agai n between 40 and 50 year s of age.
Pati ents wi th adr enal cor ti cal car ci noma usual l y pr esent wi th vague
abdomi nal symptoms secondar y to an enl ar gi ng r etr oper i toneal
mass or wi th cl i ni cal mani festati ons of over pr oducti on of one or
mor e adr enal cor ti cal hor mones. Most of these tumor s ar e functi onal
as measur ed by bi ochemi cal parameter s. F i fty per cent secr ete
cor ti sol , pr oduci ng Cushi ng syndr ome. The wor kup and tr eatment of
pati ents wi th Cushi ng syndr ome ar e descr i bed i n that secti on i n thi s
chapter. Another 10% to 20% of adr enocor ti cal
car ci nomas pr oduce andr ogens, estr ogens, or al doster one, whi ch
can cause vi r i l i z ati on i n femal es, femi ni z ati on i n mal es, or
hyper tensi on, r especti vel y.
Diagnosis
The pr eoperati ve eval uati on of these pati ents i nvol ves bi ochemi cal
scr eeni ng for cor ti sol over pr oducti on; the r esul ts of thi s scr eeni ng
ser ve to gui de per i operati ve r epl acement therapy. Scr eeni ng to
excl ude pheochr omocytoma shoul d al so be per for med. Standar d
pr eoperati ve stagi ng i n pati ents wi th suspected adr enal cancer
i ncl udes hi gh-r esol uti on abdomi nal CT or MRI. MRI may be
especi al l y hel pful i n del i neati ng tumor extensi on i nto the i nfer i or
vena cava. Chest radi ography i s hel pful i n r ul i ng out pul monar y
metastasi s. The var i ous stagi ng systems for adr enocor ti cal
car ci nomas ar e shown i n Tabl e 15.4.
Treatment
Compl ete sur gi cal r esecti on i s cur r entl y the onl y potenti al l y
curati ve therapy for l ocal i zed adr enal cor ti cal cancer. Appr oxi matel y
50% of the tumor s ar e l ocal i zed to the adr enal gl and at the ti me of
i ni ti al pr esentati on. We r ecommend an open transabdomi nal
appr oach to faci l i tate maxi mal exposur e for compl ete r esecti on,
mi ni mi ze the r i sk of tumor spi l l age, and al l ow for vascul ar contr ol
of the i nfer i or vena cava, aor ta, and r enal vessel s when necessar y.
Radi cal en bl oc r esecti on that i ncl udes adjacent or gans, i f

necessar y, pr ovi des the onl y chance for l ong-ter m sur vi val . Pati ents
who under go a compl ete r esecti on of thei r tumor have a 5-year
sur vi val rate of appr oxi matel y 40% and a medi an sur vi val of 43
months; those who under go i ncompl ete r esecti on have medi an
sur vi val durati on of l ess than 12 months. Ther efor e, the str ongest
pr edi ctor of outcome i n thi s di sease i s the abi l i ty to per for m a
compl ete r esecti on. Lapar oscopi c r esecti on of adr enal cor ti cal
car ci noma, al though techni cal l y potenti al l y feasi bl e i n the rar e
pati ent wi th a smal l , l ocal i zed adr enal cor ti cal car ci noma, has been
associ ated wi th a ver y hi gh rate of tumor r ecur r ence and per i toneal
car ci nomatosi s, pr esumabl y due to tumor fractur e and per i toneal
contami nati on. For thi s r eason, we conti nue to pr efer open
adr enal ectomy for pati ents wi th known or suspected adr enal cor ti cal
car ci noma, i ncl udi ng adr enal i nci dental oma (see Adr enal
Inci dental oma secti on i n thi s chapter ).
Common si tes of metastasi s of adr enal cor ti cal car ci noma i ncl ude
l ungs, l ymph nodes, l i ver, per i toneum, and bone. Compl ete
r esecti on of r ecur r ent di sease, i ncl udi ng pul monar y metastases, i s
associ ated wi th pr ol onged sur vi val i n some pati ents and can hel p
contr ol symptoms r el ated to excess hor mone pr oducti on. After a
potenti al l y curati ve r esecti on, pati ents whose tumor s wer e
hor monal l y acti ve shoul d be moni tor ed wi th i nter val ur i nar y ster oi d
measur ement and abdomi nal and chest i magi ng studi es. Adjuvant
therapy for adr enocor ti cal car ci noma (mi totane) has had mi ni mal
i mpact, i f any, on di sease pr ogr essi on.
Radi ati on therapy can pr ovi de pal l i ati on for bony metastases. No
chemotherapeuti c agent or combi nati on of agents has been shown to
be consi stentl y effecti ve agai nst unr esectabl e or metastati c adr enal
cor ti cal cancer. Mi totane has been one of the most commonl y used
systemi c agents because of i ts abi l i ty to
pal l i ate the endocr i ne effects of the tumor. Thi s dr ug i s an i somer of

di chl or odi phenyl tr i chl or oethane and not onl y i nhi bi ts ster oi d
pr oducti on, but al so l eads to atr ophy of adr enocor ti cal cel l s.
Mi totane i s associ ated wi th numer ous si de effects, most notabl y,
gastr oi ntesti nal and neur omuscul ar symptoms. In addi ti on, the dr ug
has a r el ati vel y nar r ow therapeuti c range, r equi r i ng cl ose
moni tor i ng of ser um l evel s and pr ovi si on of exogenous ster oi d
hor mone r epl acement to avoi d symptoms associ ated wi th adr enal
i nsuffi ci ency due to suppr essi on of the nor mal contral ateral adr enal
gl and. Other systemi c tr eatment opti ons for pati ents wi th

unr esectabl e l ocal r ecur r ence or di stant metastases i ncl ude
surami n, ketoconazol e, and systemi c chemotherapy r egi mens
contai ni ng ci spl ati n, etoposi de, doxor ubi ci n, or vi ncr i sti ne.
Table 15.4. Staging systems for adrenal c

carcinoma
Stage
MacFarlane
(1958)
Sullivan et
al. (1978)
Icard et al. Le
(1992)
(1
T1 (5
cm), N0,
M0
T1 (5
cm), N0,
M0
T1 (5
cm), N0,
M0
T1
N0
II
T2 (>5
cm), N0,
M0
T2 (>5
cm), N0,
M0
T2 (>5
cm), N0,
M0
T2
N0
III
T3 (local
invasion
without
involvement
of adjacent
organs) or
mobile
positive
T3 (local
invasion),
N0, M0 or
T1T2, N1
(positive
lymph
T3 (local
invasion)
and/or N1
(positive
regional
lymph
T3
in
de
by
ev
ad
or
in
di
ex
IV
tu
th
lymph
nodes, M0
IV
T4
(invasion of
adjacent
organs) or
fixed
positive
lymph
nodes or
M1 (distant
metastasis)
nodes), M0
nodes), M0
w
re
an
(p
re
ly
no
T4 (local
invasion),
N0, M0; or
T3, N1,
M0; or T1
T4, N0N1,
M1 (distant
metastasis)
T1T4, N0
N1, M1
(distant
metastasis)
T1
N1
(d
m
IVC, inferior vena cava.
Adrenal Incidentaloma
Wi th the wi despr ead use of abdomi nal CT i magi ng, asymptomati c
adr enal l esi ons ar e bei ng di scover ed wi th i ncr easi ng fr equency.
These l esi ons, ter med incidentalomas, ar e seen i n up to 4% of
r outi nel y per for med abdomi nal i magi ng studi es and i n up to 9% of
autopsy ser i es. Al though most of these l esi ons ar e beni gn
adenomas, some ar e hor monal l y acti ve, and a smal l mi nor i ty
r epr esents an i nvasi ve mal i gnancy.
Al l pati ents i denti fi ed wi th an i nci dental adr enal mass shoul d be
scr eened to r ul e out a hor monal l y acti ve adenoma or
pheochr omocytoma. Eval uati on of pati ents wi th an i nci dental l y
i denti fi ed adr enal mass i ncl udes measur ement of ser um el ectr ol yte
l evel s, an over ni ght 1-mg dexamethasone suppr essi on test

(descr i bed pr evi ousl y), and measur ement of pl asma metanephr i ne
l evel s (F i g. 15.2). Any hor monal l y acti ve l esi on, r egar dl ess of si ze,
shoul d be r esected. F ur ther mor e, sur ger y i s i ndi cated i f the adr enal
mass shows radi ographi c character i sti cs suggesti ve of mal i gnancy or
i f the tumor enl ar ges dur i ng fol l ow-up.
If the i nci dental oma i s nonfuncti oni ng, the r i sk of mal i gnancy i s
r el ated to i ts si ze and radi ographi c character i sti cs. Si ze i s the si ngl e
best cl i ni cal i ndi cator of mal i gnancy i n pati ents who pr esent wi th an
i nci dental adr enal mass. Adr enal cor ti cal car ci noma accounts for
2% , 6% , and 35% of i nci dental omas smal l er than 4 cm, 4.1 to 6
cm, and gr eater than 6 cm i n si ze, r especti vel y. In general , l esi ons
l ar ger than 6 cm shoul d be r esected because of the hi gh r i sk of
mal i gnancy. Obser vati on and fol l ow-up i s general l y r ecommended
for nonfuncti oni ng l esi ons smal l er than 3 cm i n di ameter, but the
management of tumor s between 3 and 6 cm i s mor e contr over si al .
Data fr om our own i nsti tuti on and el sewher e have i denti fi ed
pati ents wi th adr enal cor ti cal car ci nomas ar i si ng i n tumor s smal l er
than 5 cm. The major i ty of these smal l tumor s had CT or MRI
character i sti cs suspi ci ous for car ci noma such as heter ogenei ty and
i r r egul ar bor der s. Based on i ndi vi dual exper i ence and a r evi ew of
the l i teratur e, r ecent r ecommendati ons for r esecti on of
nonfuncti oni ng adr enal masses have ranged fr om 5 cm down to 3
cm. The r ecent success and advantages of l apar oscopi c
adr enal ectomy has l ed some i nvesti gator s to suggest operati ve
r emoval of even smal l i nci dental omas.
At M. D. Ander son, we r ecommend adr enal ectomy for al l
bi ochemi cal l y confi r med functi oni ng adr enal tumor s and those wi th
suspi ci ous radi ographi c fi ndi ngs, r egar dl ess of si ze. A r ecent
study compar i ng the i nci dence of car ci nomatosi s and l ocal

r ecur r ence i n pati ents managed wi th open ver sus l apar oscopi c
adr enal ectomy i denti fi ed a much hi gher rate of car ci nomatosi s i n
the l apar oscopi c gr oup (83% ) when compar ed wi th open
adr enal ectomy (8% ). Because of the r i sk of capsul ar fractur e and
r esul tant per i toneal car ci nomatosi s, we r eser ve the l apar oscopi c
appr oach for l esi ons wi thout wor r i some radi ographi c featur es on
cr oss-secti onal i magi ng (CT and/or MRI) and for l esi ons that ar e
l ess than 4 cm i n gr eatest transver se di ameter, whi l e an open
transabdomi nal appr oach i s used for al l l esi ons that do not meet
these cr i ter i a. Nonfuncti oni ng tumor s between 3 and 6 cm i n
di ameter ar e most appr opr i atel y managed on an i ndi vi dual basi s

wi th r espect to pati ent age and general heal th. For exampl e, a 4-cm
tumor i n an other wi se heal thy 40-year-ol d pati ent i s pr obabl y most
appr opr i atel y managed by adr enal ectomy, wher eas the same tumor
i n a 75-year-ol d pati ent wi th mul ti pl e comor bi di ti es mi ght be
obser ved. The fol l owi ng may be hel pful i n eval uati ng such pati ents
wi th i nter medi ate-si ze nonfuncti oni ng adr enal masses: MRI, a mor e
thor ough endocr i ne eval uati on, and consi derati on of age and
comor bi di ty. F i gur e 15.3 pr ovi des an over vi ew of our appr oach to
pati ents wi th adr enal i nci dental omas.
F i gur e 15.2. Al gor i thm for the eval uati on of pati ents wi th
i sol ated, i nci dental l y i denti fi ed adr enal tumor s. CT, computed
tomography; MRI, magneti c r esonance i magi ng.
Adrenal Metastases
Metastasi s of cancer s to the adr enal gl ands i s r el ati vel y common.
Based on autopsy studi es, 42% of l ung cancer s, 16% of gastr i c
cancer s, 58% of br east cancer s, 50% of mal i gnant mel anomas, and
a hi gh per centage of r enal and pr ostate cancer s have metastasi zed
to the adr enal gl ands at the ti me of death. However, cl i ni cal
pr obl ems r el ated to adr enal metastases, such as adr enal
i nsuffi ci ency, ar e onl y rar el y encounter ed. In general , mor e than

90% of the adr enal gl and must be r epl aced befor e cl i ni cal l y
detectabl e adr enal cor ti cal hypofuncti on i s appr eci ated. When
adr enal i nsuffi ci ency does occur, i t i s usual l y i n the setti ng of gr oss
enl ar gement of the adr enal gl ands as detected by CT.
Sur ger y for i sol ated metastases to the adr enal gl and may be
consi der ed i n hi ghl y sel ected pati ents. These i ncl ude good-r i sk
i ndi vi dual s i n whom ther e i s a pr ol onged di sease-fr ee i nter val and
favorabl e tumor bi ol ogy. Eval uati on of these pati ents i ncl udes
consi derati on of those who have had a si gni fi cant pr ogr essi on-fr ee
i nter val , those who have r esponded to systemi c therapy, and those
who have a hi stor y of i sol ated metachr onous metastases. In
par ti cul ar, a l onger di sease-fr ee i nter val fr om the ti me of pr i mar y
cancer therapy to adr enal metastasi s i s associ ated wi th a sur vi val
advantage fol l owi ng adr enal ectomy. Pr i mar y tumor si te al so appear s
to affect sur vi val , i n that l onger medi an sur vi val ti mes ar e obser ved
fol l owi ng r esecti on of metastases fr om pr i mar y ki dney, mel anoma,
col on, and l ung cancer s, and poor er sur vi val i n pati ents wi th
esophageal , l i ver, unknown pr i mar y tumor s, and hi gh-grade
sar comas.
Eval uati on of the pati ent wi th an adr enal mass and a hi stor y of
mal i gnancy i ncl udes an eval uati on for hor mone pr oducti on because
as many as 50% of these pati ents wi l l have occul t, functi oni ng
adr enal tumor s unr el ated to thei r pr i or mal i gnancy (e.g., a
pheochr omocytoma) (F i g. 15.3). F i ne-needl e aspi rati on bi opsy may
be hel pful i n sel ected pati ents when the r esul ts woul d
i nfl uence the tr eatment pl an; for exampl e, to confi r m a di agnosi s of
metastasi s, par ti cul ar l y i n those who ar e not sur gi cal candi dates
and i n those pati ents who have not yet had thei r pr i mar y cancer
r esected. In a study of pati ents wi th operabl e nonsmal l -cel l l ung
cancer and an adr enal mass, 40% had nonfuncti oni ng adenomas by
CT-gui ded bi opsy. In sel ected pati ents, however, sur gi cal therapy
may be pl anned sol el y based on the pati ent's hi stor y and on
noni nvasi ve studi es, and wi thout pr eoperati ve needl e bi opsy. A
hi stor y of a mal i gnancy that commonl y metastasi zes to the adr enal
gl ands, wi th favorabl e tumor bi ol ogy, negati ve
bi ochemi cal scr eeni ng for hor mone pr oducti on, and a mass that
ei ther ful fi l l s si ze cr i ter i a for sur gi cal exci si on or i s radi ographi cal l y
suspi ci ous for metastasi s may be consi der ed for r esecti on wi thout
pr eoperati ve ti ssue di agnosi s.
F i gur e 15.3. Al gor i thm for the eval uati on and sur gi cal tr eatment
of pati ents wi th extra-adr enal cancer pr esenti ng wi th an adr enal
mass. F NA, fi ne-needl e aspi rati on.
At the M. D. Ander son Cancer Center, we i nvesti gated the i nci dence
of adr enal metastasi s i n pati ents wi th ei ther a known concur r ent
extra-adr enal mal i gnancy or a pr i or extra-adr enal mal i gnancy. One
hundr ed and ni nety-si x pati ents wer e r efer r ed for adr enal ectomy,
and of these, 81 had a pr i or or concur r ent extra-adr enal
mal i gnancy. Of the 81 pati ents, 42 pati ents (52% ) had metastati c
di sease to the adr enal gl and. The thr ee most common pr i mar y
mal i gnanci es wer e fr om r enal , mel anoma, and col or ectal pr i mar i es.
Cr oss-secti onal i magi ng (CT and/or MRI) was suggesti ve of
metastati c di sease i n 17 pati ents (40% ), whi l e F NA was used i n 18
pati ents (43% ) and suppor ted a di agnosi s of cancer i n 16 (89% ) of
these pati ents. The medi an actuar i al sur vi val of these pati ents was
3.4 year s after adr enal ectomy. Ther efor e, i n sel ected pati ents wi th
a l ong di sease-fr ee i nter val , an acceptabl e per for mance status, and
contr ol l ed extra-adr enal di sease, l ong-ter m pal l i ati on may be
achi eved wi th adr enal ectomy, as seen i n pati ents who under go
metastectomy i n other or gans.
We emphasi ze that we do not r ecommend r outi ne fi ne-needl e
aspi rati on of i nci dental l y i denti fi ed adr enal tumor s i n pati ents
wi thout a pr evi ous di agnosi s of cancer. In the absence of si gns or
symptoms of a sol i d tumor mal i gnancy, uni l ateral adr enal
metastases ar e uncommon. Our r ecent exper i ence wi th mor e than
1,600 pati ents found that the i nci dence of metastasi s fr om an occul t
pr i mar y cancer was 0.2% (4 of 1,639). In al l four of these pati ents,
mal i gnancy was suspected on the basi s of tumor si ze, bi l ateral
i nvol vement, or symptoms. Ther efor e, we do not r outi nel y bi opsy
pati ents wi th smal l nonfuncti oni ng adr enal tumor s sear chi ng for
occul t metastati c di sease.
Laparoscopic Adrenalectomy
Si nce the fi r st descr i pti on of l apar oscopi c adr enal ectomy i n 1992,
thi s appr oach has been expanded and i s now consi der ed the
standar d techni que for beni gn adr enal tumor s. Most sur geons have
used an anter ol ateral transper i toneal appr oach; a poster i or or
l ateral fl ank r etr oper i toneal appr oach has al so been r epor ted. A
r etr oper i toneal l apar oscopi c appr oach i s practi cal i n pati ents wi th
pr evi ous abdomi nal operati ons who have r el ati vel y smal l adr enal
tumor s. Pati ents who under go l apar oscopi c adr enal ectomy for
r el ati vel y smal l adr enal masses have a mor e rapi d r ecover y, l ess
di scomfor t, faster r etur n to pr eoperati ve acti vi ty l evel , and better
cosmeti c r esul ts compar ed wi th pati ents who under go open
adr enal ectomy. Pati ents who shoul d be consi der ed for l apar oscopi c
adr enal ectomy i ncl ude those wi th al doster one-pr oduci ng adenomas,
other smal l (<4 cm) functi oni ng cor ti cal neopl asms, those wi th
uni l ateral , beni gn-appear i ng sporadi c pheochr omocytomas, MEN 2 or
VHL pati ents wi th a uni l ateral pheochr omocytoma, and sel ected
pati ents wi th adr enal metastasi s. Bi l ateral l apar oscopi c
adr enal ectomy can be per for med i n pati ents wi th bi l ateral adr enal
hyper pl asi a; techni cal consi derati ons suggest that a poster i or
appr oach may be si mpl er than an anter i or appr oach i n most of these
pati ents. Lapar oscopi c
cor ti cal -spar i ng par ti al adr enal ectomy has been successful l y
per for med i n pati ents wi th bi l ateral pheochr omocytomas i n the
fami l i al setti ng; however, we conti nue to pr efer an open anter i or

appr oach to maxi mi ze the oppor tuni ty for adr enal cor ti cal
pr eser vati on i n these pati ents. We conti nue to ur ge cauti on i n the
use of l apar oscopi c adr enal ectomy for pati ents wi th mal i gnant or
potenti al l y mal i gnant pr i mar y adr enal tumor s. Thi s i ncl udes the
occasi onal pati ent wi th sporadi c pheochr omocytoma i n whom
radi ographi c i magi ng rai ses suspi ci on for mal i gnancy, pati ents wi th
her edi tar y paragangl i oma syndr ome, and those wi th cor ti cal
neopl asms (functi oni ng or nonfuncti oni ng) 4 cm i n si ze or gr eater,
or those wi th radi ographi c evi dence of mal i gnancy. It i s emphasi zed
that the r eason for operati ng on pati ents wi th nonfuncti oni ng
adr enal tumor s (i nci dental omas) i s that they ar e potenti al l y
mal i gnant cor ti cal neopl asms. Ther efor e, we speci fi cal l y do not
r ecommend l apar oscopi c adr enal ectomy for pati ents i n whom
adr enal cor ti cal car ci noma i s par t of the pr eoperati ve di ffer enti al
di agnosi s.
Operative Approach
We cur r entl y pr efer to per for m l apar oscopi c adr enal ectomy vi a a
transabdomi nal i ntraper i toneal appr oach. For a l eft adr enal ectomy,
the pati ent i s pl aced i n the r i ght l ateral decubi tus posi ti on, wi th the
tabl e appr opr i atel y padded and fl exed. The abdomen and chest ar e
pr epped fr om the ni ppl e to bel ow the i l i ac cr est, and fr om the r i ght
of the umbi l i cus to the ver tebral col umn. An i nfracostal por t, 10 to
15 cm anter i or to the anter i or axi l l ar y l i ne, i s pl aced usi ng the open
techni que, abdomi nal i nsuffl ati on achi eved, and the 30-degr ee
l apar oscope i s i nser ted. Thr ee addi ti onal 10-mm tr ocar s ar e then
pl aced under di r ect vi si on. One i s pl aced at the anter i or axi l l ar y
l i ne, one i s pl aced at the poster i or axi l l ar y l i ne, and one i s pl aced 5
cm poster i or to the poster i or axi l l ar y por t, just medi al to the l eft
ki dney. Di ssecti on begi ns by mobi l i z i ng the spl eni c fl exur e of the
col on, usi ng gravi ty to car r y i t i nfer i or l y and medi al l y. Mobi l i z ati on
of the spl een i s per for med by i nci si ng the per i toneum l ateral to the
spl een. Thi s i nci si on i s devel oped ar ound to the l evel of the shor t
gastr i c vessel s. Thi s al l ows the spl een to r otate medi al l y. It i s often
hel pful to move the l apar oscope to the poster i or por t as di ssecti on
pr oceeds to maxi mi ze vi sual i z ati on of the adr enal bed. The adr enal
gl and i s di ssected fr om the r etr oper i toneal fat; the Har moni c
Scal pel (Ethi con Endo-Sur ger y) wor ks wel l for thi s di ssecti on. In
contrast to the open appr oach, techni cal consi derati ons i n
l apar oscopi c adr enal ectomy often r esul t i n del ayi ng l i gati on of the
adr enal vei n to the penul ti mate step i n the pr ocedur e, fol l owi ng
compl ete mobi l i z ati on of the tumor and the adr enal gl and, and just
pr i or to speci men r emoval . Vei n di vi si on on the l eft si de can be
safel y accompl i shed wi th ei ther the vascul ar stapl er or wi th two to
thr ee ti tani um cl i ps pl aced on the pr oxi mal si de of the vei n. The
speci men i s r emoved i n a ster i l e pl asti c r etr i eval bag thr ough the
umbi l i cal por t si te. Ri ght l apar oscopi c adr enal ectomy i s per for med
wi th si mi l ar posi ti oni ng i n the l eft l ateral decubi tus posi ti on.
Abdomi nal access i s obtai ned thr ough pl acement of four 10-mm
por ts, pl aced si mi l ar to those on the l eft si de. The most medi al por t
i s used to assi st i n r etracti on of the l i ver. The sur geon begi ns the
operati on
thr ough the two l ateral por ts; the r i ght l ateral hepati c attachments
and the r i ght tr i angul ar l i gament of the l i ver ar e di vi ded to al l ow
for medi al r etracti on of the l i ver. The adr enal gl and i s then
di ssected i nfer i or l y al ong the r enal vei n and medi al l y al ong the
vena cava. The r i ght adr enal vei n i s usual l y shor t and wi de, and
drai ns di r ectl y i nto the vena cava. Ti tani um cl i ps may not
adequatel y secur e the vei n on the r i ght si de; ther efor e, a
l apar oscopi c vascul ar stapl er i s pr efer r ed.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 6 - C a rc ino m a o f t he Thy ro id a nd Pa ra t hy ro id G la nds
16
Carcinoma of the Thyroid and
Parathyroid Glands
Keith D. A mos
Mouhammed A . Habra
Nancy D. Perrier
Thyroid Cancer
Epidemiology
Thyr oi d cancer i s the most common endocr i ne mal i gnancy and
accounts for appr oxi matel y 1% of al l human mal i gnanci es, wi th an
esti mated i nci dence i n the Uni ted States of 25,700 cases i n 2005.
The major i ty of casesappr oxi matel y 70% occur i n women.
Car ci noma of the thyr oi d gl and i s consi der ed to be an i ndol ent
di sease; many affected i ndi vi dual s di e of other causes. An esti mated
1,500 pati ents di e of thi s di sease each year.
The pr eval ence of thyr oi d nodul es i ncr eases l i near l y wi th age, wi th
spontaneous nodul es occur r i ng at a rate of 0.08% per year
begi nni ng ear l y i n l i fe and extendi ng i nto the ei ghth decade.
Cl i ni cal l y appar ent nodul es ar e pr esent i n 4% to 7% of the adul t
popul ati on and occur mor e commonl y i n women. Most nodul es ar e
not mal i gnant. Repor ted mal i gnancy rates ar e 5% to 12% i n
pati ents wi th si ngl e nodul es and 3% i n pati ents wi th mul ti pl e
nodul es. However, a hi stor y of radi ati on exposur e has been r epor ted
to i ncr ease the r i sk of mal i gnancy i n a nodul e to between 30% to
50% .
Risk Factors
Appr oxi matel y 9% of thyr oi d cancer s ar e associ ated wi th pr i or
radi ati on exposur e. The r i sk of cancer fr om radi ati on i ncr eases

l i near l y wi th doses up to 20 G y, wi th thyr oi d abl ati on occur r i ng at
hi gher dose l evel s. The r i sk of devel opi ng thyr oi d cancer i s
i nver sel y r el ated to age at exposur e. A hi stor y of exposur e to
i oni z i ng radi ati on i n chi l dhood i s a major r i sk factor for thyr oi d
mal i gnancy, al most al ways of the papi l l ar y type. Indi vi dual s 15
year s of age or ol der at exposur e do not have a demonstrabl e
radi ati on-dosedependent r i sk of thyr oi d cancer. In general ,
radi ati on-i nduced thyr oi d cancer i s bi ol ogi cal l y si mi l ar to sporadi c
thyr oi d cancer and shoul d be tr eated i n the same manner. However,
r ecent i nfor mati on r egar di ng the hi gh i nci dence of bi ol ogi cal l y
aggr essi ve thyr oi d cancer i n chi l dr en exposed to radi ati on after the
Cher nobyl nucl ear di saster suggests that radi ati on dose and tumor
behavi or may be l i nked. The pr opor ti ons of l ess wel l -di ffer enti ated
papi l l ar y thyr oi d cancer s and of sol i d-var i ant papi l l ar y thyr oi d
cancer s wer e hi gher among these chi l dr en than among pati ents
wi thout radi ati on exposur e. Addi ti onal evi dence of a l i nk between
radi ati on dose and tumor behavi or comes fr om the fi ndi ng that
exposur e to di ffer ent types of radi ati on r esul ts i n di ffer ent patter ns
of geneti c al terati ons i n thyr oi d tumor s.
Asi de fr om radi ati on exposur e, few envi r onmental r i sk factor s have
been confi r med for thyr oi d car ci noma. Hor monal factor s and di etar y
i ntake of i odi ne, r eti nol , vi tami n C, and vi tami n E have been
suggested to pl ay a r ol e i n the eti ol ogy of thyr oi d cancer that has
yet to be defi ned.
Associ ati ons have been descr i bed between thyr oi d cancer and
several other i nher i ted syndr omes, i ncl udi ng fami l i al pol yposi s,
G ar dner syndr ome, and Cowden di sease (fami l i al goi ter and ski n
hamar toma). In addi ti on, papi l l ar y thyr oi d cancer may occur wi th
i ncr eased fr equency i n some fami l i es wi th br east, ovar i an, r enal , or
central ner vous system mal i gnanci es. Medul l ar y thyr oi d cancer
occur s wi th a hi gher fr equency i n pati ents who have Hashi moto
thyr oi di ti s. The mechani sm under l yi ng these associ ati ons i s not wel l
under stood.
Over the past ten year s, si gni fi cant pr ogr ess has been made i n the
i denti fi cati on of genes l i nked to the pathogenesi s of thyr oi d cancer.
Studi es of the patter ns of geneti c al terati ons pr esent i n thyr oi d
tumor s suggest that ther e ar e di ffer ences i n the pathogenesi s of the
di ffer ent thyr oi d tumor types, whi ch most l i kel y account for the
range i n bi ol ogi cal behavi or obser ved among thyr oi d cancer s. The
RET pr oto-oncogene, whi ch i s l ocated on chr omosome 10 and
encodes a tyr osi ne ki nase r eceptor, i s bel i eved to pl ay a r ol e i n the
pathogenesi s of both her edi tar y and sporadi c medul l ar y thyr oi d

car ci nomas (MTCs) and papi l l ar y thyr oi d car ci nomas (PTCs).
Acti vati ng poi nt mutati ons i n the RET pr oto-oncogene of
parafol l i cul ar C cel l s have been detected i n vi r tual l y al l her edi tar y
for ms of MTC, i ncl udi ng fami l i al MTC, mul ti pl e endocr i ne neopl asi a
2A (MEN 2A), and MEN 2B, whi ch account for appr oxi matel y 25% of
MTCs. Mutati ons i n the RET pr oto-oncogene have al so been found i n
sporadi c MTC, al though di ffer ent codons of the RET pr oto-oncogene
ar e affected. Rear rangements of the RET pr oto-oncogene i n thyr oi d
fol l i cul ar cel l s ar e consi der ed to be an ear l y event i n the
devel opment of PTCs. Near l y al l pati ents wi th autosomal domi nant
MEN 2A or MEN 2B wi l l devel op MTC; scr eeni ng for ger ml i ne RET
mutati ons has been i nval uabl e i n the ear l y i denti fi cati on of pati ents
who have a geneti c basi s for thei r di sease. The di scover y of the RET
pr oto-oncogene has had si gni fi cant cl i ni cal i mpact, affecti ng the
scr eeni ng and pr ophyl acti c tr eatment of pati ents who ar e member s
of the MEN ki ndr eds.
Somati c mutati ons i n the Ras oncogene have been found i n both
beni gn and mal i gnant thyr oi d tumor s, and thus al so seem to be an
ear l y event i n thyr oi d tumor i genesi s, al though some r epor ts suggest
that Ras mutati ons ar e mor e pr eval ent i n fol l i cul ar thyr oi d
car ci nomas (F TCs). The fi ndi ngs of a hi gh pr eval ence of p53
mutati ons i n anapl asti c car ci nomas, but not i n wel l -di ffer enti ated
thyr oi d car ci nomas, suggest that p53 mutati ons pl ay a r ol e l ater i n
thyr oi d tumor pathogenesi sspeci fi cal l y, i n the dedi ffer enti ati ng
transi ti on to the anapl asti c phenotype. Numer ous other genes (e.g.,
PTEN, TRK, G SP, and the thyr oi d-sti mul ati ng hor mone [TSH]
r eceptor gene) have al so been i mpl i cated i n the pathogenesi s of
thyr oi d cancer, al though thei r r ol es sti l l need to be defi ned.
Cur r entl y, few of the geneti c al terati ons (e.g., p53, ras, and cer tai n
RET mutati ons, i ncl udi ng 883 and 918), RET/PTC r ear rangements
found i n thyr oi d tumor s, have been shown to have
negati ve i mpl i cati ons on pr ognosi s. Much wor k i s sti l l needed to
el uci date the mol ecul ar bi ol ogy of thyr oi d tumor s and to transl ate
thi s knowl edge i nto cl i ni cal management.
Pathology
Four tumor types account for mor e than 90% of thyr oi d
mal i gnanci es: PTC, F TC, MTC, and anapl asti c thyr oi d car ci noma
(ATC). PTC and F TC ar e fur ther gr ouped together and r efer r ed to as
di ffer enti ated thyr oi d car ci noma (DTC), whi ch accounts for
appr oxi matel y 90% of thyr oi d car ci nomas. Di ffer enti ated thyr oi d
cancer s mor e commonl y occur i n women, wher eas an equal gender
di str i buti on i s seen i n both MTC and ATC. PTC, F TC, and ATC ar e
der i ved fr om the fol l i cul ar epi thel i al cel l s of the thyr oi d gl and,
whi ch pr oduce the thyr oi d hor mones. MTC i s der i ved fr om the
cal ci toni n-secr eti ng parafol l i cul ar C cel l s. Other l ess common
thyr oi d car ci nomas i ncl ude Hr thl e cel l car ci noma (a var i ant of
fol l i cul ar car ci noma), l ymphomas, squamous cel l car ci nomas,
sar comas, and metastati c car ci nomas fr om other si tes, i ncl udi ng
r enal cel l car ci noma and mel anoma.
PTC i s the most common thyr oi d car ci noma, r epr esenti ng 80% of al l
cases. Pati ents wi th PTC usual l y pr esent dur i ng the thi r d to fi fth
decades. Femal es have a hi gher i nci dence of thi s di sease than
mal es. PTC occur s as an i r r egul ar sol i d or cysti c mass that ar i ses
fr om fol l i cul ar epi thel i um. It i s nonencapsul ated but shar pl y
ci r cumscr i bed. Mi cr oscopi cal l y, the hal l mar k i s papi l l ar y fr onds of
epi thel i um. Rounded cal ci fi ed deposi ts (psammoma bodi es) ar e
found i n 50% of l esi ons. Mul ti focal i ty i s a pr omi nent featur e of PTC
and has been documented i n up to 80% of pati ents. Cer vi cal l ymph
node metastases ar e qui te common at pr esentati on wi th a r epor ted
fr equency of between 30% and 80% i n most U.S. and Eur opean
ser i es. PTC i s the pr edomi nant tumor type found i n pati ents wi th a
hi stor y of radi ati on exposur e. The overal l pr ognosi s for pati ents
wi th PTC i s ver y good: 10-year sur vi val rates ar e 95% .
Fol l i cul ar thyr oi d car ci noma i s the second most common mal i gnancy
of the thyr oi d gl and, compr i si ng 10% to 20% of thyr oi d cancer s.
Pati ents wi th F TC often pr esent a decade l ater than pati ents wi th
PTC, dur i ng the fi fth and si xth decades. Pati ents wi th F TC al so tend
to have sl i ghtl y l ar ger tumor s at pr esentati on than pati ents wi th
papi l l ar y tumor s. Cytol ogi c di agnosi s of F TC i s often di ffi cul t due to
the si mi l ar i ti es between F TC and beni gn fol l i cul ar adenomas.
Per manent secti ons showi ng capsul ar or vascul ar i nvasi on ar e
r equi r ed to confi r m the di agnosi s. F TC i s usual l y encapsul ated and
consi sts of hi ghl y cel l ul ar fol l i cl es, most of whi ch ar e si ngl e, sol i d,
and noncysti c wi thout central necr osi s and usual l y uni focal . Cer vi cal
l ymph node metastases ar e uncommon i n F TC and ar e found i n
appr oxi matel y 10% of pati ents at pr esentati on. F TC has a gr eater
tendency to spr ead hematogenousl y to di stant si tes such as l ung
and bone, and up to 33% of pati ents have di stant metastases at
pr esentati on. F TC i s often found i n associ ati on wi th beni gn thyr oi d
di sor der s, such as endemi c goi ter. A r el ati onshi p between TSH
sti mul ati on and fol l i cul ar car ci noma has been suggested because of
the gr eater i nci dence of F TC i n i odi ne-defi ci ent ar eas. Ten-year

sur vi val rates for F TC ar e 70%
to 95% sl i ghtl y wor se than those for PTC, whi ch i s most l i kel y due
to l ater pr esentati on. When pati ents ar e matched by age and tumor
stage, ther e i s no si gni fi cant di ffer ence i n sur vi val between PTC and
F TC.
Hr thl e cel l car ci nomas r epr esent 5% of thyr oi d cancer s and ar e
consi der ed var i ants of F TC, al though Hr thl e cel l car ci nomas and
F TC ar e bel i eved to be di sti nct pathol ogi cal enti ti es because of
di ffer ences i n thei r bi ol ogi cal behavi or and natural hi stor y. As wi th
the di agnosi s of F TC, the di agnosi s of Hr thl e cel l car ci nomas
depends on the pr esence of vascul ar or capsul ar i nvasi on. Hr thl e
cel l car ci nomas ar e character i zed mi cr oscopi cal l y by pol ygonal ,
hyper chr omati c cel l s. The i nci dence of l ymph node metastases at
pr esentati on i s sl i ghtl y hi gher i n Hr thl e cel l car ci nomas
(appr oxi matel y 25% ) than i n F TC. Pati ents wi th Hr thl e cel l
car ci nomas have been r epor ted to have hi gher tumor r ecur r ence
rates and a wor se pr ognosi s when compar ed wi th pati ents wi th PTC
and F TC. Hr thl e cel l tumor s concentrate radi oacti ve i odi ne l ess
avi dl y than papi l l ar y and fol l i cul ar tumor s.
Medul l ar y thyr oi d car ci nomas r epr esent 5% of al l thyr oi d cancer s.
Ei ghty per cent of tumor s ar e sporadi c, and 25% occur as par t of an
autosomal domi nant her edi tar y syndr ome. Sporadi c MTC often
pr esents i n the fi fth decade as a uni l ateral sol i tar y nodul e. Pati ents
wi th fami l i al MTC mor e commonl y pr esent i n the four th decade wi th
mul ti focal nodul es i n the upper pol es of both thyr oi d l obes, wher e
ther e i s the gr eatest concentrati on of C cel l s. Bi l ateral C-cel l
hyper pl asi a i s bel i eved to be a pr ecur sor to the devel opment of
her edi tar y MTC. Hi stol ogi cal l y, MTC i s an i l l -defi ned,
nonencapsul ated, i nvasi ve mass composed of spi ndl e-shaped or
r ounded cel l s separated by fi br ous septa and amyl oi d deposi ts.
Posi ti ve i mmunohi stochemi cal stai ni ng for cal ci toni n,
car ci noembr yoni c anti gen, and amyl oi d ai ds i n the di agnosi s of MTC.
Medul l ar y car ci nomas ar e sl ow gr owi ng but have a pr opensi ty to
metastasi ze ear l y, usual l y befor e the pr i mar y tumor r eaches 2 cm.
F i fty per cent of pati ents have r egi onal metastases at the ti me of
di agnosi s. Cer vi cal and upper medi asti nal l ymph nodes ar e the usual
si tes i nvol ved. Ten-year sur vi val rates for MTC depend on the extent
of di sease at pr esentati on and ar e 90% when di sease i s confi ned to
the thyr oi d gl and, 70% when cer vi cal metastases ar e pr esent, and
20% when di stant metastases ar e pr esent. The pr ognosi s for
pati ents wi th MTC fal l s between that of pati ents wi th

undi ffer enti ated tumor s and pati ents wi th wel l -di ffer enti ated
tumor s. Poor pr ognosti c factor s i ncl ude age gr eater than 50 year s at
di agnosi s, metastases at the ti me of di agnosi s, and associ ati on wi th
MEN 2B. Seventy per cent of pati ents wi th MEN 2B have metastases
at the ti me of di agnosi s of MTC and of these pati ents, fewer than
50% sur vi ve 5 year s.
Anapl asti c thyr oi d car ci noma i s a rar e and hi ghl y aggr essi ve tumor
that i s consi der ed one of the deadl i est mal i gnanci es. Anapl asti c
tumor s ar e often i noperabl e at pr esentati on and account for l ess
than 5% of thyr oi d cancer s. The peak i nci dence i s i n the seventh
decade, and the i nci dence i s the same i n men and women. Pati ents
wi th ATC usual l y pr esent wi th a rapi dl y gr owi ng neck mass, often
l ar ger than 5 cm that i s fi xed to under l yi ng str uctur es and causes
symptoms of dysphagi a, dyspnea, or dysphoni a. On pathol ogi cal
exami nati on, anapl asti c tumor s ar e
nonencapsul ated and often contai n ar eas of extensi ve necr osi s.
Ther e ar e thr ee hi stol ogi c var i ants, al l of whi ch show hi gh mi toti c
acti vi ty, nucl ear pl eomor phi sm, and hi gh vascul ar i ty. At the ti me of
di agnosi s, 25% of pati ents have i nvasi on of the trachea, 90% have
r egi onal metastases, and 50% have di stant metastasesmost
commonl y to the l ung. An associ ati on between ATC and a hi stor y of
wel l -di ffer enti ated thyr oi d cancer has been r epor ted. It has been
hypothesi zed that ATC can devel op fr om wi thi n pr e-exi sti ng
di ffer enti ated thyr oi d cancer as a r esul t of dedi ffer enti ati on of a
cl one of tumor cel l s over ti me. Despi te the use of mul ti modal i ty
r egi mens, tr eatment rar el y r esul ts i n cur e, and 90% of pati ents
succumb wi thi n 6 months of di agnosi s, often as a r esul t of l ocal
pr ogr essi on of di sease causi ng ai r way obstr ucti on. The 5-year
sur vi val rate for ATC i s 7% .
Thyr oi d l ymphomas r epr esent fewer than 2% of thyr oi d cancer s.
Pati ents wi th thyr oi d l ymphomas typi cal l y pr esent i n the seventh
decade. Thi s subtype of thyr oi d cancer al so mor e commonl y affects
women and i s associ ated wi th a hi stor y of Hashi moto thyr oi di ti s.
The cl i ni cal pr esentati on of thyr oi d l ymphoma may be si mi l ar to
that of UTC, wi th a rapi dl y gr owi ng neck mass and symptoms of
dysphagi a and dysphoni a. Lymphomas may be pr i mar y or secondar y;
however, non-Hodgki n's B-cel l type l ymphomas ar e the most
common pr i mar y thyr oi d l ymphomas. Hi stol ogi cal l y, tumor cel l s
appear monomor phi c and noncohesi ve and stai n posi ti ve for
l ymphocyte mar ker s l i ke CD20. It has been r epor ted that 67% of
thyr oi d l ymphomas ar e of mucosa-associ ated l ymphoi d ti ssue (MALT)

or i gi n; these tumor s ar e associ ated wi th better sur vi val and may be
suffi ci entl y tr eated wi th radi ati on therapy al one, i nstead of the
mul ti modal i ty therapy used for non-MALT l ymphomas. Pr ognosi s i s
r el ated to the extent of di sease at the ti me of di agnosi s. When
l ymphoma i s confi ned to the thyr oi d gl and (stage IE), the 5-year
sur vi val rate i s 75% to 85% . Pati ents wi th di sease on both si des of
the di aphragm (stage IIIE) or di ssemi nated di sease (stage IVE) have
a 5-year sur vi val rate of l ess than 35% .
Diagnosis
Most pati ents wi th thyr oi d cancer have no speci fi c symptoms. These
l esi ons may be i denti fi ed i nci dental l y dur i ng r outi ne car oti d
ul trasonography and posi tr on emi ssi on tomography scanni ng for
other r easons. The most common fi ndi ng at pr esentati on i s a mass
or nodul e. Less commonl y, change i n the si ze of a thyr oi d nodul e or
pai n fr om hemor r hage i nto a nodul e wi l l pr ompt a pati ent to see a
physi ci an. Hoar seness, dysphagi a, dyspnea, and hemoptysi s ar e
symptoms r esul ti ng fr om i nvasi on of sur r oundi ng anatomi cal
str uctur es and ar e rar e i n wel l -di ffer enti ated thyr oi d car ci nomas.
Occasi onal l y, a pati ent may pr esent wi th a pal pabl e cer vi cal l ymph
node.
A thor ough hi stor y and physi cal exami nati on i s an i mpor tant fi r st
di agnosti c step. Al though the hi stor y may not be sensi ti ve or
speci fi c for detecti on of a thyr oi d mal i gnancy, i t i s i mpor tant to
ascer tai n whether ther e i s a fami l y hi stor y of thyr oi d cancer,
pr evi ous radi ati on exposur e, or the pr esence of symptoms that
suggest i nvasi veness, such as pr ogr essi ve devel opment of
hoar seness, dyspnea, and dysphagi a. The pr esence of a si ngl e,
domi nant
nodul e that i s fi xed to sur r oundi ng ti ssues and gr eater than 1 cm i n
di ameter wi th a har d consi stency i s suggesti ve of cancer. The
pr esence of di scr ete 1- to 2-cm l ymph nodes i n conjuncti on wi th a
thyr oi d nodul e i s al so suggesti ve of mal i gnancy. Pal pabl e
adenopathy i s most often found al ong the mi ddl e and l ower por ti ons
of the jugul ar vei n but may be l ocated l ateral to the
ster nocl ei domastoi d muscl e i n the l ower por ti on of the poster i or
cer vi cal tr i angl e. Other physi cal fi ndi ngs that suggest i nvasi ve
mal i gnancy i ncl ude vocal cor d paral ysi s, fi xati on of the thyr oi d
nodul e, and tracheal devi ati on or i nvasi on. Cer vi cal spi ne fl exi bi l i ty
shoul d be assessed to ensur e adequate hyper extensi on of the neck
can be achi eved i n case sur ger y i s needed. Exami nati on of the
l ar ynx and vocal cor ds shoul d be per for med ei ther i ndi r ectl y wi th a
mi r r or or di r ectl y wi th a fl exi bl e fi ber opti c scope to document the
pr eoperati ve condi ti on.
Var i ous di agnosti c tests ar e avai l abl e to hel p di sti ngui sh beni gn
fr om mal i gnant di sease. The ul ti mate goal i s to avoi d unnecessar y
operati ons on beni gn l esi ons whenever possi bl e. The i ni ti al
eval uati on of a pati ent wi th a si ngl e thyr oi d nodul e consi sts of
l aborator y thyr oi d functi on studi es and fi ne-needl e aspi rati on (F NA)
bi opsy. Bl ood tests, such as the measur ement of TSH or
thyr ogl obul i n, cannot di agnose thyr oi d car ci noma. The excepti on i s
the measur ement of ser um cal ci toni n concentrati ons that can hel p
i denti fy pati ents wi th MTC.
F NA i s safe, cost-effecti ve, and the si ngl e most useful di agnosti c
tool i n the eval uati on of thyr oi d nodul es because i t can pr ovi de
di r ect i nfor mati on about a l esi on. Lesi ons ar e cl assi fi ed as beni gn,
mal i gnant, or suspi ci ous for mal i gnancy on the basi s of F NA. If an
exper i enced physi ci an per for ms the F NA and an exper i enced
cytopathol ogi st i nter pr ets the cytol ogi c character i sti cs, the accuracy
of F NA i n the di agnosi s of thyr oi d cancer can be gr eater than 90% ,
wi th a fal se-negati ve rate of l ess than 5% . Accuracy of F NA i s
gr eatest for l esi ons between 1 and 4 cm; l esi ons l ess than 1 cm ar e
di ffi cul t to sampl e, whi l e l esi ons gr eater than 4 cm have an
i ncr eased sampl i ng er r or as a r esul t of the l ar ge ar ea of the l esi on.
The type of thyr oi d tumor can al so i nfl uence the accuracy of F NA.
Pati ents wi th the di agnosi s of fol l i cul ar neopl asm often r equi r e
sur gi cal i nter venti on for compl ete di agnosi s. A fol l i cul ar adenoma
cannot be di sti ngui shed fr om a fol l i cul ar car ci noma by F NA because
the pr esence or absence of capsul ar or vascul ar i nvasi on i s r equi r ed
to make the di agnosi s. Pati ents wi th i nadequate speci mens shoul d
under go r epeat F NA or sur ger y to obtai n a ti ssue di agnosi s.
Indi vi dual s wi th a fi ndi ng of beni gn col l oi d nodul e or thyr oi di ti s by
F NA ar e obser ved wi th or wi thout thyr oi d suppr essi on. G r owth of a
nodul e i n a pati ent r ecei vi ng thyr oi d suppr essi on i s an i ndi cati on for
sur gi cal i nter venti on. Other speci fi c i ndi cati ons for sur gi cal
i nter venti on i n thyr oi d abnor mal i ti es ar e l i sted i n Tabl e 16.1. The
i nci dence of mal i gnancy i ncr eases wi th l ar ger nodul e si ze, mal e
gender, and i ncr easi ng age. In 15% to 25% of cases, F NA wi l l yi el d
i nadequate di agnosti c mater i al , and thi s necessi tates r epeat
aspi rati on. The avai l abi l i ty of ul trasound gui dance has i ncr eased the
di agnosti c yi el d.
Ul trasonography of the thyr oi d i s an accurate method for
deter mi ni ng the character of a thyr oi d nodul e (sol i d, cysti c, or

mi xed),
the number of thyr oi d nodul es, and the status of cer vi cal l ymph
nodes. Ul trasonography i s al so useful i n gui di ng an F NA i n pati ents
wi th l esi ons that ar e di ffi cul t to pal pate and al so i n i ncr easi ng the
yi el d fr om aspi rati ons of smal l or compl ex l esi ons. Ul trasonography
i s al so useful i n the l ong-ter m fol l ow-up of pati ents wi th beni gn
thyr oi d nodul es and those tr eated for thyr oi d car ci noma. The exact
r ol e of ul trasonography i n di sti ngui shi ng beni gn fr om mal i gnant
nodul es i s sti l l unr esol ved. Several ul trasonographi c featur es wer e
pr oposed to achi eve thi s goal , i ncl udi ng the pr esence of
mi cr ocal ci fi cati ons, i r r egul ar bor der s, hypoechogeni ci ty of the
nodul e, and the absence of sur r oundi ng hal o at the mar gi n of a
nodul e.
Table 16.1. Indications for surgical

intervention for thyroid abnormalities
Fine-needle aspiration (FNA) of thyroid

nodule suspicious for carcinoma or follicular
neoplasm
Thyroid mass associated with vocal cord
paralysis, regional tissue invasion, cervical
lymph node metastasis, or fixation to
surrounding tissues
Thyroid nodule in a patient younger than 20
years or older than 60 years with FNA
findings of atypia
Thyroid nodule in a patient with a history of
irradiation exposure to the cervical region
Hyperfunctioning thyroid nodule in a young
patient who (a) fails medical management or
(b) refuses medical management or
radioactive iodine
Symptomatic multinodular goiter (dysphagia,
difficulty lying supine, or hoarseness)
Radi onucl i de sci nti graphy (9 9 Tc-per technetate, 1 2 5 I, or 1 3 1 I) was

pr evi ousl y used as the fi r st di agnosti c step i n eval uati ng pal pabl e
thyr oi d masses. Because most thyr oi d car ci nomas and many beni gn
nodul es appear col d on scan, the mai n l i mi tati on of radi onucl i de
scanni ng i s that i t cannot di sti ngui sh between beni gn and mal i gnant
l esi ons. Appr oxi matel y 16% of col d (nonfuncti oni ng) nodul es and
9% of war m (nor mal ) l esi ons har bor a mal i gnancy, but rar el y do hot
(hyper functi oni ng) l esi ons appear mal i gnant. Al though a col d l esi on
has the gr eatest pr obabi l i ty of bei ng mal i gnant, the pr esence of a
hot l esi on on a thyr oi d scan does not excl ude mal i gnancy. In
general , the use of nucl ear thyr oi d scans has been r epl aced by F NA
for di agnosi s, except i n the pr esence of subcl i ni cal or cl i ni cal
hyper thyr oi di sm wi th a pal pabl e thyr oi d nodul e.
Other di agnosti c i magi ng studi es ar e sel dom needed i n the i ni ti al
eval uati on of a pati ent wi th a thyr oi d nodul e. A chest radi ograph
shoul d be obtai ned i n cer tai n si tuati ons to assess for pul monar y
metastases and tracheal devi ati on. Computed tomography (CT) and
magneti c r esonance i magi ng (MRI) ar e useful i n the eval uati on of
l ar ge or r ecur r ent cancer s suspected of i nvasi on i nto the
sur r oundi ng soft ti ssue. When i ndi cated by the hi stor y and physi cal
fi ndi ngs, CT or MRI of the neck and upper medi asti num may be used
to del i neate extrathyr oi dal extensi on and
i nvasi on of the trachea or esophagus, or to deter mi ne the pr esence
of si gni fi cant cer vi cal or medi asti nal metastases. The use of fourdi mensi onal CT scanni ng wi th 1-mm cuts of the cer vi cal r egi on
pr ovi des excel l ent pr eoperati ve pl anni ng.
Pr eoperati ve l aborator y assessments shoul d i ncl ude thyr oi d functi on
tests and a ser um cal ci um measur ement. Al though thyr oi d functi on
tests do not ai d i n the di agnosi s of thyr oi d cancer, the pr esence of
hypothyr oi di sm or hyper thyr oi di sm i s an i mpor tant factor to take
i nto account i n a pati ent under goi ng general anesthesi a.
Parathyr oi d functi on shoul d be assessed by measur i ng the ser um
cal ci um l evel . The i nci dence of parathyr oi d adenomas and other
hyper functi oni ng anomal i es of the parathyr oi d gl ands i s hi gher i n
the pr esence of thyr oi d nodul es or car ci noma. Thyr oi d anti body

tests ar e i mpor tant when thyr oi di ti s i s a consi derati on.
Measur ement of ser um thyr ogl obul i n l evel s i s useful mai nl y for
fol l ow-up studi es after tr eatment of DTC and i s not a par t of the
i ni ti al di agnosti c eval uati on. Ser um cal ci toni n measur ements shoul d
not be done r outi nel y i n nodul ar thyr oi d di sease because cal ci toni n
measur ement can l ead to unnecessar y thyr oi dectomy wi thout
pr oven cl i ni cal benefi t. However, cal ci toni n shoul d be measur ed i n
pati ents wi th thyr oi d nodul es who have di ar r hea, fami l y hi stor y of
MTC, or MEN-2 syndr ome. Sol i tar y l esi ons at the juncti on of the
upper one-thi r d and l ower two-thi r ds of the thyr oi d gl and war rant
suspi ci on. Pati ents who have an i ncr eased cal ci toni n l evel and a
pr eoperati ve di agnosi s of MTC shoul d be scr eened for
pheochr omocytoma wi th a 24-hour ur i ne col l ecti on for
vani l l yl mandel i c aci d, metanephr i ne, fr ee catechol ami nes or pl asma
metanephr i ne, and her edi tar y MTC wi th RET pr oto-oncogene
mutati on anal ysi s. F i ve per cent to 7% of pati ents wi th appar entl y
sporadi c MTC ar e found to have a mutati on consi stent wi th
her edi tar y MTC.
Staging and Prognosis

Several cl assi fi cati ons and stagi ng schemes have been pr oposed for
DTC. However, no consensus favor i ng any one of these systems has
emer ged. The most commonl y used ar e the AMES (Age, Metastasi s,
Extent, Si ze) system, whi ch di vi des pati ents i nto l ow- and hi gh-r i sk
gr oups; the TNM (Tumor, Nodes, Metastasi s), as used by the
Amer i can Joi nt Commi ttee on Cancer ; the AG ES (Age, G rade,
Extent, Si ze) and MACIS (Metastasi s, Age, Compl eteness of
Resecti on, Invasi on, Si ze) pr oposed by the Mayo Cl i ni c; the
Uni ver si ty of Chi cago system, whi ch gr oups pati ents i nto four
categor i esdi sease l i mi ted to the gl and (I), l ymph node
i nvol vement (II), extrathyr oi dal i nvasi on (III), and di stant
metastases (IV); and the Nati onal Thyr oi d Cancer Tr eatment
Cooperati ve Study Regi str y scheme. The TNM cl assi fi cati on strati fi es
pati ents i nto four stages on the basi s of tumor si ze, nodal status,
the pr esence or absence of di stant metastases, and age at
di agnosi s.
The pr ognosi s of pati ents wi th stage I wel l -di ffer enti ated thyr oi d
car ci noma i s excel l ent, wi th 20-year sur vi val rates of near l y 100% .
Pati ents wi th stage IV di sease, i n contrast, have a 5-year sur vi val
rate of onl y 25% . Wi thi n the gr oup of pati ents wi th wel l di ffer enti ated thyr oi d cancer ar e a smal l number who have mor e
aggr essi ve di sease and for whom none of the cur r ent stagi ng
systems appl y. As mol ecul ar mar ker s of di sease ar e devel oped,
these pati ents may be abl e to be i denti fi ed at ear l i er stages and
offer ed addi ti onal tr eatment.
In general , the pr ognosi s for pati ents wi th PTC i s i nfl uenced by age,
gender, extent of di sease, and vol ume of the pr i mar y tumor. Unl i ke
most sol i d tumor s, age at di agnosi s may be the most i mpor tant
pr edi cti ve factor for sur vi val . The si gni fi cance of gender as a
pr ognosti c factor i n thyr oi d cancer i s al so gr eater than that for
other sol i d tumor s. The pr ognosti c si gni fi cance of l ymph node
metastases i n di ffer enti ated thyr oi d cancer s conti nues to be
debated; i n pati ents wi th papi l l ar y cancer who ar e younger than 40
year s of age and who fr equentl y have l ymph node i nvol vement, the
si gni fi cance of thi s fi ndi ng on mor tal i ty i s negl i gi bl e, al though i t
i ncr eases the r ecur r ence rate. The mi ni mal effect of l ymph node
metastases on pr ognosi s i s r efl ected i n the TNM stagi ng system
(Tabl e 16.2), i n whi ch l ymph node metastases ar e onl y factor ed i nto
the stagi ng of pati ents ol der than 45 year s of age. The di mi ni shed
i mpor tance of l ymph node metastases i s based on data suggesti ng
that mi cr oscopi c metastases ar e pr esent i n up to 90% of l ymph
nodes exami ned, yet cl i ni cal l y si gni fi cant di sease devel ops i n onl y
10% of pati ents.
The pr ognosi s of pati ents wi th F TC i s bel i eved to be poor er than
that of pati ents wi th PTC, per haps because of the hi gher i nci dence
of hematogenous metastases. However, tr eatment deci si ons and
pr ognosi s ar e based on wel l -di ffer enti ated thyr oi d mal i gnanci es as a
gr oup.
Treatment
Contr over sy conti nues over the extent of r esecti on necessar y i n
cases of papi l l ar y and fol l i cul ar cancer, the necessi ty and extent of
neck di ssecti on, the r ol e of postr esecti on thyr oi d hor mone
suppr essi on, and the appr opr i ate use of postoperati ve therapeuti c
radi oacti ve 1 3 1 I. At thi s ti me, no randomi zed pr ospecti ve tr i al s have
been conducted to cl ar i fy these contr over si es. Cer tai n factor s make
i t unl i kel y that a pr ospecti ve tr i al wi l l be conducted because (a)
thyr oi d cancer i s an i ndol ent di sease, whi ch woul d r equi r e that
pati ents be fol l owed for l ong per i ods of ti me to detect di ffer ences i n
outcome; and (b) gi ven the l ow i nci dence of thyr oi d cancer, Udel sma
et al . r epor ted that between 3,000 and 12,000 pati ents woul d need
to be randomi zed to conduct a pr ospecti ve tr i al . Thus, the major i ty

of tr eatment deci si ons for di ffer enti ated thyr oi d cancer have been
made based on data fr om l ar ge r etr ospecti ve ser i es.
Surgical Resection
The pr i nci pal tr eatment for thyr oi d cancer i s sur gi cal r esecti on.
Accepted sur gi cal management var i es fr om a thyr oi d l obectomy and
i sthmectomy to a total thyr oi dectomy and a compar tment-or i ented
neck di ssecti on.
The sur gi cal management of wel l -di ffer enti ated thyr oi d cancer
conti nues to be contr over si al , wi th the debate center i ng on the
extent of thyr oi dectomy. Pr oponents of total thyr oi dectomy ar gue
that thi s operati on can be per for med safel y by exper i enced sur geons
wi th a l ess than 2% i nci dence of per manent r ecur r ent ner ve i njur y
or per manent hypoparathyr oi di sm; foci of papi l l ar y
car ci noma ar e found i n both thyr oi d l obes i n up to 85% of pati ents,

and 5% to 10% of r ecur r ences occur i n the contral ateral l obe; the
pr esence of r esi dual thyr oi d ti ssue after l ess than total
thyr oi dectomy hamper s the use of thyr ogl obul i n as a mar ker of
per si stent or r ecur r ent di sease; radi oacti ve i odi ne can be used to
i denti fy and tr eat r esi dual nor mal thyr oi d ti ssue and r ecur r ent or
metastati c di sease after total thyr oi dectomy; ther e i s a l ower
r ecur r ence rate i n pati ents who have under gone bi l ateral
pr ocedur es or total thyr oi dectomy; and total thyr oi dectomy
mi ni mi zes the need for r eoperati ve sur ger y, whi ch i s associ ated wi th
i ncr eased compl i cati on rates.
Table 16.2. TNM classification system for

differentiated thyroid carcinoma
Definition
Primary tumor (T)
TX
T0
T1
Tumor 2 cm, confined to the thyroid
T2
Tumor >2 cm and <4 cm, confined to the

thyroid
T3
Tumor >4 cm, confined to the thyroid
T4a
Tumor of any size extending beyond the

thyroid capsule to invade subcutaneous
soft tissues, larynx, trachea, esophagus,
or recurrent laryngeal nerve
T4b
Tumor invades prevertebral fascia or

encases carotid artery or mediastinal
vessels
Regional lymph nodes (N) (cervical and upper

mediastinal)
NX
N0
N1

N1a metastasis to level VI (pretracheal,
paratracheal, and prelaryngeal/Delphian
lymph nodes)
N1b metastasis in bilateral, midline, or
contralateral cervical or superior
mediastinal lymph nodes

MX

assessed
M0
M1
Distant metastasis
Stages
Papillary and follicular thyroid cancer
Pati ent Age <45
Year s
Pati ent Age 45

Year s
Stage I
Any T, any N, M0
T1, N0, M0
Stage II
Any T, any N, M1
T2, N0, M0
Stage III
T3,
T1,
T2,
T3,
Stage
IVA
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, M0
T4a, N1b, M0
Stage
N0, M0
N1a, M0
N1a, M0
N1a, M0
IVB
T4b, any N1b, M0
Stage
IVC
Any T, any N, M1
Medullary thyroid cancer

Stage I
T1, N0, M0
Stage II
T2, N0, M0
Stage III
T3,
T1,
T2,
T3,
Stage
IVA
T4a, N0, M0
T4a, N1a, M0
T1, N1b, M0
T2, N1b, M0
T3, N1b, M0
T4a, N1b, M0
Stage
IVB
T4b, any N, M0
Stage
IVC
Any T, any N, M1
N0, M0
N1a, M0
N1a, M0
N1a, M0
A naplastic thyroid cancer

Stage
IVA
T4a, any N, M0
Stage
IVB
T4b, any N, M0
Stage
IVC
Any T, any N, M1
Advocates of mor e conser vati ve pr ocedur es, such as thyr oi d

l obectomy wi th i sthmectomy or near-total thyr oi dectomy, ar gue that
ther e i s a decr eased r i sk of i njur y to the r ecur r ent l ar yngeal ner ve
and the parathyr oi d gl ands wi th l ess extensi ve sur ger y; i t i s rar e
for a total thyr oi dectomy to r emove the enti r e thyr oi d gl and; occul t
foci of papi l l ar y car ci noma l eft behi nd after conser vati ve sur ger y
ar e rar el y of cl i ni cal si gni fi cance; hal f of cl i ni cal l y si gni fi cant
r ecur r ences after conser vati ve sur ger y can be safel y managed wi th
r eoperati on; and ther e i s no di ffer ence i n sur vi val between pati ents
who have under gone mor e conser vati ve pr ocedur es and pati ents
who have under gone total thyr oi dectomy.
At the M. D. Ander son Cancer Center, we per for m a total
thyr oi dectomy and central compar tment l ymph node exci si on for al l
papi l l ar y car ci nomas. Total thyr oi dectomy i s al so our tr eatment of
choi ce for fol l i cul ar car ci noma and Hr thl e cel l car ci noma;
however, these di agnoses often cannot be ascer tai ned by fr ozensecti on exami nati on at the ti me of sur ger y. If the di agnosi s of
fol l i cul ar or Hr thl e cel l car ci noma i s made postoperati vel y i n a
pati ent tr eated wi th a thyr oi d l obectomy, we suggest that a
compl eti on thyr oi dectomy be per for med i n hi gh-r i sk pati ents (i .e.,
age >45 year s, l esi ons >1 cm, or di stant metastases). Pati ents who
have under gone thyr oi d l obectomy for other r easons and ar e found
to have an i nci dental mi cr oscopi c car ci noma on per manent
hi stol ogi c studi es may not r equi r e compl eti on thyr oi dectomy. We
combi ne a therapeuti c cer vi cal node di ssecti on wi th total
thyr oi dectomy i n pati ents wi th wel l -di ffer enti ated car ci nomas and
cl i ni cal or di agnosti c evi dence of l ymph node metastases. We
r outi nel y use pr eoperati ve ul trasound to assess the central and
l ateral compar tments of the neck.
Pati ents wi th sporadi c MTC di agnosed pr eoperati vel y under go a total
thyr oi dectomy wi th i n-conti nui ty central compar tment di ssecti on
and modi fi ed radi cal neck di ssecti on on the si de of the l esi on.
Pati ents wi th pal pabl e cer vi cal l ymphadenopathy under go a bi l ateral
modi fi ed radi cal neck di ssecti on at the ti me of total thyr oi dectomy.
The goal s of our aggr essi ve sur gi cal appr oach ar e to maxi mi ze
l ocor egi onal tumor contr ol and sur vi val and to mi ni mi ze the need
for r eoperati on. Our appr oach i s suppor ted by publ i shed r epor ts
suggesti ng that pati ents who under go total thyr oi dectomy wi th
compar tment-or i ented l ymphadenectomy have both i mpr oved l ocal r egi onal di sease contr ol and i mpr oved sur vi val . Our appr oach i s al so
suppor ted by our knowl edge of the bi ol ogi cal behavi or of medul l ar y
thyr oi d cancer s: these tumor s do not concentrate radi oi odi ne, ar e
mul ti focal , metastasi ze ear l y, and ar e not adequatel y managed wi th
nonsur gi cal tr eatments.
Pati ents who have her edi tar y MTC as par t of the fami l i al MTC or
MEN-2 syndr omes di agnosed onl y by posi ti ve RET mutati onal
anal ysi s under go total thyr oi dectomy wi thout l ymphadenectomy i f
pr eoperati ve studi es show a nor mal basal cal ci toni n l evel and
nor mal fi ndi ngs on a cer vi cal sonogram. Pati ents who have an
i ncr eased basal cal ci toni n l evel or a thyr oi d nodul e detected on
physi cal exami nati on or sonography under go total thyr oi dectomy
wi th central compar tment l ymphadenectomy and modi fi ed neck
di ssecti on. Chi l dr en who ar e found to car r y a her edi tar y RET pr otooncogene mutati on shoul d under go pr ophyl acti c total thyr oi dectomy.
Chi l dr en i n fami l i es wi th MEN-2A or fami l i al MTC syndr omes shoul d
under go sur ger y at 5 year s of age, whi l e chi l dr en i n fami l i es wi th
MEN 2B shoul d under go sur ger y as ear l y as possi bl e because
i nvasi ve MTC has been found as ear l y as at bi r th i n these chi l dr en.
ATC i s an aggr essi ve l esi on that i s usual l y di agnosed by F NA. Most
anapl asti c tumor s ar e unr esectabl e at pr esentati on and ar e thus
managed pr i mar i l y by combi nati on radi ati on therapy and
chemotherapy. Sur ger y i s rar el y i ndi cated other than for ti ssue
sampl i ng or tracheostomy. In the exceedi ngl y rar e case, r esectabl e
l esi ons woul d be tr eated wi th total thyr oi dectomy and wi de l ocal
exci si on of adjacent soft ti ssues fol l owed by postoperati ve adjuvant
chemotherapy and radi ati on therapy. Al though di ffer ent
chemotherapy combi nati ons and radi ati on therapy r egi mens have
been tr i ed, no therapy has been abl e to i mpr ove the outcome of
ATC.
Neck Dissection
An under standi ng of the l ymphati c drai nage patter n of the thyr oi d
gl and i s necessar y to ensur e the nodal gr oups at hi ghest r i sk for
metastasi s ar e r emoved when node di ssecti on i s per for med. The
thyr oi d gl and has an extensi ve i ntragl andul ar networ k of l ymphati c
channel s that al l ow for drai nage wi thi n one l obe and fr om one l obe
to another. The thyr oi d l ymphati cs typi cal l y drai n fi r st i nto the

central compar tment (l evel VI), whi ch contai ns the pr etracheal and
paratracheal nodes, and subsequentl y i nto the l ateral jugul ar
r egi ons (l evel IIIV). Another r oute of l ymphati c spr ead for thyr oi d
cancer i s al ong the i nfer i or thyr oi d ar ter y because i t cour ses behi nd
the common car oti d ar ter y to the l ower por ti on of the poster i or
tr i angl e of the neck (l evel V). The super i or medi asti nal nodes al so
commonl y contai n metastases and must be cl osel y exami ned
i ntraoperati vel y. The submandi bul ar and submental nodes (l evel I)
rar el y contai n metastases i n pati ents wi th DTC. The cl assi c radi cal
neck di ssecti on, whi ch consi sts of l ymphadenectomy of l evel s II to
V, as wel l as r emoval of the i nter nal jugul ar vei n,
ster nocl ei domastoi d muscl e, and spi nal accessor y ner ve, i s
associ ated wi th hi gh mor bi di ty and rar el y per for med. We mor e
commonl y per for m central compar tment node di ssecti on, whi ch
r emoves l evel VI and super i or medi asti nal nodes, and compar tmentor i ented neck di ssecti on, whi ch spar es the i nter nal jugul ar vei n,
ster nocl ei domastoi d muscl e, and spi nal accessor y ner ve, i n pati ents
wi th wel l -di ffer enti ated thyr oi d cancer s.
The necessi ty and extent of neck di ssecti on, speci fi cal l y the r ol e of
el ecti ve node di ssecti on, for di ffer enti ated thyr oi d cancer i s another
subject of contr over sy. PTC fr equentl y spr eads to cer vi cal l ymph
nodes, wher eas F TC rar el y metastasi zes to the r egi onal l ymph
nodes. Al though the exact i nci dence of l ymph node metastases i n
papi l l ar y car ci noma i s unknown, posi ti ve nodes have been found i n
30% to 80% of pati ents who under went pr ophyl acti c neck
di ssecti ons. Mi cr oscopi c nodal metastases have been r epor ted i n up
to 90% of these pati ents. However, cl i ni cal l y si gni fi cant nodal
di sease devel ops i n onl y appr oxi matel y 10% of pati ents wi th
papi l l ar y car ci noma. At the hear t of the contr over sy i s the i ssue of
whether l ymph node metastases have an i mpact on r ecur r ence or
sur vi val . The major i ty of studi es i n the l i teratur e on DTC have
r epor ted that posi ti ve nodal status i nfl uences l ocal -r egi onal
r ecur r ence rates, but not pati ent sur vi val . The major i ty of studi es
have al so fai l ed to demonstrate a sur vi val benefi t i n pati ents wi th
di ffer enti ated thyr oi d tumor s who have under gone extensi ve,
pr ophyl acti c (el ecti ve) node di ssecti on at the ti me of i ni ti al sur ger y.
Whether el ecti ve node di ssecti on r educes l ocal -r egi onal r ecur r ence
rates i s uncl ear because ther e ar e several confl i cti ng r epor ts i n the
l i teratur e. Of note, though, al l studi es wi th pati ents who under went
extensi ve cer vi cal l ymphadenectomy r epor ted hi gher compl i cati on
rates.
For pati ents wi th papi l l ar y cancer, i f a total thyr oi dectomy i s

per for med, then we al so per for m an en bl oc central compar tment
di ssecti on. If ther e ar e cl i ni cal l y pal pabl e nodes i n the l ateral
r egi ons of the neck, an en bl oc modi fi ed radi cal neck di ssecti on on
the si de contai ni ng cl i ni cal l y suspi ci ous di sease i s al so per for med
at the ti me of total thyr oi dectomy. In pati ents wi th fol l i cul ar
tumor s, because of the l ow i nci dence of l ymph node metastases, we
do not per for m central compar tment l ymphadenectomy at the ti me
of total thyr oi dectomy, unl ess ther e i s pal pabl e adenopathy. At M.
D. Ander son, the aggr essi ve use of ul trasound, par ti cul ar l y i n hi ghr i sk pati ents, has assi sted i n the pr eoperati ve detecti on of
suspi ci ous nodes and the ear l y deter mi nati on of the need for l ymph
node di ssecti on.
A poor pr ognosi s i s associ ated wi th the pr esence of l ymph node
metastases i n pati ents wi th medul l ar y and anapl asti c cancer s. We
ther efor e per for m a central compar tment node di ssecti on and a
modi fi ed radi cal neck di ssecti on on the si de of the pr i mar y l esi on at
the ti me of total thyr oi dectomy i n pati ents wi th sporadi c MTC. A
bi l ateral modi fi ed radi cal neck di ssecti on i s al so per for med i f the
pati ent pr esents wi th pal pabl e adenopathy.
Surgical Technique
Sur gi cal r esecti on of a possi bl e thyr oi d car ci noma r equi r es
meti cul ous di ssecti on of the i psi l ateral thyr oi d compar tment,
i denti fi cati on and pr eser vati on of the r ecur r ent l ar yngeal ner ve,
and compl ete r esecti on of the affected l obe and thyr oi d i sthmus.
Sur ger y shoul d be per for med wi th general anesthesi a. Identi fi cati on
of the i psi l ateral parathyr oi d gl ands shoul d be attempted, but
pr eser vati on of the gl ands may be i mpossi bl e i f ther e i s extensi ve
i nvasi on by cancer or i f ther e ar e cl i ni cal metastases i n the
paratracheal ar ea. If the di agnosi s of thyr oi d car ci noma i s confi r med
i ntraoperati vel y by fr ozen-secti on hi stol ogi c exami nati on of the
sur gi cal speci men, total thyr oi dectomy i s compl eted by r esecti ng the
contral ateral l obe wi th speci al car e taken to i denti fy and spar e the
parathyr oi d gl ands and thei r bl ood suppl y. Once the thyr oi d gl and i s
r emoved, the poster i or sur face i s car eful l y i nspected for any
possi bl e parathyr oi d ti ssue. If suspected parathyr oi d ti ssue i s
i denti fi ed, a por ti on i s sent for fr ozen-secti on exami nati on, wi th the
r emnant kept i n a col d, ster i l e, physi ol ogi cal sal i ne sol uti on. If the
ti ssue i s confi r med to be parathyr oi d gl and on fr ozen-secti on
exami nati on, the pr eser ved por ti on i s mi nced and i mpl anted i n a
smal l pocket cr eated i n the i psi l ateral ster nocl ei domastoi d muscl e.
Other i mpor tant str uctur es such as the super i or l ar yngeal ner ve,
spi nal accessor y ner ve, ster nocl ei domastoi d muscl e, esophagus, and
trachea shoul d al so be pr eser ved unl ess i nvasi on by tumor i s
pr esent.
The appr oach to the thyr oi d gl and i tsel f i s thr ough a transver se
i nci si on, appr oxi matel y one or two fi nger br eadths above the
cl avi cl es. F l aps ar e el evated super i or l y to the l evel of the thyr oi d
notch and i nfer i or l y to the supraster nal notch i n the subpl atysmal
pl ane. Separati on of the fasci a between the strap muscl es and the
ster nocl ei domastoi d muscl es i s done to faci l i tate exposur e of the
gl and and al l ow i nspecti on of the l ower jugul ar l ymph nodes. The
strap muscl es ar e separated i n the mi dl i ne and can be di vi ded on
the si de of the pr i mar y tumor i f necessar y. Por ti ons of the strap
muscl es adher ent to the gl and ar e r esected wi th the speci men. In
the r eoperati ve setti ng, thyr oi d compar tment may be appr oached
l ateral l y al ong the anter i or bor der of the ster nocl ei domastoi d
muscl e.
Al l thyr oi d vessel s ar e i denti fi ed and l i gated cl ose to the gl and. The
thyr oi d l obe i s r etracted medi al l y and the mi ddl e thyr oi d vei n i s
i denti fi ed and di vi ded. The di ssecti on i s conti nued medi al l y, al l owi ng
for i denti fi cati on, di ssecti on, and pr eser vati on of the r ecur r ent
l ar yngeal ner ve. A nonr ecur r ent l ar yngeal ner ve on the r i ght si de
may be r ecogni zed as i t or i gi nates hi gh fr om the vagus ner ve, or i t
may be found i n pr oxi mi ty to the super i or thyr oi d vessel s or the
i nfer i or thyr oi d ar ter y.
The super i or pol e vessel s ar e then i ndi vi dual l y transected wi th a
smal l cur ved or r i ght-angl e hemostat. The super i or l ar yngeal ner ve
shoul d be i denti fi ed and pr eser ved between the thyr oi d vessel s as i t
cr osses the constr i ctor muscl e and enter s the cr i cothyr oi d muscl e.
The sur geon must exer ci se cauti on dur i ng di ssecti on of thi s ar ea as
the posi ti on of the super i or ner ve i n r el ati on to the vascul ar pedi cl e
can var y. The fasci a that secur es the gl and (vi sceral and suspensor y
l i gament) i s then meti cul ousl y i nci sed and the di ssecti on i s
conti nued medi al l y al ong the poster i or aspect of the gl and. The
l i gament of ber r y i s cauti ousl y di vi ded to el evate the gl and off the
anter i or sur face of the trachea. The r ecur r ent l ar yngeal ner ve, i f
not pr evi ousl y l ocated, i s i denti fi ed i n the paratracheal gr oove
i nfer i or to the gl and and i s di ssected super i or l y. The i nfer i or thyr oi d
ar ter y i s then i denti fi ed and i ts branches ar e i ndi vi dual l y l i gated as
they enter the thyr oi d gl and, wi th car e taken to avoi d i njur y to the
r ecur r ent l ar yngeal ner ve. The anatomi cal r el ati onshi p between the
ner ve and the i nfer i or ar ter y i s extr emel y var i abl e. Al so, the ner ve
may di vi de i nto several branches at the l evel of the i nfer i or thyr oi d
ar ter y. Al l ner ve branches shoul d be pr eser ved dur i ng the cour se of
the di ssecti on. Car eful di ssecti on i s conti nued up to wher e the
ner ve enter s the l ar ynx.
Ei ghty per cent of super i or parathyr oi d gl ands ar e l ocated wi thi n 1
cm of the i nter secti on of the r ecur r ent l ar yngeal ner ve and the
i nfer i or thyr oi d ar ter y, usual l y wi thi n the thyr oi d fasci a. They may
be l ocated wi thi n the thyr oi d capsul e, and the r emai nder i s i n the
r etr ophar yngeal or r etr oesophageal spaces. The l ocati on of the
i nfer i or parathyr oi d gl ands i s far mor e var i abl e. They ar e usual l y
poster i or and l ateral to the r ecur r ent l ar yngeal ner ve. Compr omi se
of the bl ood suppl y to the parathyr oi d gl ands i s the most common
cause of hypoparathyr oi di sm i n the postoperati ve per i od. Car eful
attenti on to di ssecti on of the i nfer i or thyr oi d vessel s and thei r
branches i s war ranted to pr eser ve the l ateral vascul ar pedi cl e.
Occasi onal l y, a smal l por ti on of thyr oi d ti ssue may have to be
spar ed of r esecti on (subtotal r esecti on) to pr eser ve the vascul ar
pedi cl e to the parathyr oi d ti ssue. Meti cul ous di ssecti on of the
parathyr oi d gl ands and thei r vascul ar suppl y, as wel l as
autotranspl antati on of devascul ar i zed parathyr oi d ti ssue, ar e
i mpor tant techni ques that have contr i buted to a l ower i nci dence of
per manent hypoparathyr oi di sm. Al l parathyr oi dl i ke ti ssue shoul d be
i nspected and l eft attached to i ndi vi dual vascul ar pedi cl es.
Di sti ngui shi ng between l ymph nodes and parathyr oi d gl ands may be
di ffi cul t. Bi opsi es shoul d be taken and sent for fr ozen-secti on
di agnosi s i f ther e i s any confusi on. Hi stol ogi cal l y confi r med
parathyr oi d gl ands shoul d be autografted to the i psi l ateral
ster nocl ei domastoi d muscl e. Di ssecti on of the opposi te
l obe, when i ndi cated, pr oceeds si mi l ar l y to the di ssecti on of the
i nvol ved l obe.
Cl i ni cal l y pal pabl e adenopathy, especi al l y i n a hi gh-r i sk pati ent,
r equi r es that a neck di ssecti on be per for med. Most l ymphoar eol ar
ti ssue i n the thyr oi d compar tment and upper medi asti num to the
l evel of the i nnomi nate vei n i s accessi bl e thr ough a col l ar i nci si on.
Rar el y, because of a pati ent's anatomy, a ster notomy may be
necessar y to al l ow for adequate cl earance of upper medi asti nal and
l ower per i tracheal nodes. Dur i ng a central compar tment
l ymphadenectomy, al l ar eol ar and l ymphati c ti ssue al ong the l ar ynx
and r ecur r ent l ar yngeal ner ves fr om the l evel of the hyoi d bone
ar ea down to the i nnomi nate vessel s ar e r emoved. Par ti cul ar

attenti on shoul d be pai d to di ssecti ng the ti ssue poster i or to the
r ecur r ent l ar yngeal ner ve. The di ssecti on i s car r i ed l ateral l y to the
i nter nal jugul ar vei ns, and the ti ssue i s r esected i n conti nui ty wi th
the tumor speci men. Attenti on must be pai d to i denti fyi ng the
i nfer i or parathyr oi d gl ands, whi ch may be di ffi cul t to separate fr om
the mass of nodal and fi br ofatty ti ssue that extends i nfer i or l y off
the l ower pol e of the thyr oi d gl and. When the r emoval of l ateral
l ymph node metastases i s i ndi cated, we per for m a compar tmentor i ented neck di ssecti on, whi ch r emoves l evel IIa, III, IV, and V
l ymph nodes and spar es the ster nocl ei domastoi d muscl e, i nter nal
jugul ar vei n, and spi nal accessor y ner ve.
Al though extrathyr oi dal extensi on of thyr oi d car ci noma i nto
sur r oundi ng ti ssues i s rar e, the tumor extent must be cl ear l y
del i neated so judi ci ous r esecti on of i nvaded str uctur esi ncl udi ng
r esecti on of l ar yngeal ner ves, tracheal r i ngs, or por ti ons of the
l ar ynxcan be per for med. Local r ecur r ence i s a sour ce of si gni fi cant
mor bi di ty and mor tal i ty; ther efor e, compl ete sur gi cal exti r pati on
shoul d be per for med to opti mi ze l ocal contr ol . For tunatel y, l ocal l y
i nvasi ve thyr oi d car ci noma can often be r esected wi th a much
nar r ower mar gi n than other car ci nomas that ar i se i n ti ssues
sur r oundi ng the thyr oi d.
Adjuvant Therapy
Contr over sy exi sts over the use of adjuvant tr eatment i n the
management of wel l -di ffer enti ated thyr oi d car ci noma. The goal of
tr eatment i s to maxi mi ze di sease-fr ee sur vi val . Retr ospecti ve
studi es of pati ent cohor ts fol l owed postoperati vel y for many year s
(often mor e than 1020 year s) suggest that mul ti modal i ty adjuvant
therapy can decr ease l ocal r ecur r ence and may i mpr ove sur vi val .
The mai nstay of adjuvant tr eatment for wel l -di ffer enti ated thyr oi d
car ci noma i s radi oacti ve 1 3 1 I tr eatment and TSH suppr essi on. The
use of therapeuti c radi oacti ve abl ati on of r emnant thyr oi d ti ssue
after thyr oi dectomy i s wel l establ i shed, but cr i ter i a for the use of
thi s tr eatment var y fr om i nsti tuti on to i nsti tuti on.
Our practi ce after total thyr oi dectomy for fol l i cul ar or papi l l ar y
car ci noma of the thyr oi d i s to del ay thyr oi d hor mone r epl acement
for 4 to 6 weeks to maxi mi ze i odi ne uptake dur i ng scanni ng.
Pati ents can r ecei ve shor t-acti ng thyr oi d hor mone r epl acement
Cytomel to al l evi ate symptoms of hypothyr oi di sm for appr oxi matel y
4 weeks after sur ger y. Al l thyr oi d hor mone r epl acement i s stopped 2
weeks pr i or to pl anned scanni ng and radi oacti ve thyr oi d abl ati on. A
tracer dose (25 mCi ) of radi oacti ve i odi ne i s then admi ni ster ed,
and a whol e-body scan i s per for med. Thi s al l ows
sci nti graphi c stagi ng of di sease, and may show the pr esence and
extent of metastases that ar e mi ni mal l y r ecogni z abl e wi th
conventi onal i magi ng techni ques.
At M. D. Ander son, thyr oi d r emnant abl ati on i s r ecommended for
pati ents wi th DTC who ar e 45 year s of age or ol der, for pati ents
whose pr i mar y tumor was gr eater than 1 cm i n di ameter or was
mul ti focal , and for pati ents wi th extrathyr oi dal di sease due to ti ssue
i nvasi on or metastases. Pati ents found to have radi oi odi ne uptake i n
the thyr oi d bed on the i ni ti al postoperati ve thyr oi d scan often
r ecei ve an empi r i c dose of 30 to 150 mCi of radi oacti ve i odi ne.
However, pati ents who have evi dence of r esi dual di sease or
metastases on thei r i ni ti al postoperati ve thyr oi d scan r ecei ve hi gher
doses of 1 3 1 I, i n the range of 150 to 200 mCi . The standar d abl ati ve
dose of 1 3 1 I for pati ents wi th PTC whose tumor was l ess than 3 cm
i n di ameter wi thout extrathyr oi dal i nvasi on and few or no l ymph
nodes i nvol ved i s 29 mCi , whi ch can be admi ni ster ed as an
outpati ent. Remnant abl ati on i n al l other pati ents wi th wel l di ffer enti ated thyr oi d car ci noma i s 100 mCi , whi ch r equi r es
over ni ght hospi tal i z ati on. Hi gher doses may be admi ni ster ed i f
subsequent thyr oi d scans demonstrate r ecur r ent or per si stent
di sease. Radi oi odi ne abl ati on has been associ ated wi th a decr ease i n
l ocal -r egi onal r el apse rates of up to 50% and a r educti on i n
di sease-speci fi c mor tal i ty.
After sur ger y and subsequent 1 3 1 I abl ati on therapy, al l pati ents
r ecei ve hor monal r epl acement tr eatment (l evothyr oxi ne sodi um) at
a dose of 2 g/kg/d. The dose may var y among pati ents and i s
adjusted to r each an appr opr i ate l evel of TSH suppr essi on for a
pati ent as deter mi ned on the basi s of the i ndi vi dual pati ent's
di sease status and the cl i ni copathol ogi cal featur es of hi s or her
tumor. TSH suppr essi on and radi oacti ve i odi ne ar e of no use i n the
management of medul l ar y and anapl asti c thyr oi d car ci nomas
because these tumor s do not show consi stent uptake of radi oacti ve
i odi ne and general l y do not contai n TSH r eceptor s, maki ng them
i nsensi ti ve to TSH suppr essi on.
The r ol e of exter nal -beam radi ati on therapy (EBRT) as par t of the
i ni ti al adjuvant tr eatment r egi men for DTC i s al so contr over si al .
However, several r etr ospecti ve ser i es have r epor ted that l ocal
contr ol can be i mpr oved wi th EBRT, speci fi cal l y i n pati ents wi th

gr oss di sease fol l owi ng sur gi cal r esecti on or pati ents consi der ed to
be at hi gh r i sk of r el apse (>45 year s of age, mi cr oscopi c r esi dual
di sease, extensi ve extrathyr oi dal i nvasi on). Cur r entl y, EBRT i s mor e
often used to pal l i ate metastati c or l ocal l y advanced di sease, such
as bone metastases or thyr oi d bed r ecur r ences. Pati ents wi th MTC
who ar e consi der ed to be at hi gh r i sk for l ocal -r egi onal r ecur r ence
because of mi cr oscopi c r esi dual di sease, extragl andul ar tumor
i nvasi on, and l ymph node metastasi s ar e al so consi der ed for
tr eatment wi th adjuvant EBRT. Br i er l ey et al . r epor ted a decr ease i n
the l ocal -r egi onal r ecur r ence rate i n pati ents wi th MTC who have
been tr eated wi th postoperati ve adjuvant EBRT.
Overal l , cytotoxi c chemotherapy has not been ver y effecti ve i n the
tr eatment of thyr oi d car ci nomas. Chemotherapy has l i mi ted use i n
the tr eatment of DTC, Hr thl e cel l car ci nomas, and MTC. However,
chemotherapy, i n combi nati on wi th EBRT and sur ger y, i s mor e
commonl y used to tr eat ATC, for whi ch ther e i s a l ack of
effecti ve therapi es. Smal l number s of pati ents wi th UTC have had
pr ol onged sur vi val wi th di ffer ent r egi mens of chemotherapeuti c
agents, most i ncl udi ng doxor ubi ci n, and EBRT. Intravenous
bi sphosphonates can be gi ven i n pati ents wi th pai nful bony
metastases. Ar ter i al embol i z ati on has been used anecdotal l y to
r educe pai n i n sel ected cases of metastati c fol l i cul ar thyr oi d
car ci noma wher e the l esi ons ar e hi ghl y vascul ar.
Surveillance
Most r ecur r ences of wel l -di ffer enti ated thyr oi d car ci noma occur
wi thi n the fi r st 5 year s after i ni ti al tr eatment, especi al l y i n the case
of F TC, but r ecur r ences can occur several decades l ater. Pati ents
wi th papi l l ar y thyr oi d tumor s often r ecur i n the neck, wher eas
pati ents wi th fol l i cul ar car ci nomas mor e commonl y r ecur at di stant
si tes. Some pati ents wi th PTC who have r ecur r ence i n the neck di e
fr om thyr oi d cancer. The most common si tes of di stant metastases
for thyr oi d cancer s ar e the l ungs, bone, soft ti ssues, brai n, l i ver,
and adr enal gl ands. Lung metastases ar e mor e common i n young
pati ents, wher eas bone metastases ar e mor e common i n ol der
pati ents.
A coor di nated pl an of fol l ow-up for thyr oi d car ci nomas must
consi der the var i ed pr esentati ons possi bl e for r ecur r ent di sease.
Most pati ents ar e seen ever y 6 months for 1 to 3 year s
postoperati vel y and year l y ther eafter. Fol l ow-up vi si ts typi cal l y
i ncl ude cl i ni cal exami nati on and bl ood tests measur i ng the ser um
thyr ogl obul i n, TSH, and fr ee T4 l evel s and ul trasonography. A chest
radi ograph i s usual l y obtai ned on an annual basi s. Thyr ogl obul i n
val ues nor mal l y dr op after thyr oi dectomy or abl ati on and ser ve as a
sensi ti ve i ndi cator of r ecur r ent or per si stent di sease. However, i t i s
i mpor tant to keep i n mi nd that thyr ogl obul i n pr oducti on i s TSH
dependent; ther efor e, TSH l evel s can affect the sensi ti vi ty of
thyr ogl obul i n measur ements i n detecti ng di sease. Twenty-fi ve
per cent of pati ents wi th di ffer enti ated thyr oi d cancer have
anti thyr ogl obul i n anti bodi es, whi ch fal sel y l ower measur ed
thyr ogl obul i n l evel s. When i ndi cated, a r epeat 1 3 1 I scan i s done
after temporar y (46 weeks) cessati on of hor monal r epl acement.
Subsequent therapeuti c doses of radi oacti ve i odi ne may be
admi ni ster ed. Ul trasonography of the neck may be added to the
fol l ow-up r egi men, especi al l y i n pati ents who had l ar ge tumor s or
nodal di sease. Thi s pr otocol may var y, dependi ng on the r i sk gr oup
of the pati ent and speci al ci r cumstances. Recombi nant human TSH
(r h TSH) i njecti ons can be used i nstead of thyr oi d hor mone
wi thdrawal to sti mul ate radi oi odi ne uptake mai nl y for di agnosti c
goal s and i n sel ected cases for tr eatment pur poses. Ser um
thyr ogl obul i n can be measur ed at the ti me of radi oi odi ne
admi ni strati on after thyr oi d hor mone wi thdrawal or after r h TSH
i njecti ons.
Fol l ow-up for medul l ar y car ci noma di ffer s i n that no scanni ng or
thyr ogl obul i n measur ements ar e used. Instead, measur ement of
cal ci toni n or pentagastr i n-sti mul ated cal ci toni n l evel s i s used to
obser ve these pati ents. Si mi l ar l y, anapl asti c car ci noma and
l ymphoma cannot be fol l owed by thyr oi d scanni ng; ther efor e,
pati ents r equi r e r egul ar fol l ow-up physi cal exami nati on and
radi ographi c or ul trasound studi es.
Parathyroid Carcinoma
Ther e ar e appr oxi matel y 100,000 new cases of pr i mar y
hyper parathyr oi di sm i n the Uni ted States each year. Pr i mar y
hyper parathyr oi di sm can be caused by parathyr oi d adenoma,
hyper pl asi a, or car ci noma. Car ci noma of the parathyr oi d gl and i s a
ver y rar e l esi on and has been r epor ted to be the cause of pr i mar y
hyper parathyr oi di sm i n onl y 0.1% to 4% of cases. The i nci dences of
parathyr oi d car ci noma ar e equal i n men and women, and the tumor
i s usual l y di agnosed i n the fi fth decade. No si gni fi cant cl uster i ng
wi thi n speci fi c ethni c or i ncome gr oups or unusual geographi c
cl uster i ng has been obser ved.
The rar i ty of parathyr oi d car ci noma has l i mi ted the accumul ati on of
data on i ts natural hi stor y and eti ol ogi c factor s. Parathyr oi d
car ci noma has been descr i bed i n associ ati on wi th chr oni c r enal
fai l ur e and di al ysi s. It has been pr oposed that mal i gnant
transfor mati on of beni gn hyper pl asti c parathyr oi d ti ssue occur r ed i n
such cases. Associ ati ons wi th fami l i al hyper parathyr oi di sm,
i ncl udi ng mul ti pl e endocr i ne neopl asi a syndr omes, and wi th sporadi c
hyper parathyr oi di sm have been descr i bed. Exter nal -beam i r radi ati on
has al so been associ ated wi th parathyr oi d neopl asms; however,
these neopl asms ar e mor e fr equentl y adenomas than car ci nomas.
Presentation
The major i ty (95% ) of parathyr oi d car ci nomas i s functi onal , and
pati ents wi th parathyr oi d car ci noma usual l y pr esent wi th sever e
hyper cal cemi a. The ser um cal ci um l evel i n parathyr oi d car ci noma
averages mor e than 14 mg per dL, compar ed wi th the l ower l evel s
of 10 or 11 mg per dL seen i n beni gn cases of hyper parathyr oi di sm.
Intact parathyr oi d hor mone l evel s i n pati ents wi th parathyr oi d
car ci noma ar e at l east fi ve ti mes the upper nor mal l i mi t of 50 to 72
pg per mL. As a r esul t, r enal (60% ) and skel etal (50% ) i nvol vement
i s si gni fi cantl y mor e common i n parathyr oi d car ci noma than i n
pati ents wi th beni gn pr i mar y hyper parathyr oi di sm, i n whi ch r enal
and skel etal di sease occur i n 48% and 20% of pati ents,
r especti vel y. Metabol i c abnor mal i ti es associ ated wi th parathyr oi d
cancer i ncl ude r enal di sor der s (e.g., nephr ol i thi asi s, r enal
dysfuncti on, pyel onephr i ti s), skel etal abnor mal i ti es (e.g., ostei ti s
fi br osa cysti ca), and pancr eati ti s. Pol yur i a, pol ydi psi a, or noctur i a i s
obser ved i n 40% of pati ents and fati gue i n 30% . Onl y 20% of
pati ents di agnosed wi th parathyr oi d cancer ar e asymptomati c
compar ed wi th up to 80% of pati ents wi th beni gn
hyper parathyr oi di sm.
The pr esence of a pal pabl e neck mass i n a pati ent wi th
hyper parathyr oi di sm shoul d rai se the suspi ci on of parathyr oi d
car ci noma. A pal pabl e neck mass i s obser ved i n 40% of pati ents
wi th parathyr oi d cancer
but i s rar e for pati ents wi th beni gn hyper parathyr oi di sm.
Hoar seness i n a pati ent wi th hyper parathyr oi di sm al so suggests

parathyr oi d cancer, al though i nvol vement of the r ecur r ent l ar yngeal
ner ve occur s i n l ess than 10% of pati ents wi th parathyr oi d cancer.
Diagnosis
A hi gh i ndex of suspi ci on of parathyr oi d car ci noma shoul d be
mai ntai ned, especi al l y for pati ents wi th ser um cal ci um l evel s hi gher
than 14 mg per dL and a pal pabl e neck mass. Pr eoperati ve F NA
bi opsy i s contrai ndi cated for pati ents wi th suspected parathyr oi d
cancer because of the r i sk of l ocal di ssemi nati on. F ur ther mor e,
di sti ngui shi ng parathyr oi d car ci noma fr om adenoma i s extr emel y
di ffi cul t, even wi th hi stol ogi c exami nati on.
Pr eoperati ve l ocal i z ati on studi es ar e useful i n parathyr oi d
car ci noma. Real -ti me ul trasound of the neck i s effecti ve for
l ocal i z ati on. Si gns of gr oss i nvasi on and mar ked i r r egul ar i ty of the
tumor mar gi ns suggest mal i gnancy.
If the di agnosi s has not been suspected befor e sur ger y,
i ntraoperati ve r ecogni ti on of parathyr oi d car ci noma i s essenti al .
Parathyr oi d adenomas appear soft, oval , and br owni sh-r ed to tan i n
col or. Parathyr oi d cancer shoul d be suspected i n the pr esence of a
gray, fi r m, adher ent parathyr oi d gl and. F i br osi s i s not seen i n
nor mal or adenomatous gl ands. Local i nvasi on of adjacent ti ssues
and cer vi cal l ymph node metastasi s fur ther suppor t the di agnosi s of
parathyr oi d car ci noma.
Unl ess the tumor i s cl i ni cal l y aggr essi ve, i t i s di ffi cul t to
di ffer enti ate beni gn fr om mal i gnant tumor s by pathol ogi cal
assessment. Invasi on of sur r oundi ng str uctur es, metastases, or
r ecur r ent tumor s r efl ect mal i gnancy. The hi stol ogi c cr i ter i a for a
di agnosi s of parathyr oi d mal i gnancy ar e fi br ous capsul e or fi br ous
trabecul ae, a trabecul ar or r osettel i ke cel l ul ar ar chi tectur e,
pr esence of mi toti c fi gur es, and capsul ar or vascul ar i nvasi on.
Natural History
Parathyr oi d car ci noma i s a sl ow-gr owi ng, per si stent, l ocal l y
r ecur r ent tumor. Most parathyr oi d car ci nomas ar e cl i ni cal l y
functi oni ng, al l owi ng them to be moni tor ed by measur i ng i ntact
parathyr oi d hor mone l evel s. The l ocal r ecur r ence rate has been
esti mated to range fr om 36% to 80% , wi th a wi de range i n the
i nter val between the i ni ti al operati on and the mani festati on of
r ecur r ence (mean 2.6 year s; range 1 month to 19 year s). Si mi l ar l y,
r ecur r ence after r eoperati on pr esents at var i abl e i nter val s.

In general , r ecur r ent di sease shoul d be tr eated wi th sur gi cal
r esecti on. Al though cur e after r ecur r ence i s rar e, some pati ents wi l l
achi eve pr ol onged di sease-fr ee i nter val s by contr ol l i ng
hyper cal cemi a, whi ch i s the major cause of death. Di stant
metastases tend to occur l ate, wi th l ung, l i ver, bone, and pancr eas
bei ng fr equent si tes. The overal l 10-year sur vi val rate i s l ess than
50% .
Ther e i s no Amer i can Joi nt Commi ttee on Cancer TNM stagi ng
system for parathyr oi d car ci noma. The avai l abl e data on tumor si ze
and l ymph node i nvol vement suggest that nei ther of these factor s
ar e i mpor tant pr ognosti c mar ker s. A mul ti var i ate anal ysi s of
pr ognosti c factor s i n parathyr oi d car ci noma i ndi cated that the
extent of sur ger y when consi sti ng of tumor r esecti on, and en bl oc
uni l ateral or bi l ateral thyr oi dectomy cor r el ates most str ongl y wi th
an i mpr oved sur vi val and r el apse-fr ee per i od. Hence, i t i s i mpor tant
to mai ntai n a hi gh l evel of suspi ci on for parathyr oi d cancer dur i ng
sur ger y.
Treatment
Sur ger y i s the most effecti ve therapy for car ci noma of the
parathyr oi d gl ands. Because parathyr oi d cancer has a pr opensi ty for
l ocal r ecur r ence and rar el y metastasi zes to r egi onal nodes, tumor s
shoul d be r esected en bl oc wi th car e to pr eser ve the i ntegr i ty of the
parathyr oi d capsul e. En bl oc r esecti on r equi r es r emoval of the
i psi l ateral central neck contents, i ncl udi ng the thyr oi d l obe and
tracheoesophageal soft ti ssues and l ymphati cs. Str uctur es such as
the r ecur r ent l ar yngeal ner ve, esophageal wal l , or strap muscl es
shoul d be r emoved i f the tumor adher es to them; thi s wi l l r educe
the r i sk of tumor spi l l age and l ocal r ecur r ence. The i ncr eased l ocal
contr ol achi eved wi th r esecti on of the r ecur r ent l ar yngeal ner ve
outwei ghs the compl i cati on of vocal cor d paral ysi s, whi ch can be
managed, i f cl i ni cal l y necessar y, wi th Tefl on i njecti on of the
paral yzed cor d. A pr ophyl acti c neck di ssecti on i s not necessar y at
the ti me of the i ni ti al pr ocedur e unl ess cl i ni cal l y posi ti ve l ymph
node metastases ar e detected or ther e i s extensi ve soft-ti ssue
i nvasi on.
As pr evi ousl y menti oned, some pati ents wi l l achi eve pr ol onged
di sease-fr ee i nter val s after one or mor e sur gi cal pr ocedur es for
r ecur r ent di sease i n the neck. Si mi l ar l y, some pati ents wi l l benefi t
fr om r esecti on of l ung metastases. Sur gi cal exci si on of r ecur r ent

car ci noma al so offer s the best contr ol of hyper cal cemi a, the
pr i nci pal cause of death i n these pati ents.
Local i z ati on of metastati c foci i s i mpor tant for tr eatment of
r ecur r ent parathyr oi d cancer. Thal l i um chl or i de sci nti scanni ng and
99m-techneti um sestami bi scanni ng ar e useful for l ocati ng cer vi cal
or upper medi asti nal r ecur r ence but fr equentl y fai l to detect l ung
metastases. CT i s effecti ve for i denti fi cati on and l ocal i z ati on of
medi asti nal or pul monar y metastases. Mor e r ecentl y, i ntraoperati ve
use of a handhel d gamma detector after pr eoperati ve sestami bi
i njecti on has been used to ai d i n the i ntraoperati ve l ocal i z ati on of
r ecur r ent parathyr oi d cancer.
Recent r epor ts have chal l enged the common i dea that radi ati on
therapy i s not effecti ve i n the tr eatment of parathyr oi d cancer. Thi s
i dea was based on anecdotal r epor ts of fai l ur e of tr eatment i n
pati ents wi th advanced unr esectabl e di sease. A r evi ew of mor e
r ecent data i ndi cated that radi ati on therapy mi ght pl ay a r ol e as an
adjuvant tr eatment for pati ents at hi gh r i sk for l ocal r el apse, such
as those wi th r esi dual mi cr oscopi c di sease and tumor spi l l age dur i ng
sur ger y.
Ther e ar e no effecti ve chemotherapeuti c agents that i nhi bi t
parathyr oi d tumor gr owth or affect the secr eti on of parathyr oi d
hor mone i n parathyr oi d car ci noma. As a r esul t, medi cal
management i s used mai nl y to contr ol hyper cal cemi a. Medi cal
therapy i s par ti cul ar l y i mpor tant i n pati ents wi th unr esectabl e
di sease or i n those wi th per si stent hyper cal cemi a and negati ve
l ocal i z ati on studi es. The acute management of sever e hyper cal cemi a
i ncl udes gener ous i ntravenous sal i ne i nfusi on wi th l oop di ur eti cs
added l ater i f necessar y to i ncr ease r enal cal ci um cl earance.
Mi thramyci n has been pr oven to be effecti ve, but toxi ci ty has
l i mi ted i ts use. Subcutaneous cal ci toni n (48 uni ts per kg ever y 68
hour s) i s a safe addi ti on that r educes cal ci um l evel s wi thi n a few
hour s, but i t i s has onl y a shor t-ter m effect. Intravenous
bi sphosphonates r educe cal ci um l evel s by i nhi bi ti ng osteocl ast
acti vi ty. Pami dr onate (3090 mg i ntravenousl y over 12 hour s) or
zol edr oni c aci d (4 mg i ntravenousl y) over at l east 15 mi nutes can
r esul t i n a var i abl e r esponse that may l ast for a few weeks i n
sel ected pati ents. Cal ci mi meti c agents i ncr ease the acti vi ty of
cal ci um-sensi ng r eceptor s and suppr ess PTH secr eti on. Ci nacal cet i s
the fi r st U.S. Food and Dr ug Admi ni strati on-appr oved agent of thi s
fami l y i n the management of hyper cal cemi a i n pati ents wi th
parathyr oi d car ci noma. Other l ess commonl y used appr oaches

i ncl ude gal l i um ni trate and, rar el y, hemodi al ysi s i n ver y sel ected
pati ents.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 7 - He m a t o lo gic M a ligna nc ie s a nd Sple nic Tum o rs
17
Hematologic Malignancies and Splenic
Tumors
W ayne A .I. Frederick
Jorge A . Romaguera
James A . Reilly Jr.
A na M. Grau
Leukemi a and l ymphoma account for 6% to 8% of adul t cancer s and
appr oxi matel y 8% of the deaths fr om mal i gnancy i n the Uni ted
States. In chi l dr en younger than 15 year s, l eukemi as ar e the most
common mal i gnanci es, wi th non-Hodgki n's l ymphoma (NHL) four th
i n fr equency. Acute l eukemi as ar e the l eadi ng cause of cancer
deaths i n pati ents younger than 35 year s.
Leukemi a and l ymphoma pati ents ar e usual l y r efer r ed to a sur geon
wi th a speci fi c r equest: di agnosti c bi opsy, vascul ar access, and
therapeuti c spl enectomy. Sur geons must be fami l i ar wi th thi s gr oup
of di sor der s, both to per for m the operati on appr opr i atel y and to
know the pr ocedur e's pr obabi l i ty of success and r i sks. At ti mes a
major pr ocedur e i s unl i kel y to achi eve the desi r ed r esul t, or the
pati ent's l i mi ted l i fe expectancy makes such an operati on unwi se.
The Leukemias
The chr oni c pr ol i ferati ve di seases appear to be a spectr um of cl onal
hematopoi eti c stem cel l di sor der s rangi ng i n i ncr easi ng sever i ty
fr om pol ycythemi a vera and essenti al thr ombocythemi a to
myel ogenous metapl asi a to chr oni c myel ogenous l eukemi a (CML).
Leukemi a ul ti matel y devel ops i n a few pati ents wi th pol ycythemi a
vera and essenti al thr ombocythemi a and a l ar ger per centage of
pati ents wi th myel ogenous metapl asi a.
Polycythemia Vera and Essential

Thrombocythemia
Pol ycythemi a vera i s associ ated wi th an autonomous expansi on of
the r ed bl ood cel l mass and vol ume wi th a var i abl e effect on whi te
bl ood cel l s (WBCs) and pl atel ets. The most accepted eti ol ogi c
mechani sm i nvol ves the exi stence of a cl one wi th an abnor mal l y
hi gh sensi ti vi ty to er ythr opoi eti n. Essenti al thr ombocythemi a i s
character i zed by an i ncr ease i n the megakar yocyte l i neage, wi th a
gr eatl y i ncr eased pl atel et count and a var i abl e effect on
er ythr ocytes and WBCs. In both di seases ther e i s an i ncr eased r i sk
of thr ombosi s and, paradoxi cal l y, of hemor r hage. Thr ee-four ths of
pati ents wi th pol ycythemi a vera have pal pabl e spl enomegal y, and
about hal f have hepati c enl ar gement. Phl ebotomy, l ow-dose
chemotherapy, or a combi nati on of these modal i ti es i s the pr i mar y
tr eatment for pati ents wi th pol ycythemi a vera and essenti al
thr ombocythemi a. The goal i s to obtai n a hematocr i t of 45% or l ess.
Because of the r i sk of hemor r hage, any operati on shoul d be avoi ded
i n these pati ents unti l the pol ycythemi a i s under contr ol . Rapi d
phl ebotomy to a nor mal hematocr i t and fl ui d r epl acement shoul d be
per for med befor e emer gency sur ger y. Pl atel etpher esi s has been
used to contr ol thr ombocytosi s.
Al though spl enectomy has l i ttl e or no r ol e i n the tr eatment of most
pati ents wi th pol ycythemi a vera or essenti al thr ombocythemi a, a
condi ti on si mi l ar to myel ogenous metapl asi a devel ops i n a few
pati ents who then r equi r e spl enectomy. The operati ve r i sks ar e
gr eater and the sur vi val i s poor er i n thi s gr oup than i n pati ents
wi th myel ogenous metapl asi a. Pati ents wi th pol ycythemi a vera and
essenti al thr ombocythemi a shoul d be tr eated wi th aggr essi ve
nonoperati ve therapy and offer ed spl enectomy onl y when pai n,
anemi a, and thr ombocytopeni a ar e r efractor y to other tr eatment.
Spl enectomy does not i ncr ease the sur vi val rate, but i t may i mpr ove
the qual i ty of l i fe.
Myelogenous Metaplasia
Myel ogenous metapl asi a i s character i zed by fi br osi s of the bone
mar r ow and extramedul l ar y hematopoi esi s, chi efl y i n the spl een,
l i ver, and l ymph nodes. F i br osi s i s pol ycl onal i n natur e and i s
thought to be a r eacti ve pr ocess to gr owth factor r el ease fr om the
cl onal cel l s. As the spl een enl ar ges, the hematopoi eti c functi on i t
ser ves may be over whel med by destr ucti ve hyper spl eni sm
(excessi ve destr ucti on of one or mor e of the bl ood components,
usual l y by an autoi mmune mechani sm).

Al though some pati ents ar e asymptomati c, most pr esent wi th
fati gue, anor exi a, and wei ght l oss, or symptomati c spl enomegal y.
Leukocytosi s and thr ombocytosi s may be pr esent; other hematol ogi c
abnor mal i ti es such as di mi ni shed WBC and pl atel et counts may
r esul t fr om passi ve spl eni c sequestrati on or acti ve destr ucti on.
Acti ve spl eni c destr ucti on may be humoral l y medi ated (r el ated to
speci fi c anti body r ecogni ti on) or cel l medi ated (pr obabl y by
acti vated macr ophages). Per i pheral bl ood smear s often demonstrate
l ar ge pl atel ets, nucl eated r ed cel l s, ani socytosi s, and i mmatur e
myel ogenous el ements. The di agnosi s i s made by bone mar r ow
bi opsy. In appr oxi matel y 5% of cases, myel ogenous metapl asi a wi l l
pr ogr ess to CML or acute myel obl asti c l eukemi a.
Ini ti al management may i ncl ude transfusi ons, ster oi ds, andr ogens,
cytotoxi c chemotherapy, and spl eni c i r radi ati on. If these measur es
ar e not effecti ve i n tr eati ng the compl i cati ons of hyper spl eni sm, a
spl enectomy may be i ndi cated. At the Uni ver si ty of Texas M. D.
Ander son Cancer Center, pati ents who have myel ogenous metapl asi a
wi th myel ofi br osi s ar e advi sed to under go spl enectomy under the
fol l owi ng condi ti ons: (a) for sever e anemi a due to hyper spl eni sm
when medi cal management i s unsuccessful ; (b) for chr oni cal l y
symptomati c spl enomegal y; or (c) for the devel opment of wor seni ng
congesti ve hear t fai l ur e caused by a shunt effect thr ough the
spl een. Spl enectomy for por tal hyper tensi on secondar y to i ncr eased
por tal fl ow associ ated wi th spl enomegal y has al so been r epor ted.
Because spl enectomy may i nadver tentl y pr ecl ude the possi bi l i ty of
per for mi ng a spl enor enal shunt, i t i s cr i ti cal to el i mi nate hepati c
por tal hyper tensi on as the cause of the spl enomegal y.
Adequate bone mar r ow acti vi ty must be ver i fi ed befor e spl enectomy
i s contempl ated. If the spl een i s the major si te of hematopoi esi s,
spl enectomy may r esul t i n sever e pancytopeni a. A bone mar r ow
bi opsy and nucl ear medi ci ne bone mar r ow scan may defi ne the
hematopoi eti c pr oducti vi ty of the mar r ow cavi ty. F ul l
coagul ati on studi es shoul d be per for med and occul t di ssemi nated
i ntravascul ar coagul ati on shoul d be contr ol l ed befor e sur ger y.
Spl enectomy does not pr ol ong sur vi val but may i mpr ove the qual i ty
of l i fe. The r esponse rate for anemi a var i es fr om 75% to 95%
fol l owi ng spl enectomy. The mor bi di ty of spl enectomy i s 35% to
75% , and the mor tal i ty rate i s 5% to 18% . Low-dose radi ati on to
the spl een may be used i n poor candi dates for sur ger y.
Chronic Myelogenous Leukemia

CML, al so known as chr oni c granul ocyti c l eukemi a, i nvol ves a cl onal
pr ol i ferati on of myel ogenous stem cel l s. Appr oxi matel y 90% of
pati ents wi l l have a transl ocati on of chr omosomes 9 and 22; thi s
transl ocati on i s cal l ed the Philadelphia chr omosome. The
Phi l adel phi a chr omosome may be obser ved cl i ni cal l y to hel p assess
r esponse to therapy.
CML has both a chr oni c beni gn phase and a phase of acute bl asti c
transfor mati on. Most pati ents pr esent wi th symptoms of the chr oni c
phase, whi ch i ncl ude fati gue, weakness, ni ght sweats, l ow-grade
fever, and abdomi nal pai n. Spl enomegal y may be an i sol ated fi ndi ng
dur i ng physi cal exami nati on. The WBC and pl atel et count may be
i ncr eased; however, the pl atel ets may not functi on nor mal l y.
Hyper spl eni sm may r esul t i n anemi a or thr ombocytopeni a. Pati ents
wi th the chr oni c phase of CML shoul d be eval uated ever y 3 to 6
months. The medi an durati on of the chr oni c phase i s about 45
months, but some pati ents may l i ve up to 20 year s wi th thi s
condi ti on. CML wi l l pr ogr ess fr om the chr oni c beni gn phase to the
acute l eukemi c transfor mati on phase i n appr oxi matel y 80% of
pati ents.
Pr ogr essi ve fati gue, hi gh fever s, i ncr easi ngl y symptomati c
spl enomegal y, anemi a, thr ombocytopeni a, basophi l i a, and bone or
joi nt pai n may heral d the acute or accel erated stage of CML. In
addi ti on to the Phi l adel phi a chr omosome, other del eti ons and
transl ocati ons may be detected. The WBC count may mar kedl y
i ncr ease and may not be r eadi l y contr ol l ed by medi cal means.
Incr eased spl eni c destr ucti on of bl ood components may be
mani fested by mor e fr equent i nfecti ons or bl eedi ng epi sodes.
Average sur vi val i s appr oxi matel y 6 months, and dur i ng thi s per i od
the di sease may become r esi stant to chemotherapy. Bl ast cr i si s i s
heral ded by l ar ge number s of these i mmatur e cel l s i n the
ci r cul ati on, wi th a decr ease i n other cel l ul ar components; thi s i s
usual l y a pr eter mi nal event.
Tradi ti onal tr eatment of CML i ncl uded conventi onal chemotherapy
wi th hydr oxyur ea or busul fan. These agents can achi eve
hematol ogi c r emi ssi ons, but no si gni fi cant r educti on of Phi l adel phi a
chr omosome cel l s has been obser ved. Inter fer on al fa (IF N al fa) can
achi eve hematol ogi c as wel l as cytogeneti c r emi ssi ons i n a
si gni fi cant number of pati ents and pr ol ong sur vi val i n pati ents who
have shown cytogeneti c r esponse. Al l ogeni c bone mar r ow transpl ant
may be curati ve, but onl y a l i mi ted number of pati ents qual i fy for i t.
Spl enectomy i s general l y used as pal l i ati on for ei ther pai nful
spl enomegal y or r efractor y anemi a. Symptoms due to spl enomegal y
wi l l l i kel y be i mpr oved by spl enectomy, but the r esponse i s var i abl e
when spl enectomy i s per for med to cor r ect
dyscrasi as. Removal of an enl ar ged spl een befor e bone mar r ow
transpl antati on has fai l ed to i mpr ove sur vi val or to decr ease the
r el apse fr equency. In these pati ents, though, spl enectomy may
el i mi nate a focus of di sease or decr ease transfusi on r equi r ements.
Pr ospecti ve randomi zed tr i al s wi l l hel p defi ne the r ol e of
spl enectomy i n the enhancement of bone mar r ow engraftment. For
pati ents wi th CML i n whom di sease becomes r esi stant to IF N al fa, a
spl enectomy may i mpr ove r esponse to thi s therapy. Spl enectomy
does not del ay bl ast transfor mati on, and i ts effect on sur vi val i s
contr over si al . A r ecent anal ysi s of the M. D. Ander son exper i ence
wi th spl enectomy i n pati ents i n the accel erated or bl asti c phase of
the di sease has shown that al though the sur vi val per i od i n these
pati ents may be l i mi ted, spl enectomy, i f i ndi cated, can be per for med
safel y i n thi s phase of the di sease and thr ombocytopeni a can be
r el i abl y r ever sed, mi ni mi z i ng transfusi on r equi r ements.
Chronic Lymphocytic Leukemia

Chr oni c l ymphocyti c l eukemi a (CLL) i s the most common l eukemi a
i n the Wester n Hemi spher e. It i s typi fi ed by an accumul ati on of
l ong-l i ved, matur e-appear i ng but functi onal l y i nacti ve B cel l s. The
medi an age of onset i s i n the seventh decade, and the i nci dence
conti nues to i ncr ease beyond that age.
CLL pati ents may pr esent wi th enl ar ged, pai nl ess l ymph nodes;
weakness; wei ght l oss; and anor exi a. As the di sease pr ogr esses,
mor e pr onounced l ymphadenopathy and spl enomegal y may devel op.
Ther e may be a decr ease i n r ed bl ood cel l count due to ei ther bone
mar r ow i nfi l trati on wi th l eukemi c cel l s or a Coombs-posi ti ve
hemol yti c anemi a. A second mal i gnancy wi l l devel op i n
appr oxi matel y 20% of pati ents, most commonl y l ung cancer,
mel anoma, or sar coma. CLL may have ei ther an i ndol ent or an
aggr essi ve cour se, wi th pati ent sur vi val rangi ng fr om 1 to 20 year s.
Pati ents wi th CLL have a pr ogr essi ve l oss of i mmune functi on, and
i nfecti on i s the most common cause of death.
Pr evi ousl y, tr eatment was wi thhel d i n the ear l y stages unti l si gns of
pr ogr essi on occur r ed. Cur r entl y, at M. D. Ander son, tr eatment i s not
general l y star ted i n the Rai stage 0 pati ents (l ymphocytosi s onl y),
but chemotherapy i s used to tr eat other ear l y stage pati ents (Rai
stage I or II) wi th poor pr ognosti c si gns and al l pati ents wi th Rai
stage III or IV di sease (Tabl e 17.1). F l udarabi ne i s used i n
conjuncti on wi th granul ocyte-macr ophage col ony-sti mul ati ng factor.
Spl enectomy may be r ecommended for pati ents who ar e r efractor y
to fl udarabi ne or wi th symptomati c spl enomegal y and for pati ents
wi th hyper spl eni sm. Exper i ence at M. D. Ander son has shown that
spl enectomy can pr ovi de an excel l ent hematol ogi c r esponse i n
pati ents wi th ei ther i sol ated anemi a or thr ombocytopeni a, but thi s
r esponse i s r el ati vel y poor i n pati ents pr esenti ng wi th both
di sor der s, suggesti ng that an adequate hematopoi eti c r eser ve i s
r equi r ed for a si gni fi cant r esponse. In addi ti on, spl enectomy
si gni fi cantl y i mpr oves sur vi val i n sel ected subgr oups of pati ents
wi th advanced stage CLL when compar ed wi th conventi onal
chemotherapy. These subgr oups i ncl ude pati ents wi th CLL and
hemogl obi n l evel s l ess than or equal to 10 g/dL or a pl atel et count
l ess than or equal to 50 109 L.
Table 17.1. Rai staging of chronic

lymphocytic leukemia
Stage Criteria
0
Lymphocytosis (WBCs >15,000/mL with

>40% lymphocytes in the bone
marrow)
Lymphocytosis with lymphadenopathy
II
Lymphocytosis with enlarged liver or

spleen (lymphadenopathy not
necessarily present)
Lymphocytosis with anemia. Anemia
III
IV
may be due to hemolysis or to

decreased production
(lymphadenopathy or
hepatosplenomegaly need not be
present)
Lymphocytosis with thrombocytopenia
(platelet count <100,000/L), anemia,
and lymphadenopathy
WBC, white blood cell.
Hairy Cell Leukemia

Hai r y cel l l eukemi a (HCL) i s a monocl onal l ymphopr ol i ferati ve
di sor der of matur e B cel l s. It compr i ses onl y 2% to 5% of al l
l eukemi as, and ther e i s a 3:1 mal e pr edomi nance. The
pathognomoni c hai r y cel l s ar e named for thei r cytopl asmi c
pr ojecti ons. These cel l s may be found i n both the bone mar r ow and
the per i pheral ci r cul ati on.
Pati ents wi th HCL may compl ai n of weakness and fati gue.
Spl enomegal y i s al most uni ver sal l y pr esent. Appr oxi matel y 10% of
pati ents wi th HCL wi l l have such mi l d symptoms that they never
r equi r e tr eatment. Most pati ents wi l l r equi r e therapy for
neutr openi a, spl enomegal y, hyper spl eni sm, or bone mar r ow fai l ur e.
Infecti on r el ated to neutr openi a i s the most common cause of death.
Ear l y effor ts to use chemotherapy to tr eat HCL wer e unsuccessful
because the degr ee of associ ated myel osuppr essi on was not
tol erabl e. Spl enectomy became the tr eatment of choi ce and was
associ ated wi th i ncr eased sur vi val . Si nce that ti me, mor e effecti ve
chemotherapeuti c agents have become avai l abl e. At M. D. Ander son,
spl enectomy i s not used i n the r outi ne tr eatment of pati ents wi th
HCL. Instead, they ar e tr eated wi th IF N al fa, deoxycofor myci n, or
chl or odeoxyadenosi ne. The overal l r esponse rate to IF N al fa i s
between 80% and 90% . If r el apse occur s, chl or odeoxyadenosi ne i s
usual l y effecti ve i n r egai ni ng contr ol of the di sease. The few
pati ents who r el apse after chl or odeoxyadenosi ne tr eatment can
achi eve second r emi ssi ons wi th r etr eatment. Spl enectomy may be
consi der ed i n the rar e cases of pur e spl eni c for m of the di sease.
Acute Lymphocytic and Myelogenous

Leukemia
Except i n cases of spl eni c r uptur e, spl enectomy has no r ol e i n the
tr eatment of pati ents wi th acute l ymphocyti c or acute myel ogenous
l eukemi a dur i ng i nducti on chemotherapy or dur i ng r el apse. In rar e
cases, pati ents i n compl ete r emi ssi on r equi r e spl enectomy because
of per si stent fungal granul omas of the spl een.
Splenic Rupture in Leukemia

Spl eni c r uptur e i s a rar e event i n l eukemi c pati ents and i s al most
al ways associ ated wi th some for m of trauma. Ther e i s no i ncr eased
r i sk wi th any par ti cul ar type of l eukemi a, but pati ents wi th
spl enomegal y may be mor e suscepti bl e to spl eni c trauma. The
r epor ted i nci dence of r uptur e fr om four ser i es was 0.72% . Leukemi c
pati ents compr i se onl y 3.5% of those wi th spontaneous spl eni c
r uptur e.
Si gns and symptoms i ncl ude abdomi nal tender ness and r i gi di ty,
shi fti ng dul l ness, and tachycar di a. The chest radi ograph may
demonstrate an el evated hemi di aphragm or a pl eural effusi on. A
hi gh i ndex of suspi ci on i s necessar y i n eval uati ng pati ents wi th
spl enomegal y and abdomi nal pai n because the pr eci pi tati ng event
may have been so mi nor as to not be r emember ed.
Sur vi val rates var y wi th the rapi di ty of di agnosi s and of
per for mance of spl enectomy. Pati ents who sur vi ve spl enectomy
fol l owi ng r uptur e have a l i fe expectancy si mi l ar to that of other
pati ents wi th the same type of l eukemi a.
The Lymphomas
Hodgkin's Disease
The pr ognosi s of pati ents wi th Hodgki n's di sease (HD) has i mpr oved
dramati cal l y over the past 20 year s. Thi s advancement i s due to
i ncr eased knowl edge of the bi ol ogy of the di sease and mor e
effecti ve use of radi ati on therapy and mul ti agent chemotherapy. The
r ol e of stagi ng l apar otomy conti nues to evol ve as nonoperati ve
stagi ng becomes i ncr easi ngl y accurate and as subsets of pati ents
ar e i denti fi ed who ar e unl i kel y to benefi t fr om the i nfor mati on

l apar otomy pr ovi des.
HD i s character i zed by the pr esence of mul ti nucl eated ReedSter nber g (RS) cel l s or one of thei r var i ants. As opposed to NHL, i n
whi ch a monocl onal popul ati on of mal i gnant l ymphocytes usual l y
pr edomi nates, i n HD the mal i gnant cel l s ar e a mi nor i ty popul ati on
outnumber ed by i nfl ammator y cel l s.
Pati ents wi th HD typi cal l y pr esent wi th nontender l ymphadenopathy.
The cer vi cal nodes ar e most commonl y i nvol ved; other r egi ons,
whi ch i ncl ude the axi l l ar y, i ngui nal , medi asti nal , and
r etr oper i toneal nodes ar e l ess fr equentl y affected at pr esentati on.
The pr esence or absence of B symptoms shoul d be el uci dated fr om
the pati ent's hi stor y. B symptoms i ncl ude any one of the fol l owi ng:
unexpl ai ned fever wi th temperatur e over 38C, ni ght sweats
si gni fi cant enough to r equi r e changi ng bed cl othes, or wei ght l oss of
mor e than 10% of body wei ght over 6 months. Al though cl assi c for
HD, the Pel -Ebstei n fever, wi th pr ogr essi vel y shor teni ng i nter val s
between fever s, i s a r el ati vel y rar e phenomenon.
The physi cal exami nati on shoul d i ncl ude an eval uati on of al l l ymph
nodebear i ng ar eas, i ncl udi ng Wal deyer 's tonsi l l ar r i ng, and
pal pati on for l i ver or spl eni c enl ar gement. Ini ti al wor kup shoul d
i ncl ude a compl ete bl ood cel l count wi th di ffer enti al count, l i ver
functi on tests, and a chest radi ograph. A bone mar r ow bi opsy i s
useful to deter mi ne the extent of the di sease. Exci si onal bi opsy of
the l ar gest node that i s l i kel y to pr ovi de the di agnosi s shoul d be
per for med. Car eful sel ecti on of the bi opsy si te i s i mpor tant
because some ar eas, par ti cul ar l y the i ngui nal r egi on, fr equentl y
contai n nondi agnosti c i nfl ammator y nodes.
Table 17.2. Ann Arbor staging system for

Hodgkin's disease
Stage Criteria
Involvement of a single lymph node

region (I) or a single extralymphatic
organ or site (IE)
II
Involvement of two or more lymph node

regions on the same side of the
diaphragm (II) or of an extralymphatic
organ and its adjoining lymph node site
(IIE)
III
Involvement of lymph node sites on

both sides of the diaphragm (III) or
localized involvement of an extralymphatic site (IIIE), spleen (IIIS), or
both (IIISE)
IV
Diffuse or disseminated involvement of

one or more extralymphatic organs with
or without associated lymph node
involvement
Asymptomatic
Fever, night sweats, or weight loss of

more than 10%
Other cl i ni cal stagi ng tool s i ncl ude computed tomography (CT),

nucl ear medi ci ne scans, and bi pedal l ymphangi ography. CT i s used
to detect medi asti nal and abdomi nal l ymphati c enl ar gement;
however, nodes contai ni ng HD often ar e not enl ar ged. G al l i um scans
have been useful i n detecti ng r esi dual di sease. Bi pedal
l ymphangi ography may detect changes i n femoral , i ngui nal , exter nal
i l i ac, and r etr oper i toneal nodes. Use of l ymphangi ography has been
questi oned i n ter ms of the cost-effecti veness. Thi s pr ocedur e can
i denti fy l ymphati c enl ar gement as wel l as changes i n the
ar chi tectur e of nor mal -si zed nodes caused by neopl asti c
i nvol vement.
The pr ognosi s of pati ents wi th HD depends on the hi stol ogi c subtype
and stage of di sease at pr esentati on. The Rye modi fi cati on of the
Lukes-Butl er cl assi fi cati on of HD i denti fi es four hi stol ogi c subtypes:
l ymphocyte pr edomi nant, nodul ar scl er osi s, mi xed cel l ul ar i ty, and
l ymphocyte depl eted. These subtypes ar e deter mi ned by the speci fi c
var i ant of RS cel l , the rati o of these cel l s to the nor mal popul ati on,
and the degr ee of scl er osi s.
The Ann Ar bor stagi ng system (Tabl e 17.2) i s used for stagi ng HD
based on the extent of di sease. Cl i ni cal stagi ng i ncl udes al l data
fr om the hi stor y and physi cal exami nati on and nonoperati ve
di agnosti c studi es. Pathol ogi c stagi ng i ncl udes addi ti onal
i nfor mati on obtai ned fr om a stagi ng l apar otomy. The Ann Ar bor
stages ar e subcl assi fi ed to r efl ect l ymphati c di sease and
i nvol vement of extranodal ar eas desi gnated by E, for i nvol vement of
an extral ymphati c si te (i .e., stomach or smal l i ntesti ne), or S, for
spl eni c i nvol vement. Di sease i s fur ther subcl assi fi ed accor di ng to
the pr esence or absence of systemi c symptoms of the di sease.
Incr easi ng knowl edge of the effect of pati ent character i sti cs,
hi stol ogi c subtype, and stage of di sease have al l owed mor e
i ndi vi dual i zed tr eatment of pati ents, wi th dramati c i mpr ovements i n
sur vi val . Stagi ng l apar otomy was fi r st i ntr oduced to defi ne
di sease extent i n al l pr esentati ons of HD. Subsequentl y,
i nvesti gator s per for med stagi ng by l apar otomy to deter mi ne whi ch
pati ents had ear l y stage di sease that coul d be tr eated by l ocal
i r radi ati on and whi ch had extensi ve di sease r equi r i ng systemi c
therapy. Pr evi ousl y, up to 40% of pati ents who under went stagi ng
l apar otomy had a change i n thei r cl i ni cal stage. Both i mpr ovements
i n the accuracy of radi ol ogi c di agnosti c pr ocedur es and mor e
i ntensi ve use of chemotherapeuti c and radi ati on tr eatments ear l i er
i n the cour se of the di sease have decr eased the number of pati ents
who r equi r e stagi ng l apar otomy.
Cur r entl y at M. D. Ander son, nonoperati ve stagi ng and pr ognosti c
factor s ar e used to gui de therapy i n al most al l the pati ents. Pati ents
who r equi r e chemotherapy wi th or wi thout radi ati on therapy
because of extensi ve di sease or poor pr ognosti c factor s do not
benefi t fr om the addi ti onal i nfor mati on gai ned fr om a stagi ng
l apar otomy. Most center s have el i mi nated stagi ng l apar otomy i n
pedi atr i c pati ents wi th HD. Thi s appr oach i s suppor ted by fai l ur e of
l ong-ter m fol l ow-up to show a si gni fi cant di ffer ence i n sur vi val
between cl i ni cal and sur gi cal stagi ng.
Components of a Staging Laparotomy

For stagi ng l apar otomy of HD, the abdomen i s enter ed thr ough a
mi dl i ne i nci si on fr om the xi phoi d pr ocess to bel ow the umbi l i cus. A
thor ough expl orati on i s per for med to i denti fy pal pabl e
abnor mal i ti es. Thi s i ncl udes bi manual pal pati on of the l i ver,
exami nati on of the bowel and mesenter y, and expl orati on of the
major nodal gr oups. Lymph nodes contai ni ng di sease ar e often
nor mal i n si ze. The ar eas most l i kel y to contai n di sease i ncl ude the
spl een and the spl eni c, cel i ac, and por tal l ymph nodes.
Spl enectomy and l i ver bi opsi es ar e per for med ear l y i n the pr ocedur e
so that ampl e ti me i s avai l abl e to ensur e hemostasi s. The spl een
shoul d r outi nel y be r emoved because i t may contai n nonpal pabl e
di sease. In chi l dr en, some sur geons advocate per for mi ng a par ti al
spl enectomy to pr event a l i feti me r i sk of aspl eni c sepsi s. Spl eni c
nodes, al ong wi th the di stal 3 cm of the spl eni c ar ter y and vei n,
shoul d be r emoved i n conti nui ty wi th the spl een. The ends of the
spl eni c vessel s ar e mar ked wi th ti tani um cl i ps to gui de futur e
radi ati on therapy i f i t becomes necessar y.
A wedge bi opsy speci men i s obtai ned fr om one or both l obes of the
l i ver, and a deeper bi opsy wi th a Tr u-cut cor e needl e i s done on
both l obes. Addi ti onal wedge bi opsi es shoul d be per for med on any
gr ossl y abnor mal ar eas of the l i ver.
As each nodal gr oup i s di ssected, i t i s sent as a separate speci men
i n ster i l e sal i ne to the pathol ogi st, and the ar ea i s mar ked wi th
ti tani um cl i ps. The gastr ohepati c l i gament i s i nci sed, and l ymph
nodes al ong the hepati c ar ter y l eadi ng to the cel i ac axi s ar e
r emoved. The senti nel node at the juncti on of the por tal vei n and
the duodenum, al ong wi th any other nodes al ong the por ta hepati s,
ar e exci sed. The transver se col on i s r etracted super i or l y, and the
smal l bowel i s r efl ected to the pati ent's r i ght to vi sual i ze the aor ta.
The r etr oper i toneum i s i nci sed over the aor ta fr om the l eft r enal
vei n down to the i l i ac bi fur cati on. The nodes between the aor ta and
the i nfer i or mesenter i c vei n ar e exci sed. Nodes al ong the i l i ac
vessel s and wi thi n the mesenter y sel dom contai n di sease, but they
shoul d be sampl ed and submi tted for r evi ew. Any
l ymph nodes that appear ed abnor mal on the l ymphangi ogram shoul d
al so be r emoved.
If a bone mar r ow bi opsy speci men has not been obtai ned
pr eoperati vel y, one shoul d be obtai ned fr om the i l i ac cr est whi l e the
pati ent i s under general anesthesi a. Oophor opexy was once
r outi nel y per for med i n femal es of r epr oducti ve age, but cur r entl y i ts
use i s l i mi ted to pati ents wi th suspected i l i ac nodal i nvol vement.
Some sur geons r ecommend per for mi ng appendectomy dur i ng the
stagi ng pr ocedur e.
The mor bi di ty rate i s general l y l ess than 10% , and deaths r el ated to
stagi ng l apar otomy ar e rar e. Compl i cati ons i ncl ude wound pr obl ems,
atel ectasi s, pneumoni a, pul monar y embol us, and i nfecti on. Any
compl i cati ons that del ay the i ni ti ati on of needed systemi c therapy
or radi ati on therapy ar e potenti al l y ser i ous. Long-ter m
compl i cati ons i ncl ude smal l -bowel adhesi ons, aspl eni c sepsi s, and
devel opment of secondar y l eukemi a.
Lapar oscopi c stagi ng of l ymphoma i s cur r entl y bei ng expl or ed as a
modal i ty i n the tr eatment of these pati ents. Case r epor ts and smal l
ser i es of l ymphoma pati ents staged l apar oscopi cal l y have been
r epor ted i n the l i teratur e. The i ndi cati ons have been the same as
those for open stagi ng, and absol ute contrai ndi cati ons ar e por tal
hyper tensi on and uncor r ectabl e coagul opathy. The components of
l apar oscopi c stagi ng i ncl ude per cutaneous and wedge l i ver bi opsi es,
l ymph node bi opsi es, and spl enectomy. Because the spl een needs to
be r emoved i ntact to al l ow compl ete pathol ogi c eval uati on, a 6- to
8-cm mi dl i ne i nci si on i s made to al l ow r emoval of the spl een. Thi s
mi dl i ne i nci si on i s then used to compl ete the l ymph node di ssecti on
under di r ect vi si on. Conver si on to open pr ocedur e has most
fr equentl y been secondar y to hemor r hage dur i ng spl enectomy and
var i es fr om 0% to 20% . Di agnosti c accuracy has been r epor ted to
be cl ose to 90% . Lapar oscopi c stagi ng of l ymphoma may r esul t i n a
shor ter hospi tal stay and r ecover y ti me, but the accuracy and
mor bi di ty of thi s techni que cannot be known unti l mor e exper i ence
i s avai l abl e.
Non-Hodgkin's Lymphoma
Pati ents i n the Uni ted States wi th NHL character i sti cal l y have a
monocl onal pr ol i ferati on of l ymphocytes, wi th 80% of cases bei ng of
B-cel l der i vati on and the r emai nder or i gi nati ng fr om T cel l s. The
di agnosi s of var i ous subsets of B-cel l NHL depends on the
i denti fi cati on of hi stopathol ogi c mar ker s usi ng monocl onal
anti bodi es and on cel l ul ar mor phol ogy; cr i ter i a assessed ar e a
di ffuse ver sus fol l i cul ar (nodul ar ) patter n of l ymph node
i nvol vement, smal l ver sus l ar ge cel l type, and cl eaved ver sus
noncl eaved nucl ear mor phol ogy. Wi th thi s i nfor mati on, the
l ymphoma can be categor i zed accor di ng to the Wor ki ng For mul ati on,
whi ch i s a modi fi cati on of the Lukes and Col l i ns schema. Al though
an i n-depth di scussi on of thi s cl assi fi cati on system i s beyond the
scope of thi s chapter, the Wor ki ng For mul ati on has si mpl i fi ed our
under standi ng of the behavi or s of these subtypes by pl aci ng them
i nto one of thr ee categor i es, dependi ng on whether pati ents have a
l ow, i nter medi ate, or hi gh r i sk of death due to the di sease. The Tcel l NHLs ar e much mor e di ffi cul t to i denti fy pr eci sel y and to pl ace
i nto pr ognosti c gr oups. Mor e r ecentl y, the pr oposed
Eur opean-Amer i can cl assi fi cati on of l ymphoi d neopl asms uses
mor phol ogy, phenotype, and cytogeneti cs to cl assi fy these
di sor der s. The cl i ni cal r el evance of thi s cl assi fi cati on i s under study,
but i t mi ght offer addi ti onal i nfor mati on to the Wor ki ng
For mul ati on.
Most pati ents wi th NHL pr esent wi th super fi ci al adenopathy, most
commonl y i n the cer vi cal l ymph nodes. These nodes ar e general l y
enl ar ged and not tender. The Ann Ar bor system (Tabl e 17.2) i s used
to stage these pati ents, but i t i s l ess hel pful i n NHL than i n HD
because mor e than hal f of NHL pati ents pr esent wi th stage III or IV
di sease and appr oxi matel y 20% pr esent wi th B symptoms. Pati ents
wi th NHL al so ar e mor e l i kel y to have hematogenous spr ead ver sus
l ymphati c spr ead as seen i n pati ents wi th HD.
Because NHLs do not spr ead i n the or der l y manner that HD does,
the sur geon i s general l y asked to per for m a di agnosti c bi opsy, to
establ i sh vascul ar access for chemotherapy, or to tr eat
compl i cati ons of therapy. Stagi ng l apar otomy i s not i ndi cated i n
these pati ents. Spl enectomy i s necessar y, al though rar el y, for
hyper spl eni sm, massi ve spl enomegal y, or a per si stent spl eni c focus
of di sease, usual l y i n those wi th l ow-grade l ymphomas. Al though
pr i mar y spl eni c l ymphoma i s unusual , spl enectomy may be
benefi ci al for pati ents wi th i sol ated spl eni c di sease. Thi s di agnosi s
i s often made onl y after spl enectomy i s per for med for
hyper spl eni sm or spl enomegal y. If the l ymphoma i s l ocal i zed to the
spl een, the pr ognosi s i s si mi l ar to that of other stage I pati ents.
Diagnostic Biopsy for Lymphoma

When l ymphoma i s suspected, pr oper pl anni ng and executi on of the
bi opsy ar e cr uci al to enabl e the pathol ogi st to make a di agnosi s.
Because pr eser vati on of the ar chi tectur e ai ds i n hi stol ogi c
di agnosi s, effor ts shoul d be made to avoi d tracti on or cauter y. The
l ar gest node found on physi cal exami nati on shoul d be bi opsi ed. If
several nodal ar eas ar e enl ar ged, bi opsy of the cer vi cal ar ea i s
pr efer r ed to bi opsy of an axi l l ar y node, whi ch i n tur n i s super i or to
bi opsy of nodes fr om the i ngui nal r egi on. In suspected extranodal
di sease or i n the case of matted nodes, i t i s i mpor tant to exci se as
gener ous an amount of ti ssue as possi bl e. Communi cati on wi th the
pathol ogi st i s i mpor tant to guarantee that adequate ti ssue i s sent
and that i t i s del i ver ed i n an acceptabl e fashi on. In general , the
speci men i s sent fr esh, i s sent i n sal i ne, or i s wrapped i n a sal i nesoaked sponge. It i s i mpor tant that the speci men be sent di r ectl y to
the pathol ogi st and that ther e i s an i ndi cati on that the di agnosi s of
l ymphoma i s suspected. Needl e bi opsi es rar el y pr ovi de an adequate
amount of ti ssue, al though they may be hel pful i n r ul i ng out a
car ci noma or sar coma or i n suspected r el apse of l ymphoma when a
ti ssue di agnosi s i s needed befor e tr eatment.
Miscellaneous Splenic Tumors

Splenic Cysts
A spl eni c cyst may be confused wi th a neopl asti c pr ocess when
detected as a pal pabl e abnor mal i ty or an unexpected radi ol ogi c
fi ndi ng. Pati ents often pr esent wi th vague symptoms, possi bl y due
to cyst enl ar gement. Al though parasi ti c cysts ar e extr emel y rar e i n
the Uni ted States, they ar e mor e common outsi de thi s
countr y. Parasi ti c cysts ar e most commonl y due to an echi nococcal
i nfecti on. Nonparasi ti c cysts compr i se 75% of spl eni c cysts i n the
Uni ted States and ar e cl assi fi ed as pr i mar y i f they have a tr ue
cel l ul ar l i ni ng or secondar y i f they l ack thi s l ayer. Pr i mar y spl eni c
cysts may be congeni tal , due to an embr yol ogi c r emnant or
neopl asti c cyst. The neopl asti c cysts i ncl ude epi der moi d cysts,
der moi d cysts, l ymphangi omas, and caver nous hemangi omas.
Secondar y cysts ar e the mor e common type of nonparasi ti c cyst and
ar e thought to be the r esul t of spl eni c i njur y and r esul tant
hematoma.
Spl eni c cysts rar el y r equi r e tr eatment unl ess they become i nfected,
hemor r hage, or per forate. Tr eatment may consi st of a par ti al or
total spl enectomy; mar supi al i z ati on or drai nage pr ocedur es shoul d
be avoi ded.
Inflammatory Pseudotumor
Infl ammator y pseudotumor, al so known as pl asma cel l granul oma,

has hi stol ogi c featur es of i nfl ammati on and mesenchymal r epai r.
Such masses can be found i n var i ous l ocati ons i n the body, i ncl udi ng
the r espi rator y system, gastr oi ntesti nal tract, or bi t, and l ymph
nodes. When a pseudotumor i s detected i n the spl een, i t may be
mi staken for l ymphoma. Pseudotumor s ar e thought to occur at si tes
of pr evi ous trauma or i nfecti on. Unfor tunatel y, the defi ni ti ve
di agnosi s can be made onl y after exci si on. Immunohi stochemi cal
stai ns and fl ow cytometr y studi es of the speci men may be useful to
r ul e out a l ymphopr ol i ferati ve di sor der.
Nonlymphoid Tumors
The spl een i s i nvol ved wi th var i ous beni gn and mal i gnant
nonl ymphoi d tumor s. Beni gn vascul ar tumor s i ncl ude hemangi oma,
l ymphangi oma, and hemangi oendothel i oma. Li poma and
angi omyol i poma ar e al so encounter ed. Angi osar coma of the spl een
confer s a poor pr ognosi s; thi s tumor has been associ ated wi th
exposur e to thor i um di oxi de, vi nyl chl or i de, and ar seni c. Kaposi 's
sar coma may be found as an i sol ated pr ocess i n the spl een. Other
spl eni c sar comas, i ncl udi ng mal i gnant fi br ous hi sti ocytoma,
fi br osar coma, and l ei omyosar coma, ar e extr emel y rar e.
Splenic Metastasis
Consi der i ng the l ar ge per centage of the total bl ood fl ow that
suppl i es the spl een, i t i s a sur pr i si ngl y rar e si te for metastasi s. In
autopsy ser i es of cancer pati ents, the fi ndi ng of metastasi s
i nvol vi ng the spl een ranges fr om 1.6% to 30% . Spl eni c metastasi s
i s rar el y a cl i ni cal l y r el evant pr obl em. Mel anoma, br east, and l ung
cancer ar e the most fr equentl y detected metastases. Spl enomegal y
i s an unusual fi ndi ng wi th sol i tar y metastasi s. Several smal l ser i es
have r epor ted the use of spl enectomy for an i sol ated spl eni c
metastasi s. Resecti on wi th curati ve i ntent i s rar el y possi bl e wi th
spl eni c metastasi s, but spl enectomy may be necessar y for
compl i cati ons such as per forati on, spl eni c vei n thr ombosi s, and
gr owth i nto adjacent vi scera.
Splenectomy
Splenectomy for Hypersplenism
Anemi a, neutr openi a, and thr ombocytopeni a may occur for a
number of r easons i n pati ents wi th hematol ogi c mal i gnanci es.

Because onl y pati ents wi th excessi ve destr ucti on of a bl ood
component wi l l benefi t fr om a spl enectomy, a car eful wor kup shoul d
be done to i denti fy the eti ol ogy of the pr ocess. Pati ents wi th
hyper spl eni sm may pr esent wi th a nor mal -si zed spl een, and other s
may have massi ve spl enomegal y wi thout hyper spl eni sm.
Infusi on of the pati ent's or nor mal donor pl atel ets tagged wi th
1 1 1 i ndi um i s hel pful i n deter mi ni ng whether the spl een i s the si te of
destr ucti on. Pati ents wi th an acqui r ed hemol yti c anemi a general l y
have a posi ti ve Coombs' test, and the detecti on of the war m
anti body i s a good i ndi cati on that spl enectomy wi l l be benefi ci al .
Al though chr omi um-l abel ed r ed bl ood cel l scans may be useful i n
demonstrati ng decr eases i n r ed bl ood cel l sur vi val , they ar e not as
hel pful i n i denti fyi ng the si te of sequestrati on. In cases of suspected
spl eni c sequestrati on, a bone mar r ow bi opsy i s i mpor tant to
deter mi ne whether adequate pr ecur sor cel l s ar e avai l abl e or
whether the pati ent depends on the hematopoi eti c acti vi ty of the
spl een.
Spl enectomy i n pati ents wi th CML has been associ ated wi th sever e
bl eedi ng pr obl ems. These may be r el ated to i mpai r ed cl ot for mati on
caused by pr oteases and serases pr oduced by granul ocytes. Pati ents
wi th CML and sever e l eukocytosi s shoul d r ecei ve chemotherapy i n
an attempt to decr ease the WBC count to appr oxi matel y 20,000
cel l s/mL. Exper i ence at M. D. Ander son suggests that spl enectomy i s
best avoi ded i n pati ents wi th CML i n whom WBC counts cannot be
contr ol l ed wi th chemotherapy. Spl enectomy shoul d al so be avoi ded
i n pati ents wi th CML who have had spl eni c i r radi ati on.
Bl eedi ng and i nfecti on ar e the gr eatest per i operati ve r i sks.
Qual i tati ve pl atel et functi on shoul d be eval uated rather than r el yi ng
on a pl atel et count. The templ ate bl eedi ng ti me i s cur r entl y the
most wi del y avai l abl e l aborator y val ue for i denti fyi ng adequacy of
pl atel et functi on. The pati ent's cur r ent and r ecent medi cati ons
shoul d be car eful l y r evi ewed to i denti fy any dr ugs that may i mpai r
coagul ati on. Because of potenti al bl eedi ng pr obl ems associ ated wi th
cer tai n anti bi oti cs, pr ophyl acti c coverage must be car eful l y chosen
to avoi d i ncr easi ng the r i sk of hemor r hage.
Al though spl enectomy may be per for med thr ough ei ther a mi dl i ne or
a subcostal appr oach, the mi dl i ne i nci si on i s pr efer r ed when
coagul ati on defects, thr ombocytopeni a, or spl enomegal y i s pr esent.
After the spl eni c pedi cl e i s cl amped, thr ombocytopeni c pati ents ar e
transfused wi th fr esh si ngl e-donor pl atel ets to achi eve a pl atel et
count of mor e than 60,000 cel l s/mL. Car eful hemostasi s at the
concl usi on of the pr ocedur e i s mandator y. Postoperati vel y, pati ents
shoul d be moni tor ed cl osel y dur i ng the fi r st 48 hour s for si gns of
bl eedi ng. A bl ood cel l count wi th di ffer enti al and pl atel et counts
shoul d be obtai ned ever y 6 hour s for the fi r st 24 hour s after the
operati on. Decr easi ng pl atel et and
bl ood counts, despi te adequate r epl acement, suggest an ongoi ng
bl eedi ng pr ocess.
Splenectomy for the Massively Enlarged

Spleen
Indi cati ons for spl enectomy i n pati ents wi th massi vel y enl ar ged
spl eens i ncl ude debi l i tati ng symptoms of spl enomegal y, excessi ve
destr ucti on of bl ood components, and concer ns of possi bl e spl eni c
r uptur e. These pati ents often compl ai n of chr oni c sever e upper
abdomi nal and back pai n, i mpai r ed r espi rati on, and ear l y sati ety.
Hyper spl eni sm may be pr esent. Dependi ng on the si ze of the spl een
and the body habi tus, the pati ent may be judged to be at i ncr eased
r i sk of spl eni c trauma.
Pr eoperati vel y, i t i s i mpor tant to check quanti tati ve and qual i tati ve
pl atel et functi on val ues and coagul ati on studi es because
hemor r hage i s the major compl i cati on of spl enectomy i n thi s gr oup.
Por tal venous contrast studi es shoul d be per for med i n pati ents wi th
possi bl e por tal hyper tensi on. If the spl eni c vei n i s thr ombosed,
spl enectomy i s appr opr i ate, but other wi se i t may depr i ve a pati ent
wi th por tal hyper tensi on of the opti on of a spl enor enal shunt.
Adequate bl ood pr oducts must be avai l abl e pr eoperati vel y. The bl ood
of these pati ents may be di ffi cul t to cr ossmatch because of
numer ous past transfusi ons, and fr esh si ngl e-donor pl atel ets may be
r equi r ed. Pati ents shoul d under go r outi ne bowel pr eparati on, and
pr ophyl acti c anti bi oti cs shoul d be gi ven.
A mi dl i ne, rather than subcostal , i nci si on i s pr efer r ed because the
r ectus muscl es ar e not sever ed, whi ch l i mi ts bl eedi ng. Wi th
i ncr easi ng si ze, the spl een becomes mor e of a mi dl i ne str uctur e and
l ends i tsel f to thi s appr oach. Befor e mobi l i z ati on of the spl een, i ts
vessel s shoul d be i sol ated. The gastr ocol i c omentum i s di vi ded, the
l esser sac i s enter ed, and the spl eni c ar ter y i s i denti fi ed al ong the
poster i or-super i or sur face of the pancr eas. The ar ter y i s l i gated but
l eft i ntact. The spl eni c vei n i s not di stur bed yet. The spl een may
decr ease 20% to 30% i n si ze at thi s poi nt and al l ow pl atel et
transfusi on wi thout consumpti on. The spl eni c fl exur e of the col on i s
mobi l i zed, the spl eni c l i gaments ar e di vi ded, and the spl een i s
del i ver ed fr om the spl eni c fossa. The nor mal l y avascul ar spl eni c
l i gaments often contai n smal l vessel s i n the pr esence of
hematol ogi c mal i gnanci es. Dense adhesi ons between the spl een and
the di aphragm may compl i cate mobi l i z ati on, and when di ssecti on i s
par ti cul ar l y di ffi cul t, i t i s better to r esect par t of the di aphragm
wi th the spl een than to r i sk hyper tr ophy of spl eni c r emnants. Such
adhesi ons ar e for med i n ar eas of spl eni c i nfar cti on and ar e the most
fr equent si tes of postoperati ve bl eedi ng i n thi s gr oup of pati ents.
After the spl een i s mobi l i zed, the ar ter y and vei n ar e sutur e l i gated
and di vi ded. Li ver bi opsy may be i ndi cated i f i nvol vement by
l ymphoma i s suspected. If an i njur y to the pancr eati c tai l i s
r ecogni zed, i t shoul d be r epai r ed and drai ned appr opr i atel y.
Achi evi ng hemostasi s i n the spl eni c bed i s cr uci al and may r equi r e
sutur e l i gati on, cauter y, pl atel et transfusi ons, and thr ombostati c
agents. Drai ns do not r el i abl y war n of postoperati ve hemor r hage or
pr event i nfecti on, and except i n cases of pancr eati c i njur y, they ar e
not r outi nel y used. Postoperati vel y, pati ents shoul d be cl osel y
moni tor ed for si gns of bl eedi ng or i nfecti on.
Laparoscopic Splenectomy
Lapar oscopi c spl enectomy has been used safel y i n pati ents wi th
beni gn hematol ogi c condi ti ons. Recentl y ther e has been i ncr easi ng
i mpl ementati on of thi s sur gi cal method i n spl enomegal y i n pati ents
wi th mal i gnant hematol ogi c di seases. The advantages appear to be a
qui cker r ecover y and r esul tant decr eased heal thcar e costs.
Pr ospecti ve randomi zed tr i al s ar e r equi r ed to confi r m these
obser vati ons. To al l ow adequate pathol ogi c exami nati on of the
speci men, the spl een needs to be r emoved i ntact thr ough a smal l
i nci si on.
Prophylaxis for Asplenic Sepsis

Pati ents wi th hematol ogi c mal i gnanci es who under go spl enectomy
ar e at gr eater r i sk for aspl eni c sepsi s than ar e those who have the
pr ocedur e for other i ndi cati ons. Some pati ents wi th hematol ogi c
mal i gnancy, especi al l y those wi th CML and CLL, ar e at i ncr eased r i sk
for sepsi s even befor e spl enectomy. The r i sk of over whel mi ng
postspl enectomy i nfecti on (OPSI) i s gr eatest for chi l dr en. The
expected death rate fr om OPSI i n chi l dr en i s one i n ever y 300 to
350 pati ent-year s, and

year s. For al l pati ents,
fol l owi ng spl enectomy,
30 or mor e year s after
i n adul ts, one i n ever y 800 to 1,000 pati entthe r i sk i s gr eatest for the fi r st few year s
but deaths attr i buted to OPSI have occur r ed
spl enectomy.
Fol l owi ng spl enectomy, ther e i s l oss of the opsoni ns, tuftsi n and
pr oper di n, a decr ease i n i mmunogl obul i n M pr oducti on, i mpai r ed
phagocytosi s, and al ter ed cel l ul ar i mmuni ty. Poor l y opsoni zed
bacter i a ar e best cl ear ed by the spl een, and fol l owi ng the spl een's
r emoval pati ents ar e par ti cul ar l y suscepti bl e to the encapsul ated
bacter i a.
Vacci nati on can decr ease the r i sk of postspl enectomy pneumococcal
i nfecti on. The 23-val ent for m of the pneumococcal vacci ne shoul d be
used. The vacci ne i s most effecti ve when gi ven several weeks
pr eoperati vel y. Never thel ess, despi te the di mi ni shed i mmuni ty
obtai ned i f the vacci ne i s gi ven after spl enectomy, adequate
pr otecti on i s sti l l achi eved i n most pati ents. In pati ents who ar e not
i mmuni zed pr eoperati vel y ther e i s no benefi t fr om del ayi ng the
i mmuni z ati on for several weeks after sur ger y, so these pati ents
shoul d be vacci nated wi thout del ay. Leukemi c pati ents may not be
abl e to devel op anti bodi es i n r esponse to pneumococcal vacci ne, but
i t may sti l l be wor thwhi l e to vacci nate thi s gr oup. Booster
i mmuni z ati ons wi th the pneumococcal vacci ne have no pr oven
benefi t, al though r ei mmuni z ati on at 3 to 5 year s may be r equi r ed i f
a decr ease i n speci fi c anti body l evel s i s documented. Cer tai n
subsets of pati ents ar e at i ncr eased r i sk of i nfecti on wi th
Haemophilus influenz ae and Neisser ia meningitidis and, ther efor e,
pati ents shoul d r ecei ve these vacci nati ons as wel l . Pati ents ar e al so
i nstr ucted to keep a suppl y of anti bi oti cs such as amoxi ci l l i n and
Augmenti n (amoxi ci l l i n; cl avul anate potassi um) wi th them, whi ch
shoul d be taken at the fi r st si gn of a febr i l e epi sode. Thi s shoul d
al so be fol l owed by i mmedi ate contact wi th a physi ci an.
Long-ter m use of pr ophyl acti c oral anti bi oti cs i s often r ecommended
i n the pedi atr i c popul ati on or i n pati ents who may have di ffi cul ty
r eachi ng a physi ci an. Peni ci l l i n i s commonl y pr escr i bed
to these pati ents. Data have shown benefi t of pr ophyl acti c peni ci l l i n
i n pr eventi ng pneumococcal i nfecti on i n chi l dr en wi th si ckl e cel l
di sease, but the benefi t of thi s practi ce has never been pr oved for
other subsets of aspl eni c pati ents.
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M.
Edition
> Ta ble o f C o nt e nt s > 1 8 - C a nc e r o f U nk no w n P rim a ry Sit e
18
Cancer of Unknown Primary Site
Gauri R. Varadhachary
Cancer of unknown pr i mar y si te (CUP) i s a heter ogeneous gr oup
that compr i ses 3% to 5% of new cancer di agnoses and can be
di ffi cul t to eval uate and tr eat. Al though chemotherapy i s the
pr i mar y tr eatment modal i ty i n pati ents wi th CUP, the sur geon
fr equentl y pl ays an i mpor tant r ol e i n both the di agnosi s and the
tr eatment of these pati ents. In par ti cul ar, sur geons ar e often asked
to eval uate pati ents wi th cancer that has spr ead to a l ymph node,
the l i ver, or the per i toneal cavi ty.
In thi s chapter, we defi ne the pr esentati on and cl i ni cal featur es of
CUP, outl i ne a practi cal appr oach to the di agnosti c eval uati on of
pati ents wi th CUP, and di scuss the r ol e of sur ger y i n var i ous cl i ni cal
scenar i os.
Definition and General Considerations

CUP i s defi ned by the pr esence of a bi opsy-pr oven cancer for whi ch
the anatomi cal or i gi n of the pr i mar y tumor i s not r eveal ed after a
thor ough medi cal hi stor y and physi cal exami nati on (i ncl udi ng br east
and pel vi c exami nati on i n women, and testi cul ar and pr ostate
exami nati on i n men), r outi ne l aborator y tests, chest X-ray,
computed tomography (CT) of the abdomen and pel vi s,
mammography i n women, and pr ostate-speci fi c anti gen (PSA) test i n
men. Thi s defi ni ti on of CUP i s not al ways used consi stentl y and
var i es dependi ng on the extent of the eval uati on. The pr evai l i ng
hypothesi s i n CUP i s that the pr i mar y tumor ei ther r emai ns
mi cr oscopi c and escapes cl i ni cal detecti on or di sappear s after
seedi ng the metastasi s, whi ch may be due to angi ogeni c
i ncompetency of the pr i mar y tumor.
These tumor s often ar e gr ouped accor di ng to hi stol ogi c subtype. The

major subtypes i ncl ude squamous cel l cancer, adenocar ci noma, and
undi ffer enti ated neopl asms, the name gi ven to a heter ogeneous
gr oup of tumor s of var i ous cel l or i gi ns. Tabl e 18.1 l i sts the
fr equenci es of each subtype (adenocar ci noma i s the most common).
As found i n l ar ge ser i es, the most common l ocati ons of CUP
metastases ar e the l ymph nodes, bones, l ungs, and l i ver. Other
metastati c si tes i ncl ude the per i toneum, brai n, meni nges, pl eura,
subcutaneous ti ssues, adr enal gl ands, ki dney, and pancr eas.
In most pati ents, the si te of or i gi n of the metastati c di sease i s
never di scer ned. In other s, the pr i mar y tumor si te fr om whi ch the
metastases ar e der i ved i s eventual l y i denti fi ed thr ough exhausti ve
sear ch dur i ng cl i ni cal exami nati ons, sur ger y, or autopsy. In onl y
25% of CUP cases i s the pr i mar y si te i denti fi abl e dur i ng the
pati ent's l i feti me; thi s number i s pr obabl y l ower wi th sophi sti cated
i magi ng techni ques (wher e basel i ne studi es have been negati ve).
Metastases fr om squamous cel l cancer s typi cal l y
or i gi nate i n the head and neck r egi on or the l ungs, wher eas
metastati c adenocar ci nomas or i gi nate i n the l ungs, br easts, thyr oi d
gl and, pancr eas, l i ver, stomach, col on, or r ectum.
Table 18.1. Histopathological subtypes of

cancer of unknown primary site
Histopathology
Percentage of CUP
Patients
Adenocarcinoma
60
Squamous cell carcinoma

adenocarcinoma
5
35
Poorly differentiated carcinoma

Poorly differentiated neoplasm
Unclassified neoplasm
CUP, cancer of unknown primary site.
The medi an sur vi val of pati ents wi th CUP i s 6 to 9 months. Speci fi c
subgr oups of pati ents wi th metastati c CUP have consi derabl y better
pr ognoses than the gr oup as a whol e, wi th appr opr i ate therapy. Thi s
i ncl udes pati ents wi th squamous cel l cancer metastati c to cer vi cal
l ymph nodes, women wi th metastati c adenocar ci noma i n axi l l ar y
l ymph nodes, men wi th undi ffer enti ated cancer and el evated human chor i oni c gonadotr opi n (-hCG ) or al pha-fetopr otei n (AF P)
l evel s, women wi th per i toneal car ci nomatosi s, and pati ents wi th
neur oendocr i ne CUP. These subgr oups ar e di scussed l ater i n thi s
chapter i n mor e detai l .
The therapeuti c goal i n eval uati ng pati ents wi th CUP i s to i denti fy
those tumor types for whi ch a cur e i s possi bl e or adequate di sease
contr ol and pal l i ati on i s l i kel y, as wel l as any symptoms for whi ch
l ocal i zed therapy may be effecti ve.
History and Physical Examination

In pati ents wi th CUP, a compl ete medi cal hi stor y and physi cal
exami nati on ar e essenti al . An i ndi vi dual hi stor y of mal i gnancy or a
fami l y hi stor y of cancer may gui de the sur geon i n establ i shi ng the
si te of an occul t pr i mar y tumor. Often, symptoms r el ated to CUP ar e
of r el ati vel y r ecent onset (<3 months), and rapi d pr ogr essi on of
di sease and per for mance status ar e cr uci al factor s i n i ndi vi dual i z i ng
tr eatment deci si ons.
Dur i ng physi cal exami nati on of a pati ent wi th CUP, several
anatomi cal si tes war rant par ti cul ar attenti on. The head and neck
shoul d be exami ned thor oughl y, par ti cul ar l y when a di agnosi s of
squamous cel l cancer has been made. Thi s i ncl udes exami nati on of
the or ophar ynx, hypophar ynx, nasophar ynx, and l ar ynx, typi cal l y
assi sted by i ndi r ect or fi ber opti c l ar yngoscopy. The thyr oi d gl and
shoul d be exami ned for enl ar gement or asymmetr y. Al l nodal basi ns,
i ncl udi ng those of the head and neck and the supracl avi cul ar,
axi l l ar y, and i ngui nal r egi ons, shoul d be exami ned for pal pabl e or
enl ar ged l ymph nodes.
In women, a car eful br east exami nati on and a thor ough bi manual
pel vi c exami nati on shoul d be per for med. For men, testi cul ar and
pr ostate exami nati ons ar e par ti cul ar l y i mpor tant. Al l
pati ents shoul d under go a thor ough ski n exami nati on and r ectal
exami nati on.
Laboratory Studies
Routi ne compl ete bl ood cel l count, bl ood chemi str y studi es, l i ver
functi on tests, and ur i nal ysi s shoul d be per for med i n al l pati ents,
and stool shoul d be checked for occul t bl ood. Beyond these basi c
tests, the cl i ni cal l aborator y has l i mi ted useful ness i n the di agnosti c
eval uati on of pati ents wi th CUP, but addi ti onal studi es shoul d be
r equested on the basi s of hi stol ogi c and radi ol ogi c fi ndi ngs.
Radiographic Evaluation
Radi ographi c eval uati ons of pati ents wi th CUP shoul d be focused on
i denti fyi ng the pr i mar y tumor and del i neati ng the extent of
metastati c di sease.
Chest X-ray and Computed Tomography Scan

of the Chest
A chest X-ray i s i ndi cated for al l pati ents to assess the pr esence of
pul monar y metastases or a pr i mar y tumor, as wel l as for
pr eoperati ve eval uati on. If a pati ent has pul monar y symptoms, an
abnor mal chest x-ray, or posi ti ve sputum cytol ogi c fi ndi ngs, a CT
scan of the chest i s i ndi cated. In practi ce, most physi ci ans or der i t
as par t of a body i magi ng study.
Computed Tomography Scan of the Abdomen

and Pelvis
CT scan of the abdomen and pel vi s i s essenti al because i t can hel p
i n l ocati ng the pr i mar y tumor, eval uati ng the extent of di sease, and
sel ecti ng the most favorabl e bi opsy si te. In a study by Abbr uz zese
et al . of pati ents who under went CT scans of the abdomen and
pel vi s, a pr i mar y tumor was found i n 179 of 879 pati ents (20% ). In
a r etr ospecti ve study by McMi l l an et al ., i n 21 of 46 pati ents (46% ),

a pr i mar y tumor was detected on CT scan, and pr evi ousl y
unsuspected metastati c di sease was detected i n 30 (65% ) pati ents.
CT was super i or to sonography and to contrast studi es of the
ur i nar y and gastr oi ntesti nal tracts i n l ocal i z i ng the pr i mar y si te.
Mammography
Women of chi l dbear i ng age or ol der, par ti cul ar l y those wi th
metastati c adenocar ci noma, shoul d under go mammography.
Unfor tunatel y, i denti fyi ng subtl e radi ographi c abnor mal i ti es i s
di ffi cul t i n younger women, who often have extr emel y dense br east
ti ssue. Magneti c r esonance i magi ng (MRI) of the br east i s i ndi cated
i n women who pr esent wi th i sol ated axi l l ar y adenopathy (i f the
mammogram and br east sonographi c fi ndi ngs ar e negati ve).
Magnetic Resonance Imaging

In most cases, MRI i s i ndi cated i f CT i s contrai ndi cated. Its most
defi ned r ol e i n CUP i s i n women who pr esent wi th i sol ated axi l l ar y
l ymph node metastases and suspected occul t pr i mar y br east
car ci noma. The r esul ts of several studi es suggest that MRI of the
br east can hel p wi th tumor detecti on i n up to 75% of pati ents. Thi s
r esul t can i nfl uence sur gi cal management, wi th a negati ve br east
MRI pr edi cti ng a l ow yi el d at mastectomy.
Positron Emission Tomography

The r ol e of posi tr on emi ssi on tomography (PET) scan usi ng 18F fl uor o-2-deoxy-D-gl ucose (18F -F DG PET) i s contr over si al . PET
i magi ng i s r ecommended i n pati ents wi th occul t pr i mar y head and
neck cancer (cer vi cal CUP) and i n those who pr esent wi th a sol i tar y
potenti al l y r esectabl e CUP l esi on. Several r ecent smal l studi es have
descr i bed the r ol e of PET i n pati ents who pr esent wi th cer vi cal CUP.
The advantages of l ocati ng the pr i mar y tumor i n pati ents who
pr esent wi th cer vi cal l ymphadenopathy (occul t head and neck
cancer ) ar e (a) smal l er postoperati ve radi ati on por ts, whi ch can
decr ease ear l y and l ate compl i cati ons; (b) better sur vei l l ance for
r ecur r ence; and (c) i mpr oved pr ognosti c deter mi nati on. Rusthoven
et al . r evi ewed 16 studi es (19942003) of 302 pati ents wi th
cer vi cal l ymph node metastases fr om unknown pr i mar y tumor s.
Conventi onal wor kup i ncl uded ei ther panendoscopy, CT, or MRI, and,
i n 10 of these 16 studi es, both tests wer e per for med befor e
di agnosi s. They r epor ted the overal l sensi ti vi ty, speci fi ci ty, and
accuracy rates of F DG PET i n detecti ng unknown pr i mar y tumor s as
88.3% , 74.9% , and 78.8% , r especti vel y. Appr oxi matel y 25% of
pr i mar y tumor s that wer e not appar ent after conventi onal wor kup
wer e abl e to be i denti fi ed on 18F -F DG PET, as wer e pr evi ousl y
undetected r egi onal or di stant metastases i n 27% of pati ents.
In general , an exhausti ve sear ch for the pr i mar y tumor si te i n these
pati ents by radi ographi c eval uati on can be expensi ve, i nconveni ent,
and traumati c for pati ents and often has no si gni fi cant effect on
pati ents therapy or the ul ti mate cour se of thei r di sease.
Pathological Evaluation
F i ne-needl e aspi rati on (F NA) bi opsy has l ar gel y r epl aced cor e bi opsy
as a fi r st pathol ogi cal test. Thi s can be fol l owed by cor e bi opsy,
i nci si onal bi opsy, or exci si onal bi opsy as needed for speci fi c
hi stol ogi c types. G ood communi cati on between the cl i ni ci an and the
pathol ogi st i s i mpor tant because detai l s of the medi cal hi stor y and
physi cal exami nati on can i nfl uence the pathol ogi cal r evi ew and
faci l i tate submi ssi on of addi ti onal ti ssue i f necessar y for an accurate
di agnosi s.
Light Microscopy
Li ght mi cr oscopy (hematoxyl i n and eosi n stai ni ng) i s or di nar i l y
suffi ci ent to deter mi ne the cel l of or i gi n. About 60% of CUPs ar e
found to be adenocar ci noma on l i ght mi cr oscopy. An addi ti onal 5%
ar e squamous cel l car ci noma, and the r emai ni ng 35% ar e di agnosed
as poor l y di ffer enti ated adenocar ci noma, poor l y di ffer enti ated
car ci noma, or poor l y di ffer enti ated neopl asm. El ectr on mi cr oscopy,
whi ch hel ps i denti fy the ul trastr uctural featur es of the cel l of or i gi n,
i s rar el y needed. For exampl e, desmosomes and i ntracel l ul ar br i dges
ar e associ ated wi th squamous cel l cancer, wher eas ti ght juncti ons,
mi cr ovi l l i , and aci nar spaces ar e associ ated wi th adenocar ci noma.
Pr emel anosomes ar e associ ated wi th mel anoma, and neur osecr etor y
granul es ar e associ ated wi th smal l cel l or neur oendocr i ne tumor s.
Lymphoma i s typi cal l y character i zed by an absence of juncti ons
between the cel l s on el ectr on
mi cr oscopy. El ectr on mi cr oscopy can be ti me-consumi ng and
expensi ve; ther efor e, wi th the avai l abi l i ty of i mmunohi stochemi cal
stai ns, the need for i t has di mi ni shed.
Immunohistochemical Analysis
Immunohi stochemi cal anal yses have become a r outi ne addi ti on to
l i ght mi cr oscopy, and a br oad range of i mmunohi stochemi cal
mar ker s ar e used to assi st i n the di agnosi s after l i ght mi cr oscopy.
Common mar ker s used for adenocar ci nomas i ncl ude cytokerati ns
(CKs) 7 and 20 and thyr oi d transcr i pti on factor (TTF -1). TTF -1, a
nucl ear pr otei n, can be posi ti ve i n l ung and thyr oi d cancer s. About
65% to 70% of l ung adenocar ci nomas and 25% of squamous cel l
l ung cancer s stai n posi ti ve for TTF -1, and i n pati ents wi th CUP, thi s
test i s hel pful i n di ffer enti ati ng between a pr i mar y l ung tumor and
metastati c adenocar ci noma (e.g., i n pati ents pr esenti ng wi th
metastati c pl eural effusi on). The CK mar ker combi nati on patter n
depi cted i n F i gur e 18.1 i s al so hel pful .
Br east mar ker s i ncl udi ng estr ogen r eceptor (ER), pr ogester one
r eceptor (PR), Her-2 neu, and gr oss cysti c di sease fi br ous pr otei n
shoul d be checked i n women who pr esent wi th adenocar ci noma,
especi al l y i sol ated axi l l ar y adenopathy. Hep-par-1, a hepatocel l ul ar
car ci noma mar ker, ai ds i n the di agnosi s of hepatocel l ul ar
cancer, and CK-19 i s someti mes used for chol angi ocar ci noma. It i s
someti mes di ffi cul t to di sti ngui sh metastati c chol angi ocar ci noma,
metastati c adenocar ci noma, and hepatocel l ul ar car ci noma i n
pati ents who pr esent wi th l i ver-onl y metastati c di sease. Other
mar ker s used i n a di r ected fashi on on the basi s of past mi cr oscopy
r esul ts i ncl ude pr ostati c aci d phosphatase and PSA for pr ostate
cancer, and neur on-speci fi c enol ase and chr omograni n for
neur oendocr i ne cancer s. G er m cel l tumor s often stai n for -hCG and
AF P.
F i gur e 18.1. Appr oach to i mmunohi stochemi cal mar ker s used i n
cancer of unknown pr i mar y si te.
No i mmunohi stochemi cal mar ker i s 100% speci fi c, and many of

these tests (as wel l as ser um mar ker s) can be confusi ng and rar el y
hel p i n the sear ch for a pr i mar y tumor or i n tr eatment pl anni ng.
Serum Tumor Markers and Cytogenetics

Unfor tunatel y, pati ents wi th CUP typi cal l y have nonspeci fi c
over expr essi on of many ser um tumor mar ker s, i ncl udi ng -hCG ,
AF P, car ci noembr yoni c anti gen, CA-125, CA 19-9, and CA 15-3. In
pati ents who pr esent wi th an undi ffer enti ated car ci noma or a poor l y
di ffer enti ated car ci noma (especi al l y wi th a mi dl i ne tumor ), -hCG
and AF P shoul d be tested to r ul e out occul t ger m-l i ne cancer s. None
of these mar ker s has been found to have adequate speci fi ci ty or
sensi ti vi ty to consi stentl y i denti fy a pr i mar y tumor, nor the
pr edi cti ve val ue for ei ther r esponse to chemotherapy or sur vi val .
Motzer et al . pr esented the mol ecul ar and cytogeneti c r esul ts for 40
pati ents wi th CUP wi th poor l y di ffer enti ated car ci noma. In 42% of
pati ents (17), the di agnosi s was made on the basi s of geneti c
anal ysi s. Thi r ty per cent (12) of pati ents had cytogeneti c changes
character i sti c of ger m cel l tumor s (i sochr omosome 12p-I[12p]),
i ncr eased 12p copy number, or del eti on of the l ong ar m of

chr omosome 12. These pati ents al so r esponded better to ci spl ati nbased chemotherapy than di d pati ents wi th other di agnoses (75%
vs. 18% ). Pantou et al . studi ed 20 bi opsy speci mens fr om pati ents
wi th CUP and found that most sampl es had mul ti pl e compl ex
cytogeneti c patter ns. Tabl e 18.2 l i sts several common tumor
mar ker s and thei r r ol es i n cl i ni cal eval uati on of pati ents wi th CUP.
Specific Disease Sites

Metastatic Cancer to Cervical Lymph Nodes
Enl ar ged cer vi cal l ymph nodes ar e often found on bi opsy to be
posi ti ve for metastati c cancer. Pati ents wi th squamous cel l cancer
metastati c to cer vi cal l ymph nodes and an unknown pr i mar y tumor
si te have a better pr ognosi s than do pati ents wi th CUP overal l .
The neck compr i ses mor e than 25 nodal basi ns. These nodes have
been gr ouped i nto si x speci fi c categor i es to standar di ze the
pathol ogi cal eval uati on of pati ents. The cl assi fi cati on of cer vi cal
l ymph nodes i s shown i n Tabl e 18.3. The most common si te of
metastasi s i n pati ents wi th head and neck squamous cel l cancer i s
the jugul odi gastr i c or l evel II upper i nter nal jugul ar chai n nodes,
fol l owed by the mi djugul ar nodes. Metastasi s to the other cer vi cal
nodal gr oups occur s wi th l ess fr equency.
Table 18.2. Clinical role of selected tumor

markers
Tumor
Marker
Role in Differential Diagnosis
AFP
Identification of hepatocellular
carcinoma or germ cell tumors
Identification of trophoblastic
-hCG
and germ cell tumors
2microglobulin
Not very useful
CA 15-3
Identification of possible breast

carcinoma, but elevated serum
levels also noted in ovarian,
lung, and GI carcinomas
CA 19-9
Identification of possible
pancreatic cancer or other GI
cancer
CA 125
Identification of possible
ovarian or uterine cancer, but
elevated serum levels may be
noted in breast, lung, or GI
cancers
Calcitonin
Screening and diagnosis of

medullary carcinoma of thyroid
CEA
Distinction of carcinoma from

mesothelioma
Cytokeratin

lymphoma or melanoma by
immunohistochemistry
Epithelial
membrane
antigen
melanoma by membrane
LCA
Identification of lymphoma or
leukemia by
PSA
Identification of prostate
carcinoma
AFP, alpha-fetoprotein; -hCG, -human

chorionic gonadotropin; GI; gastrointestinal;
CEA, carcinoembryonic antigen; LCA, leukocyte
common antigen; PSA, prostate-specific
antigen.
Table 18.3. Classification of cervical lymph

nodes
Level Nodes
I
Submental nodes
II
Upper internal jugular chain nodes
III
Middle internal jugular chain nodes
IV
Lower internal jugular chain nodes
Spinal accessory nodes

Transverse cervical nodes
VI
Tracheoesophageal groove nodes
In those pati ents wi th cer vi cal l ymph nodes fr om an occul t

squamous cel l pr i mar y tumor, a car eful head and neck exami nati on
i s par ti cul ar l y i mpor tant. Adequate l i ghti ng and mi r r or s must be
used to vi sual i ze the enti r e or ophar ynx, hypophar ynx, nasophar ynx,
and l ar ynx. A chest radi ograph i s al ways i ndi cated, and a CT scan of
the head and neck i s usual l y i ndi cated to deter mi ne the pr i mar y
tumor si te and obtai n compl ete stagi ng i nfor mati on.
If no pr i mar y tumor i s found on physi cal exami nati on and i magi ng
studi es i ncl udi ng a CT scan, panendoscopy i s a common next step.
Thi s i s nor mal l y per for med i n the operati ng r oom wi th the pati ent
under general anesthesi a. Esophagoscopy, l ar yngoscopy,
br onchoscopy, and nasophar yngoscopy ar e per for med i n an attempt
to vi sual i ze the r egi on and obtai n bi opsy speci mens fr om the most
common si tes of occul t squamous cel l cancer i n the head and neck
r egi on. Random bi opsi es of the most pr obabl e tumor si te l ocati ons
ar e per for med, on the basi s of the l ocati on of the adenopathy.
Typi cal occul t pr i mar y tumor si tes i n squamous cel l cancer ar e the
nasophar ynx, the mi dbase of the tongue, the pyr i for m si nus, and
the tonsi l s. Tabl e 18.4 shows the common patter n of cer vi cal
metastasi s fr om di ffer ent squamous cel l tumor s i n the head and
neck r egi on. On the basi s of the l ocati on of the nodal metastases,
extrapol ati on of the l i kel y sour ce of the occul t pr i mar y tumor i s
often possi bl e, and the endoscopi c exami nati on shoul d be focused
on these l ocati ons.
If the pr i mar y tumor si te cannot be i denti fi ed on endoscopy, the
standar d appr oach i s a combi nati on of radi cal neck di ssecti on and
postoperati ve radi ati on therapy. The r ol e for chemotherapy depends
on the pr esence of bul ky nodes (N3 di sease), and neoadjuvant
chemotherapy has not been wel l studi ed. On the basi s of l ar ge
ser i es, the expected 5-year sur vi val i n these pati ents i s 32% to
55% , and the overal l rate of l ocal contr ol i s 75% to 85% . Pati ents
wi th extranodal extensi on or l ymph nodes l ar ger than 6 cm (N3
di sease) have hi gher rates of both l ocal r ecur r ence and di stant
metastases.
Table 18.4. Probable sites of primary

tumors according to the location of the
cervical metastases
Location of
Nodes
Primary Tumor Site
Submental
Floor of the mouth, lips, or

anterior tongue
Submaxillary
Retromolar trigone or
glossopalatine pillar
Jugulodigastric
Hypopharynx, base of the

tongue, tonsils, nasopharynx,
or larynx
Low jugular
Thyroid, hypopharynx, or
nasopharynx
Supraclavicular
Lung (40%), thyroid (20%),

GI (12%), or GU (8%)
Posterior
triangle
Nasopharynx
GI, gastrointestinal; GU, genitourinary.
Pati ents wi th metastati c adenocar ci noma i n cer vi cal l ymph nodes

fr om an occul t pr i mar y tumor have a l ess favorabl e outcome than do
those wi th squamous cel l cancer. Retr ospecti ve ser i es have shown
that l ymphadenectomy and radi ati on therapy ar e much l ess effecti ve
i n adenocar ci noma than i n squamous cel l car ci noma; the rate of
l ocal r ecur r ence i n these cases i s near l y 100% , and the 5-year
sur vi val rate i s 0% to 10% .
Of par ti cul ar i nter est i s the pr esence of an enl ar ged Vi r chow's
(supracl avi cul ar ) node, common i n pati ents wi th metastati c
adenocar ci noma. One study r etr ospecti vel y r evi ewed 152 F NA
bi opsy sampl es of supracl avi cul ar l ymph nodes, compar i ng the si tes
of pr i mar y tumor when the metastasi s was i n the r i ght ver sus the
l eft supracl avi cul ar node. Si xteen of 19 pr i mar y pel vi c tumor s
metastasi zed to the l eft supracl avi cul ar node, and al l (6 of 6)
pr i mar y abdomi nal mal i gnanci es metastasi zed to the l eft
supracl avi cul ar node. However, thoraci c, br east, and head and neck
mal i gnanci es di d not di ffer i n patter ns of metastasi s to the r i ght and
l eft supracl avi cul ar nodes. On the basi s of thi s i nfor mati on, the
sear ch for the pr i mar y tumor shoul d be focused on the abdomen and
pel vi s i n pati ents who pr esent wi th adenocar ci noma i n a l eft-si ded
Vi r chow's node.
Metastatic Cancer to Axillary Lymph Nodes

The hi stol ogi c type of the tumor shoul d be used to gui de the
eval uati on of pati ents wi th cancer metastati c to axi l l ar y l ymph
nodes (l ymphoma i s not consi der ed a CUP; metastati c mel anoma
wi th an unknown pr i mar y i s di scussed separatel y l ater i n thi s
chapter ). Pati ents wi th squamous cel l cancer metastati c to the
axi l l ar y l ymph nodes shoul d under go a car eful ski n exami nati on, a
chest X-ray, a thor ough head and neck exami nati on, and CT scans of
the head, neck, and the chest to l ook for an occul t squamous cel l
pr i mar y tumor.
Men wi th adenocar ci noma metastati c to an axi l l ar y l ymph node and
CUP shoul d be eval uated for l ung, gastr oi ntesti nal , and
geni tour i nar y pr i mar y tumor s. Women wi th adenocar ci noma
metastati c to the axi l l ar y l ymph nodes shoul d be eval uated
si mi l ar l y, al though i n women the l i kel i hood of an occul t br east
pr i mar y tumor i s hi gh. Women wi th occul t br east cancer who
pr esent wi th axi l l ar y metastases consti tute appr oxi matel y 0.5% of
al l women wi th br east cancer. When many such pati ents ar e tr eated
for a pr esumpti ve di agnosi s of br east cancer, the r ecur r ence and
sur vi val r esul ts ar e si mi l ar to those of pati ents wi th a si mi l ar stage
of br east cancer and a known pr i mar y tumor. A r etr ospecti ve r evi ew

of the mastectomy speci mens fr om pati ents wi th occul t pr i mar y
tumor s showed that i n 50% to 65% of cases, the pr i mar y tumor was
ul ti matel y i denti fi ed i n the sur gi cal speci men. The other tumor s
wer e pr obabl y too smal l to be detected by the standar d sampl i ng
techni ques that pathol ogi sts use to study br east speci mens. Such
pati ents shoul d be exami ned car eful l y for br east tumor s, and ever y
woman shoul d under go a mammogram and br east sonography i f the
mammogram i s negati ve (especi al l y i n younger pati ents wi th dense
br easts). As i ndi cated ear l i er, MRI of the br east i s i ndi cated i n most
women who pr esent wi th axi l l ar y adenopathy and CUP (wi th
negati ve mammogram and sonographi c fi ndi ngs).
The bi opsy speci men fr om the l ymph node shoul d be subjected to
r outi ne hi stol ogi c and i mmunohi stochemi cal eval uati on for ER, PR,
and Her-2 neu. Al though nei ther hi ghl y sensi ti ve nor hi ghl y
speci fi c, the pr esence of ER or PR i n thi s cl i ni cal scenar i o str ongl y
suggests a br east pr i mar y tumor.
The tr eatment for women wi th adenocar ci noma metastati c to
axi l l ar y l ymph nodes has evol ved dramati cal l y over the l ast decade.
The thr ee general appr oaches ar e i mmedi ate mastectomy,
obser vati on, and radi ati on therapy. Immedi ate mastectomy i s not
per for med i n most pati ents i f the i magi ng studi es ar e negati ve
because the chances of fi ndi ng a pr i mar y ar e l ow. Obser vati on wi th
axi l l ar y di ssecti on can r esul t i n r ecur r ence i n the br east (25%
75% , dependi ng on the study), r equi r i ng fur ther therapy. The thi r d
appr oach i s br east conser vati on therapy wi th l ocor egi onal radi ati on
therapy, whi ch has been shown to decr ease the l ocal r ecur r ence
rate and i s the pr efer r ed appr oach for most pati ents at The
Uni ver si ty of Texas M. D. Ander son Cancer Center. Our r esul ts show
that i n pati ents who have under gone axi l l ar y l ymph node di ssecti on
al one, the i nci dence of l ocal r ecur r ence i s 65% at 10 year s,
wher eas a combi nati on of axi l l ar y l ymph node di ssecti on and
radi ati on therapy r educes the l ocal r ecur r ence rate to 25% . Wi th
thi s tr eatment, the overal l sur vi val rate was no di ffer ent fr om that
of pati ents wi th the same nodal stage of di sease who had under gone
mastectomy. The addi ti on of adjuvant chemotherapy to sur ger y and
radi ati on therapy i ncr eased the sur vi val rate fr om 60% to 85% at
10 year s. Tamoxi fen shoul d be par t of the therapy for women of any
age whose pr i mar y tumor (i f i denti fi ed) or axi l l ar y nodal metastases
expr esses ER or PR.
A r etr ospecti ve study at M. D. Ander son Cancer Center i ncl uded 45
women wi th i sol ated axi l l ar y nodal metastases wi thout a known

pr i mar y tumor. The medi an fol l ow-up durati on was 7 year s. Pati ents
under went ei ther mastectomy or br east conser vati on therapy;
exter nal -beam radi ati on therapy was used i n 71% of pati ents, and
systemi c chemotherapy was used i n 73% . No si gni fi cant di ffer ence
was found between mastectomy and br east conser vati on i n
l ocor egi onal r ecur r ence, di stant metastases, or 5-year sur vi val rate.
Regar dl ess of the sur gi cal tr eatment used, the number of i nvol ved
nodes was the onl y deter mi nant of sur vi val .
Cancer Metastatic to the Inguinal Nodes From

an Unknown Primary Site
A r el ati vel y i nfr equent pr esentati on of metastati c CUP i s metastases
to the i ngui nal l ymph nodes. Excl udi ng mel anoma, the two most
common hi stol ogi c types ar e uncl assi fi ed car ci noma and squamous
cel l car ci noma. Adenocar ci noma i s rar el y obser ved. In eval uati ng
pati ents wi th i ngui nal metastases, a thor ough i nvesti gati on for the
pr i mar y tumor shoul d i ncl ude exami nati on of the ski n of the l ower
extr emi ti es, per i neum, buttocks, anal canal , and pel vi c r egi on. If
the i ngui nal node i s the sol i tar y ar ea of pr esentati on, exci si on
fol l owed by l ocal radi ati on therapy i s the next pr efer r ed step. For
bul ky bi l ateral adenopathy, neoadjuvant chemotherapy fol l owed by
sur ger y, i ngui nal l ymph node di ssecti on, and radi ati on therapy can
be consi der ed i f ther e ar e
no other si tes of metastati c di sease. These pati ents ar e pr one to
l ymphedema after mul ti modal i ty therapy, so they shoul d be
educated r egar di ng the r i sks and under go tr eatment i f l ymphedema
devel ops.
Peritoneal Carcinomatosis of Unknown

Primary Site
Pati ents wi th per i toneal car ci nomatosi s of unknown pr i mar y si te can
pr esent wi th asci tes, bowel obstr ucti on, or nonspeci fi c
gastr oi ntesti nal symptoms. The two subgr oups i n thi s categor y
i ncl ude (a) pati ents wi th muci n-pr oduci ng adenocar ci noma wi th and
wi thout si gnet r i ng cel l s, and (b) women wi th pr i mar y per i toneal
car ci nomatosi s. Pati ents wi th muci n-pr oduci ng adenocar ci noma
often have mul ti pl e per i toneal i mpl ants, wi th the pr i mar y si te most
l i kel y bei ng the gastr oi ntesti nal tract (i .e., stomach, smal l bowel ,
appendi x, or col on). Pati ents i n thi s gr oup have a poor er pr ognosi s
and r espond poor l y to cur r entl y avai l abl e tr eatment r egi mens.
These pati ents shoul d under go an upper endoscopy and col onoscopy
to eval uate for a gastr oi ntesti nal pr i mar y tumor. If CK 20+ and CK
7 on i mmunohi stochemi cal anal ysi s, the pati ent may have col on
cancer, an aggr essi ve col on cancer r egi men shoul d be used because
of a hi gher chance of r esponse and enhanced sur vi val potenti al .
The second subset i s composed of women wi th pr i mar y per i toneal
car ci nomatosi s. A hi stopathol ogi cal anal ysi s of these pati ents
r eveal s cel l s wi th ser ous papi l l ar y featur es and, on occasi on,
psammoma bodi es. These pati ents may have el evated CA-125 l evel s
but do not have obvi ous ovar i an cancer (on CT pel vi s and
transvagi nal sonography). Several studi es have found that women
who pr esent wi th per i toneal car ci nomatosi s shoul d be tr eated i n a
si mi l ar fashi on to those wi th known advanced ovar i an cancer. Thi s
i ncl udes maxi mal sur gi cal cytor educti on at i ni ti al l apar otomy,
fol l owed by pl ati num-based combi nati on chemotherapy. One study
found a pr ol onged medi an sur vi val of 13 months i n pati ents who had
under gone pacl i taxel and car bopl ati n-based chemotherapy, and 25%
of pati ents had pr ogr essi on-fr ee sur vi val of mor e than 2 year s.
Unknown Primary Tumor With Metastatic

Liver Disease
The sur geon i s occasi onal l y i nvol ved i n the eval uati on of pati ents
who pr esent wi th metastati c l i ver di sease fr om an unknown pr i mar y
tumor. The l i ver tumor may be di scover ed when the pati ent pr esents
wi th symptoms on r outi ne physi cal exami nati on or i nci dental l y on a
radi ol ogi c study such as an abdomi nal sonogram or CT scan.
When pati ents pr esent wi th metastati c l i ver di sease and CUP, the
most common cel l type i s adenocar ci noma (appr oxi matel y 60%
65% ). However, anapl asti c or poor l y di ffer enti ated car ci noma,
smal l -cel l car ci noma, squamous cel l car ci noma, neur oendocr i ne
cancer, and uncl assi fi ed tumor s ar e al so found. The l i kel y pr i mar y
tumor s i ncl ude gastr oi ntesti nal cancer s (i ncl udi ng pancr eati c-bi l i ar y
cancer s), fol l owed by a l ung or br east tumor.
Most pati ents under go a CT scan of the chest, abdomen, and pel vi s;
mammogram (i n women); and an upper endoscopy and col onoscopy
i f suggested by mar ker data or symptoms. The overal l sur vi val of
these pati ents i s usual l y poor (medi an, 7 months),
al though a sur vi val benefi t (appr oxi matel y 12 months) can be seen
i n pati ents who have a good per for mance status and r espond to
chemotherapy.
A subgr oup of pati ents who pr esent wi th CUP and l i ver metastases
have l ow-grade neur oendocr i ne car ci noma. These may be di agnosed
i nci dental l y or when pati ents compl ai n of hor monal symptoms
(di ar r hea, fl ushi ng, or nausea) or pai n. Low-grade neur oendocr i ne
cancer s can r emai n i ndol ent for several year s wi th sl ow pr ogr essi on
and may not need tr eatment for a l ong ti me (hor monal or other ).
Tumor mar ker s, i ncl udi ng ser um chr omograni n, neur on-speci fi c
enol ase, and ur i ne 5-HIAA, may be el evated. If a pati ent has
car ci noi d symptoms, endocr i ne therapy al one for hor mone-r el ated
symptoms wi th somatostati n anal ogs shoul d be used. Speci fi c l ocal
therapi es, such as r i ght hepatectomy or chemoembol i z ati on, or
systemi c therapi es, such as chemotherapy wi th a str eptozoci n +
doxor ubi ci n fl uor ouraci l -based r egi men, ar e i ndi cated i f the
pati ent i s symptomati c wi th l ocal pai n secondar y to gr owth of the
metastasi s or uncontr ol l ed endocr i ne symptoms.
Chemotherapy for Metastatic Cancers of

Unknown Primary Site
Data fr om CUP tr i al s ar e di ffi cul t to i nter pr et because pati ents wi th
CUP ar e a heter ogeneous gr oup. When chemotherapy i s gi ven to
unsel ected gr oups of pati ents wi th metastati c CUP, an overal l 5% to
10% 5-year sur vi val rate can be anti ci pated, wi th medi an sur vi val
i n most studi es between 6 and 13 months. Pati ents wi th favorabl e
subtypes (e.g., per i toneal car ci nomatosi s or l ymph nodepr edomi nant di sease) benefi t fr om chemotherapy. Tradi ti onal l y,
ci spl ati n-based combi nati on chemotherapy r egi mens have been used
to tr eat pati ents wi th CUP. In a phase II study by Hai nswor th et al .,
55 pati ents wi th CUP wer e tr eated wi th pacl i taxel , car bopl ati n, and
oral etoposi de ever y 21 days. Most wer e pr evi ousl y untr eated, wi th
onl y 4 havi ng under gone pr evi ous chemotherapy. The overal l
r esponse rate was 47% , the medi an overal l sur vi val was 13.4
months, and the r egi men was wel l tol erated. Br i asoul i s et al . found
comparabl e r esponse rates and medi an overal l sur vi val i n 77
pati ents wi th CUP wi th pacl i taxel and car bopl ati n and wi thout oral
etoposi de. In thi s study, pati ents wi th nodal or pl eural di sease and
women wi th per i toneal car ci nomatosi s had better r esponse and an
overal l sur vi val of 13 and 15 months, r especti vel y. A phase II
randomi zed tr i al by Cul i ne et al . (the F r ench Study G r oup on
Car ci nomas of Unknown Pr i mar y 01) studi ed 80 pati ents who wer e
randoml y assi gned to r ecei ve ei ther gemci tabi ne + ci spl ati n (G C) or
i r i notecan + ci spl ati n (IC). Seventy-ei ght pati ents wer e assessabl e
for effi cacy and toxi ci ty. Objecti ve r esponses wer e obser ved i n 21
pati ents (55% ) i n the G C ar m and i n 15 pati ents (38% ) i n the IC
ar m. The medi an sur vi val was 8 and 6 months i n the G C and IC
ar ms, r especti vel y (medi an fol l ow-up of 22 months).
Pati ents wi th poor l y di ffer enti ated car ci noma, the possi bl e ger m cel l
equi val ents, have tradi ti onal l y under gone a tr i al of a ci spl ati n-based
r egi men. Pati ents wi th squamous cel l cancer or neur oendocr i ne
cancer have a si gni fi cantl y better r esponse
to chemotherapeuti c agents than do pati ents wi th other tumor
types.
The r ol e of second-l i ne chemotherapy i n CUP i s poor l y defi ned.
Hai nswor th et al . r epor ted data on 39 pati ents tr eated wi th
gemci tabi ne i n a sal vage setti ng (i n most pati ents, di sease had
fai l ed to r espond to a pr evi ous r egi men contai ni ng pl ati num and a
taxane), and onl y 21% of pati ents had ever r esponded to a pr evi ous
therapy. The overal l par ti al r esponse rate was 8% , and 25% of
pati ents had mi nor r esponses or stabl e di sease wi th i mpr oved
symptoms. The medi an ti me to pr ogr essi on for pati ents wi th par ti al
r esponses or stabl e di sease was 5 months, and the tr eatment was
wel l tol erated.
Al though cur e i s an unr eal i sti c goal for many pati ents wi th
metastati c CUP si te, sur geons often ar e i nvol ved i n the pal l i ati ve
car e of such pati ents, i ncl udi ng debul ki ng tumor s causi ng pai n or
obstr ucti on, pl aci ng enteral tubes for decompr essi on, per for mi ng
thoracentesi s for r espi rator y compr omi se fr om pl eural effusi ons, and
admi ni ster i ng radi ati on therapy for pai nful bone metastases.
Pati ents shoul d be offer ed adequate anal gesi cs to ensur e they ar e
comfor tabl e, and both pati ents and thei r fami l i es shoul d be gi ven
adequate emoti onal suppor t and access to r esour ces that opti mi ze
thei r qual i ty of l i fe.
Tr i al s wi th tar geted agents, i ncl udi ng epi der mal gr owth factor
r eceptor anti bodi es, tyr osi ne ki nase i nhi bi tor s, and anti vascul ar
endothel i al gr owth factor anti bodi es (e.g., bevaci z umab), i n
combi nati on wi th cytotoxi c agents, ar e war ranted, and thei r r ol e i n
the tr eatment of CUP wi l l evol ve over the next several year s.
Whenever possi bl e, pati ents wi th CUP who do not bel ong i n a
defi ned subgr oup shoul d be tr eated wi thi n the context of a cl i ni cal
tr i al .
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M.
Edition
> Ta ble o f C o nt e nt s > 1 9 - G e nit o urina ry C a nc e r
19
Genitourinary Cancer
Christopher G. W ood
Colin P.N. Dinney
G l obal cancer stati sti cs r eveal that geni tour i nar y cancer s
r epr esented appr oxi matel y 10.4% of new cancer s di agnosed
wor l dwi de i n 2005. These cancer s occur i n appr oxi matel y 300,000
pati ents wi thi n the Uni ted States each year, and pr ostate cancer i s
now the most common mal i gnancy and second l eadi ng cause of
cancer death i n U.S. men. Recogni z i ng these facts, practi ci ng
physi ci ans r equi r e an essenti al under standi ng of the di agnosi s and
tr eatment of these di seases. In thi s chapter, we r evi ew the cur r ent
management of pr ostate, bl adder, r enal , and testi cul ar neopl asm.
Prostate Cancer
In men, pr ostate cancer i s the most common mal i gnancy and the
second l eadi ng cause of sol i d cancer mor tal i ty. Average mor tal i ty
rates (19901997) ar e esti mated to be 54.1 per 100,000 i n Afr i can
Amer i can mal es and 23.3 per 100,000 i n whi te mal es. Pr ostate
cancer scr eeni ng was i ntr oduced i n the Uni ted States dur i ng the
mi d- to l ate 1980s. Si nce thi s i ntr oducti on, the patter n of di sease
i nci dence has changed. F r om 1988 to 1992, the annual per cent
i ncr ease of pr ostate cancer i nci dence was esti mated at 17.5% per
year. F r om 1992 to 1995, the i nci dence decr eased 10.3% per year.
Thi s decr ease has l evel ed off and fr om 1995 to 1997, the average
annual decr ease i n i nci dence was 2.1% , and the average annual
i nci dence was 149.7 cases per 100,000. These cancer tr ends ar e not
equi val ent between whi tes and Afr i can Amer i cans. Pr ostate cancer
i nci dence among Afr i can Amer i cans has i ncr eased an average of
0.7% annual l y fr om 1990 to 1997. F ur ther mor e, al though the

average annual mor tal i ty rates have decr eased 2.2% per year
(19901997) overal l , Afr i can Amer i cans have onl y exper i enced an
average mor tal i ty rate decr ease of 1.1% per year thr oughout 1990
to 1997.
Pr ostate cancer rar el y occur s befor e age 50 year s, and the i nci dence
i ncr eases thr ough the ni nth decade of l i fe; however, some of thi s
i ncr ease may be attr i butabl e to an i ncr ease i n pr ostate cancer
scr eeni ng i n the l ater decades. It i s esti mated that 30% to 50% of
men ol der than 50 year s have hi stol ogi c evi dence of pr ostate cancer
at autopsy, whi l e at age 75 or ol der, i t i s esti mated that thi s fi gur e
i ncr eases to 50% to 70% .
Many factor s have been pr oposed to be associ ated wi th the
devel opment of pr ostate cancer. The pr esence of an i ntact
hypothal ami c-pi tui tar y-gonadal axi s and advanced age ar e the most
uni ver sal l y accepted r i sk factor s. Mi grati on studi es suppor t a r ol e
for envi r onmental i nfl uences on pr ostate cancer. Hi gher rates of
pr ostate cancer have been found among popul ati ons wi th hi gher
amounts of fat i n the di et. Benefi ci al di etar y associ ati ons
i ncl ude i sofl avonoi ds, l ycopenes, sel eni um, and vi tami n E; however,
addi ti onal pr ospecti ve randomi zed tr i al s ar e needed to confi r m the
benefi ci al effects of these factor s. It i s uncl ear whether the
i ncr eased mor tal i ty rate of pr ostate cancer i n Afr i can Amer i cans i s
due to uni que raci al bi ol ogi cal and geneti c factor s, rather than
di etar y i nfl uences, the exi stence of confoundi ng medi cal comor bi d
condi ti ons, l i festyl e di ffer ences, and/or access to heal th car e i ssues.
Occupati onal exposur e to cadmi um has been associ ated wi th
i ncr eased r i sk of pr ostate cancer, but thi s r el ati onshi p i s not yet
pr oven to be causal .
Evi dence has shown that a man wi th one, two, or thr ee fi r st-degr ee
r el ati ves affected wi th pr ostate cancer has a 2, 5, or 11 ti mes
gr eater r i sk, r especti vel y, of the devel opment of pr ostate cancer
than the general popul ati on. A Mendel i an patter n of autosomal
domi nant transmi ssi on of pr ostate cancer accounts for 43% of
di sease occur r i ng befor e age 55 year s and 9% of al l pr ostate
cancer s occur r i ng by age 85 year s.
Anatomy
The nor mal pr ostate gl and wei ghs 15 to 20 g and i s di vi ded i nto
thr ee major gl andul ar zones. The per ipher al z one consti tutes 70%
of the pr ostate gl and and i s the ar ea pal pated dur i ng di gi tal r ectal
exami nati on (DRE). The ar ea ar ound the ejacul ator y ducts i s cal l ed
the centr al z one and accounts for 25% of the gl and. The tr ansitional
z one compr i ses 5% of the pr ostate gl and ar ound the ur ethra. In a
pathol ogi cal r evi ew of 104 pr ostate gl ands fr om pati ents who
under went radi cal pr ostatectomy, 68% of the cancer s wer e l ocated
i n the per i pheral zone, 24% i n the transi ti onal zone, and onl y 8%
i n the central zone. Al most al l stage A (nonpal pabl e) cancer s i n that
study wer e found i n the transi ti onal zone, the ar ea most suscepti bl e
to beni gn pr ostati c hyper pl asi a, whi ch can be associ ated wi th
ur i nar y symptoms of bl adder neck obstr ucti on.
Screening
Al though good scr eeni ng methods for pr ostate cancer ar e avai l abl e,
contr over sy sur r ounds the concept of scr eeni ng for thi s di sease. It
i s esti mated that l ess than 10% of men wi th pr ostate cancer di e
because of the di sease. Thi s l eads to a l ack of consensus on the
opti mal management of ear l y-stage di sease and to questi ons
r egar di ng the cost effecti veness of a nati onal scr eeni ng effor t for al l
men ol der than 50 year s. Cur r entl y, the Amer i can Cancer Soci ety
r ecommends a DRE and measur ement of pr ostate-speci fi c anti gen
(PSA) star ti ng at age 50 year s. For Afr i can Amer i can men or men
wi th a fami l y hi stor y of pr ostate cancer, scr eeni ng shoul d begi n at
40 year s of age.
Diagnosis
Pati ents wi th l ow-vol ume, cl i ni cal l y l ocal i zed pr ostate cancer ar e
typi cal l y asymptomati c; abnor mal i ti es ar e detected by DRE,
i ncr eased ser um PSA l evel , or both. Advanced pr ostate cancer can
be asymptomati c; pr esent as l ocal symptoms of ur i nar y hesi tancy,
fr equency, and ur gency; or pr esent as systemi c symptoms of wei ght
l oss, fati gue, and bone pai n. Rar el y, neur ol ogi c sequel ae
of i mpendi ng spi nal cor d compr essi on or ur emi a secondar y to
bi l ateral ur eteral obstr ucti on can be found i n the pr esentati on of
advanced cases.
PSA i s a ser i ne pr otease pr oduced by the epi thel i um of the pr ostate.
PSA i s not speci fi c for pr ostate cancer and can be i ncr eased i n
beni gn condi ti ons of the pr ostate such as pr ostati ti s, pr ostati c
i nfar cti on, and pr ostati c hyper pl asi a. It can al so be i ncr eased as a
consequence of r ecent ejacul ati on, and pati ents shoul d be counsel ed
to abstai n fr om sexual acti vi ty for per i ods of up to 1 week pr i or to

PSA scr eeni ng. Transur ethral r esecti on of the pr ostate (TURP) and
pr ostati c needl e bi opsy si gni fi cantl y i ncr ease the ser um PSA l evel
above basel i ne for up to 8 weeks. DRE, cystoscopy, and transr ectal
ul trasound (TRUS) do not al ter ser um PSA to a cl i ni cal l y si gni fi cant
degr ee. The posi ti ve pr edi cti ve val ue of a PSA l evel gr eater than 4
ng per mL for the detecti on of pr ostate cancer i s 34.4% , whi l e the
posi ti ve pr edi cti ve val ue for an abnor mal DRE i s 21.4% . Detecti on
rates demonstrate that DRE and PSA together (5.8% ) ar e super i or
to ei ther DRE (3.2% ) or PSA (4.6% ) al one. F r ee PSA i s a for m of
PSA not conjugated to pr otease i nhi bi tor s i n the ser um. Decr eased
per centage-fr ee PSA (<25% ) i s associ ated wi th pr ostate cancer, and
measur ement of fr ee PSA i s per for med to i mpr ove the speci fi ci ty of
PSA testi ng i n the range of 4 to 10 ng per mL and thus el i mi nate
unnecessar y bi opsi es. The pr i mar y uti l i ty of fr ee PSA i s i n the
pati ents wi th a PSA i n the 4 to 10 ng per mL range wi th a hi stor y of
pr evi ousl y negati ve pr ostati c bi opsi es. In thi s cl i ni cal scenar i o, the
fr ee to total PSA rati o, or al ter nati vel y, compl exed PSA, can be used
to deter mi ne the need for r epeat bi opsi es wi th conti nued el evati on
of the ser um PSA. A l ow fr ee to total PSA rati o (<20% ) i s an
i ndi cati on to r epeat TRUS and bi opsi es of the pr ostate to r ul e out
the pr esence of car ci noma.
TRUS i s per for med usi ng r eal -ti me i magi ng wi th a 7-MHz transducer,
whi ch al l ows both transver se and sagi ttal i magi ng of the pr ostate
gl and. Pr ostate cancer can appear as a hypoechoi c r egi on wi thi n the
pr ostate, al though most exper ts agr ee that thi s i s a nonspeci fi c
fi ndi ng. TRUS can al so be used to measur e the di mensi ons of the
pr ostate gl and to cal cul ate the gl andul ar vol ume.
Lymphati c metastases can be detected by computed tomography
(CT), l ymphangi ography, and magneti c r esonance i magi ng (MRI).
However, the onl y r el i abl e method for stagi ng pel vi c l ymph nodes i s
a pel vi c l ymphadenectomy.
Radi onucl i de bone scan r emai ns the most sensi ti ve test to detect
skel etal metastases. However, i n 1993, Oester l i ng found the yi el d of
a bone scan was 2% i f a pati ent has a PSA l evel l ess than 20 ng per
mL and evi dence of skel etal metastasi s, whi l e no pati ents had a
posi ti ve bone scan wi th a PSA l ess than 8 ng per mL. Ther efor e,
based on thi s data, radi onucl i de bone scans ar e not necessar y for
stagi ng pr ostate cancer pati ents who have a l ow ser um PSA l evel
(<10 ng per mL) and no skel etal symptoms, par ti cul ar l y i n cases of
l ow-grade cancer s. When bone metastases ar e pr esent, 80% ar e
osteobl asti c, 15% ar e mi xed osteobl asti c-osteol yti c, and 5% ar e
osteol yti c. A chest radi ograph i s per for med to detect the pr esence of
pul monar y metastases, whi ch ar e extr emel y rar e.
The di agnosi s of pr ostate cancer i s made by the hi stol ogi c fi ndi ng of
pr ostate cancer i n a pr ostati c bi opsy, i n a pr ostati c needl e
aspi rati on, i n ti ssue obtai ned fr om pr ostatectomy for beni gn
di sease, or i n the bi opsy of a suspi ci ous metastati c focus. In the
past, sextant bi opsi es of the pr ostate wer e consi der ed adequate i n
the pati ent wi th an el evated PSA, wi th si te-speci fi c bi opsi es di r ected
at pal pabl e or ul trasonographi c abnor mal i ti es (hypoechoi c r egi ons).
Mor e r ecent data based on whol e mount step secti oni ng of radi cal
pr ostatectomy speci mens suggest that sextant bi opsi es ar e
i nadequate, i n favor of 10 or 11 cor e strategi es that i ncl ude the
anter i or hor ns of the pr ostate and the transi ti on zone bi l ateral l y.
Adenocar ci noma i s the pr edomi nant cel l type of pr ostate cancer and
i s the onl y type di scussed i n thi s chapter.
Grading and Staging

The G l eason gradi ng system i s the most wi del y used gradi ng system.
It r ecogni zes fi ve hi stol ogi c patter ns of pr ostate cancer, graded on a
scal e of 1 to 5, fr om most di ffer enti ated to l east. The G l eason scor e
i s ar r i ved at thr ough the addi ti on of the pr edomi nant and secondar y
grade patter ns to yi el d a range of tumor G l eason scor es fr om 2 to
10. Pr ostate cancer i s wel l known to be mul ti focal i n natur e, so not
uncommonl y, mul ti pl e bi opsi es fr om a pr ostate may be posi ti ve,
each wi th a r epor ted G l eason scor e. The bi ol ogy of the cancer i s
fr equentl y di ctated by the most aggr essi ve var i ant found i n the
pr ostate.
The bi ol ogi cal behavi or of the tumor can be fur ther categor i zed by
stage, whi ch accounts for tumor vol ume and l ocati on. Pr ostate
cancer typi cal l y spr eads to the pel vi c l ymph nodes, bone, and l ungs.
The 2002 Amer i can Joi nt Commi ttee on Cancer /Inter nati onal Uni on
Agai nst Cancer TNM stagi ng cl assi fi cati on i s shown i n Tabl e 19.1.
Management of Early Disease

In 1987, the Nati onal Cancer Insti tute publ i shed a consensus
statement on the tr eatment of ear l y-stage pr ostate cancer. The
r epor t concl uded: Radi cal pr ostatectomy and radi ati on therapy ar e
cl ear l y effecti ve for ms of tr eatment i n the attempt to cur e tumor s
l i mi ted to the pr ostate for appr opr i atel y sel ected pati ents. What
r emai ns uncl ear i s the r el ati ve mer i t of each i n pr oduci ng l i fel ong
fr eedom fr om cancer r ecur r ence. Pr oper l y desi gned and compl eted
randomi zed tr i al s that eval uate both di sease contr ol and qual i ty of
l i fe after moder n radi ati on therapy compar ed wi th radi cal
pr ostatectomy ar e essenti al . These cr i ter i a have yet to be ful fi l l ed
and pr obabl y never wi l l ; however, ther e appear s to be l i ttl e
di ffer ence i n cl i ni cal and bi ochemi cal outcomes between the two
modal i ti es when si mi l ar pati ent gr oups ar e compar ed.
Surgery
The sur gi cal exci si on of pr ostate cancer by compl ete r emoval of the
pr ostate gl and, semi nal vesi cl es, and ampul l ae of the vasa
defer enti a was fi r st per for med i n the ear l y 1900s. Thi s pr ocedur e,
known as a r adical pr ostatectomy, can be per for med usi ng a
per i neal or r etr opubi c appr oach. Newer, mi ni mal l y i nvasi ve sur gi cal
techni ques such as l apar oscopi c radi cal pr ostatectomy and r obotassi sted l apar oscopi c pr ostatectomy ar e now becomi ng
mor e mai nstr eam, wi th si mi l ar oncol ogi c outcomes to open
techni ques.
Table 19.1. Staging systems for prostate

cancer
Primary tumor clinical (T)
TX
T0
T1
Clinically inapparent tumor not palpable

or visible by imaging
T1a: Tumor incidental histologic finding in
5% or less of tissue resected
T1b: Tumor incidental histologic finding in
more than 5% of tissue resected
T1c: Tumor identified by needle biopsy

because of increased PSA
T2
Tumor confined within the prostate gland

T2a: Tumor involves one-half of one lobe
or less
T2b: Tumor involves more than one-half
of one lobe, but not both lobes
T2c: Tumor involves both lobes
T3
Tumor extends through the prostate

capsule
T3a: Extracapsular extension (unilateral
or bilateral)
T3b: Seminal vesicle invasion
T4
Invasion of bladder neck, rectum,

external sphincter, levator muscles, or
pelvic side wall

NX
N0
N1
Metastasis in regional lymph node or

nodes

MX
M0
M1
Distant metastasis
M1a: Nonregional lymph nodes
M1b: Bone(s)
M1c: Other site(s)
PSA, prostate-specific antigen.

In 1994, Zi ncke et al . r epor ted thei r exper i ence wi th radi cal
pr ostatectomy i n 1,143 pati ents wi th 10- and 15-year cause-speci fi c
sur vi val rates of 90% and 83% and metastasi s-fr ee sur vi val of 83%
and 77% , r especti vel y. Compl i cati on rates ar e l ow. Mor tal i ty i s l ess
than 0.7% and the i nci dence of sever e i nconti nence i s 1.4% . In
1992, Leandr i et al . r epor ted on 620 pati ents and found a 6.9%
ear l y compl i cati on rate, 1.3% l ate compl i cati on rate, and 0.2%
mor tal i ty rate. Sexual potency was mai ntai ned i n
71% i n whom a ner ve-spar i ng techni que was used, and 5%
exper i enced str ess i nconti nence after 1 year. Factor s that pr edi ct
for postoperati ve potency i ncl ude pr eoperati ve er ecti l e functi on,
pati ent age, and number of caver nosal ner ve fi ber s spar ed. Factor s
that i nfl uence conti nence r esul ts i ncl ude ner ve spar i ng, pati ent age,
and obesi ty.
Radiation Therapy
Exter nal -beam radi ati on therapy i s used for the defi ni ti ve tr eatment
of l ocal i zed and r egi onal l y extensi ve pr ostati c adenocar ci noma. At
M. D. Ander son Cancer Center, 60 to 70 G y was gi ven to 114
pati ents wi th l ocal i zed pr ostate cancer as pr i mar y therapy. The 5and 10-year uncor r ected sur vi val rates ar e comparabl e to radi cal
sur ger y (89% and 68% , r especti vel y). In thi s ser i es, ther e was no
di ffer ence i n sur vi val between pati ents wi th stage A and B di sease.
Skel etal metastases wer e the most common si te of r el apse. Ser i ous
compl i cati ons devel oped i n onl y 1.8% of tr eated pati ents. Confor mal
radi ati on therapy and i ntensi ty modul ated radi ati on therapy ar e
cur r entl y used to decr ease adver se l ocal si de effects of radi ati on
therapy and i ncr ease total dosage to the pr ostate. Lar ger doses ar e
used i n sel ect pati ents; however, l onger fol l ow-up i s needed to ful l y
defi ne the r ol e of dose escal ati on. At M. D. Ander son, we
r ecommend radi cal pr ostatectomy for the tr eatment of ear l y-stage
pr ostate cancer i n the pati ent wi th mi ni mal comor bi di ti es, l ess than
70 year s of age. Pr i mar y radi ati on therapy i s r eser ved for pati ents
wi th si gni fi cant comor bi d medi cal i l l nesses or pati ents ol der than 70
year s of age.
Management of Locally Advanced Prostate

Cancer/Lymph Node Metastasis
Local l y advanced pr ostate cancer i nvol ves ar eas outsi de the
pr ostati c capsul e, such as fat, semi nal vesi cl es, l evator muscl es, or
other adjacent str uctur es. Local l y advanced pr ostate cancer i s
associ ated wi th a 53% i nci dence of l ymph node metastases and
decr eased overal l sur vi val rate compar ed wi th ear l y-stage di sease.
At M. D. Ander son, l ocal l y advanced di sease wi th or wi thout l ymph
node metastasi s i s tr eated wi th pr i mar y radi ati on therapy and
andr ogen abl ati on wi th a 6-year bi ochemi cal fai l ur e rate of 13% .
Longer fol l ow-up i s sti l l needed. These pati ents wi th l ocal l y
advanced di sease at hi gh r i sk for r el apse ar e fr equentl y enr ol l ed i n
cl i ni cal pr otocol s that use neoadjuvant systemi c therapy i n
combi nati on wi th sur gi cal exti r pati on of the pr ostate to i mpr ove
pati ent outcome. Our exper i ence wi th l ocal l y advanced di sease
tr eated wi th pr i mar y radi ati on therapy demonstrated 5-, 10-, and
15-year uncor r ected actuar i al sur vi val rates of 72% , 47% , and
17% , r especti vel y. The l ocal contr ol rate was 75% at 15 year s of
fol l ow-up.
Tr eatment modal i ti es other than radi ati on therapy used for l ocal l y
advanced di sease i ncl ude radi cal pr ostatectomy, TURP, and hor monal
therapy. Tumor grade, stage, bul k of tumor, and semi nal vesi cl e
i nvol vement i n l ocal l y advanced di sease ar e associ ated wi th a
decr eased i nter val between radi cal pr ostatectomy and di sease
pr ogr essi on. The actuar i al 5-year sur vi val rate for pati ents wi th
l ocal l y advanced di sease who have under gone TURP i s 64% ,
maki ng TURP an opti on for pati ents wi th shor t l i fe expectanci es who
have si gni fi cant l ocal symptoms associ ated wi th thei r pr ostate
cancer such as ur i nar y obstr ucti on or i ntractabl e hematur i a. Thi s
strategy may be i deal i n the el der l y and i n those wi th ser i ous
coexi sti ng medi cal pr obl ems.
Systemic Prostate Cancer

Pati ents wi th metastati c pr ostate cancer have a medi an sur vi val
durati on of 30 months, wi th an esti mated 5-year sur vi val rate of
20% . The tr eatment of metastati c pr ostate cancer i s andr ogen
abl ati on therapy. Tr i al s exami ni ng the r ol e of chemotherapy i n
combi nati on wi th andr ogen abl ati ve therapy have not, as yet,
demonstrated an addi ti onal benefi t wi th r egar d to pr ogr essi on-fr ee
or overal l sur vi val when compar ed wi th andr ogen abl ati on al one.
The hypothal amus pr oduces l utei ni z i ng hor mone-r el easi ng hor mone
(LHRH) and cor ti cotr opi n-r el easi ng factor, whi ch sti mul ate the
anter i or pi tui tar y gl and to r el ease adr enocor ti cotr opi c hor mone
(ACTH) and l utei ni z i ng hor mone (LH). LH sti mul ates testoster one
pr oducti on by the testes, and ACTH sti mul ates the adr enal gl ands to
pr oduce andr ostenedi one and dehydr oepi andr oster one, pr ecur sor s of
testoster one and di hydr otestoster one (DHT). Al though the testes
ar e the major sour ce of testoster one, the adr enal gl ands can suppl y
up to 20% of the DHT found i n the pr ostate gl and.
Andr ogen abl ati on therapy consi sts of ei ther bi l ateral or chi ectomy
or LHRH agoni sts, whi ch chr oni cal l y sti mul ate the pi tui tar y gl and,
r esul ti ng i n a decr ease i n LH r el ease. Di r ect LHRH antagoni sts ar e
now al so avai l abl e, but they have not gai ned wi despr ead acceptance
over the agoni sts that have a mor e extensi ve cl i ni cal backgr ound.
Decr ease i n LH l eads to castrate l evel s of testoster one pr oducti on
by the testes, defi ned typi cal l y as l ess than 50 ng per mL. Several
oral anti andr ogens exi st that wor k by bl ocki ng uptake or bi ndi ng of
andr ogen i n tar get ti ssues. Combi nati on of anti andr ogens wi th
ei ther sur gi cal or medi cal andr ogen abl ati on i s ter med total
andr ogen bl ockade.
Bi l ateral or chi ectomy and LHRH agoni sts appear to have equal
effi cacy when used as monotherapy for metastati c pr ostate cancer.
The Medi cal Resear ch Counci l of the Uni ted Ki ngdom per for med a
randomi zed pr ospecti ve tr i al wi th 934 pati ents and found that
i mmedi ate andr ogen abl ati on del ays di sease pr ogr essi on and
decr eases pathol ogi cal fractur es. We r ecommend i mmedi ate
andr ogen suppr essi on for sel ect pati ents. Total andr ogen abl ati on
wi th an LHRH agoni st pl us an anti andr ogen i s contr over si al . Many
studi es have shown no benefi t of combi ned therapy wi th an
anti andr ogen ver sus LHRH agoni st monotherapy. Inter mi ttent
andr ogen therapy has been demonstrated to i mpr ove qual i ty of l i fe,
but i ts l ong-ter m effects on sur vi val ar e unknown. The medi an ti me
to hor mone r efractor y pr ostate cancer i n pati ents wi th metastati c
pr ostate cancer tr eated wi th hor monal therapy i s appr oxi matel y 2
year s. The medi an sur vi val of pati ents wi th hor mone r efractor y
di sease i s on the or der of 12 to 18 months. Chemotherapeuti c
r egi mens ar e the mai nstay of therapy for hor mone r efractor y
pr ostate cancer wi th taxane-based r egi mens showi ng si gni fi cant
acti vi ty that i ncl udes decr eases i n
PSA, i mpr oved qual i ty of l i fe, objecti ve di sease r egr essi on, and
pr ol onged sur vi val . Cl i ni cal tr i al s conti nue to be the mai n and best
tr eatment opti on for pati ents; however, some tr eatment opti ons
(pr i mar i l y taxane-based chemotherapy r egi mens) now exi st that
demonstrate objecti ve benefi t wher e none exi sted pr evi ousl y.
Cl i ni cal r esear ch i s now focused on the effi cacy of mor e tar geted
therapi es that act on speci fi c mol ecul ar pathways i nvol ved i n
metastati c pr ogr essi on i n the management of hor mone r efractor y
di sease.
Bladder Cancer
Bl adder cancer i s the second most common geni tour i nar y
mal i gnancy i n the Uni ted States. It i s the four th most common
cancer i n men and the tenth most common cancer i n women. In
2005, mor e than 50,000 new cases wer e r epor ted, and
appr oxi matel y 12,000 deaths wer e attr i buted to bl adder cancer. The
i nci dence i s l owest i n Afr i can Amer i can femal es (6 per 100,000) and
hi ghest i n whi te mal es (31 per 100,000). Whi te mal es al so have the
hi ghest mor tal i ty rate: 5.8 deaths per 100,000.
The eti ol ogy of ur othel i al cancer s, of whi ch bl adder cancer i s the
most common, i s wel l establ i shed. Ci gar ette smoki ng has been
l i nked to 30% to 40% of al l cases of bl adder cancer. The chemi cal s
1-naphthyl ami ne, 2-naphthyl ami ne, benz i di ne, and 4-ami nobi phenyl
have been shown to pr omote ur othel i al car ci nogenesi s. Wor ker s i n
the texti l e, l eather, al umi num r efi ni ng, r ubber, and chemi cal
i ndustr i es who ar e exposed to hi gh l evel s of these chemi cal s have
an i ncr eased i nci dence of bl adder cancer. Other chemi cal s that have
been l i nked to ur othel i al cancer ar e MBUCCA (pl asti cs i ndustr y),
phenaceti n, and the anti neopl asti c agent cycl ophosphami de. In
addi ti on, r ecur r ent bl adder i nfecti ons, as wel l as i nfecti ons wi th the
parasi te Schistosoma haematobium, have been associ ated wi th
squamous cel l car ci noma of the bl adder.
Pathology
The ur i nar y bl adder i s a hol l ow vi scus that functi ons i n both the
storage and the evacuati on of ur i ne. Hi stol ogi cal l y, the bl adder i s
composed of mucosa, l ami na pr opr i a, muscul ar i s, and ser osa
(l i mi ted to the dome). Local i zed bl adder cancer i s cl assi fi ed as
super ficial disease, whi ch i s l i mi ted to the mucosa and l ami na
pr opr i a, or invasive disease, whi ch extends i nto the muscul ar i s and
beyond. Appr oxi matel y 70% of newl y di agnosed bl adder cancer s ar e
super fi ci al , wher eas the r emai ni ng 30% ar e i nvasi ve or metastati c.
Once a bl adder cancer extends thr ough the basal l ayer of the
mucosa, i t may i nvade bl ood vessel s and l ymphati cs, ther eby
pr ovi di ng a r oute of metastasi s. Car ci noma i n si tu, an aggr essi ve
for m of super fi ci al di sease, i s composed of anapl asti c cel l s l i mi ted to
the mucosal l ayer.
The Wor l d Heal th Or gani z ati on (WHO) cl assi fi es epi thel i al tumor s of
the bl adder i nto four hi stol ogi c types: transi ti onal cel l car ci noma
(TCC) (91% ), squamous cel l car ci noma (7% ), adenocar ci noma (2% ),
and undi ffer enti ated car ci noma (<1% ). However, up to 20% of TCCs
contai n ar eas of squamous di ffer enti ati on, and up
to 7% contai n ar eas of adenomatous di ffer enti ati on. The r emai nder
of thi s secti on di scusses TCC.
Ei ghty per cent of al l pati ents who pr esent wi th bl adder car ci noma
have gr oss or mi cr oscopi c hematur i a, typi cal l y pai nl ess and
i nter mi ttent. Appr oxi matel y 20% of pati ents compl ai n of symptoms
of vesi cal i r r i tabi l i ty, i ncl udi ng ur i nar y fr equency, ur gency, dysur i a,
and strangur i a. Other symptoms i ncl ude pel vi c pai n, fl ank pai n
(fr om ur eteral obstr ucti on), and l ower-extr emi ty edema. Pati ents
wi th systemi c di sease may pr esent wi th anemi a, wei ght l oss, and
bone pai n.
Diagnosis
A pati ent who pr esents wi th hematur i a or other symptoms of
bl adder cancer shoul d under go a thor ough ur ol ogi c eval uati on
consi sti ng of a hi stor y, physi cal exami nati on, ur i nal ysi s, i ntravenous
ur ogram, cystoscopi c exami nati on of the ur i nar y bl adder, and voi ded
ur i ne for cytol ogi c exami nati on. A debate conti nues i n the ur ol ogi c
l i teratur e as to whether a CT scan of the abdomen and pel vi s shoul d
r epl ace the i ntravenous ur ogram i n the wor kup of hematur i a,

par ti cul ar l y wi th the tr emendous r esol uti on seen wi th moder n spi ral
CT scanner s. The most useful of these steps i s the exami nati on of
the bl adder usi ng a r i gi d or fl exi bl e cystoscope. Papi l l ar y and sessi l e
tumor s ar e easi l y vi sual i zed thr ough the cystoscope; car ci noma i n
si tu, however, can appear as nor mal mucosa or as er ythematous
patches thr oughout the bl adder. Fewer than 60% of bl adder tumor s
can be seen on an i ntravenous ur ogram, but thi s exami nati on i s
obtai ned pr i mar i l y to i denti fy other abnor mal i ti es that may be
pr esent i n the upper geni tour i nar y tract. Ur i ne cytol ogy i s r epor ted
as posi ti ve i n 30% of pati ents wi th grade 1 tumor s, 50% of pati ents
wi th grade 2 tumor s, and fr om 65% to 100% of pati ents wi th hi ghgrade tumor s or car ci noma i n si tu (see the next secti on for
defi ni ti on of grades).
Grading and Staging

The WHO uses a gradi ng system based on the cytol ogi c featur es of
the tumor. G rade 1 r epr esents a wel l -di ffer enti ated tumor ; grade 2,
a moderatel y di ffer enti ated tumor ; and grade 3, a poor l y
di ffer enti ated bl adder cancer.
Once a bl adder tumor i s di agnosed, the ur ol ogi st must accuratel y
stage the tumor. The i ni ti al transur ethral r esecti on of the bl adder
tumor (TURBT), typi cal l y done i n associ ati on wi th random bi opsi es
of the bl adder and pr ostati c ur ethra, wi l l deter mi ne the hi stol ogi c
depth of i nvasi on of the tumor and the pr esence or absence of
dyspl asi a or car ci noma i n si tu. A bi manual exami nati on shoul d be
per for med at the ti me of r esecti on to deter mi ne whether a mass i s
pr esent and, i f so, whether i t i s fi xed or mobi l e.
F ur ther wor kup for detecti ng metastasi s consi sts of a CT scan, l i ver
functi on tests, a chest radi ograph, and a bone scan (i f the al kal i ne
phosphatase l evel i s el evated or the pati ent's symptoms suggest
systemi c di sease). Amer i can Joi nt Commi ttee on Cancer
Inter nati onal Uni on Agai nst Cancer TNM stagi ng systems
ar e l i sted i n Tabl e 19.2.
Table 19.2. Staging systems for bladder

cancer

TX
T0
Ta
Noninvasive papillary carcinoma
Tis
Carcinoma in situ
T1
Tumor invades subepithelial connective

tissue
T2
Tumor invades muscle

T2a: Tumor invades superficial muscle
T2b: Tumor invades deep muscle
T3
Tumor invades perivesical tissue

T3a: Microscopically
T3b: Macroscopically (extravesical mass)
T4
Invasion of any of the following: prostate

gland, uterus, vagina, pelvic wall, or
abdominal wall
T4a: Tumor invades prostate, uterus, or
vagina
T4b: Tumor invades pelvic or abdominal
wall
NX
N0
N1
Metastasis in single lymph node 2 cm or

less in the largest dimension
N2
Metastasis in single lymph node greater

than 2 cm in the largest dimension but
less than 5 cm, or multiple lymph nodes,
none larger than 5 cm in greatest
dimension
N3
Metastasis in a lymph node larger than 5

cm in greatest dimension

MX
M0
M1
Distant metastasis
Management
Superficial Bladder Cancer
Appr oxi matel y two-thi r ds of bl adder cancer s pr esent as super fi ci al
di sease (e.g., Ta, T1, or Ti s). An esti mated 70% of these super fi ci al
cancer s ar e Ta and 30% ar e T1. Ten per cent of al l bl adder cancer s
pr esent wi th Ti s or car ci noma i n si tu (CIS). After the i ni ti al
tr eatment of super fi ci al bl adder cancer, the cancer can be cur ed,
can r ecur wi th the same stage and grade, or can r ecur wi th

pr ogr essi on of stage or grade. Ri sk factor s associ ated wi th both
di sease r ecur r ence and pr ogr essi on i ncl ude a hi gh tumor grade,
l ami na pr opr i a i nvasi on, dyspl asi a el sewher e i n the bl adder,
posi ti ve ur i nar y cytol ogy fi ndi ngs, tumor di ameter l ar ger than 5 cm,
vascul ar or l ymphati c i nvasi on, mul ti centr i ci ty, and expr essi on of
ei ther epi der mal gr owth factor or transfor mi ng gr owth factor-al pha.
Mutati ons i n the P53 gene may al so be associ ated wi th a si gni fi cant
r i sk of di sease pr ogr essi on.
Ini ti al tr eatment of super fi ci al bl adder cancer focuses on eradi cati on
of the exi sti ng di sease and pr ophyl axi s agai nst di sease r ecur r ence
or pr ogr essi on. TURBT has been the standar d tr eatment for exi sti ng
stage Ta and T1 tumor s and vi si bl e stage Ti s tumor s. Laser
ful gurati on i s another therapeuti c opti on that r esul ts i n fewer
bl eedi ng compl i cati ons. The advantage of transur ethral r esecti on
over l aser ful gurati on i s that i t pr ovi des ti ssue for hi stol ogi c
exami nati on.
Pati ents wi th Ti s, hi gh-grade Ta or T1 l esi ons, mul ti pl e tumor s,
r ecur r ent tumor s, tumor s l ar ger than 5 cm, or per si stentl y posi ti ve
cytol ogy fi ndi ngs may be candi dates for adjuvant i ntravesi cal
therapy. Intravesi cal agents can be used as therapeuti c, adjuvant,
or pr ophyl acti c tr eatment for bl adder cancer. Thi otepa, mi tomyci n C,
and doxor ubi ci n ar e the chemotherapeuti c agents used most
fr equentl y. Baci l l e Cal mette-G ur i n (BCG ), a l i ve attenuated
tuber cul osi s or gani sm, has become the most wi del y used
i ntravesi cal agent i n super fi ci al bl adder cancer, ei ther al one or i n
combi nati on wi th al pha-i nter fer on. BCG enhances the pati ent's own
i mmune r esponse agai nst the tumor, pr ovi di ng r esi stance to di sease
r ecur r ence and pr ogr essi on. Al though speci fi c dose schedul i ng
var i es, most tr eatment r egi mens i ncl ude i ntravesi cal tr eatment
weekl y for 4 to 8 weeks, fol l owed by an opti onal ser i es of
mai ntenance tr eatments admi ni ster ed over many months. BCG has
been shown to el i mi nate CIS i n 80% of pati ents at a 5-year fol l owup, r educe tumor r ecur r ence rate for pati ents wi th T1 di sease to
30% at 4 year s, and el i mi nate r esi dual tumor i n up to 59% of
pati ents. Mai ntenance therapy r egi mens wi th BCG appear to offer
the best outcomes for pati ents. In 2000, Lamm et al . randomi zed
384 pati ents wi th super fi ci al bl adder cancer to r ecei ve i nducti on and
mai ntenance BCG or just i nducti on BCG therapy onl y. Medi an
r ecur r ence-fr ee sur vi val ti me was l onger for those who r ecei ved
i nducti on and mai ntenance therapy; however, at 5-year fol l ow-up
ther e was no di ffer ence i n sur vi val .

Ther e i s good evi dence that T1 hi gh-grade cancer has a hi gh rate of
pr ogr essi on and ther efor e confer s a hi gh r i sk of death. Ther efor e,
we r ecommend ear l y radi cal cystectomy for sel ect pati ents wi th
hi gh-grade T1 bl adder cancer. F ur ther mor e, we al so r ecommend
cystectomy for pati ents who r ecur despi te an adequate tr i al of BCG
therapy because these pati ents have been shown to be at hi gh r i sk
for di sease pr ogr essi on i f thei r bl adder r emai ns i n si tu.
Invasive Bladder Cancer

Tumor s that have penetrated the muscul ar i s pr opr i a ar e consi der ed
i nvasi ve. Several opti ons ar e avai l abl e for tr eatment of pati ents
wi th i nvasi ve tumor s. A smal l subset of pati ents may be el i gi bl e for
bl adder-spar i ng therapy. In 2001, Her r demonstrated a 76% overal l
sur vi val rate, wi th 57% of the pati ents pr eser vi ng thei r bl adder s i n
45 pati ents tr eated wi th aggr essi ve transur ethral r e-r esecti on of
i nvasi ve bl adder tumor s (medi an
fol l ow-up: 61 months). Pati ents wi th a muscl e-i nvasi ve tumor that
i s pr i mar y and sol i tar y, does not have sur r oundi ng ur othel i al atypi a,
and al l ows for a 2-cm sur gi cal mar gi n may be candi dates for par ti al
cystectomy. At M. D. Ander son, data have shown that appr oxi matel y
5% of pati ents ar e actual l y sui tabl e for bl adder-spar i ng sur ger y; 5year sur vi val rates have been comparabl e to those achi eved wi th
radi cal cystectomy, when negati ve mar gi ns of r esecti on can be
achi eved.
Pr i mar y exter nal -beam radi ati on therapy has been used to tr eat
i nvasi ve bl adder cancer. Tr eatment pr otocol s advocate doses of 65
to 70 G y. F i ve-year sur vi val rates range fr om 21% to 52% for stage
B2 and fr om 18% to 30% for stage C. Local r ecur r ence occur s i n
50% to 70% of these pati ents. Stage T4 l esi ons far e wor se, wi th 5year sur vi val rates consi stentl y l ess than 10% . Our exper i ence at
M. D. Ander son found a 26% 5-year sur vi val rate wi th pr i mar y
exter nal -beam radi ati on. Thus, exter nal -beam radi ati on therapy
may be useful i n pati ents who do not want to have sur ger y or for
whom radi cal sur ger y i s medi cal l y contrai ndi cated; however, the
r esul ts wi th radi ati on therapy, stage for stage, ar e si gni fi cantl y
wor se than those seen wi th radi cal sur ger y.
In an attempt to i mpr ove sur vi val and bl adder pr eser vati on rates,
mul ti modal i ty strategi es have combi ned TURBT, chemotherapy, and
radi ati on. In 1997, Kachni c et al . fr om Massachusetts G eneral
Hospi tal r epor ted on 106 pati ents wi th stages T2 to T4 bl adder

cancer s who wer e tr eated wi th TURBT, two cycl es of MCV, and 40 G y
radi ati on therapy pl us concur r ent ci spl ati n. Overal l 5-year sur vi val
was 52% , and overal l 5-year sur vi val rate wi th the bl adder i ntact
was 43% . These r esul ts ar e comparabl e to contemporar y radi cal
cystectomy ser i es; however, thi s r egi men i nvol ves si gni fi cant
mor bi di ty and pati ent i nvestment i n compl ex tr eatment schedul es.
Mor eover, pati ents ar e subjected to a consi derabl e r i sk of eventual
cystectomy and super fi ci al bl adder cancer r ecur r ence.
Radi cal cystectomy wi th pel vi c l ymphadenectomy i s per for med wi th
the i ntent of r emovi ng al l l ocal i zed and l ymphati c di sease. At M. D.
Ander son, the 5-year actuar i al sur vi val rates for pati ents wi th
i nvasi ve bl adder car ci noma after radi cal cystectomy al one ar e 79%
for stage B, 46% for stage C, 54% for stage D wi th nodal spr ead,
and 32% for stage D wi th vi sceral metastases. The l ocal r ecur r ence
rate i s 7% , and the operati ve mor tal i ty rate i s 1.1% . Four teen
per cent of pati ents under goi ng cystectomy wi th l ymphadenectomy
ar e found to have unsuspected metastases to the pel vi c l ymph
nodes. The major i ty of these cases i nvol ve one or two nodes l i mi ted
to an ar ea bel ow the bi fur cati on of the common i l i ac ar ter i es and
medi al to the exter nal i l i ac ar ter y.
Once a pati ent under goes cystectomy, the ur eter s must be di ver ted
i nto an al ter nate drai nage system. The most common ur i nar y
di ver si on used today i s the or thotopi c ur i nar y di ver si on wi th an
i l eal segment used for bl adder substi tuti on. Catheter i z abl e
cutaneous r eser voi r s ar e al so used as methods of ur i nar y di ver si on
i n sel ected pati ents. Pati ents who ar e unabl e to under go an
or thotopi c di ver si on i ncl ude pati ents wi th el evated ser um
cr eati ni ne, evi dence of l ymph node metastasi s, pr ostati c ur ethral
i nvasi ve TCC or CIS, or i nfl ammator y bowel di sease. F ur ther mor e,
these pati ents must be wi l l i ng and abl e to under go a vi gor ous
voi di ng
r e-educati on pr ogram. Radi ati on therapy may r ender conti nence
di ffi cul t; ther efor e, some pati ents may not benefi t fr om thi s type of
di ver si on. In the end, i f they ar e unabl e to ful fi l l these cr i ter i a,
then a cutaneous i l eal condui t i s r ecommended.
Metastatic Disease
Ci spl ati n appear s to be the si ngl e agent wi th the gr eatest acti vi ty
agai nst TCC of the bl adder ; however, si ngl e-agent therapy r esponse
rates ar e onl y i n the range of 10% to 30% . Tradi ti onal l y,

chemotherapy for bl adder cancer i ncl uded ci spl ati n, methotr exate,
vi nbl asti ne, and doxor ubi ci n (M-VAC). In the M. D. Ander son tr i al of
M-VAC, a compl ete r esponse rate of 35% and a par ti al r esponse rate
of 30% wer e obser ved. Other tr i al s have documented si mi l ar
r esponse rates, wi th medi an sur vi val of appr oxi matel y 1 year. Newer
r egi mens usi ng gemci tabi ne and ci spl ati n have demonstrated no
si gni fi cant di ffer ence i n sur vi val when compar ed wi th M-VAC, but
adver se si de effects and toxi ci ty ar e l ess wi th the newer r egi men.
At M. D. Ander son, adjuvant and neoadjuvant chemotherapy i s used
for sel ect pati ents wi th unfavorabl e di sease character i sti cs.
Unfavorabl e featur es i ncl ude r esected nodal metastases,
extravesi cal i nvol vement, l ymphovascul ar per meati on, or
i nvol vement of pel vi c vi scera. Pr evi ousl y, tr eatment i n sel ect
pati ents wi th adjuvant chemotherapy at M. D. Ander son r esul ted i n
a 70% 5-year sur vi val rate, whi ch i s comparabl e to pati ents wi thout
unfavorabl e featur es. Randomi zed pr ospecti ve tr i al s ar e now bei ng
compl eted to confi r m these r esul ts for neoadjuvant chemotherapy.
Renal Cancer
Tumor s of the r enal and per i r enal ti ssues compr i se 3% of cancer
i nci dence and mor tal i ty i n the Uni ted States. Renal cel l car ci noma
(RCC) r epr esents 85% of al l r enal par enchymal tumor s and i s the
onl y r enal tumor di scussed i n thi s chapter. In 2005, an esti mated
31,500 peopl e wer e di agnosed wi th ki dney cancer, and 12,000
peopl e di ed of thi s di sease. F r om 1975 to 1995, both the i nci dence
and mor tal i ty rates of RCC have i ncr eased. The upwar d tr end i n
mor tal i ty rates suggests that the i ncr eased i nci dental di agnosi s of
ear l y-stage asymptomati c tumor s does not ful l y account for the
overal l i ncr ease i n i nci dence. Mal es ar e affected twi ce as often as
femal es. RCC most fr equentl y occur s i n the fi fth to si xth decades of
l i fe.
Several r i sk factor s have been i denti fi ed to be associ ated wi th RCC.
Case-contr ol studi es have found str ong cor r el ati ons wi th smoki ng
and obesi ty. Hyper tensi on, di abetes mel l i tus, and di ur eti c use have
al so been found to be associ ated wi th RCC; however, i t i s uncl ear
whether thi s i s a causal r el ati onshi p. RCC can occur ei ther
sporadi cal l y or geneti cal l y. Her edi tar y RCC tends to occur at an
ear l i er age of onset and tends to be bi l ateral and mul ti focal . A wel l -
descr i bed fami l i al syndr ome i s von Hi ppel -Li ndau (VHL) di sease,
whi ch i s character i zed by cer ebel l ar hemangi obl astoma, r eti nal
angi omata, bi l ateral RCC, and i sl et cel l tumor s of the pancr eas.
Both sporadi c and VHL di sease types have a common geneti c
mechani sm that i ncl udes l oss of a r egi on
of chr omosome 3. Appr oxi matel y 70% of cl ear cel l r enal cel l
car ci nomas ar e bel i eved to have l oss of the VHL gene ei ther thr ough
mutati on, del eti on, or si l ence by methyl ati on. Her edi tar y
nonpapi l l ar y RCC i s an autosomal domi nant syndr ome associ ated
wi th the same chr omosome 3 abnor mal i ti es, whi l e her edi tar y
papi l l ar y RCC (type 1) i s an autosomal domi nant syndr ome
associ ated wi th abnor mal i ti es of the met gene on chr omosome 7.
Other geneti c RCC syndr omes i ncl ude her edi tar y papi l l ar y RCC (type
2) associ ated wi th mutati ons i n the Kr ebs cycl e enz yme fumarate
hydratase, and Bi r t-Hogg-Dube syndr ome, whi ch i s mani fest as
bi l ateral mul ti focal tumor s wi th both chr omophobe RCC and
oncocytoma hi stol ogy. RCC i s al so associ ated wi th pol ycysti c ki dney
di sease, tuber ous scl er osi s, hor seshoe ki dneys, and acqui r ed r enal
cysti c di sease.
Pathology
Most RCCs or i gi nate i n the pr oxi mal tubul ar cel l s of the ki dney. The
tumor i s mul ti focal i n 6.5% to 10% of cases. The r enal capsul e and
G er ota's fasci a sur r oundi ng the ki dney l i mi t l ocal extensi on of the
tumor. The pr edomi nant cel l type i s cl ear cel l , but granul ar and
spi ndl e-shaped cel l s al so may be pr esent. The tumor cel l s ar e
typi cal l y r i ch i n gl ycogen and l i pi d, gi vi ng the tumor a cl ear cel l
appearance mi cr oscopi cal l y and a character i sti c yel l ow appearance
gr ossl y. Less common pathol ogi es i ncl ude papi l l ar y and
chr omophobe RCC. Uncl assi fi ed RCC i s a waste basket cl assi fi cati on
for tumor s that do not fi t the cr i ter i a of the cl assi cal l y descr i bed
hi stol ogi es. Sar comatoi d di ffer enti ati on, once bel i eved to be a
separate hi stol ogi c cl assi fi cati on, i s now r ecogni zed as a
dedi ffer enti ati on pathway that can occur wi th any hi stol ogy,
i ncl udi ng cl ear cel l , papi l l ar y, and chr omophobe. Oncocytoma i s a
beni gn tumor wi th no mal i gnant potenti al that can be pr obl emati c to
di ffer enti ate fr om chr omophobe r enal cel l car ci noma on needl e
bi opsy.
RCC was tradi ti onal l y cal l ed the i nter ni st's tumor because of i ts
subtl e pr esentati on. Now mor e than 40% of cl i ni cal l y unsuspected

tumor s ar e found i nci dental l y by abdomi nal i magi ng done for other
r easons. G r oss or mi cr oscopi c hematur i a, the most common
pr esenti ng symptom, i s pr esent i n mor e than hal f of pati ents wi th
RCC. The cl assi c too l ate tr i ad of hematur i a, abdomi nal mass, and
fl ank pai n occur s i n appr oxi matel y 19% of pati ents. Paraneopl asti c
syndr omes occur i n 10% to 40% of cases and consi st of pyr exi a,
anemi a, er ythr ocytosi s, hyper cal cemi a, l i ver dysfuncti on (Stauffer
syndr ome), and hyper tensi on. Other symptoms can i ncl ude bone
pai n and central ner vous system abnor mal i ti es because up to 30%
of pati ents pr esent wi th bone and brai n metastases.
Diagnosis
The wor kup of a pati ent wi th the pr ecedi ng symptoms shoul d i ncl ude
a hi stor y, physi cal exami nati on, compl ete bl ood cel l count, ser um
chemi str y panel (i ncl udi ng al kal i ne phosphatase and l i ver functi on
tests), ur i nal ysi s, ur i ne cul tur e, and a contrast-enhanced CT scan.
In most cases, the CT scan wi l l defi ne the natur e of
the mass. If any of the studi es obtai ned suggests i nvol vement of the
r enal vei n or vena cava, an MRI or CT scan wi th thr ee-di mensi onal
r econstr ucti on shoul d be obtai ned to assess the extent of the tumor
thr ombus. In contrast to the management of other r enal tumor s,
RCC may be tr eated sur gi cal l y wi thout pr eoperati ve hi stol ogi c
di agnosi s of the tumor. Bi opsy of a r enal mass i s rar el y i ndi cated
unl ess the radi ographi c character i sti cs of the mass suggest an
eti ol ogy other than RCC, such as l ymphoma, TCC, or a metastasi s
fr om another mal i gnant pr i mar y.
If a mass suggests RCC, a metastati c wor kup consi sti ng of a chest
radi ograph, CT scan (i f not al r eady obtai ned), and l i ver functi on
tests shoul d be per for med. The most common si tes of metastases of
RCC i n decr easi ng or der ar e the l ung, bone, and r egi onal l ymph
nodes. If the pati ent does not have an i ncr eased al kal i ne
phosphatase l evel or skel etal pai n, a bone scan i s usual l y not
r equi r ed. A CT scan of the brai n can be per for med i f ther e i s any
suspi ci on of brai n metastases; however, thi s i s not done r outi nel y i n
the absence of symptoms r eferabl e to the CNS.
Grading and Staging

The most wi del y used gradi ng system for RCC i s the F uhr man
system, whi ch i s based on nucl ear and nucl eol ar mor phol ogy, rated
on a scal e of 1 to 4.
The TNM system i s the most commonl y used for stagi ng i n the
Uni ted States. Pl ease r efer to Tabl e 19.3.
Management
Localized Renal Cell Carcinoma
To date, sur gi cal exci si on r emai ns the onl y pr oven effecti ve
tr eatment of l ocal i zed RCC. In a radi cal nephr ectomy, the ki dney,
i psi l ateral adr enal gl and, and sur r oundi ng G er ota's fasci a ar e al l
r esected en bl oc. Al though no randomi zed study has pr oved i ts
benefi t over si mpl e nephr ectomy, radi cal nephr ectomy has the
theor eti cal advantage of r emovi ng the l ymphati cs wi thi n the
per i nephr i c fat. Up to 20% of pati ents can have evi dence of r egi onal
l ymphati c metastases wi thout di stant di sease, al though the
i nci dence of occul t nodal i nvol vement i s i n the range of 3% to 5% .
The 5-year sur vi val rates for pati ents wi th posi ti ve l ymph nodes
range fr om 8% to 35% ; however, pati ents wi th papi l l ar y hi stol ogy
and node metastases that under go aggr essi ve sur gi cal r esecti on can
enjoy an extended pr ogr essi on-fr ee and overal l sur vi val , i n contrast
to those pati ents wi th nodal metastases fr om cl ear cel l hi stol ogy.
Extended l ymphadenectomy has never been pr oved to be of benefi t
i n pati ents who under go radi cal nephr ectomy, except i n the
pr esence of cl i ni cal l y posi ti ve l ymph nodes, and many sur geons
pr efer a l i mi ted node di ssecti on, whi ch has l i mi ted mor bi di ty, for
pr ognosti c i nfor mati on. Ther e i s cl ear evi dence that al l evi dence of
gr oss di sease shoul d be r emoved, i f feasi bl e, at the ti me of
nephr ectomy.
The sur gi cal appr oach to radi cal nephr ectomy i s deter mi ned by the
si ze and l ocati on of the tumor and the sur geon's pr efer ence. A
modi fi ed fl ank, mi dl i ne, or subcostal (chevr on) i nci si on can be used.
Lar ge upper-pol e tumor s may be appr oached thr ough a
thoracoabdomi nal i nci si on for gr eater exposur e. Because the
i nci dence of i psi l ateral adr enal metastasi s i n l ower-pol e tumor s i s
rar e, not r emovi ng the adr enal gl and at the ti me of nephr ectomy for
a l ower-pol e l esi on i s accepted.
Table 19.3. Staging systems for renal cell
cancer
TX
T0
T1
Tumor 7 cm or less in greatest dimension,

limited to the kidney
T1a: Tumor 4 cm, confined to kidney
T1b: Tumor >4 cm, 7 cm, confined to
kidney
T2
Tumor >7 cm in greatest dimension,

confined to the kidney
T3
Tumor extends into major veins or

invades adrenal gland or perinephric
tissues (perinephric fat or renal sinus),
but not beyond Gerota's fascia
T3a: Tumor invades adrenal gland or
perinephric tissues, but not beyond
Gerota's fascia
T3b: Tumor grossly extends into renal
vein(s) or vena cava below diaphragm
T3c: Tumor grossly extends into vena
cava above diaphragm
T4
Tumor invades beyond Gerota's fascia

NX
N0
N1
Metastasis in single regional lymph node
N2
Metastasis in multiple regional,

contralateral, or bilateral nodes

MX
M0
M1
Distant metastasis
Appr oxi matel y 15% to 20% of RCCs i nvade the r enal vei n, and 8%
to 15% i nvade the vena cava. Invol vement of RCC i n the r enal vei n
usual l y does not pose a si gni fi cant sur gi cal pr obl em. Vena caval
i nvol vement, however, may r equi r e addi ti onal extensi ve pr ocedur es
to compl etel y exci se the tumor. Vena caval thr ombi have been
di vi ded by many author s i nto thr ee gr oups. Type 1 thr ombi (50% )
ar e compl etel y i nfrahepati c, type 2 (40% ) ar e i ntrahepati c, and
type 3 (10% ) extend up i nto the r i ght atr i um of the hear t. In cases
wi th vena caval i nvol vement, i t i s i mperati ve that the sur geon be
fami l i ar wi th techni ques of vascul ar sur ger y, and consi derati on
shoul d be gi ven to consul ti ng wi th a car di othoraci c
sur geon, especi al l y for type 3 thr ombi . Car di opul monar y bypass,
deep hypother mi c ar r est, and venovenous bypass have been used i n
the r esecti on of these l ocal l y advanced tumor s that extend to the
suprahepati c vena cava.
Ther e ar e si tuati ons i n whi ch nephr on-spar i ng sur ger y i s i ndi cated
for pati ents wi th RCC. For exampl e, i n cases of bi l ateral tumor
i nvol vement, r enal i nsuffi ci ency, sol i tar y ki dney, or VHL, a
par enchyma-spar i ng pr ocedur e may be i ndi cated. In thi s pr ocedur e,
the r enal ar ter y i s temporar i l y occl uded, the ki dney cool ed down,
and par ti al nephr ectomy or wedge r esecti on per for med. F r ozen
secti ons of the sur gi cal mar gi ns ar e typi cal l y anal yzed to ensur e
adequacy of r esecti on. After r estorati on of ar ter i al bl ood fl ow, the
r enal capsul e i s cl osed or, al ter nati vel y, per i r enal fat or
bi odegradeabl e hemostati c mater i al i s sutur ed to the defect to
pr omote heal i ng and hemostasi s. F i ve-year sur vi val rates after
par ti al nephr ectomy for pati ents wi th stage I or II di sease ar e
appr oxi matel y 90% and 70% , r especti vel y. Most ur ol ogi c oncol ogi sts
agr ee that par ti al nephr ectomy has demonstrated oncol ogi c
equi poi se wi th radi cal nephr ectomy i n pati ents wi th anatomi cal l y
favorabl e tumor s, even those gr eater than 4 cm.
Al though radi cal nephr ectomy r emai ns the standar d tr eatment i n
pati ents wi th l ocal i zed RCC and a nor mal contral ateral ki dney,
nephr on-spar i ng sur ger y for pati ents wi th a tumor 4 cm or l ess (or
even l ar ger tumor s that ar e anatomi cal l y favorabl e for a par ti al
nephr ectomy appr oach) yi el ds 5-year cancer-speci fi c sur vi val rates
of 92% to 97% . The i nci dence of tumor r ecur r ence wi thi n the r enal
r emnant i s r epor ted to be fr om 0% to 6% . Ther efor e, nephr onspar i ng sur ger y and radi cal nephr ectomy pr ovi de equal l y effecti ve
curati ve tr eatments for si ngl e, smal l , wel l -l ocal i zed tumor s.
Mor e r ecent advances i n the sur gi cal therapy of l ocal i zed RCC have
focused on mi ni mal l y i nvasi ve strategi es. Lapar oscopi c radi cal
nephr ectomy, per for med ei ther thr ough standar d or hand-assi sted
appr oaches, i s rapi dl y becomi ng the gol d standar d for the tr eatment
of pati ents wi th l ocal i zed RCC that i s not amenabl e to nephr onspar i ng appr oaches. Lapar oscopi c par ti al nephr ectomy has al so been
r epor ted wi th some success, al though hemostasi s i ssues, pr ol onged
r enal i schemi a ti mes, and i ncr eased r i sk of posi ti ve mar gi ns have
pr evented thi s mi ni mal l y i nvasi ve techni que fr om bei ng wi del y
assi mi l ated. Mor e r ecent cl i ni cal r esear ch has focused on ener gy
abl ati ve strategi es such as cr yotherapy and radi ofr equency abl ati on,
ei ther thr ough l apar oscopi c or per cutaneous appr oaches, as
strategi es to tr eat the smal l (<4 cm) r enal mass. These ener gy
abl ati ve strategi es sti l l r emai n i nvesti gati onal and shoul d be used
pr i mar i l y i n the setti ng of a cl i ni cal tr i al or for pati ents wher e
sur gi cal therapy i s contrai ndi cated.
Advanced Renal Cell Carcinoma

Appr oxi matel y 40% to 50% of pati ents ei ther pr esent wi th or
devel op metastases dur i ng the cour se of the natural hi stor y of thei r
di sease. The medi an sur vi val for pati ents wi th metastati c RCC i s 12
months. Two randomi zed phase III tr i al s have demonstrated a
si gni fi cant sur vi val benefi t for pati ents who under go cytor educti ve
nephr ectomy pr i or to the admi ni strati on of systemi c therapy i n
those that pr esent wi th metastati c di sease and thei r pr i mar y
tumor i n si tu. The pr esence of nodal metastases, i n the setti ng of
di stant metastati c di sease, por tends a wor se pr ognosi s and
decr eased r esponse to systemi c therapy, whi ch may be al ter ed by
aggr essi ve sur gi cal r esecti on of the nodes at the ti me of
cytor educti ve sur ger y.
Di stant metastati c di sease can be categor i zed as a sol i tar y
metastasi s or bul ky metastati c di sease. Several studi es have shown
hi gher 3-year sur vi val rates, rangi ng fr om 20% to 60% , after
radi cal nephr ectomy wi th r emoval of a sol i tar y metastasi s. Sol i tar y
l ung metastases appear to be associ ated wi th better sur vi val rates
than metastases to other or gan si tes. Mul ti pl e metastases or
mul ti pl e si tes of metastases por tend a si gni fi cantl y wor se pr ognosi s
and ar e usual l y appr oached wi th systemi c therapy opti ons, al though
the benefi t of sur gi cal consol i dati on fol l owi ng maxi mum r esponse to
systemi c therapy has been demonstrated i n metastati c RCC, i n
sel ected pati ents.
Cytotoxi c chemotherapy has been l ar gel y i neffecti ve i n RCC; the
hi ghest objecti ve r esponse rate for si ngl e-agent therapy i s onl y
16% . Mor e r ecentl y, r egi mens wi th gemci tabi ne and capeci tabi ne
have shown si gni fi cant acti vi ty i n sel ected pati ents. Inter l euki n-2
(IL-2) has yi el ded durabl e r esponse rates of 15% to 19% i n var i ous
tr i al s, pr i mar i l y wi th the use of hi gh-dose bol us i ntravenous
r egi mens. Subcutaneous IL-2, ei ther al one or i n combi nati on wi th
i nter fer on, i s bel i eved to be i nfer i or to i ntravenous IL-2 r egi mens,
but associ ated wi th si gni fi cantl y l ess toxi ci ty. Unti l r ecentl y, IL-2
was the gol d standar d of therapy for pati ents wi th metastati c
di sease, but r ecent i nr oads i nto the under standi ng of the mol ecul ar
pathways associ ated wi th r enal cel l car ci nogenesi s and pr ogr essi on
have r esul ted i n the devel opment of speci fi c mol ecul ar tar geted
therapi es that have rapi dl y r epl aced IL-2 i n the ar mamentar i um of
the oncol ogi st. Just thi s year, two tyr osi ne ki nase i nhi bi tor s,
sorafeni b and suni ti ni b, r ecei ved an F DA i ndi cati on for the
tr eatment of advanced RCC. Pr el i mi nar y r esul ts wi th these agents

demonstrate i mpr essi ve di sease r esponse rates, acceptabl e toxi ci ty
pr ofi l es, wi th si gni fi cant pr ol ongati on of ti me to di sease pr ogr essi on
and sur vi val i n tr eated pati ents. Other tar geted therapi es that ar e
demonstrati ng acti vi ty i n RCC and hol d pr omi se for the futur e
i ncl ude the VEG F i nhi bi tor bevaci z umab, CCI-779, and other s.
Testicular Cancer
Mal i gnant tumor s of the testi s ar e rar e. It i s esti mated that 7,000
cases of testi cul ar cancer wer e di agnosed i n 2005, but onl y 300
men wi l l di e of thi s di sease. Ni nety-fi ve per cent of these tumor s ar e
of ger m cel l or i gi n. Al though testi cul ar tumor s can occur at any age,
speci fi c tumor types tend to occur at di ffer ent ages.
Chor i ocar ci nomas tend to occur between 24 and 28 year s of age,
embr yonal car ci nomas fr om 26 to 34 year s of age, semi nomas fr om
32 to 42 year s of age, and l ymphomas and sper matocyti c semi nomas
after the age of 50 year s.
The most wel l -known eti ol ogi c factor i n the devel opment of
testi cul ar cancer i s cr yptor chi di sm. Between 3% and 11% of al l
cases of testi s cancer occur i n cr yptor chi d testes. Al though trauma
to
the testi s has been l i nked to testi s cancer, ther e i s no evi dence of a
defi ni te r el ati onshi p. G eneti c factor s may al so pl ay a si gni fi cant
r ol e.
Car ci noma i n si tu i s a pr ecur sor of testi cul ar ger m cel l cancer. F i ve
per cent to 6% of men wi th a uni l ateral ger m cel l tumor have CIS i n
the contral ateral testi s, and a ger m cel l tumor wi l l devel op i n 50%
of these men. Other men wi th a hi gh r i sk of CIS ar e i ndi vi dual s wi th
i nter sex, cr yptor chi di sm, i nfer ti l i ty, or an extragonadal ger m cel l
tumor.
Testi cul ar cancer typi cal l y pr esents as a pai nl ess testi cul ar
enl ar gement. Advanced di sease can pr esent as back pai n, fl ank
pai n, or systemi c symptoms. The di ffer enti al di agnosi s i ncl udes
var i cocel e, hydr ocel e, hematoma, epi di dymi ti s, or chi ti s, and
i ngui nal her ni a.
Diagnosis
Al though the di agnosi s i s usual l y evi dent at physi cal exami nati on to
an exper i enced cl i ni ci an, scr otal ul trasound can be useful i n
establ i shi ng the di agnosi s. Any sol i d testi cul ar mass i s consi der ed a
testi cul ar tumor unti l pr oved other wi se. Pati ents wi th testi cul ar
enl ar gement that i s bel i eved to be i nfl ammator y i n natur e
(epi di dymo-or chi ti s) must be r e-exami ned after the i nfecti on has
been tr eated to r ul e out the pr esence of an occul t testi cul ar mass.
Once a testi cul ar tumor i s suspected, the pati ent's l evel s of the
tumor mar ker s al pha-fetopr otei n (AF P) and human chor i oni c
gonadotr opi n (hCG ) shoul d be tested. Fol l owi ng thi s, the pati ent
shoul d under go a radi cal (i ngui nal ) or chi ectomy. Ther e i s no r ol e for
fi ne-needl e aspi rati on or Tr u-cut bi opsy i n the wor kup of thi s
di sease.
After radi cal or chi ectomy, a CT scan of the chest, abdomen, and
pel vi s shoul d be per for med. If they wer e i ni ti al l y el evated, tumor
mar ker s shoul d be r eanal yzed fol l owi ng or chi ectomy, after al l owi ng
the appr opr i ate ti me for each mar ker to r etur n to basel i ne. Thi s
woul d be appr oxi matel y 1 week for hCG and 5 weeks for AF P.
Staging
The Amer i can Joi nt Commi ttee on Cancer and Inter nati onal Uni on
Agai nst Cancer TNM testi cul ar cancer stagi ng system i s outl i ned i n
Tabl e 19.4. In ter ms of bi ol ogi cal behavi or and therapy, testi cul ar
tumor s can be categor i zed as semi nomatous or nonsemi nomatous
ger m cel l tumor s (NSG CTs). Semi nomas ar e radi ati on-sensi ti ve and
chemosensi ti ve tumor s that under go l ymphati c spr ead i n an or der l y
fashi on. In contrast, NSG CTs ar e l ess radi ati on sensi ti ve and have a
hi gher metastati c potenti al than semi nomas.
Management
Seminomatous Germ Cell Tumors
After radi cal or chi ectomy, stage I and IIA semi nomas ar e typi cal l y
tr eated wi th radi ati on therapy to the i psi l ateral i l i ac and per i aor ti c
ar eas up to the l evel of the di aphragm after radi cal or chi ectomy.
Usi ng radi ati on therapy, the cur e rate for stage I
di sease appr oaches 100% . Al though 10% to 15% of pati ents wi th

stage IIA di sease have r el apses, mor e than hal f of these r espond
successful l y to sal vage therapy, yi el di ng a sur vi val rate of 95% for
pati ents wi th stage IIA di sease.

Cancer/ International Union Against Cancer
Systems for Testicular Cancer
pTX
pT0
No evidence of primary tumor (scar in

testis)
pTis
Intratubular germ cell neoplasia

(carcinoma in situ)
pT1
Tumor limited to the testis and

epididymis and no vascular/lymphatic
invasion
Tumor may invade into the tunica
albuginea but not the tunica vaginalis
pT2
Tumor limited to the testis and

epididymis with vascular/lymphatic
invasion or tumor invading into the
tunica albuginea with involvement of the
tunica vaginalis
pT3
pT4
Tumor invades the spermatic cord with

or without vascular/lymphatic invasion
Tumor invades the scrotum with or
without vascular/lymphatic invasion

NX

assessed
N0
N1
Lymph node mass 2 cm or less in

greatest dimension; or multiple lymph
nodes masses, none more than 2 cm in
greatest dimension
N2
Lymph node mass, more than 2 cm but

not more than 5 cm in greatest
dimension; or multiple lymph node
masses, any one mass greater than 2 cm
but not more than 5 cm in greatest
dimension
N3
Lymph node mass more than 5 cm in

greatest dimension

MX
M0
No distant metastases
M1
Presence of distant metastases

M1a: Nonregional nodal or pulmonary
metastases
M1b: Distant metastases other than to
nonregional lymph nodes and lungs
Serum tumor markers
Stage
LDH
hCG
(mIU/mL)
AF P
(ng/mL)
S0
Nor mal
S1
<1.5
Nor mal
<5,000
<1,000
S2
1.510
Nor mal
5,000
50,000
1,000
10,000
S3
>10
Nor mal
>50,000
>10,000
pTi s
N0
M0
S0
IA
T1
N0
M0
S0
IB
T2T4
N0
M0
S0
Stage 0
Stage I
IS
Any T
N0
M0
S1S3
Stage II
IIA
Any T
N1
M0
S0S1
IIB
Any T
N2
M0
S0S1
IIC
Any T
N3
M0
S0S1
Stage III
IIIA
Any T
Any N
M1
S0S1
IIIB
Any T
Any N
M0
M1
S2
IIIC
Any T
Any N
M0
M1
S3
LDH, lactic dehydrogenase; hCG, human

chorionic gonadotropin; AFP, alpha-fetoprotein.
Stage IIB or III di sease i s usual l y tr eated wi th ci spl ati n- or
car bopl ati n-based chemotherapy. Sur ger y i s general l y r eser ved for
l ymphati c di sease that does not r espond to chemotherapy or
radi ati on therapy and i s rar el y per for med i n the setti ng of
metastati c semi noma fol l owi ng radi ati on and/or chemotherapy.
Usi ng thi s appr oach, 5-year di sease-fr ee sur vi val rates of 86% and
92% have been obtai ned for pati ents wi th stages IIB and III
di sease, r especti vel y.
Nonseminomatous Germ Cell Tumors

The opti mal therapy for stage I di sease i s contr over si al ; opti ons
i ncl ude sur vei l l ance, r etr oper i toneal l ymph node di ssecti on
(RPLND), and pr i mar y systemi c chemotherapy. Overal l ,
appr oxi matel y 20% to 30% of pati ents wi th stage I di sease who
under go sur vei l l ance exper i ence r el apse. In 1989, Wi shnow et al . at
M. D. Ander son found that pati ents wi th vascul ar i nvasi on i n thei r
tumor, AF P l evel s gr eater than 80 ng per mL, or mor e than 80%
embr yonal el ements i n thei r tumor wer e at hi gh r i sk for r el apse.
Hi gh-r i sk pati ents have been offer ed two cour ses of car bopl ati n,
etoposi de, and bl eomyci n (CEB). Low-r i sk pati ents ar e offer ed
obser vati on. At 30 month's fol l ow-up, no pati ents tr eated wi th CEB
exper i enced r el apse.
The r ecur r ence rate after RPLND for l ow-vol ume stage II di sease i s
l ess than 20% . Thus, both RPLND and pr i mar y systemi c
chemotherapy have been used to tr eat l ow-vol ume r etr oper i toneal
di sease. Sur vi val rates of 97% or better have been associ ated wi th
both for ms of therapy. At M. D. Ander son, pati ents wi th stage II
di sease ar e tr eated wi th pr i mar y chemotherapy, and RPLND i s used
to r emove r esi dual di sease.
Because of the hi gh r ecur r ence rates associ ated wi th RPLND for
stage IIB, IIC, and III NSG CTs, pr i mar y systemi c chemotherapy i s
the tr eatment of choi ce for thi s di sease. RPLND i s used to r emove
any r esi dual di sease that may be pr esent after pr i mar y
chemotherapy and to deter mi ne the need for fur ther therapy.
Recent exper i ence wi th chemotherapy for advanced NSG CT at M. D.
Ander son has shown 5-year sur vi val rates of 96% and 76% for l owand hi gh-vol ume stage III di sease, r especti vel y.
Because a major i ty of NSG CTs pr oduce ei ther AF P or -hCG , these
mar ker s ar e hel pful i n moni tor i ng the pati ent for tr eatment
r esponse and r ecur r ent di sease.
Despi te the r el ati vel y ear l y age of onset of testi cul ar cancer, thi s
di sease r emai ns one of the most curabl e cancer s i n humans.
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M.
Edition
> Ta ble o f C o nt e nt s > 2 0 - G y ne c o lo gic C a nc e rs
20
Gynecologic Cancers
Brian M. Slomovitz
Pamela T. Soliman
Judith K. W olf
Sur gi cal oncol ogi sts ar e often consul ted by general obstetr i ci an/
gynecol ogi sts to assi st i n the management of pati ents wi th pr i mar y
gynecol ogi c mal i gnanci es. The sur gi cal oncol ogi st shoul d under stand
the sur gi cal stagi ng pr ocedur es i nvol ved wi th each di sease pr ocess
(i .e., ovar i an, fal l opi an tube, uter i ne, cer vi cal , vul var, and vagi nal ).
Thi s chapter di scusses the basi c pr i nci pl es of gynecol ogi c oncol ogy
so appr opr i ate management can occur when these neopl asms ar e
unexpectedl y encounter ed. Emphasi s i s pl aced on di agnosi s, stagi ng,
and sur gi cal management.
Ovarian Cancer
Ovar i an cancer i s the deadl i est of gynecol ogi c mal i gnanci es. In the
Uni ted States, appr oxi matel y 20,180 new cases wi l l be di agnosed,
and appr oxi matel y 15,310 women wi l l di e i n 2006. Ovar i an cancer s
ar e heter ogeneous, and subtypes ar e defi ned by hi stol ogy. The most
common, and typi cal , i s epi thel i al ovar i an cancer. Other l ess
common subtypes ar e ger m cel l tumor s and sex cor d str omal
tumor s.
Epithelial Ovarian Cancer

Incidence
Epi thel i al ovar i an cancer occur s i n 1 i n 70 women and consti tutes
90% of al l ovar i an cancer s. The medi an age at di agnosi s i s 61
year s. Appr oxi matel y 10% of these cases ar e her edi tar y, and these
ar e transmi tted i n an autosomal domi nant fashi on. Her edi tar y
br east ovar i an cancer syndr ome (BRCA-1 and BRCA-2 mutati ons)
and Lynch syndr ome/her edi tar y nonpol yposi s col or ectal cancer
(HNPCC) (i n whi ch col on, endometr i al , ovar i an, and other cancer s
cl uster i n fi r st- and second-degr ee r el ati ves) ar e known her edi tar y
for ms of ovar i an cancer ; other geneti c mutati ons l i kel y r emai n to be
i denti fi ed.
Risk Factors
Var i ous factor s ar e bel i eved to i ncr ease the r i sk of a woman
devel opi ng epi thel i al ovar i an cancer. These i ncl ude i ncr eased age
(peak age i s 70 year s), nul l i par i ty, ear l y menar che, l ate
menopause, del ayed chi l dbear i ng, and Ashkenaz i Jewi sh descent.
Ear l y studi es suggested an associ ati on wi th fer ti l i ty dr ugs (i .e.,
cl omi phene and gonadotr opi n), but mor e r ecent studi es have not
confi r med thi s l i nk. The use of oral contracepti ves for mor e than 5
year s appear s to pr otect agai nst the devel opment of epi thel i al
ovar i an cancer.
Pathology
Tumor subtypes ar e l i sted i n Tabl e 20.1. The i nci dence of
concomi tant endometr i al car ci noma i s 15% to 30% i n cases
of endometr i oi d ovar i an car ci noma. Cases of synchr onous
appendi ceal and ovar i an muci nous tumor s have al so been r epor ted,
but because i t i s not unusual for appendi ceal cancer to spr ead to
the ovar i es, i t can be di ffi cul t to deter mi ne the tr ue si te of the
pr i mar y di sease.
Table 20.1. Percentage distribution of

epithelial ovarian carcinomas and
percentage that are bilateral, by histologic
subtype
Histologic
Subtype
Percentage
Distribution
Bilaterality
(%)
Serous
46
73
Mucinous
36
47
Endometrioid
33
Clear cell
13
Transitional
Mixed
Undifferentiated
<2
53
Unclassified
<1
Routes of Spread and Sites of Metastasis

Because exfol i ated cel l s tend to assume the ci r cul ator y path of the
per i toneal fl ui d and i mpl ant al ong thi s path, the most common r oute
of metastasi s i s by seedi ng. Epi thel i al ovar i an cancer may al so
metastasi ze to the l ymph nodes, but hematogenous spr ead i s
uncommon.
Clinical Features
Symptoms
The i nter val fr om onset of di sease to di agnosi s i s often pr ol onged
because of a l ack of speci fi c symptoms, and di agnosi s i s often not
made unti l pati ents have di ssemi nated di sease. Appr oxi matel y 65%
of cases ar e stage III or IV di sease at di agnosi s. Symptoms
suggesti ve of ovar i an cancer i ncl ude abdomi nal ful l ness, ear l y
sati ety, wei ght l oss, dyspepsi a, ur i nar y fr equency, consti pati on,
unexpl ai ned pel vi c pai n, and i ncr eased fl atul ence. Pati ents wi th
stage IV di sease and mal i gnant pl eural effusi ons may pr esent wi th a
cough. It i s uncommon for ovar i an cancer to be di agnosed by

abnor mal Papani col aou (Pap) smear r esul ts.
Physical Findings
An adnexal mass noted on r outi ne pel vi c exami nati on and a
pal pabl e fl ui d wave ar e often found i n pati ents wi th advanced-stage
epi thel i al ovar i an cancer. F i ve per cent of pati ents wi th pr esumed
ovar i an cancer have another pr i mar y tumor that has metastasi zed
to the ovar y. The most common pr i mar y cancer s that metastasi ze to
the ovar y ar e br east, gastr oi ntesti nal tract, and other gynecol ogi c
cancer s.
Pretreatment Workup
Car eful physi cal exami nati on, i ncl udi ng pel vi c exami nati on wi th
r ectovagi nal exam, i s r equi r ed. Other components of the
pr etr eatment wor kup i ncl ude cl i ni cal tests (e.g., compl ete bl ood cel l
count, ser um gl ucose, bl ood ur ea ni tr ogen, cr eati ni ne, l i ver
functi on, ser um al bumi n, CA-125 [whi ch i s el evated i n
appr oxi matel y 80% of cases]), chest radi ography, and
mammography. Computed tomography (CT) anal ysi s may hel p
deter mi ne the extent of di sease. Bar i um enema i s useful i n
exami ni ng the col on and can be par ti cul ar l y hel pful i n di sti ngui shi ng
between a pr i mar y ovar i an and pr i mar y col on cancer, whi ch may
pr esent i n the same way.
Staging
The sur gi cal stagi ng schema for epi thel i al ovar i an cancer i s outl i ned
i n Tabl e 20.2.
Treatment
The i ni ti al step i n tr eatment i s sur gi cal cytor educti on wi th
appr opr i ate i ntraoperati ve stagi ng pr ocedur es, i ncl udi ng abdomi nal
and pel vi c cytol ogi c anal ysi s (or col l ecti on of asci tes), car eful
expl orati on of al l abdomi nal and pel vi c str uctur es and sur faces,
total abdomi nal hyster ectomy and bi l ateral sal pi ngo-oophor ectomy
(except i n cases of concer n about fer ti l i ty or of ear l y-stage
di sease), omentectomy, and sel ecti ve pel vi c and para-aor ti c l ymph
node sampl i ng. In pati ents wi th a muci nous tumor or an i nvol ved
appendi x, appendectomy shoul d be per for med. Pr i mar y
cytor educti on i s a key component i n advanced cases because

sur vi val i s di r ectl y cor r el ated to the amount of r esi dual tumor
r emai ni ng. Opti mal tumor r educti ve sur ger y i s l oosel y defi ned as
the di ameter of the l ar gest r esi dual tumor i mpl ant bei ng l ess than 1
cm. If the r esi dual mass i s l ar ger than 1 cm, then cytor educti on i s
deemed subopti mal .
Al though second-l ook l apar otomy or l apar oscopy was r outi nel y
per for med i n the past, i t i s no l onger per for med unl ess r equi r ed as
par t of an i nvesti gati onal tr i al .
After sur gi cal cytor educti on, pati ents shoul d be tr eated wi th
combi nati on pl ati num- and taxane-based chemotherapy. After si x to
ei ght cour ses of chemotherapy, tr eatment deci si ons ar e based on
the pr esence of per si stent di sease or the di sease-fr ee i nter val .
In sel ect cases, ther e may be a r ol e for neoadjuvant (up-fr ont)
chemotherapy fol l owed by an i nter val cytor educti on pr ocedur e. In
pati ents wi th stage IV di sease (i .e., mal i gnant pl eural effusi ons or
i ntrapar enchymal l i ver di sease), neoadjuvant chemotherapy may be
war ranted for those wi th mul ti pl e medi cal comor bi di ti es that
pr ecl ude aggr essi ve sur gi cal debul ki ng or extensi ve di sease that
cannot be opti mal l y r educed (as deter mi ned by CT scan or
di agnosti c l apar otomy or l apar oscopy). The effect of thi s appr oach
on sur vi val , however, i s unpr oven i n pati ents wi th advanced or
bul ky di sease. A cur r ent phase III tr i al i n Eur ope may deter mi ne
whether ther e i s a sur vi val advantage to neoadjuvant chemotherapy
as fi r st-l i ne tr eatment.
Prognostic Factors
Pr ognosti c pathol ogi cal factor s i ncl ude tumor grade (Tabl e 20.3),
hi stol ogi c subtype, tumor grade, and DNA pl oi dy. Cl i ni cal factor s of
pr ognosti c si gni fi cance i ncl ude sur gi copathol ogi cal stage, extent of
r esi dual di sease r emai ni ng after pr i mar y cytor educti on (Tabl e 20.3),
vol ume of asci tes, pati ent age, and pati ent per for mance status.
Pati ents wi th poor per for mance status befor e
tr eatment (Kar nofsky scor e <70% ) have si gni fi cantl y shor ter
sur vi val than do pati ents wi th good per for mance status.
Table 20.2. Surgical staging of epithelial
ovarian cancer
Tumor
Description
Stage
I
Growth limited to the ovaries
IA
Growth limited to one ovary, no

ascites, no tumor on the external
surfaces, intact capsules
IB
Growth in both ovaries, no ascites, no

tumor on the external surfaces, intact
capsules
IC
Stage IA or IB characteristics but

with tumor on the surface of one or
both ovaries, ruptured capsules, or
malignant ascites with positive
peritoneal cytologic results
II
IIA
IIB
Growth involving one or both ovaries

with pelvic extension
Extension and/or metastases to the
uterus and/or tubes
Extension to other pelvic tissues
Stage IIA or IIB characteristics but
with tumor on the surface of one or
IIC
both ovaries, ruptured capsules, or

malignant ascites with positive
peritoneal cytologic results
III

with peritoneal implants outside the
pelvis and/or positive retroperitoneal
or inguinal nodes; superficial liver
metastasis equal to stage III; tumor
limited to the true pelvis but with
histologically proved malignant
extension to the small bowel or
omentum
IIIA
Tumor grossly limited to the true

pelvis with negative nodes but
histologically confirmed microscopic
seeding of abdominal peritoneal
surfaces
IIIB
Tumor involving one or both ovaries

with histologically confirmed implants
of abdominal peritoneal surfaces 2
cm in diameter; negative nodes
IIIC
Abdominal implants >2 cm in

diameter and/or positive
retroperitoneal or inguinal nodes
with distant metastases; positive
cytologic results from pleural effusion
IV
or pathological confirmation of
parenchymal liver metastases
Table 20.3. Five-year survival rates for

patients with epithelial ovarian cancer, by
tumor stage and grade, amount of residual
disease, and disease status
Survival Rate %
Tumor
Stage
All
Grades
Grade
1
Grade 2
Grade
3
I
IA
85
92.5
86
63
IB
69
85
90
79
IC
59
78
49
51
IIA
62
64
65
39
IIB
51
79
43
42
IIC
43
68
46
20
II
III
IIIA
31
58
38
20
IIIB
38
73
42
21
IIIC
18
46
22
14
14
IV
Survival
Rate %
Amount of residual disease after primary
cytoreductive surgery
Microscopic (residual
disease)
4075
Macroscopic (optimal
debulking)
30
Macroscopic (suboptimal
debulking)
Disease status at second look

No evidence of disease
50
Microscopic disease
35
Macroscopic disease
Ovarian Tumors of Low Malignant Potential

These tumor s, someti mes r efer r ed to as bor der l i ne tumor s,
consti tute as many as 5% to 15% of epi thel i al ovar i an
mal i gnanci es. The hi ghest i nci dence i s among whi te women, and the
mean age at di agnosi s i s 39 to 45 year s (appr oxi matel y 10 to 15
year s younger than that for epi thel i al ovar i an cancer ). No r i sk
factor s have been i denti fi ed, and pr egnancy and exogenous
hor mones do not appear to be pr otecti ve. Ther e i s no appar ent
associ ati on wi th fami l y hi stor y.
The most common hi stol ogi c subtypes of ovar i an tumor s of l ow
mal i gnant potenti al (LMP) ar e ser ous and muci nous (Tabl e 20.4).
Di agnosi s r equi r es the absence of frank str omal i nvasi on. Di sti nct
pathol ogi cal featur es that may be associ ated wi th a mor e aggr essi ve
di sease cour se i ncl ude mi cr opapi l l ar y ar chi tectur e, mi cr oi nvasi on,
and i nvasi ve i mpl ants.
Pati ents wi th ovar i an tumor s of LMP, as wel l as those wi th epi thel i al
ovar i an cancer s, pr esent si mi l ar l y. The most common
symptoms ar e l ower abdomi nal pai n or di scomfor t, ear l y sati ety,
dyspepsi a, and a sense of abdomi nal enl ar gement. Ovar i an tumor s
of LMP can al so be i denti fi ed as an adnexal mass on r outi ne pel vi c
exami nati on. The CA-125 l evel s may be el evated i n ser ous tumor s.
Table 20.4. Distribution of ovarian tumors

of low malignant potential, by tumor stage
and histologic type
Histologic Type (%)
Tumor Stage
Serous
I
65
Mucinous
89.5
II
14
III
20
IV
0.5
Compar ed wi th pati ents wi th i nvasi ve epi thel i al ovar i an cancer, i t i s

mor e common for pati ents wi th ovar i an tumor s of LMP to be
di agnosed wi th ear l y-stage di sease. Recommended tr eatment for al l
pati ents i s pr i mar y sur ger y; fer ti l i ty-spar i ng pr ocedur es shoul d be
per for med i n pati ents wi th stage I di sease who desi r e chi l dr en i n
the futur e. Ther e has been no pr oven benefi t to adjuvant therapy i n
tr eati ng thi s cancer, even i n pati ents wi th advanced-stage di sease.
Typi cal l y, these tumor s have an i ndol ent cl i ni cal cour se and may
r ecur after a l ong di sease-fr ee i nter val . Tumor stage i s the most
i mpor tant pr edi ctor of sur vi val (Tabl e 20.5). Secondar y
cytor educti on can be consi der ed i n sel ect pati ents wi th r ecur r ent
di sease.
Ovarian Germ Cell Tumors

Incidence
G er m cel l tumor s ar e the second most common type of ovar i an
tumor. Among per sons 20 year s of age or younger, 70% of ovar i an
tumor s ar e of ger m cel l or i gi n, and one-thi r d of these ar e
mal i gnant. The mean age at di agnosi s i s 19 year s; ger m cel l tumor s
rar el y occur after the thi r d decade of l i fe. Si xty to 75% of cases ar e
stage I at di agnosi s.

patients with ovarian tumors of low
malignant potential, by tumor stage
Tumor Stage Survival Rate (%)
95
II
7580
III
6570
Pathology
The hi stol ogi c subtypes of ger m cel l tumor s and thei r i nci dences ar e
l i sted i n Tabl e 20.6.

G er m cel l tumor s have the same potenti al as epi thel i al ovar i an
tumor s to metastasi ze.
Clinical Features
G er m cel l mal i gnanci es gr ow rapi dl y and ar e often character i zed by
pai n secondar y to tor si on, hemor r hage, or necr osi s. They may al so
cause bl adder, r ectal , or menstr ual abnor mal i ti es. Dysger mi nomas
account for 20% to 30% of mal i gnant ovar i an tumor s di agnosed
dur i ng pr egnancy. Embr yonal car ci nomas may pr oduce estr ogen and
cause pr ecoci ous puber ty.
Pretreatment Workup
Car eful physi cal exami nati on, i ncl udi ng pel vi c exami nati on, i s
r equi r ed. Other components of the pr etr eatment wor kup i ncl ude
cl i ni cal tests (e.g., compl ete bl ood cel l count, ser um gl ucose, bl ood
ur ea ni tr ogen, cr eati ni ne, l i ver functi on, ser um al bumi n) and chest
radi ography. Ser um mar ker s, i ncl udi ng -fetopr otei n, -human
chor i oni c gonadotr opi n (-hCG ), and l acti c dehydr ogenase, shoul d
be measur ed (Tabl e 20.6). The kar yotype shoul d be checked i n
pr emenopausal women wi th an ovar i an mass because the i nci dence
of dysgeni c gonads i s i ncr eased i n pati ents wi th these tumor s.
Staging
The sur gi cal stagi ng cr i ter i a ar e the same as those for epi thel i al
ovar i an cancer (Tabl e 20.2).
Treatment
In general , sur gi cal stagi ng i ncl udes uni l ateral sal pi ngooophor ectomy (i f ther e i s a desi r e to pr eser ve fer ti l i ty), per i toneal
cytol ogy, omentectomy, and sel ecti ve bi opsi es of r etr oper i toneal
l ymph nodes and abdomi nal str uctur es. For pati ents whose di sease
i s i nadequatel y staged, ther e ar e two opti ons: sur gi cal r eexpl orati on and appr opr i ate stagi ng, or i ni ti ati on of chemotherapy
wi thout r e-expl orati on. In most cases, i t i s i mpr udent to del ay
chemotherapy by r e-expl orati on and stagi ng because these tumor s
ar e hi ghl y chemosensi ti ve.
Chemotherapy i s r ecommended for al l pati ents wi th ger m cel l
tumor s, except those wi th stage I tumor s. Chemotherapy shoul d
begi n 7 to 10 days after sur gi cal expl orati on because of rapi d tumor
gr owth. The fi r st-l i ne r egi men i s bl eomyci n, etoposi de, and ci spl ati n
admi ni ster ed for thr ee or four cycl es i n 21-day i nter val s.
Radi otherapy may have a l i mi ted r ol e i n tr eatment of
dysger mi nomas.
Prognostic Factors
The sur vi val rates for i ndi vi dual ovar i an ger m cel l tumor subtypes
ar e l i sted i n Tabl e 20.7. Dysger mi nomas l ar ger than 10 to 15 cm i n
di ameter or wi th a hi gh mi toti c i ndex and anapl asi a ar e
mor e l i kel y to r ecur. Pr ognosti c factor s for i mmatur e teratomas

i ncl ude tumor grade, extent of di sease at di agnosi s, and amount of
r esi dual tumor. The tumor grade of i mmatur e teratomas i s
deter mi ned by the pr esence of i mmatur e neural el ements. Tumor
stage i s al so an i mpor tant pr ognosti c factor for al l ovar i an ger m cel l
tumor s (Tabl e 20.8).
Table 20.6. Clinical features of ovarian ger

tumors, by histologic subtype
T
Ma
Histologic
Subtype
Incidence Bilaterality
(%)
AFP
40
10%15%
of cases
22
Rare;
dermoids
common in
contralateral
ovary
Immature
teratoma
20
Rare;
dermoids
common in
contralateral
ovary
Embryonal
carcinoma
13
Rare
Choriocarcinoma
13
Rare
Polyembryonal
13
Rare
Varies
Dysgerminoma
Endodermal
sinus tumor
Mixed tumor
1015
AFP, -fetoprotein; -hCG, beta subunit of human c

gonadotropin; LDH, lactic dehydrogenase; -, negat
result; , positive/negative result; +, positive resu
Table 20.7. Survival rates for patients with

ovarian germ cell tumors, by histologic
subtype, tumor stage or grade, and time
interval
Histologic Subtype
and Tumor Stage or
Grade
Dysgerminoma
Interval
Survival Rate
(y)
5
Stage I
90%95%
All stages
60%90%
Endodermal sinus
tumor
Stages I and II
90%
Stages III and IV
50%
Immature teratoma
Stage I
90%95%
All stages
70%80%
Grade 1
82%
Grade 2
62%
Grade 3
30%
Embryonal carcinoma
39%
Choriocarcinoma
Low
Polyembryonal
Low
Mixed tumor
Variable;
depends on
tumor
composition
Sex Cord Stromal Tumors

Incidence
Sex cor d str omal tumor s account for 5% to 8% of ovar i an
mal i gnanci es and up to 5% of chi l dhood mal i gnanci es. Occur r ence
befor e menar che i s often associ ated wi th pr ecoci ous puber ty.

patients with ovarian germ cell tumors, by
tumor stage
I
72
II
38
III
18
IV
Table 20.9. Major classifications of sex cord

stromal tumors
Granulosa cell tumors
Adult
Juvenile
Thecomas and fibromas-fibrosarcomas
Stromal tumors with minor sex cord elements
Sertoli stromal cell tumors
Sertoli cell
Leydig cell
Sertoli-Leydig cell
Gynandroblastomas
Sex cord tumors with annular tubules
Unclassified tumors
Pathology
As thei r name suggests, these tumor s ar e der i ved fr om sex cor ds or
str oma. Der i vati ves i ncl ude granul osa cel l s, theca cel l s, str omal
cel l s, Ser tol i cel l s, Leydi g cel l s, and cel l s r esembl i ng embr yoni c
pr ecur sor s of these cel l types (Tabl e 20.9).
The patter n and si tes of metastati c spr ead ar e anal ogous to that of
epi thel i al ovar i an cancer s.
Clinical Features
Granulosa Cell Tumors
G ranul osa cel l tumor s compr i se 1% to 2% of ovar i an tumor s. Adul ttype tumor s (90% to 95% of granul osa cel l tumor s) ar e
character i zed by secr eti on of excess estr ogen. Pati ents may
exper i ence menstr ual i r r egul ar i ti es or postmenopausal bl eedi ng.
F i ve per cent of pati ents pr esent wi th an acute abdomen caused by
tumor hemor r hage. Pati ents wi th juveni l e-type granul osa cel l
tumor s (5% to 10% of granul osa cel l tumor s) can al so pr esent wi th
menstr ual abnor mal i ti es, abdomi nal pai n, and (rar el y)
postmenopausal bl eedi ng. Because granul osa cel l tumor s pr oduce
estr ogen, coexi sti ng endometr i al pathol ogi cal pr ocesses occur i n up
to 30% of pati ents. In rar e cases, these tumor s may pr oduce
testoster one and cause some vi r i l i z i ng featur es.
Thecomas
Thecomas ar e one-thi r d as common as granul osa cel l tumor s. The
mean age at di agnosi s i s 53 year s, and 2% to 3% of these tumor s
ar e bi l ateral . Menstr ual abnor mal i ti es and postmenopausal bl eedi ng
ar e the most common pr esenti ng symptoms. Thecomas al so pr oduce
estr ogen.
Fibromas and Fibrosarcomas

F i br omas and fi br osar comas ar e the most common sex cor d str omal
tumor s and consti tute 4% of ovar i an neopl asms. The mean age at
di agnosi s i s 46 year s. Ten per cent of these l esi ons ar e bi l ateral .
Symptoms i ncl ude asci tes i n 50% of pati ents wi th tumor s l ar ger
than 6 cm i n di ameter, i ncr eased abdomi nal gi r th, Mei gs syndr ome
(r i ght pl eural effusi on and asci tes), and G or l i n syndr ome wi th basal
nevi . These tumor s ar e pr i mar i l y i ner t but may secr ete smal l
amounts of estr ogen.
Sertoli Cell Tumors

The average age at di agnosi s of Ser tol i cel l tumor s i s 27 year s, but
these tumor s can occur at any age. Ser tol i cel l tumor s ar e
uni l ateral . Seventy per cent of pati ents have symptoms r el ated to
excess estr ogen, wher eas 20% exhi bi t si gns of vi r i l i z ati on. Rar el y,
hyperal doster onemi a mani fested as hyper tensi on and hyper kal emi a
may devel op. Seventy per cent of these tumor s pr oduce both
estr ogen and andr ogens, wher eas 20% pr oduce andr ogens al one.
Leydig Cell Tumors

Leydi g cel l tumor s occur at an average age of 50 to 70 year s but
can occur at any age. These tumor s ar e often uni l ateral . Ei ghty
per cent pr oduce andr ogens and 10% pr oduce estr ogen, whi ch often
r esul ts i n hor monal l y r el ated si de effects. Leydi g cel l tumor s ar e
often associ ated wi th thyr oi d di sease and may be her edi tar y.
Sertoli-Leydig Cell Tumors

Ser tol i -Leydi g cel l tumor s occur at an average age of 25 to 40 year s
but can occur at any age. These tumor s ar e rar el y bi l ateral .
Symptoms i ncl ude amenor r hea, and vi r i l i z ati on may occur i n up to
50% of pati ents. Most of these tumor s pr oduce testoster one, and
some may pr oduce -fetopr otei n.
Gynandroblastomas
G ynandr obl astomas ar e uni l ateral tumor s that can occur at any age.
Pati ents may exper i ence estr ogeni c effects or vi r i l i z ati on secondar y
to the hor mone pr oducts of these tumor s. Hi stol ogi cal l y, both
granul osa cel l and Ser tol i -Leydi g cel l components may be pr esent i n
these tumor s. These tumor s may pr oduce andr ogens or estr ogen, or
they may be i ner t.
Sex Cord Tumors With Annular Tubules

The average age of pati ents wi th sex cor d tumor s wi th annul ar
tubul es i s 25 to 35 year s. These tumor s may be associ ated wi th
Peutz-Jegher s syndr ome, and i n these cases, 66% ar e bi l ateral and
most pr oduce estr ogen. Among those that occur i n women wi thout
Peutz-Jegher s syndr ome, onl y 40% pr oduce excess estr ogen. These
tumor s ar e al so associ ated wi th endocer vi cal adenocar ci nomas.
Pretreatment Workup
ur ea ni tr ogen, cr eati ni ne, l i ver functi on, ser um al bumi n, CA-125),

chest radi ography, and mammography. Eval uati on of ser um
concentrati ons of estradi ol , dehydr oepi andr oster one, testoster one,
17-OH-pr ogester one, and hydr ocor ti sone may be hel pful i n
di agnosi s. CT and ul trasonography shoul d be per for med to eval uate
the adr enal gl ands and ovar i es. Al though i magi ng studi es may be
hel pful , they do not often change the pl anned stagi ng pr ocedur e.
Staging
In general , sur gi cal stagi ng of sex cor d str omal tumor s can be
accompl i shed by uni l ateral sal pi ngo-oophor ectomy (i f ther e i s a
desi r e to mai ntai n fer ti l i ty), per i toneal cytol ogy, i nfracol i c
omentectomy, sel ecti ve bi opsi es of nodes and abdomi nal str uctur es,
and appr opr i atel y tar geted bi opsi es. If a hyster ectomy i s not
per for med at the ti me of sur ger y, di l atati on and cur ettage
and endocer vi cal cur ettage shoul d be per for med to eval uate any
coexi stent pathol ogi cal pr ocesses. These tumor s ar e sur gi cal l y
staged accor di ng to the cr i ter i a used for epi thel i al ovar i an cancer
(Tabl e 20.2).

patients with sex cord stromal tumors, by
histologic subtype
Histologic Subtype
Survival Rate
Granulosa cell tumor

Tumors confined to
the ovary
85%90%
Tumors with
extraovarian
extension
55%60%
Sertoli or Leydig cell

tumor with poor
differentiation
Low
Other tumors of sex

cord stromal origin
Consistent with benign

processes and low-grade
malignancies
Treatment
Tumor s of str omal or i gi n (i .e., thecomas and fi br omas) and Leydi g
cel l tumor s general l y fol l ow a beni gn cour se; sur ger y i s the onl y
tr eatment. Ser tol i cel l or granul osa cel l tumor s ar e general l y of l ow
mal i gnant potenti al , tend to r ecur l ate, and rar el y metastasi ze.
Chemotherapy shoul d be consi der ed for advanced di sease.
Postoperati ve adjuncti ve therapy wi th bl eomyci n, etoposi de, and
ci spl ati n or other pl ati num-based chemotherapy shoul d be
consi der ed i n pati ents wi th Ser tol i cel l or Leydi g cel l tumor s wi th
poor di ffer enti ati on and heter ol ogous components and i n pati ents
wi th advanced or r ecur r ent str omal tumor s; pel vi c radi ati on therapy
can al so pl ay a r ol e i n tr eatment of these pati ents. Sur vi val rates
ar e descr i bed i n Tabl e 20.10.
Management of Incidental Cancers Found at

Laparotomy
The fi ndi ng of an unsuspected ovar i an mass at the ti me of
expl orator y l apar otomy or at l apar otomy for an unr el ated condi ti on
can pose a therapeuti c di l emma to the sur geon. Appr opr i ate
tr eatment depends on several factor s, i ncl udi ng the pati ent's age,
the si ze and consi stency of the mass, possi bl e bi l ateral i ty, and gr oss
i nvol vement of other str uctur es. Infor med consent i s a key
component to the deci si on maki ng. Unl ess ther e i s a l i fethr eateni ng si tuati on, a hyster ectomy and bi l ateral sal pi ngooophor ectomy shoul d be per for med onl y wi th pr oper i nfor med
consent, especi al l y i n women of chi l dbear i ng age.
Ovarian Mass in Premenopausal Women
An unsuspected mass i n a young pati ent i s most l i kel y beni gn. The
most fr equentl y found beni gn masses i nvol vi ng the adnexa ar e
functi onal cysts, whi ch ar e r el ated to the pr ocess of ovul ati on.
These cysts ar e si gni fi cant pr i mar i l y because they cannot be easi l y
di sti ngui shed fr om tr ue neopl asms on cl i ni cal gr ounds al one. If
ovul ati on does not occur, a cl ear, fl ui d-fi l l ed fol l i cul ar cyst up to 10
cm i n di ameter
may devel op. Thi s fol l i cul ar cyst usual l y r esol ves spontaneousl y
wi thi n several days to 2 weeks. Ovul ati ng women can al so pr esent
wi th functi onal ovar i an cysts. These ar e usual l y asymptomati c but
can cause l ower abdomi nal or pel vi c pai n; si gns of an acute
abdomen ar e rar e. The cor pus l uteum, whi ch i s for med dur i ng
ovul ati on, may become abnor mal l y l ar ge i f ther e i s hemor r hage
wi thi n i t. A pati ent wi th a hemor r hagi c cor pus l uteum may pr esent
wi th an acute abdomen, whi ch necessi tates l apar otomy. Often the
bl eedi ng ar ea may be over sewn wi thout the need for r emoval of the
cyst, fal l opi an tube, or ovar y.
Si mpl e cysts up to 5 cm i n di ameter may be found i nci dental l y at
the ti me of sur ger y. These can often be obser ved safel y i n women
who ar e i n thei r r epr oducti ve year s. If i t i s a functi onal cyst, i t
shoul d r esol ve after the pati ent's next menstr ual per i od. Resol uti on
can be eval uated wi th physi cal exami nati on al one or i n conjuncti on
wi th pel vi c ul trasonography. F uncti onal cysts ar e mor e common i n
pati ents who have anovul ator y cycl es, such as women who ar e
obese or those who have pol ycysti c ovar i an syndr ome.
Der moi d cysts, or beni gn cysti c teratomas, ar e the most common
ovar i an tumor s i n women i n the second and thi r d decades of l i fe.
These cysti c masses may be of any si ze, and up to 15% ar e
bi l ateral . Tor si on i s the most fr equent compl i cati on and commonl y
occur s i n chi l dr en, young women, and pr egnant women. Sever e
acute abdomi nal pai n i s usual l y the i ni ti al symptom, and thi s
condi ti on consti tutes an emer gency. Tr eatment i s cystectomy and
cl ose i nspecti on of the other ovar y, and i s usual l y possi bl e even for
l ar ge l esi ons.
Other common beni gn neopl asms that occur i n young pati ents ar e
ser ous and muci nous cystadenomas. These ar e tr eated wi th
uni l ateral sal pi ngo-oophor ectomy i f the other ovar y appear s nor mal .
Endometr i omas, whi ch ar e al so cal l ed chocol ate cysts of
endometr i osi s, can al so occur i n young women. These pati ents may
have a hi stor y of endometr i osi s or chr oni c pel vi c pai n. Often, other
endometr i osi s i mpl ants may be seen i n the pel vi s or abdomi nal
cavi ty; thi s fi ndi ng may be hel pful i n establ i shi ng the di agnosi s. The
tr eatment of endometr i omas may be cystectomy or uni l ateral
oophor ectomy and depends on the degr ee of the r emai ni ng nor mal appear i ng ovar i an ti ssue. Ever y effor t shoul d be made to sal vage
the nor mal -appear i ng por ti on of ovar y.
If asci tes i s pr esent on openi ng of the abdomen, i t shoul d be
evacuated and submi tted for cytol ogi c anal ysi s. After car eful
i nspecti on and pal pati on, i f the ovar i an mass appear s to be confi ned
to one ovar y and mal i gnancy i s suspected, uni l ateral sal pi ngooophor ectomy i s appr opr i ate i n most ci r cumstances. If the mass i s
bel i eved to be beni gn, ovar i an cystectomy may be pr eferabl e. The
ovar i an capsul e shoul d be i nspected for any evi dence of r uptur e,
adher ence, or excr escence. Once r emoved, the ovar i an speci men
shoul d be sent for fr ozen-secti on exami nati on. If mal i gnancy i s
di agnosed, sur gi cal stagi ng shoul d be per for med. Thi s shoul d
i ncl ude bi opsi es of the omentum, per i toneal sur faces of the pel vi s
and upper abdomen, and r etr oper i toneal l ymph nodes (i ncl udi ng
both the para-aor ti c and the bi l ateral pel vi c r egi ons).
If the contral ateral ovar y appear s nor mal , random bi opsy or wedge
r esecti on i s pr obabl y not i ndi cated because i t may i nter fer e wi th
futur e fer ti l i ty due to per i toneal adhesi ons or ovar i an fai l ur e. If the
hi stol ogi c di agnosi s i s questi onabl e at the ti me sampl es ar e taken
for fr ozen secti on, i t i s al ways pr eferabl e to wai t for per manent
secti on r esul ts befor e pr oceedi ng wi th a hyster ectomy and bi l ateral
sal pi ngo-oophor ectomy i n a young pati ent. G eneral cr i ter i a for
conser vati ve management i ncl ude young pati ents desi r ous of futur e
chi l dbear i ng; pati ent and fami l y consent and agr eement to cl ose
fol l ow-up; no evi dence of dysgeneti c gonads; any uni l ateral
mal i gnant ger m cel l , str omal , or bor der l i ne tumor ; and stage IA
i nvasi ve epi thel i al tumor.
Advances i n assi sted r epr oducti on have gr eatl y i nfl uenced
i ntraoperati ve management deci si ons. Tradi ti onal l y, i f a bi l ateral
sal pi ngo-oophor ectomy i s i ndi cated, a hyster ectomy has al so been
per for med. Cur r ent technol ogy for donor oocyte transfer and
hor monal suppor t, however, al l ow a woman wi thout ovar i es to
sustai n a nor mal i ntrauter i ne pr egnancy. Si mi l ar l y, i f the uter us and
one tube and ovar y ar e r emoved because of tumor i nvol vement,
cur r ent techni ques al l ow for r etr i eval of oocytes fr om the pati ent's
r emai ni ng ovar y, i n vi tr o fer ti l i z ati on wi th sper m fr om her par tner,
and i mpl antati on of the embr yo i nto a sur r ogate's uter us.
Ovarian Mass in Postmenopausal Women

The r i sk of an ovar i an mass bei ng mal i gnant begi ns to i ncr ease at
40 year s of age and r i ses steadi l y ther eafter. Ther efor e, the fi ndi ng
of an unsuspected ovar i an mass i n a postmenopausal woman i s mor e
omi nous. The most common mal i gnant neopl asms i n thi s age gr oup
ar e mal i gnant epi thel i al tumor s; ger m cel l and str omal cel l tumor s
rar el y occur. Beni gn l esi ons, such as epi thel i al cystadenomas and
der moi d cysts, can sti l l occur i n thi s popul ati on, al though they do so
much l ess fr equentl y than i n younger pati ents. Tr eatment of an
unanti ci pated ovar i an mass i n a postmenopausal pati ent i ncl udes
sal pi ngo-oophor ectomy and fur ther stagi ng i f the fr ozen secti on
r eveal s a di agnosi s of cancer. Appr opr i ate stagi ng bi opsi es shoul d
al so be per for med. A gynecol ogi c oncol ogi st shoul d be consul ted.
Laparoscopy for the Management of Ovarian

Cancer
Lapar oscopy has been wi del y used as the standar d sur gi cal appr oach
for beni gn and suspi ci ous adnexal masses. The r ol e of l apar oscopy
i n the tr eatment of ovar i an cancer i s l ess cl ear, but some studi es
have suggested that i t can be used safel y at the ti me of second-l ook
sur ger y or to stage and tr eat pati ents wi th ear l y ovar i an cancer. The
r ol e of l apar oscopy i n tr eati ng ovar i an cancer sti l l needs to be
defi ned, al though l apar oscopi c sur ger y i s associ ated wi th
si gni fi cantl y l ess mor bi di ty than l apar otomy.
Fallopian Tube Cancer

Incidence
Fal l opi an tube cancer accounts for 0.1% to 0.5% of gynecol ogi c
mal i gnanci es. The average age at di agnosi s i s 55 year s.
Risk Factors
No known r i sk factor s exi st for the devel opment of thi s di sease.
Pathology
The most common hi stol ogi c subtype i s adenocar ci noma, and the
most common tumor s of the fal l opi an tube ar e metastati c l esi ons
fr om other si tes. To establ i sh a di agnosi s of pr i mar y fal l opi an tube
cancer, Hu's cr i ter i a must be met: The mai n tumor must be i n the
fal l opi an tube, the mucosa shoul d be i nvol ved mi cr oscopi cal l y and
exhi bi t a papi l l ar y patter n, and the transi ti on between beni gn and
mal i gnant tubal epi thel i um shoul d be demonstrated i f the tubal wal l
i s si gni fi cantl y i nvol ved wi th the tumor.

Fal l opi an tube cancer metastasi zes i n a manner si mi l ar to that of
epi thel i al ovar i an cancer. Lymphati c spr ead tends to pl ay mor e of a
r ol e i n fal l opi an tube cancer, l i kel y because of the pr esence of
par ti cul ar l y extensi ve l ymphati cs i n the fal l opi an tubes. One-thi r d
of pati ents wi th fal l opi an tube cancer exhi bi t evi dence of nodal
metastases.
Clinical Features
The cl assi c tr i ad of pr i mar y fal l opi an tube cancer i s water y vagi nal
di schar ge, pel vi c pai n, and a pel vi c mass. However, thi s tr i ad i s
pr esent i n l ess than 15% of pati ents. Water y di schar ge and vagi nal
bl eedi ng ar e the most commonl y r epor ted symptoms.
Pretreatment Workup
ur ea ni tr ogen, cr eati ni ne, l i ver functi on, ser um al bumi n, CA-125),
chest radi ography, and mammography. Imagi ng studi es may be
hel pful but usual l y do not change the pl anned stagi ng pr ocedur e. CT
may hel p deter mi ne the extent of di sease. Bar i um enema i s useful
i n exami ni ng the col on. It can al so be par ti cul ar l y hel pful i n
di sti ngui shi ng a col oni c pr i mar y i n ol der pati ents fr om ei ther
fal l opi an tube or ovar i an cancer, whi ch may pr esent wi th si mi l ar
symptoms. Intravenous pyel ography i s al so hel pful i n cer tai n cl i ni cal
si tuati ons.
Staging
Ther e i s no offi ci al Inter nati onal Federati on of G ynecol ogy and
Obstetr i cs (F IG O) stagi ng system for fal l opi an tube cancer. By
conventi on, the sur gi cal stagi ng cr i ter i a used for epi thel i al ovar i an
cancer i s used (Tabl e 20.2).
Treatment
Tr eatment of fal l opi an tube cancer i s anal ogous to that of epi thel i al
ovar i an cancer.
Prognostic Factors
It i s di ffi cul t to deter mi ne the pr ognosti c factor s speci fi c to fal l opi an
tube cancer because thi s di sease i s rar e, but they ar e l i kel y
si mi l ar to those of epi thel i al ovar i an cancer. The overal l 5-year
sur vi val rate i s esti mated to be 40% , whi ch i s hi gher than the 5year sur vi val rate for pati ents wi th epi thel i al ovar i an cancer. Thi s
di ffer ence i n sur vi val i s l i kel y r el ated to di agnosi s at an ear l i er
stage i n fal l opi an tube cancer than i n ovar i an cancer.
Uterine Cancer
Cancer s of the uter us ar e di vi ded i nto thr ee mai n categor i es: those
ar i si ng fr om the endometr i um (endometr i al cancer ), those ar i si ng
fr om the myometr i um or muscl e l ayer (uter i ne sar comas), and those
associ ated wi th pr egnancy (gestati onal tr ophobl asti c di sease).
Endometrial Cancer
Incidence
Endometr i al cancer i s the most common mal i gnancy of the femal e
geni tal tract and the four th most common cancer among women i n
the Uni ted States (fol l owi ng br east, l ung, and col on cancer s).
Appr oxi matel y 40,000 new cases ar e di agnosed annual l y, and
appr oxi matel y 7,000 women di e year l y fr om thi s di sease. The
medi an age at onset i s 63 year s, al though up to 25% of pati ents ar e
pr emenopausal at the ti me of di agnosi s. Up to 10% of cases of
endometr i al cancer ar e her edi tar y. Lynch syndr ome/HNPCC i s a
her edi tar y cancer pr edi sposi ti on syndr ome character i zed by the
devel opment of mul ti pl e cancer s, i ncl udi ng endometr i al , col or ectal ,
and ovar i an cancer.
Risk Factors
Ri sk factor s for endometr i al cancer i ncl ude nul l i par i ty, ear l y
menar che, l ate menopause, obesi ty, unopposed estr ogen therapy,
and chr oni c di seases such as di abetes mel l i tus and hyper tensi on.
Pathology
Ni nety per cent of endometr i al cancer s ar e endometr i oi d
adenocar ci nomas (70% grade 1, 15% grade 2, and 15% grade 3),
5% to 7% ar e papi l l ar y ser ous car ci nomas, and the r emai ni ng 3%
to 5% ar e cl ear cel l car ci nomas. The l atter two hi stol ogi c subtypes
ar e mor e aggr essi ve. Al though l ess common than the endometr i oi d
subtype, papi l l ar y ser ous and cl ear cel l car ci nomas account for mor e
than 50% of the r ecur r ences and deaths due to endometr i al cancer.

Endometr i al cancer metastasi zes pr i mar i l y by myometr i al i nvasi on
and di r ect extensi on to adjacent str uctur es, i ncl udi ng the cer vi x,
vagi na, and adnexa. Lymphati c embol i z ati on and hematogenous
di ssemi nati on can al so occur.
Clinical Features
Ni nety per cent of pati ents pr esent to thei r physi ci ans compl ai ni ng of
abnor mal uter i ne bl eedi ng or postmenopausal bl eedi ng;
appr oxi matel y 15% of pati ents wi th postmenopausal bl eedi ng have
uter i ne cancer. Pati ents may al so exper i ence pel vi c pr essur e
and pel vi c pai n. Other associ ated fi ndi ngs i ncl ude pyometra,
hematometra, heavy menses, i nter menstr ual bl eedi ng, and, i n some
cases, an abnor mal Pap smear r esul t. The pr esence of atypi cal
gl andul ar cel l s on a Pap smear r equi r es that an endometr i al bi opsy
be per for med to r ul e out mal i gnancy.
Pretreatment Workup
r equi r ed. Pathol ogi cal confi r mati on of the di sease by endometr i al
bi opsy or di l atati on and cur ettage i s essenti al . Other components of
the pr etr eatment wor kup i ncl ude cl i ni cal tests (e.g., compl ete bl ood
cel l count, ser um gl ucose, bl ood ur ea ni tr ogen, cr eati ni ne, CA-125),
chest radi ography, and mammography. Di agnosti c tests, i ncl udi ng
CT, bar i um enema, pr octosi gmoi doscopy, cystoscopy, and, i n some
cases, magneti c r esonance i magi ng (MRI), shoul d be per for med as
i ndi cated by symptoms or exami nati on fi ndi ngs.
Staging
The sur gi cal stagi ng schema for endometr i al cancer i s descr i bed i n
Tabl e 20.11. The F IG O gradi ng schema i s based on the pr eval ence of
a nonsquamous or nonmor ul ar sol i d gr owth patter n (grade 1, 5% or
l ess; grade 2, mor e than 5% and l ess than 50% ; grade 3, 50% or
hi gher ) (Tabl e 20.12).
Table 20.11. Surgical staging of

endometrial cancer
Tumor
Description
Stage
Carcinoma confined to the uterine
corpus
I
IA
Tumor limited to the endometrium
IB
Invasion of half or less of the

myometrium
IC
Invasion of more than half of the

myometrium
II
IIA
IIB
Extension of cancer to the cervix but

not outside the uterus
Endocervical glandular involvement
only
Cervical stromal invasion
III
IIIA
IIIB
IIIC
IV
Extension of the tumor outside the

uterus but confined to the true pelvis
or para-aortic area
Tumor invasion of the serosa and/or
adnexa, with or without positive
cytologic results
Metastases to the vagina
Metastases to the pelvic and/or paraaortic lymph nodes
Distant metastases or involvement of
adjacent pelvic organs
IVA
Tumor invasion of the bowel or

bladder mucosa
IVB
Distant metastases, including intraabdominal and/or inguinal lymph nodes
Table 20.12. International federation of

gynecology and obstetrics grading of
endometrial cancer
Tumor
Grade
Description
5% a nonsquamous or nonmorular
solid growth pattern
>5%50% a nonsquamous or
nonmorular solid growth pattern
>50% a nonsquamous or nonmorular

solid growth pattern
Treatment
Unl ess a pati ent has comor bi di ti es that do not al l ow for sur gi cal
i nter venti on, expl orator y l apar otomy, hyster ectomy, and possi bl y
bi l ateral sal pi ngo-oophor ectomy ar e r equi r ed for pati ents wi th
endometr i al cancer. Addi ti onal sur gi cal stagi ng bi opsi es,
omentectomy, and l ymph node di ssecti on ar e al so r ecommended i n
cer tai n cases. Up to 20% of pati ents wi th endometr i al cancer have a
synchr onous or metastati c ovar i an mal i gnancy, so i n young pati ents
who want to pr eser ve thei r ovar i an functi on, the ovar i es shoul d be
car eful l y i nspected at the ti me of expl orati on. After sur gi cal
stagi ng, adjuvant chemotherapy, radi ati on, or both may be
i ndi cated. For pati ents at r i sk for pel vi c or vagi nal cancer
r ecur r ence, whol e pel vi c radi otherapy wi th vagi nal brachytherapy
has been shown to decr ease l ocal r ecur r ence. However, radi ati on
has not been shown to i mpr ove overal l sur vi val .
For pati ents wi th advanced-stage or r ecur r ent di sease,
chemotherapy i s i ndi cated. Chemotherapy i s al so i ndi cated for
pati ents wi th hi gh-r i sk hi stol ogi c subtypes (papi l l ar y ser ous and
cl ear cel l car ci nomas). The most acti ve chemotherapeuti c agents i n
the tr eatment of endometr i al cancer ar e pl ati num agents,
doxor ubi ci n, and taxanes. Admi ni ster ed al one, these agents pr oduce
a 30% r esponse rate; combi ned, the r esponse rate i s appr oxi matel y
50% . Pr ogesti n therapy may be used to tr eat metastati c tumor s that
expr ess the pr ogester one r eceptor ; r esponse occur s i n 25% to 30%
of cases. Hor monal therapy wi th tamoxi fen pr oduces a r esponse i n
appr oxi matel y 20% of cases.
Prognostic Factors
Tumor stage i s the most i mpor tant pr ognosti c var i abl e for
endometr i al cancer (Tabl e 20.13). Other pr ognosti c factor s ar e
myometr i al i nvasi on, l ymphovascul ar space i nvasi on, nucl ear grade,
hi stol ogi c subtype, tumor si ze, pati ent age, posi ti ve per i toneal
cytol ogi c fi ndi ngs, hor mone r eceptor status, and type of pr i mar y
tr eatment used (sur ger y vs. radi ati on therapy).
Recommended Surveillance
Physi cal and pel vi c exami nati ons shoul d be per for med ever y 3
months i n the fi r st year after di agnosi s, ever y 4 months i n year s 2
and 3, ever y 6 months i n year s 4 and 5, and annual l y ther eafter. A
Pap smear and chest radi ograph shoul d al so be obtai ned annual l y.

patients with endometrial cancer, by tumor
stage
I
90
II
75
III
40
IV
10
Uterine Sarcomas
Incidence
Uter i ne sar comas account for appr oxi matel y 3% to 5% of uter i ne
cancer s.
Risk Factors
Most pati ents have no known r i sk factor s. A smal l number of
pati ents have a hi stor y of pel vi c i r radi ati on.
Pathology
Uter i ne sar comas ar i se fr om mesoder mal der i vati ves that i ncl ude
uter i ne smooth muscl e, endometr i al str oma, and bl ood and
l ymphati c vessel wal l s. The number of mi toses per 10 hi gh-power
fi el ds, the degr ee of cytol ogi c atypi a, and the pr esence of
coagul ati ve necr osi s ar e the most r el i abl e pr edi ctor s of bi ol ogi cal
behavi or. Thi s di sease i s cl assi fi ed accor di ng to the types of
el ements i nvol ved (pur e: onl y mesoder mal el ements pr esent;
mi xed: both mesoder mal and epi thel i al el ements pr esent) and
whether mal i gnant mesoder mal el ements ar e nor mal l y pr esent i n
the uter us (homol ogous: onl y smooth muscl e and str oma pr esent;
heter ol ogous: str i ated muscl e and car ti l age pr esent) (Tabl e 20.14).
Hal f of endometr i al sar comas ar e mal i gnant mi xed ml l er i an
tumor s. Other common hi stol ogi c subtypes ar e l ei omyosar comas
(40% ) and endometr i al str omal sar comas (8% ). Less common
subtypes ar e adenosar comas, pur e heter ol ogous sar comas, and
other var i ants, whi ch together compr i se 1% to 2% of uter i ne
sar comas.

Sar comas demonstrate a pr opensi ty for ear l y hematogenous
di ssemi nati on and l ymphati c spr ead. Metastasi s i s exhi bi ted i n onethi r d of pati ents.
Pretreatment Workup
r equi r ed. Cl i ni cal featur es of uter i ne sar comas ar e l i sted i n Tabl e
20.15. Endometr i al bi opsy, di l atati on and cur ettage, or both ar e
essenti al to pr ovi di ng pathol ogi cal confi r mati on of di sease. Other
components of the pr etr eatment wor kup i ncl ude cl i ni cal tests (e.g.,
compl ete bl ood cel l count, ser um gl ucose, bl ood ur ea ni tr ogen,
cr eati ni ne, l i ver functi on), chest radi ography,
mammography, and cystoscopy or pr octoscopy, dependi ng on the
si te and extent of the l esi on. Pr eoperati ve medi cal cl earance i s
necessar y for pati ents wi th chr oni c di sease or other appr opr i ate
i ndi cati ons.
Table 20.14. Classification of uterine

sarcomas
Tumor
Homologous
Type
Pure
Mixed
Heterologous
Leiomyosarcoma
Rhabdomyosarcoma
Endometrial
stromal sarcoma
Chondrosarcoma
Osteosarcoma
Liposarcoma
Mixed
mesodermal
(mllerian)
sarcoma or
malignant mixed
mesodermal
(mllerian)
tumor with
homologous
components (also
called
carcinosarcoma)
Mixed mesodermal
(mllerian)
sarcoma or
malignant mixed
mesodermal
(mllerian) tumor
with heterologous
components
Staging
No offi ci al stagi ng system exi sts for uter i ne sar comas. The F IG O
sur gi cal stagi ng schema for endometr i al cancer i s used i nstead
(Tabl e 20.11).
Treatment
Sur gi cal exci si on i s the onl y tr eatment of curati ve val ue. Pel vi c
radi ati on therapy has a r ol e i n l ocal contr ol of the tumor, but
because of the pr opensi ty of uter i ne sar comas for ear l y
hematogenous spr ead, thi s tr eatment does not affect outcome.
Lei omyosar comas general l y do not r espond to radi ati on therapy.
Ci spl ati n, doxor ubi ci n, and i fosfami de have shown some acti vi ty
agai nst uter i ne sar comas; l ei omyosar comas ar e mor e sensi ti ve to
doxor ubi ci n. Ther e may be some benefi t to hor monal therapy wi th
megestr ol acetate; tamoxi fen i s r ecommended i n cases wher e
hor mone r eceptor s have been i denti fi ed. Hor monal therapy i s the
tr eatment of choi ce for l ow-grade endometr i al str omal sar comas.
Prognostic Factors
The most i mpor tant pr ognosti c factor for uter i ne sar comas i s tumor
stage: Di agnosi s at stage I has a 5-year sur vi val rate of 50% ,
wher eas di agnosi s at any other stage has a 5-year sur vi val rate of
15% or l ess (Tabl e 20.16). Sar comatous over gr owth and deep
myometr i al i nvasi on must be consi der ed i n cases of adenosar coma
because they adver sel y affect pr ognosi s.
Table 20.15. Clinical features of uterine sarc

and basis for pathological confirmation of
disease, by histologic subtype
Histologic
Subtype
Patient's Signs and

Age
Symptoms
Vaginal
bleeding
Uterine
Pathol
Basis f
Confirm
of Dise
Endometrial
stromal
sarcoma
Leiomyosarcoma
Malignant mixed
mesodermal
tumor
4253 y
enlargement
Lower
abdominal
pain or
pressure
EMB or
4555 y
Vaginal
bleeding
Rapid
uterine
enlargement
Lower
abdominal
pain or
pressure
Preope
diagno
difficul
15%
diagno
EMB or
6575 y
Several
factors in
common
with
endometrial
cancer
(e.g.,
nulliparity,
obesity,
diabetes)
Vaginal
bleeding
Uterine
enlargement
EMB or
in up t
of case
tumor
protrud
throug
cervix
Adenosarcoma
Any age,
but most
common
in the
fifth
decade
of life
Vaginal
bleeding
Uterine
enlargement
EMB or
in up t
of case
tumor
protrud
throug
cervix
EMB, endometrial biopsy; D&C, dilatation and curet

uterine sarcomas, by tumor stage
I
50
IIIV
15
Gestational Trophoblastic Disease

Incidence
G estati onal tr ophobl asti c di sease i s character i zed by an abnor mal
pr ol i ferati on of tr ophobl asti c ti ssue; al l for ms devel op i n associ ati on
wi th pr egnancy. Because thi s di sease i s associ ated wi th a
gestati onal event, the age of occur r ence spans the enti r e
r epr oducti ve spectr um. In the Uni ted States, hydati di for m mol es
occur i n 1 i n 600 therapeuti c abor ti ons and 1 i n 1,000 to 2,000
pr egnanci es; of these, appr oxi matel y 20% devel op mal i gnant
sequel ae, i ncl udi ng i nvasi ve mol es, pl acental si te tr ophobl asti c
tumor s, and gestati onal chor i ocar ci noma. Chor i ocar ci noma i s
esti mated to occur i n 1 i n 20,000 to 40,000 pr egnanci es. One-hal f
of these cases fol l ow ter m gestati ons, one-four th fol l ow mol ar
gestati ons, and one-four th fol l ow other gestati onal events.
Risk Factors
A number of wel l -establ i shed r i sk factor s ar e posi ti vel y associ ated
wi th hydati di for m mol e. These i ncl ude age younger than 20 year s or
ol der than 40 year s, pr evi ous mol ar pr egnancy (women who have
had one mol ar pr egnancy have a 0.5% to 2.5% r i sk of a second
occur r ence, and women who have had two mol ar pr egnanci es have a
33% r i sk of a thi r d occur r ence), pr evi ous spontaneous abor ti on (the
r i sk i ncr eases wi th each subsequent spontaneous abor ti on), and
Asi an race. Bl ack race i s negati vel y associ ated wi th hydati di for m
mol e.
Pathology
G estati onal tr ophobl asti c di sease i s categor i zed as hydati di for m
mol e, i nvasi ve mol e, pl acental si te tr ophobl asti c tumor, and
chor i ocar ci noma. Nonmetastati c di sease after mol ar evacuati on may
be hydati di for m (i nvasi ve) mol e or chor i ocar ci noma. G estati onal
tr ophobl asti c di sease per si sti ng after a nonmol ar pr egnancy i s
pr edomi nantl y chor i ocar ci noma or, rar el y, pl acental si te
tr ophobl asti c tumor. Metastati c gestati onal tr ophobl asti c di sease
di agnosed i n the ear l y months after mol ar evacuati on may be
hydati di for m mol e or chor i ocar ci noma. When gestati onal
tr ophobl asti c di sease i s found r emote fr om a gestati onal event, i t i s
character i sti cal l y chor i ocar ci noma.

Mal i gnant gestati onal tr ophobl asti c di sease spr eads pr i mar i l y by a
hematogenous r oute. The most fr equent si te of metastasi s i s i n the
l ung (80% ). Other common si tes ar e the vagi na (30% ); pel vi s
(20% ); brai n (10% ); l i ver (10% ); and, bowel , ki dney, and spl een
(l ess than 5% each).
Table 20.17. Classification of hydatidiform

moles
Feature
Complete Mole
Partial
Mole
Hydatidiform
swelling of villi
Diffuse
Focal
Trophoblast
Cytotrophoblastic
and syncytial
hyperplasia
Syncytial
hyperplasia
Embryo
Absent
Present
Villous
capillaries
No fetal red
blood cells
Many fetal
red blood
cells
Gestational age
at diagnosis
816 wk
1022 wk
-hCG
concentration
Usually >50,000
mIU/mL
Usually
>50,000
mIU/mL
Proportion that
progress to
choriocarcinoma
15%25%
5%10%
Karyotype
46XX (95%),
46XY (5%)
Triploid
(80%)
Uterine size for gestational dates
Small
33%
65%
Large
33%
10%
-hCG, beta subunit of human chorionic

gonadotropin.
Clinical Features
Hydatidiform Mole
Vagi nal bl eedi ng, uter us si ze l ar ger than expected for gestati onal
age, and the pr esence of pr omi nent theca l utei n ovar i an cysts ar e
character i sti c cl i ni cal featur es of hydati di for m mol e. Featur es of
par ti al and compl ete hydati di for m mol es ar e l i sted i n Tabl e 20.17.
Other associ ated fi ndi ngs i ncl ude toxemi a, hyper emesi s,
hyper thyr oi di sm, and r espi rator y symptoms such as dyspnea and
r espi rator y di str ess. Pati ents wi th par ti al mol es may pr esent i n the
same manner as those wi th mi ssed or i ncompl ete abor ti ons: vagi nal
bl eedi ng and the passage of ti ssue thr ough the vagi na.
Malignant Gestational Trophoblastic Disease

Mal i gnant gestati onal tr ophobl asti c di sease can be categor i zed as
nonmetastati c or l ocal l y i nvasi ve, or as metastati c. The cl i ni cal
featur es of mol ar pr egnancy and the associ ated i nci dences of
mal i gnant gestati onal tr ophobl asti c di sease ar e shown i n Tabl e
20.18.
Pretreatment Workup for Molar Pregnancy

ur ea ni tr ogen, cr eati ni ne, l i ver functi on, ser um al bumi n, thyr oi d
functi on tests, ser um -hCG [i n l ess than 5% of cases, the -hCG
anti gen ti ter may be el evated wi thout cl i ni cal or radi ographi c
evi dence of di sease]), and chest radi ography.
Table 20.18. Clinical features of molar

pregnancy and associated incidences of
malignant gestational trophoblastic disease
Clinical Feature
Incidence of Malignant
Gestational
Trophoblastic Disease
Delayed postmolar
evacuation
hemorrhage
75
Theca lutein cyst >5

cm
60
Acute pulmonary
insufficiency after
mole evacuation
58
Uterus large for

gestational dates
45
Serum -hCG
concentration
>100,000 mIU/mL
45
Second molar
gestation
40
Maternal age >40 y
25
-hCG, beta subunit of human chorionic

gonadotropin.
Metastatic Workup for Malignant or

Persistent Gestational Trophoblastic Disease
Metastati c wor kup for mal i gnant or per si stent gestati onal
tr ophobl asti c di sease consi sts of the tests descr i bed for mol ar
pr egnancy pl us pel vi c sonography; CT scan of the abdomen, pel vi s,
brai n, and chest; and MRI of the brai n. Metastati c l esi ons (e.g., a
vagi nal nodul e) shoul d not be bi opsi ed because these l esi ons ar e
ver y vascul ar and pati ents have exsangui nated fr om such bi opsi es.
Table 20.19. International federation of

gynecology and obstetrics staging of
gestational trophoblastic disease
Tumor
Stage
Description
Confined to the uterine corpus
II
Metastasis to the pelvis and vagina
III
Metastasis to the lung
IV
Distant metastasis to the brain, liver,

kidneys, or gastrointestinal tract
Staging
The F IG O stagi ng schema of gestati onal tr ophobl asti c di sease i s

outl i ned i n Tabl e 20.19.
Treatment
Molar Pregnancy
Di l ati on and cur ettage i s the standar d tr eatment for mol ar
pr egnancy and i s fol l owed by cl ose moni tor i ng of the -hCG anti gen
ti ter. Hyster ectomy may be per for med i f fer ti l i ty i s not an i ssue.
Nonmetastatic Gestational Trophoblastic

Disease (FIGO Stage I)
If pr eser vi ng fer ti l i ty i s not a consi derati on, a total hyster ectomy
can be offer ed. If pr eser vi ng fer ti l i ty i s desi rabl e, adjuvant si ngl eagent chemotherapy wi th methotr exate i s the most common
tr eatment choi ce. Chemotherapy shoul d be conti nued unti l at l east
one menstr ual cycl e beyond nor mal i z ati on of the -hCG anti gen
ti ter. If ther e i s di sease r esi stance (i .e., the -hCG anti gen ti ter
i ncr eases or pl ateaus), the pati ent shoul d be tr eated wi th an
al ter nate si ngl e agent, most commonl y dacti nomyci n. If r esi stance
per si sts, combi nati on chemotherapy wi th EMA-CO (etoposi de,
methotr exate, dacti nomyci n, cycl ophosphami de, and vi ncr i sti ne) or
MAC (methotr exate, acti nomyci n, and cycl ophosphami de) shoul d be
admi ni ster ed.
Metastatic Gestational Trophoblastic Disease

(FIGO Stages II to IV)
Low-risk Disease (World Health Organization Risk
Score 0 to 6)
For i ni ti al tr eatment, pati ents general l y r ecei ve si ngl e-agent
therapy wi th methotr exate. If ther e i s di sease r esi stance, the
pati ent shoul d be tr eated wi th an al ter nate si ngl e agent, typi cal l y
dacti nomyci n. If r esi stance per si sts, combi nati on chemotherapy wi th
EMA-CO or MAC shoul d be admi ni ster ed. If ther e i s r esi stance to
EMA-CO and MAC, sal vage therapy i ncl udes the combi nati on of
ci spl ati n, bl eomyci n, and vi nbl asti ne. Ifosfami de may have a r ol e i n
r efractor y cases.
High-risk Disease (World Health Organization Risk

Score 7 or Higher)
Combi nati on chemotherapy i s the tr eatment of choi ce. EMA-CO i s
the i ni ti al chemotherapeuti c r egi men, and ci spl ati n, bl eomyci n, and
vi nbl asti ne ar e used as sal vage tr eatment.
Special Considerations
Pati ents wi th brai n metastases may be tr eated wi th radi otherapy for
l ocal contr ol and pr ophyl axi s agai nst hemor r hage. Pati ents wi th
r esi dual sol i tar y l i ver or l ung l esi ons may be candi dates for sur gi cal
r esecti on.
Prognostic Factors
Factor s that may affect a pati ent's pr ognosi s and r esponse to
tr eatment ar e outl i ned i n Tabl e 20.20. The cur e rate for stage I, II,
and III di sease i s gr eater than 80% , wher eas the cur e rate for stage
IV di sease i s appr oxi matel y 50% .
Posttr eatment sur vei l l ance i s essenti al l y the same for al l cases of
gestati onal tr ophobl asti c di sease, except for pati ents wi th stage IV
di sease, who r equi r e a l onger per i od of sur vei l l ance. -hCG anti gen
ti ter s ar e measur ed weekl y unti l the l evel i s nor mal for 3
consecuti ve weeks and then measur ed monthl y unti l the l evel i s
nor mal for 12 consecuti ve months. Pati ents wi th stage IV di sease
ar e typi cal l y fol l owed for 24 months after nor mal i z ati on of -hCG
anti gen ti ter val ues. Contracepti on i s mandator y thr oughout the
fol l ow-up per i od.
Table 20.20. Prognostic indicators for pat

gestational trophoblastic disease, by Wor
Organization prognostic index sco
World Health Organization Prog
Prognostic
Indicator
Score
0
<39
>39
Hydatidiform
mole
Abortion
Interval
between
antecedent
pregnancy
and start of
chemotherapy
(mo)
<4
46
71
-hCG
concentration
(mIU/mL)
<10 3
10 3 10 4
10 4 1
Age (y)
Type of
antecedant
pregnancy
Diameter of
largest tumor
(cm)
Site of
metastasis
Number of
metastases
35
Lung,
vagina,
pelvis
Spleen,
kidney
14
Term
>5
Gastroint
tract, l
48
identified
Prior
chemotherapy
1 dru
-hCG, beta subunit of human chorionic gonadotrop

Low risk 06, high risk >6.
Management of Incidental Uterine Masses

Found at Laparotomy
The fi ndi ng of an enl ar ged or abnor mal uter us at the ti me of
expl orator y l apar otomy or sur ger y for an unr el ated condi ti on can
pose a therapeuti c di l emma to the sur geon. Uter i ne fi br oi ds, whi ch
ar e beni gn tumor s of the uter us, ar e the most common cause of
uter i ne enl ar gement. In most cases, i mmedi ate sur gi cal i nter venti on
i s unnecessar y. Unl ess the si tuati on i s l i fe thr eateni ng,
hyster ectomy and bi l ateral sal pi ngo-oophor ectomy shoul d be
per for med onl y after pr oper i nfor med consent has been obtai ned,
especi al l y i n women of chi l dbear i ng age.
Laparoscopy for the Management of

Endometrial Cancer
The use of l apar oscopy i n the tr eatment of ear l y-stage endometr i al
cancer has gai ned popul ar i ty. Thi s appr oach combi nes ei ther a
l apar oscopi c-assi sted vagi nal hyster ectomy or a total l apar oscopi c
hyster ectomy wi th a l apar oscopi c l ymphadenectomy. If thi s appr oach
i s used, thor ough i nspecti on of the per i toneal cavi ty, per i toneal
washi ngs and appr opr i ate stagi ng bi opsi es ar e sti l l i mpor tant.
Lapar oscopi c sur gi cal stagi ng has not yet been pr oven to be
equi val ent i n r egar d to cancer outcome. The G ynecol ogi c Oncol ogy
G r oup i s cur r entl y eval uati ng data fr om a randomi zed tr i al of these
two appr oaches.
Cervical Cancer
Incidence
Appr oxi matel y 500,000 women wor l dwi de devel op cer vi cal cancer
each year. It i s the most common cause of cancer-r el ated death
among women i n under devel oped countr i es. In the Uni ted States, an
esti mated 9,710 new cases of cer vi cal cancer and 3,700 deaths due
to thi s di sease wi l l occur i n 2006.
Risk Factors
Cer vi cal cancer i s a sexual l y transmi tted di sease. It was the fi r st
sol i d tumor to be l i nked to a vi r us: Infecti on wi th human
papi l l omavi r us, speci fi cal l y types 16 and 18, i s associ ated wi th the
devel opment of thi s di sease. Other r i sk factor s i ncl ude ear l y age at
fi r st i nter cour se, mul ti pl e sexual par tner s, mul ti par i ty, smoki ng,
and other behavi or s associ ated wi th exposur e to the human
papi l l omavi r us. Hal f of women wi th newl y di agnosed i nvasi ve
cer vi cal cancer have never had a Pap smear, and another 10% have
not had a Pap smear i n the pr evi ous 5 year s.
Pathology
Ei ghty-fi ve per cent of cer vi cal cancer s ar e squamous cel l
car ci nomas, and 10% to 15% ar e adenocar ci nomas, i ncl udi ng the
l ess common adenosquamous subtype. Less common hi stol ogi c
subtypes i ncl ude smal l cel l tumor s, sar comas, l ymphomas, and
mel anomas.

Cer vi cal cancer spr eads thr ough var i ous mechani sms. It can di r ectl y
i nvade sur r oundi ng str uctur es, i ncl udi ng the parametr i a, the cor pus,
and the vagi na. Lymphati c spr ead commonl y occur s
i n an or der l y and pr edi ctabl e sequence i nvol vi ng the parametr i al ,
pel vi c, i l i ac, and fi nal l y para-aor ti c l ymph nodes. Hematogenous
metastases and i ntraper i toneal i mpl antati on can al so occur.
Clinical Features
Symptoms
Di schar ge and abnor mal bl eedi ng, i ncl udi ng postcoi tal ,
i nter menstr ual , menor r hagi a, and postmenopausal bl eedi ng, ar e
often the fi r st si gns of cer vi cal cancer. F r equent voi di ng and pai n on
ur i nati on can al so occur and may i ndi cate advanced di sease.
Physical Findings
F i ndi ngs on exami nati on var y dependi ng on the si te of the l esi on
(endocer vi x or ectocer vi x). Car eful i nspecti on and pal pati on,
i ncl udi ng bi manual and r ectovagi nal exami nati ons, ar e r equi r ed to
deter mi ne the si ze and extent of the l esi on.
Pretreatment Workup
Car eful physi cal exami nati on must be per for med, i ncl udi ng pel vi c
exami nati on and bi opsy of the l esi on. Other components of the
functi on), chest radi ography, and mammography.
Cer vi cal cancer i s staged by the r esul ts of the cl i ni cal exami nati on.
Ther efor e, unl i ke endometr i al and ovar i an cancer, stagi ng i s
per for med befor e tr eatment pl anni ng and not at the ti me of
di agnosi s. The fol l owi ng studi es shoul d be per for med for pati ents
wi th stage IB2 to stage IV cer vi cal cancer : cystoscopy, pr octoscopy,
i ntravenous pyel ography (or CT of the abdomen or pel vi s), and
chest X-ray or CT. MRI may be useful , especi al l y i n di sti ngui shi ng
endometr i al and endocer vi cal l esi ons.
Staging
The cl i ni cal stagi ng scheme for cer vi cal cancer i s outl i ned i n Tabl e
20.21. The ter m mi cr oi nvasi ve cer vi cal cancer i s someti mes used
i nter changeabl y wi th stage IA l esi ons. Thi s di agnosi s must be made
fr om a cone bi opsy or hyster ectomy speci men.
Treatment
Stage IA1
Lesi ons that sati sfy mi cr oi nvasi ve di sease may be tr eated
conser vati vel y wi th si mpl e hyster ectomy, cer vi cal coni z ati on i n
cases wher e mai ntenance of fer ti l i ty i s an i ssue, or i ntracavi tar y
radi ati on therapy for pati ents who do not qual i fy for sur ger y.
Stage IA2
Lesi ons that have >3 mm of i nvasi on ar e si gni fi cantl y mor e l i kel y to
r ecur when tr eated conser vati vel y; ther efor e, radi cal hyster ectomy
and l ymph node di ssecti on or radi ati on therapy shoul d be
per for med.
Stages IB and IIA

Sur ger y or chemosensi ti z i ng radi ati on therapy r esul t i n si mi l ar cur e
rates when pati ents ar e car eful l y sel ected; pati ents wi th squamous
l esi ons 4 to 5 cm i n di ameter and adenocar ci nomas smal l er than 3
cm i n di ameter ar e potenti al sur gi cal candi dates. The standar d
sur gi cal opti on i s radi cal hyster ectomy wi th pel vi c l ymph node
di ssecti on. Nonsur gi cal management may i ncl ude sensi ti z i ng
radi ati on therapy wi th
weekl y chemotherapy and 40 to 45 G y exter nal -beam i r radi ati on
fol l owed by two i ntracavi tar y systems. Among pati ents who under go
sur ger y, chemoradi ati on i s used postoperati vel y i n those bel i eved to
be at hi gh r i sk for di sease r ecur r ence. Si mpl e hyster ectomy after
pel vi c radi ati on therapy i s i ndi cated pr i mar i l y for pati ents whose
tumor s r espond sl owl y to radi ati on therapy or when pel vi c anatomy
pr ecl udes opti mal i ntracavi tar y pl acement.
Stages IIB to IVA

Radi ati on therapy i s the tr eatment of choi ce for l ocal l y advanced
di sease. Sur ger y may be used as adjuvant therapy for stage IVA
di sease wi thout parametr i al i nvol vement and i n cases of central
di sease per si sti ng after radi ati on therapy.
Table 20.21. Clinical staging of cervical

cancer
Tumor
Description
Stage
I
Lesions generally confined to the

cervix; uterine involvement is
disregarded
Preclinical cervical cancers diagnosed
IA
IA1
IA2
IB
by microscopic analysis alone

Stromal invasion 3 mm deep and
7 mm wide
Stromal invasion >3 mm but 5 mm
deep and 7 mm wide
Lesions larger than stage IA lesions,
regardless of whether seen clinically
IB1
Clinical lesions 4 cm
IB2
Clinical lesions >4 cm
II
Extension beyond the cervix but not to

the pelvic sidewall or the lower third of
the vagina
IIA
No obvious parametrial involvement
IIB
Parametrial involvement
III
Extension to the pelvic wall with no

cancer-free space between the tumor
and the pelvic wall; tumor involving
the lower third of the vagina;
hydronephrosis or nonfunctioning
kidney unless secondary to an
unrelated cause
IIIA
Involvement of the lower third of the

vagina; no extension to the pelvic
sidewall
IIIB
Extension to the pelvic wall,

hydronephrosis, or nonfunctioning
kidney
IV
Extension beyond the true pelvis or

clinical involvement of the mucosa of
the bladder or rectum
IVA
Spread to adjacent organs
IVB
Spread to distant organs
Stage IVB
Stage IVB di sease i s tr eated pr i mar i l y wi th chemotherapy because
the di sease i s di ssemi nated. Ci spl ati n i s the most studi ed acti ve
agent; other opti ons i ncl ude i fosfami de and mi tomyci n C. Cur r ent
cl i ni cal tr i al s usi ng vi nor el bi ne (Navel bi ne) have al so demonstrated
some acti vi ty i n cer vi cal cancer.
Radi ati on therapy may be used i n cer tai n cases for l ocal contr ol and
pal l i ati on of symptoms.
Table 20.22. Incidence of cervical cancer

lymph node metastasis, by tumor stage
Incidence (%) as
Indicated by Lymph Node
Tumor Stage
Metastasis
Pelvic
Para-aortic
IA2 (lesion 1
3 mm in
diameter)
0.6
IA2 (lesion 3
5 mm in
diameter)
4.8
<1
15.9
2.2
IIA
24.5
11
IIB
31.4
19
44.8
30
55
40
I
IA1
IB
II
III
IVA
Recurrent Disease
Tr eatment of r ecur r ent cer vi cal cancer depends on the l ocati on of
the di sease and the type of pr i mar y tr eatment the pati ent r ecei ved.
Central r ecur r ence may be managed wi th pel vi c exenterati on i f no

contrai ndi cati ng factor s ar e pr esent. Pati ents who have had pr i or
radi ati on therapy and extensi ve pel vi c r ecur r ence or di stant
metastati c di sease ar e tr eated wi th systemi c chemotherapy.
Prognostic Factors
The most i mpor tant pr ognosti c factor s for stage I di sease i ncl ude
l ymphovascul ar space i nvol vement, tumor si ze, depth of i nvasi on,
and pr esence of l ymph node metastases (Tabl e 20.22). For pati ents
wi th stage II to stage IV di sease, tumor stage, pr esence of l ymph
node metastases, tumor vol ume, age, and the pati ent's per for mance
status ar e key pr ognosti c factor s. The sur vi val rates for pati ents
wi th cer vi cal cancer ar e shown i n Tabl e 20.23.
months i n the fi r st year after di agnosi s, ever y 4 months i n year s 2
and 3, ever y 6 months i n year s 4 and 5, and annual l y ther eafter. A
Pap smear and chest radi ograph shoul d al so be obtai ned annual l y.
Among pati ents who have r ecur r ent cer vi cal cancer, mor e than 50%
ar e di agnosed wi th the r ecur r ence wi thi n 1 year after pr i mar y
tr eatment i s compl eted. Seventy-fi ve per cent of pati ents ar e
di agnosed wi th thei r r ecur r ent di sease wi thi n 2 year s, and 95%
wi thi n 5 year s.

patients with cervical cancer, by tumor
stage and histologic subtype
Tumor Stage and Histologic
Subtype
Survival Rate
(%)
Stage I
Squamous
6590
Adenocarcinoma
7075
Stage II
Squamous
4580
Adenocarcinoma
3040
Stage III
Squamous
Adenocarcinoma
Stage IV (both types)
60
2030
<15
Vulvar Cancer
Incidence
Vul var cancer accounts for 3% to 5% of gynecol ogi c mal i gnanci es
and 1% of mal i gnanci es i n women. Between 2,000 and 3,000 new
cases ar e di agnosed annual l y i n the Uni ted States. The i nci dence of
vul var cancer tends to be bi modal l y di str i buted. Most cases ar e
sol i tar y l esi ons that occur i n postmenopausal women, and the
tumor s ar e often associ ated wi th chr oni c vul var dystr ophy. Recentl y,
a subset of tumor s has been i denti fi ed i n a younger popul ati on;
these tumor s tend to be mul ti focal and ar e associ ated wi th human
papi l l omavi r us i nfecti on.
Risk Factors
The cause of vul var cancer appear s to be mul ti factor i al . Ri sk factor s
i ncl ude human papi l l omavi r us i nfecti on (al though the associ ati on i s
not as str ong as that wi th cer vi cal cancer ), advanced age, l ow
soci oeconomi c status, hyper tensi on, di abetes mel l i tus, pr i or l ower
geni tal tract mal i gnancy (e.g., cer vi cal cancer ), and
i mmunosuppr essi on.
Pathology
Ei ghty-fi ve per cent of vul var mal i gnanci es ar e squamous cel l
car ci nomas, and 8% ar e mal i gnant mel anomas. Less common
hi stol ogi c subtypes i ncl ude basal cel l car ci nomas, Bar thol i n gl and
car ci nomas, Paget di sease, and adenocar ci nomas ar i si ng fr om sweat
gl ands.

Vul var cancer spr eads by di r ect extensi on to the vagi na, ur ethra,
and r ectum. Embol i z ati on to r egi onal l ymphati cs (e.g., the gr oi n)
and hematogenous spr ead to di stant si tes can al so occur.
Clinical Features
Symptoms
Chr oni c pr ur i tus, ul cerati on, and nodul es on the vul va ar e the most
common pr esenti ng symptoms of thi s di sease.
Physical Findings
Lesi ons may ar i se fr om the l abi a majora (40% ), l abi a mi nora
(20% ), per i cl i toral ar ea (10% ), and per i neum or poster i or
four chette (15% ). Lesi ons may appear as a domi nant mass, war ty
ar ea, ul cerated ar ea, or thi ckened whi te epi thel i um.
Diagnosis
F i ve per cent of cases ar e mul ti focal . Any suspi ci ous ar ea must
under go bi opsy, usi ng a Keye punch bi opsy and l i docai ne wi thout
epi nephr i ne for anesthesi a.
Pretreatment Workup
Car eful physi cal exami nati on, i ncl udi ng pel vi c exami nati on and
measur ement of the l esi on, i s r equi r ed. Other components of the
functi on), chest radi ography, mammography, and cystoscopy or

pr octoscopy, dependi ng on the si te and extent of the l esi on. Bar i um
enema, CT, and MRI shoul d be per for med i f i ndi cated. Pr eoperati ve
medi cal cl earance i s necessar y for pati ents wi th chr oni c di sease or
other appr opr i ate i ndi cati ons.
Staging
Si nce 1988, vul var cancer has been sur gi cal l y staged usi ng a
system that i ncor porates TNM (tumor, node, metastasi s)
cl assi fi cati on (Tabl e 20.24). Modi fi cati ons to the TNM system wer e
added i n 1995.
Treatment
Stage I
Wi de l ocal exci si on shoul d be per for med i f the l esi on has l ess than 1
mm of i nvasi on i nto the under l yi ng ti ssue. Wi de radi cal exci si on
wi th a tradi ti onal 2-cm gr oss mar gi n (measur ed wi th a r ul er ) and
super fi ci al di ssecti on of the i psi l ateral gr oi n ar e appr opr i ate for al l
other stage I l esi ons. Bi l ateral super fi ci al gr oi n di ssecti on shoul d be
per for med i f the l esi on i s wi thi n 2 cm of the mi dl i ne.
Stage II
Radi cal vul vectomy wi th di ssecti on of bi l ateral nodes, i ncl udi ng
super fi ci al and deep i ngui nal nodes, i s the standar d appr oach to
stage II di sease. The l ocal r ecur r ence rate i s si mi l ar when the mor e
conser vati ve appr oach of radi cal wi de exci si on i s used i nstead of
radi cal vul vectomy. Adjuvant radi ati on therapy may be i ndi cated i f
the tumor-fr ee mar gi n of r esecti on i s l ess than 8 mm, the tumor i s
thi cker than 5 mm, or the l ymphovascul ar space i nvasi on i s pr esent.
Stage III
Tr eatment must be i ndi vi dual i zed for each pati ent wi th stage III
di sease. Opti ons i ncl ude sur ger y, radi ati on, and a combi nati on of
tr eatment modal i ti es. A modi fi ed radi cal vul vectomy (or a radi cal
wi de l ocal exci si on) wi th i ngui nal and femoral node di ssecti on can
be per for med; pel vi c and gr oi n radi ati on therapy shoul d be
admi ni ster ed i f posi ti ve gr oi n nodes ar e found. Pr eoperati ve
radi ati on therapy (wi th or wi thout
radi ati on-sensi ti z i ng chemotherapy) can be gi ven to i ncr ease the

operabi l i ty of the l esi on and decr ease the extent of r esecti on, and i s
fol l owed by radi cal exci si on wi th bi l ateral super fi ci al and deep gr oi n
node di ssecti on. Radi ati on therapy al one i s an opti on i f the pati ent
i s i nel i gi bl e for radi cal sur ger y or the l esi on appear s to be
i noperabl e.
Table 20.24. Surgical staging of vulvar

cancer and corresponding TNM
classification
Tumor Stage
and
Corresponding Description
TNM
Classification
I (T1N0M0)
Tumor confined to the vulva

and/or perineum; lesion 2
cm in diameter; negative
nodes
IA
Stromal invasion 1 mm
IB
Stromal invasion >1 mm
II (T2N0M0)
Tumor confined to the vulva

and/or perineum; lesion >2
cm in diameter; negative
nodes
Tumor of any size with
III (T3N0M0,
T1N1M0,
T3N1M,
T2N1M0)
adjacent spread to the lower

urethra, vagina, or anus, or
unilateral regional lymph node
metastasis
IV
IVA (T1N2M0,
T3N2M0,
TxNxM0)
IVB (TxNxM1)
Tumor invasion of the upper

urethra, bladder mucosa,
rectal mucosa, or pelvic bone,
and/or bilateral regional
metastasis
Any distant metastasis,
including to the pelvic nodes
Tx, any T; Nx, any N.
Stage IV
Tr eatment of stage IV di sease must al so be i ndi vi dual i zed. Opti ons
i ncl ude radi cal vul vectomy and pel vi c exenterati on, radi cal
vul vectomy fol l owed by radi ati on therapy, pr eoperati ve radi ati on
therapy (wi th or wi thout radi ati on-sensi ti z i ng chemotherapy)
fol l owed by radi cal sur gi cal exci si on, and radi ati on therapy (wi th or
wi thout radi ati on-sensi ti z i ng chemotherapy) i f the pati ent i s
i nel i gi bl e for sur ger y or the l esi on i s deemed i noperabl e.
Recurrent Disease
Tr eatment of r ecur r ent di sease depends on the si te and extent of
the r ecur r ence. Opti ons i ncl ude radi cal wi de exci si on wi th or
wi thout radi ati on therapy (dependi ng on pr i or tr eatment and extent
of r ecur r ence), gr oi n node debul ki ng fol l owed by radi ati on therapy
(dependi ng on pr i or tr eatment), and pel vi c exenterati on. Regi onal
or di stant metastasi s i s di ffi cul t to tr eat, and pal l i ati ve therapy i s

often the onl y opti on.
Prognostic Factors
The pr ognosti c factor s for vul var car ci noma ar e var i ous. Ingui nal
node metastasi s appear s to be the si ngl e most i mpor tant
pr ognosti c var i abl e. Other factor s i ncl ude l ymphovascul ar space
i nvasi on, tumor stage (Tabl e 20.25), l esi on si ze, l esi on si te,
hi stol ogi c grade, and depth of i nvasi on.

patients with vulvar cancer, by tumor stage
I
95
II
7585
III
IV
IVA
20
IVB
months the fi r st year, ever y 4 months i n year s 2 and 3, ever y 6
months i n year s 4 and 5, and annual l y ther eafter. A Pap smear
shoul d be per for med annual l y.
Vaginal Cancer
Incidence
Pr i mar y vagi nal cancer r epr esents 1% to 2% of mal i gnanci es of the
femal e geni tal tract. The average age at di agnosi s i s 60 year s. Most
vagi nal neopl asms r epr esent metastases fr om another pr i mar y
sour ce.
Risk Factors
Ri sk factor s associ ated wi th vagi nal cancer i ncl ude l ow
soci oeconomi c status, hi stor y of human papi l l omavi r us i nfecti on,
chr oni c vagi nal i r r i tati on, pr i or abnor mal Pap smear r esul t wi th
cer vi cal i ntraepi thel i al neopl asi a, pr i or hyster ectomy (59% of
pati ents wi th pr i mar y vagi nal cancer ), pr i or tr eatment for cer vi cal
cancer, and i n uter o exposur e to di ethyl sti l bestr ol dur i ng the fi r st
hal f of pr egnancy. Di ethyl sti l bestr ol was used fr om 1940 to 1971 to
pr event pr egnancy compl i cati ons such as thr eatened abor ti on and
pr ematur i ty. Cl ear cel l car ci noma of the vagi na devel oped i n
appr oxi matel y 1 i n 1,000 women exposed to di ethyl sti l bestr ol i n
uter o. Si nce thi s agent i s no l onger avai l abl e, the i nci dence of thi s
di sease has dramati cal l y decl i ned.
Pathology
Ei ghty-fi ve per cent of vagi nal cancer s ar e squamous cel l neopl asms.
Other hi stol ogi c subtypes i ncl ude adenocar ci noma (9% ), sar coma
(6% ), mel anoma (<1% ), and cl ear cel l car ci noma (<1% ).

Vagi nal cancer metastasi zes vi a di r ect extensi on to adjacent
str uctur es. It can al so spr ead thr ough a wel l -establ i shed l ymphati c
drai nage di str i buti on. Lesi ons of the upper two-thi r ds of the vagi na
metastasi ze di r ectl y to pel vi c l ymph nodes, and l esi ons of the l ower
thi r d of the vagi na metastasi ze pr i mar i l y to the i ngui nofemoral
nodes and secondar i l y to pel vi c nodes. Hematogenous spr ead i s
l i kel y a l ate occur r ence because, i n most cases, the di sease i s
confi ned pr i mar i l y to the pel vi s.
Clinical Features
Symptoms
Pai nl ess vagi nal bl eedi ng and vagi nal di schar ge ar e the pr i mar y
symptoms associ ated wi th vagi nal cancer. Bl adder symptoms,
tenesmus, and pel vi c pai n, whi ch ar e usual l y i ndi cati ve of l ocal l y
advanced di sease, ar e l ess commonl y seen.
Physical Findings
Lesi ons ar e l ocated pr i mar i l y i n the upper thi r d of the vagi na,
usual l y on the poster i or wal l . The appearance of l esi ons var i es.
Sur face ul cerati on i s usual l y not pr esent, except i n advanced cases.
Vi sual i z ati on of l esi ons i denti fi ed by Pap smear may r equi r e
col poscopy.
Pretreatment Workup
Car eful physi cal exami nati on, i ncl udi ng pel vi c exami nati on wi th
col poscopy, i s r equi r ed unl ess the l esi on i s vi si bl e. Other
components of the pr etr eatment wor kup i ncl ude cl i ni cal tests (e.g.,
compl ete bl ood cel l count, ser um gl ucose, bl ood ur ea ni tr ogen,
cr eati ni ne, l i ver functi on), chest radi ography, mammography, and
cystoscopy or pr octoscopy, dependi ng on the si te and extent of the
l esi on. Bar i um enema, CT, and MRI shoul d be per for med i f i ndi cated.
Pr eoperati ve medi cal cl earance i s necessar y for pati ents wi th
chr oni c di sease or other appr opr i ate i ndi cati ons.
Staging
The cl i ni cal stagi ng scheme for vagi nal cancer s i s outl i ned i n Tabl e
20.26.
Table 20.26. Clinical staging of vaginal

cancer
Tumor
Description
Stage
Carcinoma in situ, intraepithelial

carcinoma
Carcinoma limited to the vaginal wall
II
Carcinoma involving subvaginal tissue

but not extending to the pelvic wall
III
Extension to the pelvic wall
IV
Extension beyond the true pelvis, or

involvement of the bladder or rectal
mucosa
IVA
Spread to adjacent organs and/or

direct extension beyond the pelvis
IVB
Spread to distant organs

patients with vaginal cancer, by tumor
stage
I
80
II
45
III
35
IV
10
Treatment
Stage 0
Stage 0 di sease may be tr eated by sur gi cal exci si on, l aser abl ati on,
and, i n some cases, topi cal 5-fl uor ouraci l .
Stage I
Lesi ons of the upper vagi nal for ni ces may be tr eated wi th radi cal
hyster ectomy and l ymphadenectomy or wi th radi ati on therapy
al one. Al l stage I l esi ons (i ncl udi ng l esi ons of the upper vagi nal
for ni ces) may be tr eated wi th radi ati on therapy, usual l y i n the for m
of an i ntracavi tar y cyl i nder.
Stages II to IV
Exter nal -beam radi ati on therapy and i ntracavi tar y or i nter sti ti al
radi ati on therapy ar e used for stage II to stage IV di sease. If the
tumor i nvol ves the l ower thi r d of the vagi na, radi ati on to the gr oi n
nodes shoul d be i ncl uded i n the tr eatment pl an.
Recurrent Disease
Tr eatment of r ecur r ent vagi nal cancer depends on the extent of
r ecur r ence. Opti ons i ncl ude wi de l ocal exci si on, par ti al vagi nectomy,
and exenterati on. Chemotherapy may be gi ven for di stant
metastati c di sease; however, the effi cacy of chemotherapy i s not
wel l known because of the rar i ty of the di sease.
Prognostic Factors
The most i mpor tant pr ognosti c factor for vagi nal cancer i s the tumor
stage (Tabl e 20.27).
months the fi r st year, ever y 4 months i n year s 2 and 3, ever y 6

months i n year s 4 and 5, and annual l y ther eafter. A Pap smear
shoul d be per for med annual l y.
Recommended Reading
Epithelial Ovarian Cancer
Ber ek JS, Hacker NF. Pr actical G ynecologic Oncology. 3r d ed.
Bal ti mor e, Md: Wi l l i ams & Wi l ki ns; 2000.
Canni stra SA. Cancer of the ovar y. N Engl J Med 1993;329:1550.
Dembo AJ, Davy M, Stenwi g AE. Pr ognosti c factor s i n pati ents
wi th stage I epi thel i al ovar i an cancer. Obstet G ynecol
1990;75:263.
Ei nz i g AI, Wi er ni k PH, Sasl off J, et al . Phase II study and l ongter m fol l ow-up of pati ents tr eated wi th taxol for advanced ovar i an
adenocar ci noma. J Clin Oncol 1992;10:1748.
Ei senhauer EA, ten Bokkel Hui ni nk WW, Swener ton KD, et al .

Eur opean-Canadi an randomi zed tr i al of pacl i taxel i n r el apsed
ovar i an cancer : hi gh-dose ver sus l ow-dose and l ong ver sus shor t
i nfusi on. J Clin Oncol 1994;12:2654.
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M.
Edition
> Ta ble o f C o nt e nt s > 2 1 - O nc o lo gic Em e rge nc ie s
21
Oncologic Emergencies
Jeffrey D. W ayne
Richard J. Bold
Tr ue oncol ogi c emer genci es ar e rar e, and often do not r equi r e
sur ger y, such as super i or vena cava (SVC) syndr ome, spi nal cor d
compr essi on, and paraneopl asti c syndr omes. However, sur geons ar e
often asked to consul t on how to manage pati ents wi th mal i gnanci es
who have compl i cati ons fr om tumor pr ogr essi on, or fr om cytotoxi c
therapi es. Thi s chapter fi r st descr i bes some of the mor e common
extra-abdomi nal pr obl ems among sur gi cal pati ents wi th cancer, and
then focuses speci fi cal l y on the acute abdomi nal condi ti ons for
whi ch sur gi cal consul tati on i s obtai ned.
Extra-abdominal Emergencies
Superior Vena Cava Syndrome
Obstr ucti on of the SVC r esul ts i n a constel l ati on of si gns and
symptoms col l ecti vel y known as the super i or vena cava syndr ome
(SVCS). Impedance of outfl ow fr om the SVC may r esul t fr om
exter nal compr essi on by neopl asti c di sease, fi br osi s secondar y to
i nfl ammati on, or thr ombosi s. In up to 97% of pati ents wi th SVCS,
thi s condi ti on i s caused by mal i gnancy. Lung cancer and l ymphoma
ar e the most fr equent causes. An i ncr easi ngl y common eti ol ogy of
SVCS i s thr ombosi s secondar y to i ndwel l i ng central venous
catheter s. The under l yi ng sour ce of obstr ucti on of the SVC must be
establ i shed, as thi s i nfor mati on i s used to gui de therapy and to
deter mi ne pr ognosi s. In the past, pati ents wi th SVCS wer e
emer gentl y tr eated wi th medi asti nal i r radi ati on. However, because
radi ati on-i nduced ti ssue necr osi s often fr ustrates l ater attempts at
ti ssue di agnosi s, empi r i c radi ati on therapy i s no l onger advocated.
Therapy based on the speci fi c type of tumor can often pr ovi de

substanti al pal l i ati on and even a cur e for pati ents pr esenti ng wi th
SVCS.
The SVC i s the pr i mar y condui t for venous drai nage of the head,
neck, upper extr emi ti es, and upper thorax. Thi s thi n-wal l ed,
compl i ant vessel i s sur r ounded by mor e r i gi d str uctur es, i ncl udi ng
the medi asti nal and paratracheal l ymph nodes, the trachea and
r i ght mai nstem br onchus, the pul monar y ar ter y, and the aor ta. It i s
ther efor e suscepti bl e to exter nal compr essi on by any spaceoccupyi ng l esi on. Obstr ucti on of outfl ow fr om the SVC r esul ts i n
venous hyper tensi on of the head, neck, and upper extr emi ti es,
whi ch i n tur n mani fests as SVCS. In most cases, obstr ucti on of the
SVC i s not an acute event, and the si gns and symptoms of SVCS
devel op gradual l y. The most common symptoms i ncl ude dyspnea,
whi ch occur s i n 63% of pati ents wi th SVCS, and faci al ful l ness i n
50% of pati ents. Physi cal fi ndi ngs commonl y associ ated wi th SVCS
i ncl ude faci al edema, venous engor gement of the neck and chest
wal l , cyanosi s, and pl ethora. Symptoms wor sen when the pati ent
bends for war d or r ecl i nes. Obstr ucti on of the SVC becomes a tr ue
emer gency when associ ated l ar yngeal edema
l eads to substanti al i mpedence of the ai r way, or when i ntracrani al
pr essur e i s el evated.
Pati ents wi th SVCS shoul d be thor oughl y eval uated, begi nni ng wi th
a di r ected hi stor y and physi cal exami nati on. A hi stor y of
mal i gnancy, heavy smoki ng, or symptoms such as cough, fever, and
ni ght sweats shoul d be noted. It i s i mpor tant to exami ne al l l ymph
node basi ns and to note the pr esence of a central venous catheter.
Chest radi ography r eveal s an abnor mal i ty i n 84% of pati ents wi th
SVCS, al though the fi ndi ngs ar e often nonspeci fi c. A computed
tomography (CT) scan of the chest i s the i ni ti al test of choi ce and
wi l l deter mi ne whether the obstr ucti on i s due to exter nal
compr essi on, or to thr ombosi s. CT scans al so pr ovi de anatomi c
detai l of tumor masses, and can be used as a gui de for per cutaneous
bi opsy. Magneti c r esonance i magi ng (MRI) i s an al ter nati ve for
pati ents wi th r enal i nsuffi ci ency or an al l er gy to contrast. Mi ni mal l y
i nvasi ve techni ques of ti ssue di agnosi s i ncl ude sputum cytol ogy, CTgui ded per cutaneous bi opsy, br onchoscopy, l ymph node bi opsy, and
bone mar r ow bi opsy. Invasi ve pr ocedur es, such as medi asti noscopy
and thoracotomy, shoul d be consi der ed i f al l i ni ti al measur es fai l to
establ i sh a di agnosi s. These i nvasi ve pr ocedur es can be per for med
safel y i n most pati ents wi th SVCS. Usi ng these techni ques to gui de
i ndi vi dual i zed tr eatment i s pr eferabl e to pr oceedi ng wi th nonspeci fi c

therapy.
When the eti ol ogy of SVCS i s mal i gnancy, tr eatment i s based on
tumor type. Usi ng di ur eti cs and el evati on of the head mi ti gate the
symptoms of SVCS, and usi ng ster oi ds r educes i nfl ammati on. Onl y
those pati ents wi th evi dence of i mpendi ng ai r way obstr ucti on or
el evated i ntracrani al pr essur e shoul d be consi der ed for emer gent
radi ati on therapy. Even i n such cases, i ntubati on, mechani cal
venti l ati on, and osmoti c di ur eti cs can suspend the pr ogr essi on of
symptoms for a per i od suffi ci ent to al l ow for a ti ssue di agnosi s.
Once the di agnosi s i s made, tumor-speci fi c therapy shoul d be
i ni ti ated. Smal l cel l l ung cancer and l ymphoma ar e best tr eated wi th
combi nati on chemotherapy; radi ati on therapy may be used for
consol i dati on. In a ser i es of 56 pati ents wi th smal l cel l l ung cancer,
SVCS was r esol ved i n al l 23 pati ents tr eated wi th chemotherapy
al one, i n 64% of those tr eated wi th radi ati on therapy al one, and i n
83% of those tr eated wi th combi nati on therapy. Nonsmal l cel l l ung
cancer i s most often tr eated wi th radi ati on therapy. One commonl y
used fracti onati on schedul e pr ovi des hi gh-dose tr eatment (34
G y/day) for 3 days fol l owed by conventi onal dose fracti onati on
(1.82.0 G y/day) to a total of 50 to 60 G y. About 70% of pati ents
on such a tr eatment schedul e r espond wi thi n 2 weeks.
Pati ents wi th SVCS secondar y to catheter-i nduced thr ombosi s may
be successful l y tr eated wi th thr ombol yti c agents fol l owed by
systemi c anti coagul ati on. Thr ombol yti c agents ar e most effecti ve
when pati ents ar e tr eated wi thi n 5 days after the onset of
symptoms. Al ter nati vel y, catheter r emoval fol l owed by systemi c
anti coagul ati on often r esul ts i n gradual r ecanal i z ati on of the SVC
and r esol uti on of symptoms. For SVCS r efractor y to such measur es,
bal l oon angi opl asty and expandabl e stents ar e pal l i ati ve modal i ti es.
Sur gi cal i nter venti on consi sti ng of i nnomi nate vei nr i ght atr i al
bypass i s general l y r eser ved for pati ents i n whom the SVCS ar i ses
fr om causes other than mal i gnancy.
Spinal Cord Compression

Spi nal cor d compr essi on i s the second most common neur ol ogi c
compl i cati on of cancer, wi th an esti mated 20,000 new cases
annual l y i n the Uni ted States al one. Autopsy studi es suggest that
5% of pati ents wi th mal i gnanci es have evi dence of spi nal cor d
i nvol vement. Ear l y r ecogni ti on and di agnosi s ar e essenti al , as spi nal
cor d compr essi on can pr oduce paral ysi s and l oss of sphi ncter contr ol
i f l eft untr eated. Pati ents i n whom symptoms pr esent ear l y and i n
whom neur ol ogi c defi ci ts ar e mi ni mal have the most favorabl e
pr ognosi s. Unfor tunatel y, near l y 80% of pati ents ar e unabl e to wal k
at the ti me of pr esentati on.
Spi nal cor d compr essi on i n pati ents wi th cancer usual l y i nvol ves
extradural metastati c l esi ons of the ver tebral body or neural ar ch.
Tumor s expand poster i or l y, r esul ti ng i n anter i or compr essi on of the
dural sac. Rar el y, metastasi s can occur i n i ntradural l ocati ons
wi thout bony i nvol vement. Paraspi nal tumor s can al so cause spi nal
cor d compr essi on by penetrati ng the i nter ver tebral foramen.
Most of the data on spi nal cor d compr essi on i n mal i gnancy ar e fr om
ani mal model s. If spi nal cor d compr essi on devel ops gradual l y,
decompr essi on can be del ayed wi thout i mpai r i ng the r etur n of
neur ol ogi c functi on; however, i n cases of rapi d compr essi on of the
spi nal cor d, therapeuti c i nter venti on must be per for med
i mmedi atel y to avoi d i r r ever si bl e neur ol ogi c defi ci ts. Spi nal cor d
edema al so pl ays an i mpor tant r ol e i n the devel opment of
neur ol ogi c i njur y.
Al though spi nal cor d compr essi on can occur as the i ni ti al
mani festati on of di sease, most pati ents who pr esent wi th spi nal cor d
compr essi on due to mal i gnancy have been pr evi ousl y di agnosed wi th
cancer. The i nter val fr om i ni ti al di agnosi s to epi dural spi nal cor d
compr essi on var i es wi th the type of pr i mar y tumor i nvol ved. Lung
cancer may have an aggr essi ve pr esentati on, wi th epi dural spi nal
cor d compr essi on devel opi ng wi thi n a few months after di agnosi s of
the pr i mar y l esi on. Conver sel y, pati ents wi th car ci noma of the
br east have been r epor ted to mani fest spi nal cor d compr essi on up to
20 year s after i ni ti al pr esentati on of di sease.
The i nci dences of i nvol vement of the thr ee spi nal cor d segments
(cer vi cal , 10% ; thoraci c, 70% ; l umbosacral , 20% ) r efl ect the
number of ver tebrae i n each anatomi c segment. Mor e than 90% of
pati ents wi th spi nal cor d compr essi on due to mal i gnancy pr esent
wi th l ocal i zed back pai n, whi ch may be exacer bated by movement,
r ecumbency, coughi ng, sneez i ng, or strai ni ng. The pai n due to
spi nal cor d compr essi on can be radi cul ar i n di str i buti on. Pai n i s
usual l y pr esent for several weeks befor e neur ol ogi c symptoms
devel op. Left untr eated, weakness and numbness occur, usual l y
begi nni ng i n the toes and ascendi ng to the l evel of the l esi on.
Autonomi c dysfuncti on usual l y occur s l ate i n the di sease pr ocess.
The onset of ur i nar y r etenti on and consti pati on r epr esents an
omi nous si gn, i ndi cati ng possi bl e pr ogr essi on to i r r ever si bl e

parapl egi a.
Physi cal exami nati on may r eveal tender ness, upon pal pati on, over
the i nvol ved ver tebrae. Strai ght l eg rai se and neck fl exi on may
pr oduce pai n at the l evel of the i nvol ved ver tebrae. Weakness,
spasti ci ty, abnor mal r efl exes, and extensor pl antar r esponse
(Babi nski 's si gn) may be evi dent on physi cal exami nati on. A
pal pabl e ur i nar y bl adder or decr eased anal sphi ncter tone may be
pr esent.
Pati ents wi th si gns of i mpendi ng neur ol ogi c defi ci ts shoul d under go
i mmedi ate eval uati on and tr eatment. Dependi ng on the hi stor y and
physi cal exami nati on, pati ents shoul d be tr eated wi th
dexamethasone 10 mg IV fol l owed by 4 mg IV or PO ever y 6 hour s.
Rapi d radi ographi c assessment shoul d be per for med si mul taneousl y.
In mor e than two thi r ds of pati ents wi th spi nal cor d compr essi on,
pl ai n fi l ms of the spi ne show evi dence of bony abnor mal i ti es.
Radi ographi c fi ndi ngs suggesti ve of a spi ne metastasi s i ncl ude
er osi on or l oss of ver tebral pedi cl es, par ti al or compl ete col l apse of
ver tebral bodi es, and paraspi nal soft-ti ssue masses. However,
nor mal spi ne radi ographs do not excl ude the possi bi l i ty that
epi dural metastases ar e pr esent. In fact, pati ents wi th l ymphoma
typi cal l y have nor mal spi ne radi ographs even when epi dural tumor s
ar e pr esent.
Cur r entl y, MRI i s the study of choi ce for eval uati ng pati ents wi th
suspected spi nal cor d compr essi on after pl ai n radi ographs have been
obtai ned. MRI has several advantages over CT myel ogram. Lumbar
punctur e, whi ch i s r equi r ed for a myel ogram, i s associ ated wi th
substanti al mor bi di ty i n pati ents who have a space-occupyi ng l esi on
and wi th potenti al bl eedi ng compl i cati ons i n pati ents who have
coagul opathi es. MRI i s useful i n defi ni ng the extent of tumor
i nvol vement, desi gni ng por tal s for radi ati on therapy, and pl anni ng
sur gi cal i nter venti on. MRI al so di sti ngui shes extradural fr om
i ntradural l esi ons. G adol i ni um contrast i s usual l y not r equi r ed for
extradural l esi ons, but opti mal i magi ng of extramedul l ar y and
i ntramedul l ar y i ntradural l esi ons r equi r es the use of thi s agent. If
MRI r esul ts i n equi vocal or negati ve fi ndi ngs, then CT myel ography
shoul d be per for med.
Ear l y i nter venti on i s essenti al i n the management of mal i gnant
spi nal cor d compr essi on. The functi onal status at the ti me of
pr esentati on cl ear l y cor r el ates wi th the post-tr eatment outcome.
For exampl e, fewer than 10% of pati ents who pr esent wi th

parapl egi a become ambul ator y after tr eatment. Radi otherapy and/or
sur gi cal i nter venti on ar e the standar d tr eatment modal i ti es.
Typi cal l y, 3,000 cG y i s gi ven i n dose fracti ons of 300 to 500 cG y,
wi th excel l ent r esol uti on of pai n and neur ol ogi c symptoms.
Lami nectomy i s effecti ve i n managi ng pati ents wi th epi dural masses
but has l i mi ted use i f the tumor i s gr owi ng i n a di r ecti on anter i or to
the spi nal cor d. In sel ect cases, sur gi cal r esecti on may pr ovi de
symptomati c r el i ef, but car eful pati ent sel ecti on i s essenti al .
Chemotherapy may hel p i n managi ng pati ents wi th epi dural spi nal
cor d compr essi on due to l esi ons that ar e sensi ti ve to cer tai n agents;
however, a r ol e for chemotherapy as an adjuvant or a pr i mar y
tr eatment has not been cl ear l y defi ned.
Pericardial Tamponade
Tamponade i n pati ents wi th cancer most often r esul ts fr om
mal i gnant obstr ucti on of per i car di al l ymphati cs, l eadi ng to the
accumul ati on of fl ui d wi thi n the per i car di al sac. Whi l e both pr i mar y
neopl asms of the hear t and metastati c l esi ons can i nci te the
devel opment of per i car di al effusi ons, metastati c di sease to
the per i car di um i s the most fr equent eti ol ogy. Lung cancer, br east
cancer, l ymphoma, l eukemi a, and mel anoma ar e the mal i gnanci es
most commonl y i mpl i cated i n per i car di al tamponade. Al ter nati vel y,
per i car di al effusi ons i n the cancer pati ent can al so occur as a r esul t
of radi ati on therapy.
The per i car di al sac nor mal l y contai ns 20 mL of fl ui d at a mean
pr essur e bel ow the val ues of the r i ght and l eft ventr i cul ar enddi astol i c pr essur es. As per i car di al fl ui d accumul ates, thi s pr essur e
r i ses unti l the i ntraper i car di al pr essur e equal s or sur passes the
ventr i cul ar end-di astol i c pr essur e. At thi s poi nt, di astol i c fi l l i ng i s
compr omi sed and car di ac output fal l s. The devel opment of symptoms
depends on the rate of accumul ati on and the vol ume of per i car di al
fl ui d, as wel l as on the compl i ance of the per i car di al sac. A
per i car di al effusi on as smal l as 150 mL may i nduce
hemodynami cal l y si gni fi cant tamponade. In cases of mor e gradual
accumul ati on, effusi ons may r each vol umes up to 2 l i ter s.
The symptoms of per i car di al tamponade ar e often vague. F r equent
compl ai nts i ncl ude chest pai n, anxi ety, and dyspnea. Cl i ni cal si gns
i ncl ude tachycar di a, di mi ni shed hear t sounds, jugul ar venous
di stenti on, pul sus paradoxus, and ul ti matel y, shock. The
el ectr ocar di ogram r eveal s l ow vol tage thr oughout al l l eads, wi th

si nus tachycar di a. Two-di mensi onal echocar di ography best
demonstrates the pr esence of per i car di al fl ui d and i s the test of
choi ce for stabl e pati ents wi th suspected per i car di al tamponade.
The tr eatment of per i car di al tamponade i s r emoval of the per i car di al
effusi on, whi ch may be accompl i shed vi a needl e per i car di ocentesi s.
A drai nage catheter may then be i nser ted i nto the per i car di al space
over a gui dewi r e. If r eadi l y avai l abl e, echocar di ography wi l l hel p
mi ni mi ze compl i cati ons. Removal of a smal l amount of fl ui d r esul ts
i n a dramati c and i mmedi ate i mpr ovement for the pati ent i n
extr emi s. Wi thout addi ti onal tr eatment, mal i gnant per i car di al
effusi ons often r ecur. Thus, a drai nage catheter shoul d be l eft i n
pl ace so that the rate of fl ui d accumul ati on can be moni tor ed. The
opti ons for pr eventi ng r eaccumul ati on i ncl ude tetracycl i ne scl er osi s,
sur ger y, and radi ati on therapy. The i nsti l l ati on of 500 to 1,000 mg
of tetracycl i ne i nto the per i car di al sac i nduces an i nfl ammator y
r esponse, wi th subsequent fi br osi s and obl i terati on of the
per i car di al space. Mul ti pl e i nsti l l ati ons ar e usual l y necessar y.
Tr eatment shoul d be r epeated unti l the drai nage i s l ess than 25 mL
per 24 hour s. Successful contr ol of effusi ons i s obtai ned i n 86% of
pati ents who under go needl e per i car di ocentesi s.
Sur gi cal opti ons to r esol ve per i car di al tamponade i ncl ude
subxi phoi d per i car di otomy, wi ndow per i car dectomy, and compl ete
per i car dectomy. The subxi phoi d appr oach i s usual l y pr efer r ed, as i t
avoi ds the thoracotomy r equi r ed by the other pr ocedur es and can be
per for med under l ocal anesthesi a. Mul ti pl e ser i es have documented
a r ecur r ence rate of 7% after thi s techni que. Compl ete
per i car di ectomy i s r eser ved for pati ents wi th radi ati on-i nduced
effusi ons. Radi ati on therapy i s useful i n stabl e pati ents wi th a
mal i gnant effusi on secondar y to l ymphoma; tr eatment i s gi ven i n
dose fracti ons of 2 to 3 G y to a total dose of 20 to 40 G y.
Outcome after tr eatment of per i car di al tamponade depends i n par t
on tumor type. The medi an sur vi val ti mes range fr om
3.5 months for pati ents wi th l ung cancer to as l ong as 18.5 months
i n pati ents wi th br east cancer.
Paraneoplastic Crises
Some tumor s r etai n the bi ochemi cal character i sti cs of thei r cel l type
of or i gi n and secr ete bi ol ogi cal l y acti ve substances. Other tumor s
can devel op the abi l i ty to synthesi ze and pr oduce hor mones that
have a wi de range of bi ol ogi c effects. The secr eti on of these

substances i s often unr egul ated, thus di sr upti ng homeostasi s. These
states have been ter med paraneopl asti c syndr omes. In pati ents wi th
cancer, these syndr omes may cause sever e symptoms that r equi r e
emer gent tr eatment. The ful l spectr um of paraneopl asti c syndr omes
i s extensi ve; thi s secti on descr i bes the mor e common syndr omes,
hi ghl i ghti ng the physi ol ogi c mani festati ons, pathophysi ol ogy, and
tr eatment of each.
Hypercalcemia
Hyper cal cemi a i s the most common metabol i c compl i cati on of
mal i gnancy, occur r i ng i n appr oxi matel y 10% to 20% of cancer
pati ents. Tumor s most commonl y associ ated wi th hyper cal cemi a
i ncl ude car ci nomas of the br east, l ung, and ki dney, as wel l as
mul ti pl e myel oma. Pati ents wi th parathyr oi d car ci noma
character i sti cal l y pr esent wi th i ntractabl e hyper cal cemi a. Al though
mor e than 80% of pati ents wi th hyper cal cemi a have bone
metastasi s, ther e i s no cor r el ati on between the extent of bone
i nvol vement and the degr ee of hyper cal cemi a, nor between the
pr esence of bony metastasi s and the devel opment of hyper cal cemi a.
Cur r ent data suggest that the hyper cal cemi a of mal i gnancy i s
medi ated by tumor-i nduced humoral factor s. Parathyr oi d hor moner el ated pr otei n (PTHRP), osteocl ast-acti vati ng factor (OAF ),
pr ostagl andi ns, and numer ous other cytoki nes may pl ay a r ol e i n
the devel opment of hyper cal cemi a i n pati ents wi th mal i gnanci es.
Cal ci um homeostasi s i s nor mal l y a ti ghtl y contr ol l ed pr ocess.
Parathyr oi d hor mone (PTH), 1,25-di hydr oxyvi tami n D3 , and
cal ci toni n ar e the pr i mar y r egul ator s of the ser um cal ci um l evel .
These hor mones ensur e that the net absor pti on of cal ci um by the
gastr oi ntesti nal tract i s bal anced by the amount excr eted by the
ki dney. Under nor mal condi ti ons, the ser um cal ci um l evel i s
mai ntai ned between 8.5 mg/dL and 10.5 mg/dL. Appr oxi matel y 45%
of cal ci um exi sts i n the i oni zed, metabol i cal l y acti ve for m, and the
other 55% i s pr otei n-bound. Most cases of hor monal l y medi ated
hyper cal cemi a i n cancer pati ents r esul t fr om the acti vi ty of PTHRP,
whi ch l i ke PTH, enhances r enal tubul ar r esor pti on of cal ci um. Unl i ke
pati ents wi th hyper parathyr oi di sm, pati ents wi th hyper cal cemi a
secondar y to PTHRP have i mpai r ed pr oducti on of 1,25di hydr oxyvi tami n D3 and show no evi dence of r enal bi car bonate
wasti ng. Thi s mechani sm i s par ti cul ar l y pr eval ent i n sol i d tumor s,
especi al l y epi der moi d car ci nomas.
OAF i s r esponsi bl e for hyper cal cemi a i n pati ents wi th mul ti pl e

myel oma and l ymphoma. Thi s osteol yti c pol ypepti de sti mul ates
osteocl ast pr ol i ferati on and the r el ease of l ysosomal enz ymes and
col l agenase. Despi te the potent osteol yti c acti vi ty of OAF i n vi tr o,
pati ents wi th el evated OAF l evel s do not devel op hyper cal cemi a
unl ess ther e i s associ ated r enal i nsuffi ci ency. Transfor mi ng
gr owth factor, epi der mal gr owth factor, i nter l euki n-1, pl atel etder i ved gr owth factor, tumor-der i ved hematopoi eti c col onysti mul ati ng factor s, tumor necr osi s factor (TNF ) (par ti cul ar l y TNF ), and l ymphotoxi n ar e al l potent i nducer s of bone r esor pti on i n
vi tr o and may have a r ol e i n the hyper cal cemi a of mal i gnancy.
Mul ti pl e or gan systems ar e i nvol ved i n the constel l ati on of
symptoms caused by hyper cal cemi a. These symptoms ar e
nonspeci fi c, and thei r sever i ty i s di r ectl y r el ated to the degr ee of
cal ci um el evati on. Neur omuscul ar symptoms often pr edomi nate. If
l eft untr eated, i ni ti al mani festati ons of fati gue, weakness, l ethar gy,
and apathy can pr ogr ess to pr ofound mental status changes and
psychoti c behavi or. Nausea, vomi ti ng, anor exi a, obsti pati on, i l eus,
and abdomi nal pai n ar e among the gastr oi ntesti nal symptoms that
may accompany hyper cal cemi a. Renal tubul ar dysfuncti on can occur
and i s mani fested by the devel opment of pol ydi psi a, pol yur i a, and
noctur i a. Sever e vol ume contracti on occur s, potenti ati ng ser um
cal ci um el evati on. Wi thout pr ompt therapy, pr ol onged hyper cal cemi a
may pr ogr ess to per manent r enal tubul ar damage.
Because cal ci um acts as a neur otransmi tter, the myocar di um i s
par ti cul ar l y pr one to hyper cal cemi a-i nduced toxi ci ty. Acute
hyper cal cemi a can sl ow the hear t rate and shor ten ventr i cul ar
systol e. Wi th moderate el evati on of the cal ci um l evel , the QT
i nter val i s shor tened, and atr i al and ventr i cul ar ar r hythmi as may
occur. El ectr ocar di ographi c changes seen wi th el evated ser um
cal ci um l evel s i ncl ude bradycar di a, pr ol onged PR i nter val , shor tened
QT i nter val , and wi dened T waves. Under extr eme ci r cumstances, an
acute r i se i n ser um cal ci um can r esul t i n sudden death fr om car di ac
ar r hythmi as.
Laborator y studi es cr i ti cal i n the wor kup of pati ents wi th
hyper cal cemi a i ncl ude ser um cal ci um, phosphate, al kal i ne
phosphatase, PTH, el ectr ol ytes, bl ood ur ea ni tr ogen, total pr otei n,
al bumi n, and cr eati ni ne l evel s. In pati ents wi th sever e
hypoal bumi nemi a, the i oni zed cal ci um l evel i s mor e accurate than
the ser um cal ci um l evel . Al so, abnor mal bi ndi ng of cal ci um to
parapr otei n wi thout an el evati on i n the i oni zed cal ci um l evel can be
seen i n pati ents wi th mul ti pl e myel oma. El evated i mmunor eacti ve

PTH l evel s i n associ ati on wi th hypophosphatemi a suggest ectopi c
PTH secr eti on. Hyper cal cemi a secondar y to mal i gnancy usual l y has
an acute onset, a hi gh ser um cal ci um l evel (>14 mg/dL), a l ow
ser um chl or i de l evel , and el evated or nor mal ser um phosphate and
bi car bonate l evel s. These l aborator y fi ndi ngs hel p di ffer enti ate
hyper cal cemi a caused by cancer fr om that secondar y to
hyper parathyr oi di sm, whi ch i s associ ated wi th an el evated ser um
cal ci um l evel i n the pr esence of decr eased ser um phosphate and
bi car bonate l evel s.
Pr ompt i denti fi cati on and tr eatment of hyper cal cemi a ar e essenti al .
Symptomati c pati ents and those pati ents wi th a ser um cal ci um l evel
of 12 mg/dL or gr eater r equi r e ur gent tr eatment. Intravenous
hydrati on wi th r estorati on of i ntravascul ar vol ume i ncr eases
gl omer ul ar fi l trati on rate and i s the mai nstay of i ni ti al
management. Di ur eti cs that bl ock cal ci um r esor pti on i n the
ascendi ng l oop of Henl e and augment r enal cal ci um excr eti on (e.g.,
fur osemi de) may be hel pful after i ntravascul ar vol ume has been
r epl eted. The i ni ti al dose of fur osemi de i n pati ents wi thout r enal
i mpai r ment i s 40 mg IV, fol l owed by 40 to 80 mg ever y 2 to 4 hour s
as needed.
Bi sphosphonates bl ock osteocl asti c bone r esor pti on and
substanti al l y r educe ser um cal ci um l evel s. Eti dr onate di sodi um was
the fi r st bi phosphonate appr oved for use i n the Uni ted States. A
typi cal dose r egi men i s 7.5 mg/kg per day IV for several days,
fol l owed by 20 mg/kg per day oral l y. Pami dr onate, a secondgenerati on bi phosphonate, i s mor e effecti ve than eti dr onate and
has the advantage of i nhi bi ti ng bone r esor pti on caused by osteocl ast
acti vi ty whi l e l eavi ng bone mi neral i z ati on uni mpai r ed. F ur ther mor e,
pami dr onate has a faster onset, a l onger effect, and a mor e durabl e
r esponse. The dose of pami dr onate i s 60 to 90 mg gi ven IV. Pati ents
usual l y begi n to noti ce r el i ef of symptoms wi thi n hour s, and the
effect usual l y l asts for 2 to 3 weeks. Mai ntenance therapy can be
gi ven vi a i nter mi ttent IV i nfusi on ever y 3 to 4 weeks, or conti nuous
oral admi ni strati on. Oral dosages between 400 and 1,200 mg/day i n
di vi ded doses have achi eved fai r l y good r esponse rates.
The anti bi oti c pl i camyci n (Mi thraci n), an effecti ve i nhi bi tor of bone
r esor pti on, general l y i nduces a decl i ne i n ser um cal ci um wi thi n 6 to
48 hour s. Pl i camyci n has l i mi ted anti neopl asti c acti vi ty; however,
when used at doses of 25 mg/kg per day by IV i nfusi on, the dr ug
pr ovi des a mar ked r educti on i n bone r esor pti on. Toxi ci ti es of
pl i camyci n i ncl ude thr ombocytopeni a, hypotensi on, and hepati c and
r enal i nsuffi ci ency. These adver se effects ar e rar e when the dosage
i s r estr i cted to l ess than 30 mg/kg per day.
G al l i um ni trate i s another potent i nhi bi tor of bone r esor pti on.
Admi ni strati on of thi s agent to pati ents wi th mal i gnant di sease and
hyper parathyr oi di sm causes pr ofound r educti ons i n ser um cal ci um.
Incor porati on of gal l i um ni trate i nto bone causes hydr oxyapati te to
become l ess sol ubl e and mor e r esi stant to cel l -medi ated r esor pti on.
In addi ti on, gal l i um ni trate i mpai r s osteocl ast aci di fi cati on of bone
matr i x by decr easi ng transmembrane pr oton transpor t. Thi s agent
may al so enhance bone for mati on by sti mul ati ng bone col l agen
synthesi s and i ncr easi ng cal ci um i ncor porati on i nto bone. These
acti ons r esul t i n a net r educti on of ser um cal ci um. When gi ven at a
dosage of 100 to 200 mg/kg per day vi a conti nuous IV i nfusi on, for
5 to 7 days, nor mal ser um cal ci um l evel s ar e achi eved i n 80% to
90% of pati ents. Nephr otoxi ci ty, the dose-l i mi ti ng factor, may be
mi ni mi zed by pr etr eatment IV hydrati on pr i or to tr eatment.
Hyponatremia/Syndrome of Inappropriate
Antidiuretic Hormone
Consi derabl e neur ol ogi c dysfuncti on can occur when the ser um
sodi um l evel fal l s abr uptl y or decr eases to l evel s bel ow 115 to 125
mg/dL. Mental status changes, sei z ur es, coma, and, ul ti matel y,
death may r esul t i f therapeuti c i nter venti on i s not ur gentl y
i nsti tuted. The syndr ome of i nappr opr i ate anti di ur eti c hor mone
(SIADH) may be associ ated wi th cancer s of the pr ostate, adr enal
gl ands, esophagus, pancr eas, col on, and head and neck as wel l as
wi th car ci noi d tumor s and mesothel i omas. Smal l cel l car ci noma of
the l ung i s the most common mal i gnancy associ ated wi th SIADH.
Di l uti onal hyponatr emi a i s caused by excessi ve water r esor pti on i n
the col l ecti ng ducts. Thi s i ncr ease i n i ntravascul ar vol ume l eads to
i ncr eased r enal per fusi on al ong wi th a substanti al decr ease i n
pr oxi mal tubul ar absor pti on of sodi um. In the pr esence of r enal
i nsuffi ci ency, ther e i s i ncr eased ADH secr eti on and excessi ve water
r eabsor pti on fr om the col l ecti ng ducts, r esul ti ng i n di l uti onal
hyponatr emi a.
Pati ents wi th mi l d hyponatr emi a fr equentl y compl ai n of anor exi a,
nausea, myal gi a, headaches, and subtl e neur ol ogi c symptoms. When
the onset of hyponatr emi a i s rapi d or the absol ute ser um sodi um
l evel fal l s bel ow 115 mg/dL, pati ents devel op sever e neur ol ogi c
dysfuncti on. Al terati ons i n mental status can range fr om l ethar gy to

confusi on and can ul ti matel y pr ogr ess to coma. Sei z ur es and
psychoti c behavi or can occur at l ow ser um sodi um l evel s as wel l .
Physi cal fi ndi ngs i n pati ents wi th pr ofound hyponatr emi a i ncl ude
al terati ons i n mental status, abnor mal r efl exes, papi l l edema, and,
occasi onal l y, focal neur ol ogi c si gns.
Laborator y data and di agnosti c studi es ai d cl i ni ci ans i n deter mi ni ng
the eti ol ogy of hyponatr emi a. Pseudo-hyponatr emi a i s due to
hyper pr otei nemi a, hyper gl ycemi a, or hyper l i pi demi a. Ser um pr otei n
el ectr ophor esi s, gl ucose, and l i pi d deter mi nati ons can r ul e thi s out.
The possi bi l i ty of dr ug-i nduced hyponatr emi a shoul d al so be
consi der ed. Such chemotherapeuti c agents as vi ncr i sti ne and
cycl ophosphami de, as wel l as manni tol , mor phi ne and di ur eti cs, may
contr i bute to hyponatr emi a, as may the abr upt wi thdrawal of
cor ti coster oi ds.
A detai l ed hi stor y and physi cal exami nati on, al ong wi th car eful
eval uati on of the pati ent's fl ui d i ntake and output i s often suffi ci ent
to deter mi ne a pati ent's i ntravascul ar vol ume and can el i mi nate
water toxi ci ty as a possi bl e cause of hyponatr emi a. Laborator y
i nvesti gati on shoul d i ncl ude measur ement of ser um and ur i ne
el ectr ol ytes and cr eati ni ne. A typi cal fi ndi ng i n pati ents wi th SIADH
i s that the ur i ne sodi um concentrati on i s i nappr opr i atel y hi gh for
the l evel of hyponatr emi a. Al so, the ur i ne osmol al i ty i s often
gr eater than the pl asma osmol al i ty, and the ur i ne i s never
maxi mal l y di l uted. Other fi ndi ngs i ndi cati ve of SIADH i ncl ude a l ow
BUN, hypour i cemi a, and hypophosphatemi a, whi ch r esul t fr om
decr eased r enal pr oxi mal tubul ar r esor pti on. A chest radi ograph and
head CT scan shoul d be done to excl ude unsuspected pathol ogy of
the pul monar y or central ner vous system (CNS).
Ideal l y, therapy for SIADH shoul d be di r ected towar d the under l yi ng
cause. In the case of smal l cel l l ung cancer, effecti ve mul ti -dr ug
chemotherapy usual l y r esul ts i n r esol uti on of hyponatr emi a. SIADH
r esul ti ng fr om CNS metastasi s may i mpr ove wi th the use of
cor ti coster oi ds and radi ati on therapy. If the eti ol ogy of SIADH
cannot be i denti fi ed, then the therapy for pati ents wi th sever e
hyponatr emi a i s water r estr i cti on: a r estr i cti on of fr ee water to 500
to 1,000 mL/day shoul d cor r ect the hyponatr emi a wi thi n 5 to 10
days. If the ser um sodi um l evel does not i mpr ove after r estr i cti on of
fr ee water for thi s per i od, demecl ocycl i ne shoul d be used.
Demecl ocycl i ne i s an ADH antagoni st that pr oduces a dosedependent, r ever si bl e nephr ogeni c di abetes i nsi pi dus. The
r ecommended i ni ti al dose of demecl ocycl i ne i s 600 mg dai l y (gi ven
i n two or thr ee di vi ded doses). The potenti al adver se effect of

nephr otoxi ci ty wi th demecl ocycl i ne i s usual l y seen onl y when
extr emel y
hi gh doses ar e used (1,200 mg/day). Because thi s agent i s secr eted
i n ur i ne and bi l e, dose adjustments must be made i n pati ents wi th
r enal or hepati c i nsuffi ci ency.
When sever e hyponatr emi a pr oduces sei z ur es or coma, 3%
hyper toni c sal i ne or nor mal sal i ne i nfusi on wi th IV fur osemi de
shoul d be used. The rate of cor r ecti on of the ser um sodi um l evel
shoul d be l i mi ted to 0.5 to 1.0 mEq per hour to mi ni mi ze the r i sk of
CNS toxi ci ty.
Hypoglycemia
Insul i n-pr oduci ng i sl et cel l tumor s (i nsul i nomas) ar e the
pr ototypi cal l esi ons associ ated wi th hypogl ycemi a. However, other
tumor s that often r esul t i n hypogl ycemi a i ncl ude hepatomas,
adr enocor ti cal tumor s, and tumor s of mesenchymal or i gi n.
Mesenchymal tumor s compr i se mor e than 50% of non-i sl et cel l
neopl asms seen i n associ ati on wi th hypogl ycemi a. Of these,
mesothel i oma, fi br osar coma, neur ofi br osar coma, and
hemangi oper i cytoma ar e the most common.
The mechani sm of hypogl ycemi a r esul ti ng fr om i nsul i nomas i nvol ves
the unr egul ated and i nappr opr i ate secr eti on of excess i nsul i n. In
contrast, the ser um i nsul i n l evel i s nor mal i n cases of non-i sl et cel l
tumor s. Substances wi th non-suppr essi bl e i nsul i n-l i ke acti vi ti es
(NSILAs) have been detected i n pati ents wi th mal i gnancy-associ ated
hypogl ycemi a. Two cl asses of compounds have been i sol ated based
on mol ecul ar wei ght and ethanol sol ubi l i ty. The l ow-mol ecul arwei ght compounds consi st of i nsul i n gr owth factor (IG F )-I, IG F -II,
somatomedi n A, and somatomedi n C. IG F -I and IG F -II have ami no
aci d sequences si mi l ar to pr oi nsul i n but do not r eact wi th anti i nsul i n anti bodi es. The metabol i c acti vi ty of these compounds i s
onl y 1% to 2% that of i nsul i n. Appr oxi matel y 40% of cancer
pati ents wi th symptomati c hypogl ycemi a have el evated pl asma
l evel s of NSILAs.
Incr eased gl ucose use may account for the hypogl ycemi a seen i n
associ ati on wi th l ar ge tumor s. Hepati c gl ucose pr oducti on (700
g/day) may fal l shor t of dai l y gl ucose r equi r ements i n the pr esence
of tumor s wei ghi ng mor e than 1 kg, whi ch use 50 to 200 g/day of
gl ucose. Defects i n the usual counter-r egul ator y mechani sm of
gl ucose contr ol may al so account for mal i gnancy-i nduced

hypogl ycemi a. Cancer-r el ated hypogl ycemi a usual l y devel ops
gradual l y and does not al l ow the usual i ncr ease i n counterr egul ator y hor mones seen wi th hypogl ycemi a ar i si ng fr om
nonmal i gnant eti ol ogi es.
Symptoms of hypogl ycemi a i ncl ude excessi ve fati gue, weakness,
di z z i ness, and confusi on. In mal i gnancy-associ ated hypogl ycemi a,
neur ol ogi c symptoms usual l y pr edomi nate and may pr ogr ess to
sei z ur es and coma i f l eft untr eated. These mor e sever e neur ol ogi c
compl i cati ons ar e usual l y associ ated wi th ser um gl ucose l evel s
bel ow 40 to 45 mg/dL.
Befor e cancer i s deter mi ned to be the eti ol ogy of hypogl ycemi a, al l
other potenti al causes must be excl uded. Exogenous i nsul i n or oral
hypogl ycemi c agents, adr enal i nsuffi ci ency, pi tui tar y i nsuffi ci ency,
ethanol abuse, and mal nutr i ti on ar e among the common causes of
hypogl ycemi a. In cases of cancer, measur ement of fasti ng ser um
gl ucose and i nsul i n l evel s wi l l ai d i n deter mi ni ng whether
hypogl ycemi a i s due to an i sl et cel l tumor or to a non-i sl et
cel l tumor. Pati ents wi th i nsul i nomas have i ncr eased i nsul i n l evel s,
wi th fasti ng gl ucose l evel s bel ow 50 mg/dL. In contrast, cases of
non-i sl et cel l tumor s ar e mar ked by a nor mal or l ow i nsul i n l evel
associ ated wi th hypogl ycemi a. Al so, because i nsul i nomas pr oduce
l ar ge amounts of pr oi nsul i n, they tend to have an el evated
pr oi nsul i n-to-i nsul i n rati o.
Under i deal ci r cumstances, compl ete exti r pati on of the tumor i s the
opti mal therapeuti c i nter venti on for hypogl ycemi a secondar y to
sol i d tumor s. In cases of an i nsul i noma, si mpl e enucl eati on or
subtotal pancr eatectomy fr equentl y pr ovi des a cur e. About 90% of
these tumor s ar e beni gn. Di azoxi de may benefi t pati ents wi th
i nsul i n-secr eti ng tumor s by i nhi bi ti ng i nsul i n secr eti on. Thi s dr ug i s
not effecti ve i n the tr eatment of non-i sl et cel l tumor s. In some
cases, radi ati on therapy r educes tumor bul k and pr ovi des pal l i ati on
of hypogl ycemi a. Di et modi fi cati on shoul d be used as the second
l i ne of therapy, i .e., when r esecti on i s not possi bl e. F r equent
feedi ngs can r educe hypogl ycemi c attacks. Cor ti coster oi ds and
gr owth hor mone may pr ovi de temporar y r el i ef. Subcutaneous
gl ucagon i njecti ons can al so be used to ai d i n gl ucose r egul ati on.
Tumor Lysis Syndrome

Tumor l ysi s syndr ome i s a cr i ti cal compl i cati on of cytotoxi c therapy
that r equi r es a team appr oach i n the i ntensi ve car e uni t to pr event
the sequel ae of per manent r enal fai l ur e and death. The syndr ome i s
tr i gger ed by rapi d cel l tur nover and i ncr eased r el ease of
i ntracel l ul ar contents i nto the bl oodstr eam, and i s character i zed by
hyper ur i cemi a, hyper kal emi a, hyper phosphatemi a, and
hypocal cemi a. Occasi onal l y, thi s syndr ome occur s spontaneousl y i n
pati ents wi th l ymphomas and l eukemi a; however, i t i s mor e common
after cytotoxi c chemotherapy-i nduced rapi d cel l l ysi s. The rapi d
r el ease of i ntracel l ul ar contents can over whel m the excr etor y abi l i ty
of the ki dneys, and el ectr ol yte l evel s can become danger ousl y
el evated. Pati ents wi th l ar ge, bul ky tumor s that ar e sensi ti ve to
cytotoxi c chemotherapy ar e par ti cul ar l y pr one to thi s syndr ome, as
ar e pati ents under goi ng tr eatment for Bur ki tt's or non-Hodgki n's
l ymphoma, acute l ymphobl asti c l eukemi a, acute nonl ymphobl asti c
l eukemi a, or chr oni c myel ogenous l eukemi a i n bl ast cr i si s. Tumor
l ysi s syndr ome can al so occur after tr eatment of smal l cel l l ung
cancer, metastati c br east cancer, and metastati c medul l obl astoma.
Tumor l ysi s syndr ome occur s not onl y wi th cytotoxi c chemotherapy
but al so fol l owi ng radi ati on therapy, hor monal therapy (e.g.,
tamoxi fen), and cr yotherapy of pr i mar y and metastati c tumor s of
the l i ver.
Metabol i c abnor mal i ti es associ ated wi th tumor l ysi s syndr ome
i ncl ude hyper ur i cemi a, hyper kal emi a, and hyper phosphatemi a wi th
hypocal cemi a. The pathol ogi c pr ocesses seen wi th thi s syndr ome ar e
due to the pr opensi ty of ur i c aci d, xanthi ne, and phosphate to
pr eci pi tate i n the r enal tubul es. Thi s pr eci pi tati on can i mpai r r enal
excr etor y functi on and cause fur ther el evati on of these metabol i tes
i n the ser um. Renal i nsuffi ci ency typi cal l y does not devel op fr om
the metabol i c derangements al one; a combi nati on of l ow ur i ne fl ow
rates and el evated ser um metabol i tes i s usual l y r equi r ed to
pr eci pi tate r enal dysfuncti on. Thus, ol i gur i c
pati ents ar e at si gni fi cantl y hi gher r i sk of devel opi ng r enal fai l ur e
dur i ng rapi d cel l ul ar l ysi s.
Hyper kal emi a r esul ts fr om the r el ease of i ntracel l ul ar contents and
i s fur ther per petuated by r enal i nsuffi ci ency. Potassi um el evati on
can have l i fe-thr eateni ng consequences and r equi r es i mmedi ate
i nter venti on. Car di ac toxi ci ty i s evi denced by the character i sti c
el ectr ocar di ographi c changes seen wi th potassi um l evel s above 6
mEq/dL. These changes i ncl ude l oss of P waves, peaked T waves, a
wi dened QRS compl ex, and depr essed ST segments. Hear t bl ock and
di astol i c car di ac ar r est may r esul t i f hyper kal emi a i s l eft untr eated.
Rapi d tumor l ysi s can al so cause hyper phosphatemi a, whi ch i s

usual l y accompani ed by hypocal cemi a. Hypocal cemi a i n tumor l ysi s
syndr ome i s thought to be due to the for mati on of cal ci umphosphate sal ts that pr eci pi tate i n soft ti ssues. Hyper phosphatemi a
i s fur ther exacer bated by the for mati on of these cal ci um-phosphate
compl exes i n r enal tubul es, causi ng pr ogr essi ve r enal i nsuffi ci ency.
Pr eventi ve measur es can be taken to mi ni mi ze the toxi ci ti es of
tumor l ysi s. Pati ents shoul d under go vi gor ous IV hydrati on befor e
tr eatment wi th potenti al l y toxi c chemotherapeuti c agents i s begun.
Another i mpor tant pr eventi ve measur e i s to al kal i ni ze the ur i ne
dur i ng the fi r st 1 to 2 days of cytotoxi c tr eatment. These measur es
counteract hyper ur i cemi a by i ncr easi ng the sol ubi l i ty of ur i c aci d.
Al l opur i nol has al so been shown to effecti vel y decr ease the
for mati on of ur i c aci d and to r educe the i nci dence of ur i c aci d
nephr opathy. In pati ents wi th l ar ge, bul ky tumor s that ar e known to
have a hi gh gr owth fracti on, al l opur i nol shoul d be admi ni ster ed
befor e pl anned chemotherapeuti c i nter venti on.
An el ectr ocar di ogram shoul d be obtai ned i n al l pati ents wi th
hyper kal emi a or hypocal cemi a, and conti nuous car di ac moni tor i ng
shoul d be i nsti tuted. Hyper kal emi a shoul d be tr eated wi th the
standar d measur es for acutel y l ower i ng the ser um potassi um l evel .
These measur es i ncl ude IV admi ni strati on of i nsul i n and gl ucose,
l oop di ur eti cs, and sodi um bi car bonate. Cal ci um shoul d be gi ven to
stabi l i ze the myocar di um. Regar dl ess of measur es used to acutel y
l ower the ser um potassi um, a sodi um-potassi um exchange r esi n
shoul d be gi ven to l ower the total body potassi um l oad (15 g sodi um
pol ystyr ene sul fonate [Kayexal ate] oral l y or by r ectum ever y 6
hour s). If ther e i s evi dence of wor seni ng r enal functi on wi th poor
r esol uti on of the metabol i c abnor mal i ti es, hemodi al ysi s shoul d be
consi der ed.
Central Venous Catheter Sepsis

The use of i ndwel l i ng vascul ar access catheter s i s wi despr ead i n
moder n cancer car e. Catheter-based i nfecti on i s a major sour ce of
mor bi di ty. When catheter i nfecti on i s suspected, the access si te
shoul d be car eful l y exami ned. Er ythema, i ndurati on, and
suppurati on ar e si gns of si te i nfecti on, whi ch r equi r e i mmedi ate
catheter r emoval . Bacter emi a and sepsi s fr om catheter i nfecti on
shoul d be documented by drawi ng bl ood cul tur es fr om both the
catheter and per i pheral si tes. Coagul ase-negati ve staphyl ococci ar e
the most common pathogens i sol ated i n catheter-based i nfecti on,
al though numer ous gram-posi ti ve, gram-negati ve, and
fungal speci es may al so be r esponsi bl e. Mor e than 80% of catheterbased i nfecti ons can be tr eated effecti vel y wi th a 10- to 14-day
cour se of IV anti bi oti cs. Anti bi oti c therapy shoul d be gi ven thr ough
the i nfected catheter and r otated between por ts when mul ti l umen
catheter s ar e pr esent. Per si stence of posi ti ve bl ood cul tur es or si gns
of systemi c sepsi s, par ti cul ar l y i n neutr openi c pati ents, necessi tates
i mmedi ate catheter r emoval . In pati ents wi th vascul ar grafts or
i mpl anted pr ostheses, i mmedi ate catheter r emoval i s i ndi cated once
an i nfecti on has been documented.
Abdominal Emergencies
Intestinal Obstruction
Bowel obstr ucti on conti nues to be a consi derabl e sour ce of
mor bi di ty and mor tal i ty i n pati ents wi th cancer. The deci si ons
r egar di ng the ti mi ng and the extent of sur ger y r emai n di ffi cul t, and
few studi es offer much gui dance. Appr oxi matel y two thi r ds of
pati ents wi th ovar i an cancer pr esent wi th at l east one epi sode of
bowel obstr ucti on, and near l y al l pati ents wi th car ci nomatosi s suffer
some sor t of i ntesti nal compl i cati on. In up to one thi r d of al l
pati ents wi th a hi stor y of cancer who pr esent wi th a bowel
obstr ucti on, the cause of the obstr ucti on i s a beni gn sour ce (e.g.,
adhesi ons, her ni as, and radi ati on enter i ti s). In the other two thi r ds
of these pati ents, ei ther pr i mar y or metastati c di sease i s the sour ce
of thei r i ntesti nal obstr ucti on. The i ntra-abdomi nal mal i gnanci es
most often associ ated wi th obstr ucti on of the gastr oi ntesti nal tract
ar e car ci nomas of the ovar y, col on, and stomach. Extra-abdomi nal
mal i gnanci es may metastasi ze to the per i toneal cavi ty and cause
obstr ucti on; i n such cases, the most common sour ces ar e
car ci nomas of the l ung, br east, and mel anoma.
F uncti onal obstr ucti on of the bowel wi thout a mechani cal cause
(col oni c pseudo-obstr ucti on or Ogi l vi e's syndr ome) i s a common
pr obl em i n pati ents wi th cancer. Nar coti c anal gesi cs, el ectr ol yte
abnor mal i ti es, radi ati on therapy, mal nutr i ti on, and pr ol onged
bedr est may al l contr i bute to del ayed i ntesti nal moti l i ty. The
tr eatment consi sts of cor r ecti ng the under l yi ng cause and
decompr essi ng the bowel wi th a nasogastr i c tube. Col onoscopi c
decompr essi on shoul d be consi der ed when the si ze of the cecum
r eaches 10 cm. Sur ger y i s i ndi cated i f the degr ee of i ntesti nal
di l atati on pr ogr esses to the poi nt of i mpendi ng per forati on or i f the
pati ent shows any evi dence of per i toni ti s. Tube cecostomy i s the
pr ocedur e of choi ce i n these often-debi l i tated pati ents, wi th

r esecti on and i l eostomy for mati on r eser ved for cases of frank
per forati on. Another measur e that has been r ecentl y descr i bed
i nvol ves the admi ni strati on of neosti gmi ne (2.02.5 mg IV). Thi s
therapy has shown pr omi se i n a number of smal l ser i es, but shoul d
onl y be consi der ed for pati ents i n a cl osel y moni tor ed setti ng.
The eval uati on of i ntesti nal obstr ucti on i n pati ents wi th cancer
shoul d be si mi l ar to that i n pati ents wi th beni gn di sease. After a
compl ete hi stor y, physi cal exami nati on, and eval uati on of l aborator y
and radi ol ogi c data, the degr ee and si te of obstr ucti on shoul d be
del i neated. Immedi ate l apar otomy i s i ndi cated for those pati ents
who have si gns or symptoms of i ntesti nal i schemi a,
necr osi s, or frank per forati on (abdomi nal tender ness, l eukocytosi s,
fever, or tachycar di a). Near l y 10% of pati ents wi l l have concur r ent
smal l - and l ar ge-bowel obstr ucti on. To excl ude the possi bi l i ty of
col oni c obstr ucti on befor e l apar otomy, a G astografi n enema may be
obtai ned, par ti cul ar l y i n pati ents wi th mul ti pl e si tes of i ntraabdomi nal tumor. Ei ther an upper gastr oi ntesti nal ser i es wi th smal l bowel fol l ow-thr ough or enter ocl ysi s may be useful i n pati ents wi th
r ecur r ent par ti al smal l -bowel obstr ucti ons. F i nal l y, a CT scan of the
abdomen and pel vi s usi ng oral and r ectal contrast may hel p i denti fy
the l ocati on and eti ol ogy of the obstr ucti on. Befor e l apar otomy, al l
pati ents shoul d under go standar d r esusci tati on i ncl udi ng IV fl ui d
admi ni strati on, cor r ecti on of el ectr ol yte abnor mal i ti es, and
pl acement of a nasogastr i c tube.
In pati ents wi th a par ti al smal l -bowel obstr ucti on, a tr i al of medi cal
management i s wor thwhi l e. Up to 50% of pati ents r espond to
conser vati ve tr eatment, whi ch may r equi r e up to 2 weeks of
i ntesti nal decompr essi on. Sur ger y i s advocated for pati ents who do
not r espond to medi cal management or whose condi ti on pr ogr esses
to compl ete obstr ucti on. Medi cal management i s rar el y successful i n
pati ents wi th a compl ete obstr ucti on at any l evel , and these
pati ents shoul d under go expl orati on. The goal of sur ger y i s to
pr ovi de r el i ef of the obstr ucti on, al though thi s goal cannot al ways
be accompl i shed. The sur geon shoul d ful l y expl or e the abdomen and
attempt to i denti fy the cause of the obstr ucti on. Beni gn adhesi ons
shoul d be l ysed wi th car e. In cases of radi ati on enter i ti s, gentl e
handl i ng of the bowel i s essenti al . Resecti on may be adequate for
shor t segments of i ntesti ne but l ong segments ar e best tr eated by
i nter nal bypass. A si mi l ar appr oach shoul d be taken i n r el i evi ng
bowel obstr ucti on caused by mal i gnancy, al though occasi onal l y the
extent of the mal i gnant di sease i s too extensi ve to al l ow for any of

these opti ons. In such cases, pl acement of a venti ng gastr ostomy
for symptomati c r el i ef i s al l that i s i ndi cated. A gastr ostomy
pr ovi des consi derabl e r el i ef fr om conti nued emesi s and avoi ds the
need for pr ol onged pl acement of a nasogastr i c tube.
Expl orati on r el ated to a mal i gnant bowel obstr ucti on i s associ ated
wi th substanti al mor bi di ty and mor tal i ty. Al most 10% of pati ents di e
because of sur ger y, and another 30% suffer operati ve
compl i cati ons. F ur ther mor e, pati ents have a mean sur vi val of onl y
about 6 months fol l owi ng l apar otomy for a mal i gnant bowel
obstr ucti on. Bowel obstr ucti on fr om beni gn di sease i s rar e i n
pati ents wi th known r esi dual or r ecur r ent i ntra-abdomi nal tumor.
Ther efor e, bowel obstr ucti on i n pati ents wi th documented i ntraabdomi nal di sease can be vi ewed as a pr emor bi d event, wi th
pr ol onged sur vi val unl i kel y despi te any i nter venti on. G i ven such a
poor pr ognosi s, i t i s often mor e appr opr i ate to pur sue nonsur gi cal
opti ons (e.g., pl acement of a per cutaneous endoscopi c gastr ostomy
tube).
Another r ecentl y empl oyed management strategy for mal i gnant
obstr ucti on of the r ectum i s the use of sel f-expandi ng metal stents.
These stents may be used ei ther as a defi ni ti ve measur e or as an
adjunct to al l ow for bowel decompr essi on and cl eansi ng i n
pr eparati on for sur ger y. Whi l e col oni c per forati on i s a potenti al
compl i cati on, these devi ces may al l ow pati ents wi th
near-compl ete obstr ucti ons to avoi d an ostomy and thus enjoy
better qual i ty of l i fe.
Intestinal Perforation
Per forati on of the gastr oi ntesti nal tract i n pati ents wi th cancer may
occur at near l y any ti me i n the cour se of the di sease. Indeed, the
condi ti on may be the pr esenti ng si gn of cancer, such as i n cases of
per forated pr i mar y col or ectal car ci noma. The per forati on may occur
dur i ng tr eatment (ei ther chemotherapy or radi ati on therapy), or i t
may be the r esul t of metastati c tumor l ater i n the cour se of the
di sease. Most per forati ons of the gastr oi ntesti nal tract of cancer
pati ents ar e fr om beni gn causes (e.g., pepti c ul cer di sease,
di ver ti cul i ti s, and appendi ci ti s) and shoul d be tr eated accor di ng to
standar d sur gi cal pr i nci pl es. Sur ger y i s associ ated wi th si gni fi cant
mor bi di ty and mor tal i ty but i s often the onl y therapeuti c opti on
avai l abl e for thi s l i fe-thr eateni ng compl i cati on. Pati ents must be
wel l i nfor med of the r i sks of sur ger y and must under stand that an
ostomy i s a possi bi l i ty befor e an emer gency l apar otomy. Nonsur gi cal
tr eatment, comfor t car e, or both may be appr opr i ate, dependi ng on
the pati ent's wi shes, pr ognosi s, and overal l medi cal status.
Intesti nal per forati on i s the pr esenti ng symptom of di sease i n a
smal l gr oup of pati ents wi th undi agnosed col or ectal car ci noma.
However, on fur ther questi oni ng, these pati ents usual l y state that
they have had some symptoms, whether r el ated to obstr ucti on or to
bl eedi ng, attr i butabl e to the tumor. The per forati on may be the
r esul t of ful l -thi ckness col oni c i nvol vement wi th the tumor and
subsequent necr osi s of a r egi on of the i ntesti nal wal l . A car ci noma
that near l y or compl etel y obstr ucts the l umen of the col on may al so
pr esent wi th per forati on pr oxi mal i n the i ntesti nal tract, usual l y the
cecum. In general , pati ents who pr esent wi th ei ther per forated or
obstr ucti ng col or ectal cancer have a poor er overal l pr ognosi s, stage
for stage, than do pati ents wi thout these pr esentati ons.
F ur ther mor e, the operati ve mor tal i ty rate associ ated wi th
emer gency l apar otomy for per forated col or ectal cancer appr oaches
30% .
Per forati on of the gastr oi ntesti nal tract fol l owi ng chemotherapy for
metastati c sol i d tumor s i s a potenti al l y fatal compl i cati on. The rate
of operati ve mor tal i ty has been r epor ted to be as hi gh as 80% for
an emer gency l apar otomy i n pati ents wi th metastati c cancer
r ecei vi ng chemotherapy. Factor s associ ated wi th a hi gh rate of
compl i cati ons i ncl ude chemotherapy-i nduced myel oi d toxi ci ty,
pr otei n mal nutr i ti on, and i mmunosuppr essi on. F ur ther mor e,
tradi ti onal si gns of an acute sur gi cal abdomen may be masked i n
these pati ents, l eadi ng to a del ay i n di agnosi s. F i nal l y, because the
pr ognosi s of these pati ents i s poor, the deci si on to pr oceed wi th
expl orator y l apar otomy i s di ffi cul t and i s often made l ate i n the
cl i ni cal cour se.
Most cases of gastr oi ntesti nal per forati on r el ated to mal i gnant
di sease ar e caused by hematol ogi c mal i gnanci es, wi th sol i d tumor s,
such as ovar i an car ci noma, bei ng an extr emel y uncommon cause.
Lymphoma wi th i ntesti nal i nvol vement i s the mal i gnancy most l i kel y
to l ead to gastr oi ntesti nal per forati on fol l owi ng systemi c
chemotherapy. In such cases, per forati on i s often r el ated to
transmural i nvol vement of the i ntesti ne,
r esul ti ng i n ful l -thi ckness necr osi s fol l owi ng chemotherapy.
F ur ther mor e, because of the extensi ve i nvol vement of the
gastr oi ntesti nal tract by l ymphoma and the r el ati ve
chemosensi ti vi ty of thi s neopl asm, per forati on i s not uncommon

fol l owi ng chemotherapy. Conver sel y, metastases fr om sol i d or gan
tumor s ar e often l i mi ted to the ser osal sur face and ther efor e do not
l ead to ful l -thi ckness necr osi s fol l owi ng chemotherapy.
Radi ati on therapy di r ected at the abdomen may damage the
gastr oi ntesti nal tract. The extent of i njur y depends on the dose of
radi ati on del i ver ed, the radi ati on fi el ds uti l i zed, the ener gy of the
i oni z i ng radi ati on, and the use of adjuncti ve methods to shi el d the
i ntesti nes. Immedi ate effects i ncl ude damage and subsequent
sl oughi ng of the mucosal l ayer of the i ntesti nal tract. Most of the
i mmedi ate effects l ead to substanti al nausea and vomi ti ng, whi ch
ar e usual l y temporar y. Most pati ents can be managed as
outpati ents, and oral agents can be used to pal l i ate symptoms.
However, a smal l but si gni fi cant fracti on of pati ents r equi r e
hospi tal i z ati on for i ntravenous admi ni strati on of fl ui d and
anti emeti cs. F i nal l y, i n i ts sever est for m, radi ati on-i nduced i njur y
l eads to ful l -thi ckness i njur y of the i ntesti nal tract wi th subsequent
per forati on. Such an i njur y usual l y occur s l ater i n the cour se of the
radi ati on therapy or fol l ows the compl eti on of tr eatment. Once the
di agnosi s i s made, the management of thi s condi ti on i s si mi l ar to
that of any i ntesti nal per forati on.
Upon abdomi nal expl orati on, the ar ea of per forati on shoul d be
r esected, i f possi bl e. A conser vati ve appr oach to r eestabl i shi ng
gastr oi ntesti nal conti nui ty shoul d be used, especi al l y for pati ents
wi th poor nutr i ti onal status, al ter ed host i mmune r esponse or
i mpendi ng shock. Ostomi es shoul d be used l i beral l y and may be
r ever sed at a subsequent pr ocedur e, i f appr opr i ate. F ur ther mor e,
str ong consi derati on shoul d be gi ven to the pl acement of
gastr ostomy and feedi ng jejunostomy tubes. Such devi ces obvi ate
the need for pr ol onged nasogastr i c i ntubati on and al l ow for ear l y
enteral feedi ng.
Biliary Obstruction
Bi l i ar y obstr ucti on by metastases to the hi l um of the l i ver or por tal
l ymph nodes i s an uncommon but tr oubl esome pr obl em i n pati ents
wi th cancer. Such obstr ucti ons may be caused by a var i ety of tumor
types, i ncl udi ng l ymphoma, mel anoma, and car ci noma of the br east,
col on, stomach, l ung, or ovar y. Obstr ucti on of the bi l i ar y tr ee due
to pr i mar y car ci nomas of the common bi l e duct and pancr eas i s
di scussed el sewher e. Eval uati on i s best per for med wi th CT scan,
whi ch pr ovi des i nfor mati on on the si te of obstr ucti on, r eveal s the
degr ee of bi l i ar y obstr ucti on, al l ows eval uati on of the r emai nder of
the abdomen, and often gi ves cl ues as to the cause of obstr ucti on.
When necessar y, endoscopi c ul trasound or CT-gui ded fi ne-needl e
aspi rati on can be per for med i n thi s r egi on to obtai n a ti ssue
di agnosi s.
The pr ognosi s for pati ents wi th bi l i ar y obstr ucti on fr om metastati c
di sease i s poor. In one publ i shed ser i es of 12 pati ents wi th bi l i ar y
obstr ucti on fr om metastases, 11 pati ents had di sease ei ther i n other
i ntra-abdomi nal si tes or i n extra-abdomi nal l ocati ons. The 60-day
mor tal i ty rate i n thi s gr oup has been r epor ted to be as hi gh as 67% .
Thus, tr eatment shoul d
ai m to pal l i ate jaundi ce and to pr event chol angi ti s. Endoscopi c
r etr ograde chol angi opancr eatography and stent pl acement best
accompl i sh drai nage of the bi l i ar y tr ee. If thi s appr oach i s
unsuccessful , per cutaneous transhepati c drai nage i s i ndi cated.
Exter nal -beam i r radi ati on, wi th or wi thout chemotherapy, may al so
pr ovi de substanti al pal l i ati on, especi al l y i n cases of obstr ucti on due
to pr i mar y bi l i ar y or pancr eati c car ci noma. Sur ger y shoul d be
r eser ved for pati ents who ar e at l ow-r i skthat i s pati ents for whom
the r i sk of metastati c di sease i s l ow and the chance for l ong-ter m
sur vi val i s hi gh.
Neutropenic Enterocolitis
The ter ms neutr openi c enter ocol i ti s, typhl i ti s, necr oti z i ng
enter opathy, and i l eocecal syndr ome have al l been used to descr i be
a cl i ni cal enti ty character i zed by febr i l e neutr openi a, abdomi nal
di stensi on, r i ght-si ded abdomi nal pai n, tender ness, and di ar r hea.
The syndr ome most often occur s i n pati ents under goi ng
chemotherapy for a hematol ogi c mal i gnancy, but may al so occur i n
pati ents wi th sol i d tumor s. Si gns and symptoms character i sti cal l y
devel op after neutr openi a l asti ng 7 days or mor e. The i ni ti al
pr esentati on consi sts of r i ght-si ded abdomi nal pai n, tender ness, and
fever and may mi mi c appendi ci ti s. The di agnosi s i s made cl i ni cal l y,
often by excl usi on of other pathol ogi c causes. Ser i al exami nati ons
by the same exami ner ar e cr i ti cal for pr oper di agnosi s and
tr eatment. Abdomi nal fi l ms character i sti cal l y r eveal a nonspeci fi c
i l eus patter n wi th some di l ati on of the cecum. Pneumatosi s i s an
i nconsi stent fi ndi ng. The CT fi ndi ngs for neutr openi c enter ocol i ti s
ar e al so nonspeci fi c, consi sti ng mai nl y of bowel -wal l thi ckeni ng and
edema. However, CT scans ar e i nval uabl e to r ul e out other
pathol ogi c condi ti ons. Compl ete wor kup shoul d i ncl ude stool
cul tur es for bacter i a and Clostr idium difficile toxi n.
The sever i ty of neutr openi c enter ocol i ti s var i es, and therapy must
be i ndi vi dual i zed. Medi cal management, whi ch i ncl udes bowel r est,
nasogastr i c sucti on, br oad-spectr um anti bi oti cs, and IV
hyperal i mentati on, i s successful i n most cases. Al though
granul ocyte transfusi on has never been pr oven to be effecti ve,
granul ocyte col ony-sti mul ati ng factor s, whi ch shor ten the
neutr openi c per i od, l i kel y i mpr ove outcome. Sur gi cal i nter venti on i s
i ndi cated i n cases of per forati on, uncontr ol l ed hemor r hage, sepsi s,
and pr ogr essi on of symptoms on medi cal therapy. Ri ght
hemi col ectomy wi th or wi thout i l eostomy i s the sur ger y of choi ce i n
most cases.
Hemorrhage
Mal i gnant tumor s ar e rar el y the sour ce of si gni fi cant i ntraabdomi nal hemor r hage, even i n pati ents wi th known cancer. Pepti c
ul cer di sease and gastr i ti s, the most common causes of bl eedi ng i n
unsel ected ser i es, ar e the l eadi ng eti ol ogi es i n 54% to 75% of
pati ents wi th cancer. G astr oi ntesti nal l ymphomas and metastati c
tumor s ar e the l esi ons that most commonl y i ni ti ate massi ve
hemor r hage. Because spontaneous hemor r hage caused by tumor s
rar el y occur s, i ndi vi dual s wi th cancer shoul d r ecei ve the same
systemati c appr oach to di agnosi s and tr eatment as do those wi thout
mal i gnant di sease. Whi l e r esusci tati on wi th cr ystal l oi d and bl ood
pr oducts i s under way, the di agnosti c wor kup to defi ne the
si te and eti ol ogy of bl eedi ng shoul d begi n. Bl eedi ng pr oxi mal to the
l i gament of Tr ei tz i s mar ked cl i ni cal l y by hematemesi s or bl ood per
nasogastr i c aspi rate. Upon the fi ndi ng of such si gns, upper
endoscopy shoul d be per for med pr omptl y.
Br i ght r ed bl ood per r ectum shoul d i ni ti ate i nvesti gati on of a col oni c
or r ectal sour ce. In such cases, ei ther pr octoscopy or si gmoi doscopy
ser ves as an expedi ent i ni ti al di agnosti c maneuver. Angi ography and
nucl ear r ed cel l scans ar e often useful to l ocal i ze bl eedi ng si tes i n
the col on and smal l bowel . Mi l d bl ood l oss due to a col oni c neopl asm
can usual l y be tr eated endoscopi cal l y wi th el ectr ocauter y or
pl acement of topi cal hemostati c agents i f the l esi on i s wi thi n the
r ectum. Some pati ents r equi r e ur gent sur gi cal r esecti on of a col oni c
neopl asm for conti nued bl eedi ng, but thi s pr ocedur e can usual l y be
del ayed to al l ow for l ocal i z ati on of the si te of bl eedi ng and unti l the
bowel has been mechani cal l y cl eansed to al l ow for a pr i mar y
anastomosi s. If the bl eedi ng cannot be l ocal i zed and the
hemor r hage i s massi ve, i mmedi ate expl orati on wi th i ntraoperati ve
endoscopy shoul d be consi der ed. Expl orati on, endoscopy, or both
may al l ow l ocal i z ati on of the bl eedi ng si te so that sur gi cal r esecti on
may be di r ected; however, total abdomi nal col ectomy may be
needed i f the hemor r hage cannot be pr eci sel y l ocal i zed. Smal l bowel tumor s rar el y pr esent wi th massi ve gastr oi ntesti nal
hemor r hage, al though gastr i c car ci noma may occasi onal l y pr esent
wi th acute bl eedi ng. The eval uati on and tr eatment appr oaches ar e
near l y i denti cal to those for si mi l ar condi ti ons ar i si ng fr om a col oni c
sour ce, wi th endoscopy as the fi r st l i ne of tr eatment and sur gi cal
r esecti on r eser ved for a mor e el ecti ve setti ng.
Extral umi nal , i ntra-abdomi nal hemor r hage shoul d be suspected
when ther e i s si gni fi cant bl ood l oss wi thout hematemesi s, mel ena,
or hematochez i a. The r etr oper i toneum i s the most fr equent si te of
occul t i ntra-abdomi nal hemor r hage. If thi s condi ti on i s suspected,
CT scan i s the best method of eval uati on. Therapy for i ntraabdomi nal hemor r hage i s i ni ti al l y di r ected at r esusci tati on and
cor r ecti on of any exi sti ng coagul opathy. A hi stor y of aspi r i n or
nonster oi dal anti -i nfl ammator y use wi thi n 1 week must rai se
suspi ci on of pl atel et dysfuncti on, and a bl eedi ng ti me shoul d be
obtai ned. After the si te and sour ce of bl eedi ng have been i denti fi ed,
speci fi c therapy i s i nsti tuted. Under contr ol l ed condi ti ons, i nvasi ve
therapi es, such as angi ographi c embol i z ati on, may be attempted.
The ti mi ng of sur gi cal i nter venti on i s based on the rate and vol ume
of bl ood l oss, the under l yi ng pathol ogy, and the pati ent's overal l
pr ognosi s.
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216:492497.
Chen HS, Sheen-Chen SM. Obstr ucti on and per forati on i n
col or ectal adenocar ci noma: an anal ysi s of pr ognosi s and cur r ent
tr ends. Sur ger y 2000;127:370376.

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docetaxel -based chemotherapy i n pati ents wi th metastati c br east
cancer. Lancet 2000;355:281283.
Lefor AT. Per i operati ve management of the pati ent wi th cancer.
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Mi l l er M. Inappr opr i ate anti di ur eti c hor mone secr eti on. Cur r Ther
Endocr inol Metab 1997;6:206209.
Nussbaum SR. Pathophysi ol ogy and management of sever e
hyper cal cemi a. Endocr inol Metab Clin Nor th Am 1993;22:343
362.
Ostl er PJ, Cl ar ke DP, Watki nson AF, et al . Super i or vena cava
obstr ucti on: a moder n management strategy. Clin Oncol
1997;9:8389.
Ponec RJ, Saunder s MD, Ki mmey MB. Neosti gmi ne for the
tr eatment of acute col oni c pseudo-obstr ucti on. N Engl J Med
1999;341:137141.
Reed CR, Sessl er CN, G l auser F L, et al . Central venous catheter
i nfecti ons: concepts and contr over si es. Intensive Car e Med
1995;21:177183.
Reyes CV, Thompson KS, Massarani -Wafai R, et al . Uti l i z ati on of

fi ne-needl e aspi rati on cytol ogy i n the di agnosi s of neopl asti c
super i or vena cava syndr ome. Diagn Cytopathol 1998;19:8488.
Schi ndl er N, Vogel z ang RL. Super i or vena cava syndr ome.
Exper i ence wi th endovascul ar stents and sur gi cal therapy. Sur g
Clin Nor th Am 1999;79:683694.
Tang E, Davi s D, Si l ber man H. Bowel obstr ucti on i n cancer
pati ents. Ar ch Sur g 1995;130:832836.
Ther i aul t RL. Hyper cal cemi a of mal i gnancy: pathophysi ol ogy and
i mpl i cati ons for tr eatment. Oncology 1993;7:4750.
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Cancer 1992;69:1723.

M.
Edition
> Ta ble o f C o nt e nt s > 2 2 - Bio lo gic a l C a nc e r The ra py
22
Biological Cancer Therapy
Daniel A lbo
Thomas N. W ang
George P. Tuszynski
Introduction
Bi ol ogi cal therapy i s cancer tr eatment that pr oduces anti tumor
effects pr i mar i l y thr ough the mani pul ati on of natural defense
mechani sms of the host. Bi ol ogi cal therapy i nduces, uses, or
modi fi es the host's i mmune system to effi ci entl y r ecogni ze and
destr oy cancer cel l s. Bi ol ogi cal therapy has emer ged as an
i mpor tant four th modal i ty for the tr eatment of cancer, joi ni ng
sur ger y, radi ati on therapy, and chemotherapy i n our
ar mamentar i um agai nst cancer. The i ncr easi ng appl i cati on of
bi ol ogi cal therapy i s the r esul t of a better under standi ng of the
basi c concepts of host defense mechani sms. Basi c sci ence r esear ch
on the i mmune system has taken bi ol ogi cal therapy out of i ts
i nfancy and i nto cl i ni cal tr i al s. Al though several types of bi ol ogi cal
therapi es tar geti ng cytoki nes, vacci nes, cel l ul ar therapi es,
monocl onal anti bodi es (MAbs), and gene therapi es have shown
pr omi se i n the tr eatment of human cancer s, i t i s i n the fi el d of
anti angi ogeni c therapi es wher e some of the better under stood and
mor e pr omi si ng agents ar e bei ng devel oped. Because detai l ed
descr i pti on of al l avai l abl e bi ol ogi cal cancer therapi es i s not feasi bl e
i n onl y one chapter, we focus pr i mar i l y on anti angi ogeni c therapi es.
Angi ogenesi s, or the for mati on of new bl ood vessel s fr om pr eexi sti ng ones, i s a compl ex pr ocess that nor mal l y occur s i n adul ts
onl y under speci fi c condi ti ons such as wound heal i ng, i nfl ammati on,
and devel opment of the cor pus l uteum i n the menstr ual cycl e.
Al though smal l number s of tumor cel l s can potenti al l y sur vi ve
wi thout sti mul ati ng angi ogenesi s, tumor si ze i s l i mi ted, and i n thi s
si tuati on, gr owth i s bal anced by apoptosi s. F ur ther gr owth of the
tumor r equi r es an angi ogeni c swi tch, such that the tumor i nduces
the gr owth of a bl ood suppl y fr om exi sti ng vessel s. Ther e ar e at
l east four potenti al mechani sms by whi ch tumor s can sti mul ate
angi ogenesi s. The fi r st hypothesi s, put for th by Judah Fol kman i n
the 1970s, suggested that tumor s sti mul ate the spr outi ng of new
bl ood vessel s, by secr eti ng pr oangi ogeni c gr owth factor s such as
vascul ar endothel i al gr owth factor (VEG F ), basi c fi br obl ast gr owth
factor (bF G F ), transfor mi ng gr owth factor-beta (TG F -), and other s.
The second mechani sm suggests that tumor s can co-opt exi sti ng
vascul atur e. Thi r d, the r egul ati on of angi ogenesi s may, i n par t, be
contr i buted to by ci r cul ati ng hematopoi eti c pr ecur sor s. The four th
potenti al mechani sm i s known as vascul ar mi mi cr y, a pr ocess by
whi ch aggr essi ve tumor cel l s for m a patter n of vascul ogeni cl i ke
networ ks i n thr ee-di mensi onal cul tur e, wi th concomi tant expr essi on
of vascul ar-associ ated cel l mar ker s.
Tumor angi ogenesi s begi ns by mutual sti mul ati on between tumor
cel l s and endothel i al cel l s by paracr i ne mechani sms. Angi ogenesi s
r equi r es tumor cel l s or str omal cel l s to r el ease sti mul ator y factor s
and endothel i al cel l s to r espond to them such that
endothel i al cel l s can r el ease pr oteol yti c enz ymes to degrade the
extracel l ul ar matr i x for mi grati on and pr ol i ferati on. Endothel i al
pr ol i ferati on typi cal l y occur s at the l eadi ng edge of the mi grati on at
potenti al l y hundr eds of ti mes that obser ved i n qui escent
vascul atur e. Thi s i s fol l owed by l umen for mati on and stabi l i z ati on of
the new vessel . A new basement membrane i s cr eated and suppor t
cel l s (i ncl udi ng per i cytes and smooth muscl e cel l s) ar e r ecr ui ted.
Cel l adhesi on pr otei ns cal l ed i ntegr i ns r egul ate the i nvasi on,
mi grati on, and pr ol i ferati on of endothel i al cel l s. Changes i n
expr essi on of cer tai n i ntegr i ns on the newl y for med spr outs ar e
cr i ti cal for the for mati on of new vessel s. The r esul ti ng chaoti c
tumor vascul atur e i s tor tuous and di l ated wi th heter ogeneous fl ow
and per meabi l i ty.
Under standi ng angi ogenesi s and i ts uni que character i sti cs i n tumor
gr owth has pr ovi ded i nsi ght i nto numer ous ways to i nter r upt thi s
pr ocess. Si nce the mi d-1990s, r esear ch on anti angi ogeni c agents
has expl oded, al ong wi th publ i c i nter est i n i ts potenti al . We now
have a cl ear er under standi ng of the pr ocess of tumor angi ogenesi s,
i ncl udi ng key cytoki nes, di ffer ences between nor mal and i mmatur e
tumor vascul atur e, and endogenous i nhi bi tor s, al ong wi th methods
to quanti fy angi ogenesi s. As a r esul t of thi s, numer ous

anti angi ogeni c agents ar e cur r entl y i n both pr ecl i ni cal and cl i ni cal
tr i al s. However, no cl ear si l ver bul l et has yet emer ged fr om the
agents i nvesti gated thus far. In thi s chapter, we r evi ew the di ffer ent
types of angi ogenesi s i nhi bi tor s avai l abl e for cancer tr eatment and
pr eventi on, and how they have far ed i n cl i ni cal tr i al s. F ur ther mor e,
we anal yze the potenti al pi tfal l s i n tr i al desi gn and i nter pr etati on of
tr i al r esul ts, as wel l as potenti al futur e di r ecti ons i n thi s exci ti ng
r esear ch fi el d.
Angiogenesis Inhibitors
Wi th r espect to thei r tar get, angi ogenesi s i nhi bi tor s can be
subdi vi ded i nto two cl asses: di r ect and i ndi r ect. Di r ect angi ogenesi s
i nhi bi tor s, such as endostati n, tar get the mi cr ovascul ar endothel i al
cel l s that ar e r ecr ui ted to the tumor bed. Di r ect angi ogenesi s
i nhi bi tor s pr event vascul ar endothel i al cel l s fr om pr ol i ferati ng,
mi grati ng, or avoi di ng cel l death i n r esponse to a spectr um of
pr oangi ogeni c pr otei ns (i .e., VEG F, bF G F ) (Tabl e 22.1). Di r ect
angi ogenesi s i nhi bi tor s ar e the l east l i kel y to i nduce acqui r ed dr ug
r esi stance because they tar get geneti cal l y stabl e endothel i al cel l s
rather than unstabl e mutati ng tumor cel l s.
Indi r ect angi ogenesi s i nhi bi tor s general l y pr event the expr essi on of
or bl ock the acti vi ty of a tumor pr otei n that acti vates angi ogenesi s
or the expr essi on of i ts r eceptor on endothel i al cel l s (Tabl e 22.2).
Many of these tumor cel l pr otei ns ar e the pr oducts of oncogenes
that dr i ve the angi ogeni c swi tch. Tar geti ng oncogene pr oducts not
onl y affects cancer cel l pr ol i ferati on and cel l death, but al so
di sr upts the pr oducti on of angi ogeni c factor s. Reacti vati on of tumor
suppr essor s such as p53 can al so i nhi bi t angi ogenesi s by di ffer ent
mechani sms.
It i s i mpor tant for cl i ni cal r esear cher s to r ecogni ze that anti cancer
dr ugs that tar get an oncogene pr oduct can i nhi bi t angi ogenesi s
because thi s can affect dr ug dose and schedul e. A dr ug that i nhi bi ts
angi ogenesi s i ndi r ectl y mi ght be di sconti nued pr ematur el y because
of r esi stance, whi ch i s deter mi ned by
i ncr eased tumor angi ogenesi s. Instead, a second i nhi bi tor coul d be
added to the therapeuti c r egi men. For exampl e, trastuz umab, an
anti body that bl ocks ERBB2 (al so known as HER2/neu) r eceptor
tyr osi ne ki nase si gnal i ng, suppr esses cancer cel l pr oducti on of
angi ogeni c factor s such as TG F -, angi opoi eti n-1 and pl asmi nogen-
acti vator i nhi bi tor-1 (PAI1), and possi bl y al so VEG F. If the tumor,
however, begi ns to expr ess a di ffer ent angi ogeni c pr otei n, such as
bF G F or IL-8, the tumor under tr eatment mi ght seem to have
become r esi stant to trastuz umab, and the therapy wi l l be
di sconti nued. But thi s practi ce mi ght not be
pr udent for a dr ug wi th si gni fi cant anti angi ogeni c acti vi ty. It mi ght
be mor e effecti ve to add a second anti angi ogeni c dr ug to the
r egi men.
Table 22.1. Direct inhibitors of

angiogenesis in clinical trials
Drug
Mechanism
Trial
Direct-acting inhibitors of endothelial

cells/receptor antagonists
Thalidomide
Decrease
TNF, bFGF,
VEGF
Phase I malignant
glioma, melanoma
Phase II
melanoma,
ovarian,
metastatic
prostate,
colorectal,
lymphoma,
gynecologic
sarcomas, liver,
CLL
Phase III non
small-cell lung,
prostate, multiple
myeloma, renal
cell
SU6668
Blocks
VEGF-R2,
FGF-R,
PDGF-R
Phase I advanced
solid tumors
Squalamine
Inhibits
sodiumhydrogen
exchanger
(NHE3)
Phase I advanced
solid tumors
Phase II non
small-cell lung,
ovarian, brain
ZD1839
EGF-R
inhibitor
Phase III non

small-cell lung
Erbitux
(C225)
Monoclonal
antibody
against EGFR
Phase II advanced
solid tumors
Phase III
advanced solid
tumors
IMC-1C11
VEGF-R2
inhibitor
Phase I metastatic
colorectal
Angiozyme
Inhibits
VEGF-R2
and VEFGR2
Phase II breast,
colorectal
Endostatin
Glypican,
tropomyosin,
v3
integrin,
MMP
Phase II
neuroendocrine
tumors,
metastatic
melanoma
Angiostatin
ATP
synthase,
Angiomotin,
v 3 integrin
Phase I advanced
solid tumors
TNF, tumor necrosis factor-; bFGF, basic

fibroblast growth factor; VEGF, vascular
endothelial growth factor; MMP, matrix
metalloproteinase; ATP, adenosine
triphosphate.
Table 22.2. Indirect inhibitors of

angiogenesis in clinical trials
Drug
Mechanism
Trial
Indirect-acting/growth factor inhibitors

Phase II head and
neck, metastatic
renal cell,
advanced
colorectal,
Rhu Mab
VEGF
Monoclonal
antibody
against
VEGF
metastatic breast,
non-Hodgkin
lymphoma,
hematologic
malignancies,
metastatic
prostate,
inflammatory
breast, cervical,
nonsmall-cell
lung
Phase III non
small-cell lung,
metastatic
colorectal,
metastatic breast
MMP inhibitors
BMS275291
Synthetic
MMP
inhibitor
Phase I Kaposi
sarcoma, non
small-cell lung,
brain
COL-3
MMP-2,
MMP-9
inhibitor
Phase II Kaposi
sarcoma, brain
Neovastat
Natural MMP
inhibitor
Phase II multiple
myeloma
Phase III renal
cell, nonsmall-
cell lung
Inhibitors of adhesion molecules/integrins
signaling
Vitaxin
Monoclonal
antibody
against v 3
Phase I/II
irinotecanrefractory
advanced
colorectal cancer
EMD121974
Small
molecule
blocker of
integrin
(anti- v 3 )
Phase I Kaposi
sarcoma
Phase III
anaplastic glioma
Unknown or nonspecific mechanism of

action
Interferon
-2a
Panzem (2ME)
Celecoxib
Decrease
bFGF, VEGF
Phase I/II
advanced solid
tumors
Unknown
Phase I/II
advanced solid
tumors
COX-2
inhibitor
Phase I prostate,
cervical
Phase II cervical,
basal cell,
metastatic breast
IL-12
CAI
IM862
Upregulation
of interferon
Phase I/II Kaposi

sarcoma
Inhibitor of
calcium
influx
Phase I solid
tumors
Phase II ovarian,
metastatic renal
cell
Unknown
Phase II
metastatic
colorectal, ovarian
VEGF, vascular endothelial growth factor; MMP,

matrix metalloproteinase; bFGF, basic
fibroblast growth factor.
Wi th r espect to how they functi on, angi ogenesi s i nhi bi tor s can be
subdi vi ded i nto several categor i es, such as (a) agents that i nhi bi t
vascul ar endothel i al acti vati on; (b) agents that i nhi bi t vascul ar
endothel i al mi grati on, pr ol i ferati on, and/or sur vi val ; (c) agents that
i nhi bi t degradati on of extracel l ul ar matr i x; and (d) agents that
i nhi bi t i ntegr i n acti vati on, among other s.
Agents That Inhibit Vascular Endothelial

Activation: Vascular Endothelial Growth
Factor
One of the key sti mul ator y factor s for endothel i al cel l s found to be
hi ghl y upr egul ated i n angi ogenesi s i s the pi votal cytoki ne VEG F.
VEG F i s par ti cul ar l y notabl e as a gr owth factor for endothel i al cel l s
because i t i s r el ati vel y endothel i al cel l speci fi c and wi l l pr omote the
gr owth of most tumor cel l s onl y due to paracr i ne effects fr om

endothel i al cel l s. Over expr essi on of VEG F has been r epor ted to
occur i n the major i ty of cl i ni cal l y i mpor tant human tumor s
exami ned.
The endothel i al cel l speci fi ci ty of VEG F i s due to the near l y
excl usi ve expr essi on of i ts r eceptor s F l t-1 (VEG F R1) and F l k-1/KDR
(VEG F R2) on endothel i al cel l s. Acti vati on of the F l k-1/KDR r eceptor
i s consi der ed most cl osel y associ ated wi th si gnal s for pr ol i ferati on,
mi grati on, per meabi l i ty, and tube for mati on. Thi s i nfor mati on l ed to
the sear ch for and the devel opment of compounds to i nhi bi t the
tyr osi ne ki nase acti vi ty of the r eceptor or anti bodi es to bl ock
r eceptor acti vi ty. A smal l mol ecul e tyr osi ne ki nase i nhi bi tor,
SU5416 (Pfi zer, New Yor k, NY), whi ch i s membrane per meabl e and
i nhi bi ts the VEG F -dependent phosphor yl ati on of tyr osi ne r esi dues
on the F l k-1 r eceptor, i s cur r entl y i n phase I/II and III tr i al s.
Another r el ated smal l mol ecul e tyr osi ne ki nase i nhi bi tor (SU6668)
cur r entl y i n phase I cl i ni cal tr i al s has been shown to have
si gni fi cantl y gr eater effect on mouse tumor and endothel i al cel l
apoptosi s than SU5416 wi th a cor r espondi ng decr ease i n l i ver
metastases of CT-26 col on cancer cel l s. Both SU5416 and SU6668
i nhi bi t tumor endothel i al cel l pr ol i ferati on and decr ease tumor
vascul ar i z ati on. In other studi es, oral l y or i ntraper i toneal l y
admi ni ster ed SU6668 demonstrated anti tumor acti vi ty wi thout toxi c
effect i n mi ce wi th xenografts of var i ous cancer cel l l i nes. Because
i nhi bi ti on of VEG F may be r equi r ed on a chr oni c basi s, the
devel opment of oral i nhi bi tor s such as SU6668 and ZD4190 (an
i nhi bi tor of both the F l k-1 and F l t-1 r eceptor s) may pr ove val uabl e.
Inhi bi ti on of the VEG F F l k-1/KDR r eceptor and decr eased tumor
gr owth has al so been demonstrated usi ng MAbs. In addi ti on to
anti bodi es agai nst the VEG F r eceptor s, the MAb A.4.6.1 agai nst
VEG F pr otei n has i nhi bi ted tumor gr owth and metastases i n
pr ecl i ni cal studi es. RhuMAb VEG F (G enentech, South San F ranci sco,
CA), a humani zed for m of the anti body, has been studi ed i n
pr ecl i ni cal tr i al s, wher e i t has been wel l tol erated, and i s cur r entl y
bei ng used i n phase II and III cl i ni cal tr i al s.
In addi ti on to pr ecl i ni cal and cl i ni cal tr i al s to eval uate VEG F and
VEG F r eceptor i nhi bi ti on, tr i al s combi ni ng these anti angi ogeni c
agents wi th other tradi ti onal cytotoxi c strategi es have been
i ni ti ated. A pr ecl i ni cal mouse study combi ni ng anti-VEG F
r eceptor anti body wi th the chemotherapeuti c agents
cycl ophosphami de, vi nbl asti ne, Taxol , or doxor ubi ci n demonstrated
that combi ned tr eatment potenti ates the anti tumor effect of ei ther
dr ug al one. A phase I/II tr i al combi ni ng SU5416, a VEG F -r eceptor
i nhi bi tor, wi th pacl i taxel , a chemotherapy agent affecti ng both
mi cr otubul es and angi ogenesi s, i s ongoi ng i n pati ents wi th advanced
mal i gnanci es. In addi ti on, combi nati on anti-VEG F therapy has al so
been suggested for pati ents under goi ng andr ogen abl ati on therapy
or i n combi nati on wi th exter nal -beam radi ati on.
Agents That Inhibit Vascular Endothelial

Migration, Proliferation, and/or Survival
TNP-470 (AGM-1470)
TNP-470 (TAP Phar maceuti cal s, Lake For est, IL) i s a potent anal og
of the anti bi oti c fumagi l l i n and i s cur r entl y i n phase II cl i ni cal tr i al s
on var i ous sol i d tumor s. It i nhi bi ts endothel i al mi grati on,
pr ol i ferati on, and tube for mati on, as wel l as the gr owth and
metastasi s of numer ous human xenografts and mur i ne tumor s. It
has demonstrated l i ttl e toxi ci ty i n pati ents and has been associ ated
wi th par ti al r esponses such as di sease stabi l i z ati on or tumor
fl atteni ng i n some (18% ) Kaposi sar coma pati ents, di sease
stabi l i z ati on of some cer vi cal cancer (33% ) pati ents, and decr eased
pr ostate-speci fi c anti gen l evel i n 1 of 32 pr ostate cancer pati ents.
Tr eatment wi th TNP-470 has been shown to be mor e effecti ve at
l i mi ti ng the gr owth of mi cr ometastases than l i mi ti ng the gr owth of
establ i shed pr i mar y tumor s. The effect of TNP-470 as an
anti angi ogeni c agent used i n combi nati on wi th other anti angi ogeni c
agents, other chemotherapeuti c agents, and i oni z i ng radi ati on i s
al so cur r entl y bei ng i nvesti gated.
Thalidomide
Thal i domi de (Cel gene Cor porati on, Summi t, NJ), or i gi nal l y
pr escr i bed as an oral sedati ve that pr oduced stunted l i mb gr owth
when used i n the fi r st 2 months of pr egnancy, has been found to
i nhi bi t angi ogenesi s. When used i n nonpr egnant adul ts, i t has been
associ ated wi th few si de effects. It i s cur r entl y bei ng used r outi nel y
to tr eat l epr omatous l epr osy and to i nhi bi t the gr owth of sol i d
tumor s i n pr ecl i ni cal and cl i ni cal tr i al s (phase II). The speci fi c
mechani sm by whi ch thal i domi de i nhi bi ts angi ogenesi s i s cur r entl y
unknown. As thal i domi de bl ocks angi ogenesi s i nduced by both bF G F
and VEG F, i t may tar get mul ti pl e pathways. It has al so been
hypothesi zed that i t may downr egul ate v3 i ntegr i n r eceptor s.
Thal i domi de may al so di sr upt l ater-stage events i n angi ogenesi s and

has been shown to i nduce fenestrati ons i n bl ood vessel s of tr eated
ani mal s that ar e not obser ved i n contr ol ani mal s. Al though
thal i domi de has mi ni mal anti tumor effects when used al one, i ts
appar ent abi l i ty to i ncr ease effi cacy of tr eatment i n combi ned
therapy (i .e., wi th Cytoxan, Adr i amyci n, or 5-F U) studi es i s
i ntr i gui ng.
Angiostatin and Endostatin

Angi ostati n i s a fragment of human pl asmi nogen, and endostati n i s
a fragment of col l agen XVIII that i s 30 ti mes mor e potent than
angi ostati n. Both agents have been shown to bl ock endothel i al
pr ol i ferati on, mi grati on, and tube for mati on i n vi tr o, and
angi ogenesi s and metastasi s i n vi vo. Concer ns that angi ostati n
therapy may r equi r e hi gh dosages, r epeated i njecti ons, and l ongter m therapy have made i t l ess attracti ve for cl i ni cal tr i al s.
A ver y di ffer ent and much mor e opti mi sti c potenti al for the use of
angi ostati n i s i ts potenti al use i n combi nati on wi th exter nal -beam
radi ati on. Exper i mental data pr ovi de suppor t for combi ni ng i oni z i ng
radi ati on wi th angi ostati n to i mpr ove tumor eradi cati on wi thout
i ncr easi ng del eter i ous effects, suggesti ng that angi ostati n may be
most effecti ve i n cl i ni cal tr i al s when used i n combi nati on therapy,
rather than as pr i mar y therapy.
Endostati n i s cur r entl y i n phase I cl i ni cal studi es of sol i d tumor s. In
studi es i n whi ch the effi cacy of endostati n has been compar ed wi th
angi ostati n, endostati n appear ed mor e effecti ve i n i nhi bi ti ng tumor
gr owth at several stages of gr owth. However, the combi nati on of
endostati n wi th angi ostati n has pr oven mor e effecti ve than
endostati n or angi ostati n al one i n pr ecl i ni cal studi es.
Agents That Inhibit Degradation of

Extracellular Matrix
For new vessel s to devel op, degradati on of the basement membrane
by pr oteol yti c enz ymes i s necessar y for tumor i nvasi on, metastasi s,
gr owth, and angi ogenesi s. In addi ti on, thi s degradati on r el eases
gr owth factor s or i nhi bi tor s fr om the extracel l ul ar matr i x (ECM).
ECM pr oteol ysi s occur s by the acti vi ty of two types of pr oteol yti c
enz ymes, pl asmi n and the matr i x metal l opr otei nases (MMPs).
Incr eased expr essi on of MMPs has been l i nked to i nvasi ve behavi or
and metastati c potenti al , and i ncr eased expr essi on of MMPs has
been documented i n numer ous human cancer s. Several i nhi bi tor s
ar e now i n advanced cl i ni cal tr i al s and i ncl ude mar i mastat (phase
I/II/III) and AG 3340 (phase II/III).
Marimastat
Mar i mastat i s a second-generati on, pepti domi meti c MMP i nhi bi tor
wi th oral bi oavai l abi l i ty devel oped fr om bati mastat. Li ke bati mastat,
mar i mastat i s r el ati vel y nonspeci fi c, i nhi bi ti ng the acti vi ty of MMP1, -2, -3, -7, and -9. In pr ecl i ni cal studi es, mar i mastat i nhi bi ted
tumor metastasi s. Ther e wer e dose-l i mi ti ng toxi ci ti es, i ncl udi ng
muscul oskel etal si de effects (sever e i nfl ammator y pol yar thr i ti s) i n
al l the studi es, par ti cul ar l y of the ar ms and hands. Despi te some
ear l y di scouragi ng r esul ts, a r ecent phase III cl i ni cal tr i al has
shown a sur vi val benefi t for pati ents wi th metastati c gastr i c cancer
tr eated wi th mar i mastat. The gr eatest benefi t was obser ved i n
pati ents that had pr evi ousl y r ecei ved chemotherapy (5-F Ubased).
In addi ti on, a phase II cl i ni cal tr i al of gl i obl astoma pati ents showed
a sur vi val advantage for pati ents tr eated wi th mar i mastat and
temozol omi de combi nati on therapy. These tr i al s showed that MMP
i nhi bi tor s can act syner gi sti cal l y wi th other chemotherapeuti c
and/or bi ol ogi cal agents. In addi ti on, a phase III cl i ni cal tr i al of
pancr eati c cancer pati ents showed that the effect of mar i mastat was
comparabl e to that of the toxi c chemotherapeuti c agent
gemci tabi ne. The r esul ts of these cl i ni cal tr i al s ar e i ndeed ver y
pr omi si ng because they r epr esent the fi r st cl ear i ndi cati on that
anti angi ogeni c agents can offer
a si gni fi cant sur vi val advantage i n cancer pati ents. F ur ther mor e,
these tr i al s onl y i ncl uded pati ents wi th advanced di sease
(di ssemi nated metastasi s), not the i deal tar get popul ati on for these
type of agents. Ther efor e, usi ng these agents i n pati ents wi th l ess
advanced di sease coul d yi el d potenti al l y even better r esul ts.
AG3340
AG 3340 (Agour on Phar maceuti cal s, Inc., San Di ego, CA) i s a
hydr oxami ni c aci d der i vati ve MMP i nhi bi tor based on MMP X-ray
cr ystal l ography. AG 3340 potentl y i nhi bi ts MMP-2, -9, -3, -13, and
-14. AG 3340 decr eases tumor angi ogenesi s and has si gni fi cant
anti metastati c and anti tumor acti vi ty. The l ar ge magni tude of
i nhi bi ti on by AG 3340 i s i n contrast to the modest i nhi bi ti on by
other MMP i nhi bi tor s. Combi nati on therapy of MMP i nhi bi ti on wi th
cytotoxi c chemotherapy may pr ove mor e effecti ve than ei ther

modal i ty used al one. Thi s agent i s cur r entl y i n phase II/III studi es,
i ncl udi ng combi nati on studi es wi th Taxol and car bopl ati n.
Agents That Inhibit Integrin Activation

Integr i ns ar e heter odi mer i c transmembrane pr otei ns r esponsi bl e not
onl y for cel l -extracel l ul ar matr i x adhesi on, but al so for the
r egul ati on of entr y i nto and wi thdrawal fr om the cel l cycl e.
Appr opr i ate i ntegr i n acti vati on on endothel i al cel l s i s r equi r ed for
maturati on of angi ogeni c vessel s because bl ockade of cer tai n
i ntegr i ns dur i ng angi ogenesi s may r esul t i n apoptosi s of endothel i al
cel l s on newl y for med vascul ar spr outs wi th decr eased angi ogenesi s.
One of these i ntegr i ns, the v3 r eceptor, i s abl e to bi nd numer ous
extracel l ul ar matr i x pr otei ns vi a an ar g-gl y-asp (RG D) sequence.
Intense r esear ch has been focused on thi s r eceptor because i t i s
expr essed onl y at l ow l evel s on qui escent vascul ar, i ntesti nal , and
uter i ne smooth muscl e cel l s but i s hi ghl y acti vated on cytoki nesti mul ated endothel i al cel l s and smooth muscl e cel l s, par ti cul ar l y
those on newl y for med vessel s ar ound tumor s. Exper i mental data
show that thi s r eceptor pl ays a si gni fi cant r ol e i n tumor
angi ogenesi s and tumor pr ogr essi on.
Vi taxi n (IXSYS, Inc., Lajol l a, CA), the humani zed for m of the MAb
v3 i nhi bi tor LM609, i s now i n phase II cl i ni cal tr i al s i n cancer
pati ents. Vi taxi n i nduced ei ther stabl e di sease or tumor shr i nkage
i n 8 of 14 pati ents wi th no appar ent toxi ci ty at al l dose l evel s.
In addi ti on to the MAb LM609, cycl i c RG D pepti des have been
devel oped that speci fi cal l y i nhi bi t the v3 r eceptor, i ncl udi ng
EMD121974 (Mer ck & Co., Inc., Whi tehouse Stati on, NJ), a cycl i c
pentapepti de cur r entl y i n phase I tr i al s. Such smal l cycl i c pepti des
ar e easi l y synthesi zed, ar e r esi stant to pr oteol ysi s, and have onl y
weak i mmunogeni ci ty. Cycl i c RG D pepti des syner gi ze wi th anti bodycytoki ne fusi on pr otei ns to eradi cate pr i mar y tumor s and metastasi s
i n syngenei c mouse model s. For thi s strategy, i nfl ammator y cel l s
that ar e acti vated and di r ected to the tumor mi cr oenvi r onment by
tumor-speci fi c anti body-IL-2 fusi on pr otei ns medi ate the tumor cel l speci fi c therapy. The anti angi ogeni c tr eatment may suppr ess
mi cr ometastases-i nduced neovascul ar i z ati on and thus pr ecl ude
enl ar gement of metastati c foci . Thi s woul d faci l i tate eradi cati on of
mi cr ometastases by tumor-di r ected
therapi es, whi ch ar e opti mal l y effecti ve i n the mi ni mal r esi dual
di sease setti ng. The si mul taneous tar geti ng of the vascul ar and
tumor compar tments pr oved ver y effecti ve i n these model s; i t
combi ned a decr ease i n tumor cel l nour i shment wi th the acti ve
destr ucti on of tumor cel l s, l eadi ng to a r egr essi on of pr i mar y tumor s
and the eradi cati on of di stant metastases. The r esul ts suggest that
combi nati ons of speci fi c anti angi ogeni c and tumor cel l -tar geted
therapi es may fr equentl y syner gi ze i n r egr essi on of pr i mar y tumor s
and eradi cati on of mi cr ometastases.
Antiangiogenic Agents: Chemoprevention

The potenti al to bl ock tumor gr owth i n the ear l y stages of tumor
devel opment by i nhi bi ti ng neoangi ogeni c pr ocesses r epr esents an
i ntr i gui ng appr oach to the tr eatment of cancer. The hi gh
pr ol i ferati on rate i n the tumor depr i ved of pr oper vascul ar i z ati on
woul d be bal anced by cel l death due to l ack of di ffusi on of nutr i ents
and oxygen. Anti angi ogeni c agents can pr event the fur ther gr owth
of mi cr ometastases. Incr easi ng evi dence i ndi cates that the
angi ogeni c swi tch, defi ned as the poi nt at whi ch a tumor i nduces
angi ogenesi s, occur s ver y ear l y i n tumor i genesi s i n both mur i ne
model s and human tumor s, and that ear l y i nter venti on can cur tai l
tumor gr owth.
Cancer chemopr eventi on i s the use of agents to sl ow or i nhi bi t the
pr ogr essi on of car ci nogenesi s wi th the ai m of l ower i ng the r i sk of
devel opi ng i nvasi ve or cl i ni cal l y si gni fi cant di sease. Several agents
shown to have chemopr eventi ve acti vi ty i n exper i mental test
systems or cl i ni cal tr i al s al so show si gni fi cant anti angi ogeni c
acti vi ti es. The anti angi ogeni c acti vi ty of many chemopr eventi ve
compounds, or angi opr eventi on, may actual l y be a common and
cr i ti cal effect for the i nhi bi ti on of cancer by these agents thr ough
bl ocki ng or r etar di ng the devel opment of the tumor vascul atur e.
Var i ous substances pr oposed as possi bl e cancer chemopr eventi ve
agents show anti angi ogeni c pr oper ti es when tested i n i n vi tr o and i n
vi vo angi ogenesi s model s. We br i efl y r evi ew several di ver se
chemi cal l y unr el ated chemopr eventi ve agents that appar entl y shar e
common mechani sms to exer t anti angi ogeni c acti vi ty.
Thiols
Modul ati on of extracel l ul ar and i ntracel l ul ar thi ol s i s bei ng
i nvesti gated as a pr omi si ng strategy i n cancer pr eventi on. In
pr ecl i ni cal studi es, N-acetyl -L-cystei ne (NAC), a fr ee oxygen radi cal
scavenger that al so i nhi bi ts COX-2 expr essi on and COX-1-medi ated
acti vati on of car ci nogens, has been shown to i nhi bi t i ni ti al tumor

take, tumor cel l i nvasi on i n vi tr o, and metastasi s for mati on i n vi vo.
NAC i s abl e to cause i nhi bi ti on of secr eted MMP-2 and MMP-9, the
type IV col l agenases typi cal l y over expr essed by tumor s, and
acti vated endothel i al cel l s i nvol ved i n i nvasi on and angi ogenesi s.
NAC coul d al so affect angi ogenesi s by modul ati ng VEG F expr essi on
by tumor cel l s.
Polyphenolic Compounds
F l avonoi ds ar e the most abundant pol yphenol s i n our di et. They ar e
natural estr ogeni c compounds der i ved fr om soybeans, tea, fr ui ts,
and vegetabl es that have been pr oposed to act as chemopr eventi ve
agents. The i sofl avone geni stei n, a pol yphenol found
i n soy pr oducts, i s a potent i nhi bi tor of tyr osi ne ki nases and, al ong
wi th fl avonoi ds such as kaempfer ol and api geni n, i s an i nhi bi tor of
topoi somerases I and II, enz ymes cr uci al to cel l ul ar pr ol i ferati on.
G eni stei n has been shown to i nhi bi t tumor cel l i nvasi on thr ough
i nhi bi ti on of MMP-9 expr essi on i n i n vi tr o and i n vi vo model s of
br east cancer pr ogr essi on. In addi ti on, i t has al so been shown to
i nhi bi t angi ogenesi s by decr easi ng vessel densi ty and l evel s of VEG F
and TG F -1. The benefi ci al effects of gr een tea and i ts acti ve
components have been abundantl y documented i n the l i teratur e,
and i ncl ude cancer chemopr eventi on; i nhi bi ti on of tumor cel l
gr owth, i nvasi on, and metastasi s; and anti vi ral and anti i nfl ammator y acti vi ti es. G r een tea contai ns numer ous pol yphenol s,
most of whi ch ar e fl avonol s commonl y known as catechi ns.
Epi gal l ocatechi n-3-gal l ate (EG CG ), the mai n fl avonol found i n gr een
tea extracts, appear s to act as a di r ect i nhi bi tor of MMP-2 and, wi th
sl i ghtl y l ower effi cacy, of MMP-9. A r ecent study demonstrated that
thi s compound al so i nhi bi ts i n vi vo gr owth and angi ogenesi s of
tumor s der i ved by the col on car ci noma HT29 cel l l i ne by bl ocki ng
the i nducti on of VEG F.
NSAIDs
NSAIDs ar e effecti ve col on cancer chemopr eventi ve agents that
mi ght al so be useful i n pr eventi ng other types of cancer. Recent
r epor ts i ndi cate that NSAIDs i nhi bi t tube for mati on by endothel i al
cel l s i n i n vi tr o model s of angi ogenesi s. The anti angi ogeni c effect of
the sel ecti ve COX-2 i nhi bi tor cel ecoxi b has been demonstrated i n a
rat model of angi ogenesi s. Inhi bi ti on of angi ogenesi s by NSAIDs
appar entl y fol l ows mor e than one pathway, pr ostagl andi n dependent
and i ndependent. Ear l y angi ogeni c sti mul i al so use the MAP ki nase
pathway, whi ch i n tur n can l ead to acti vati on of ni tr i c oxi de
synthase (NOS). Al though the i nhi bi tor y effects of NO on
tumor i genesi s have been associ ated wi th an anti angi ogeni c effect,
the i mpor tance of the di ffer ent i sofor ms of NOS for tumor
vascul ar i z ati on i s not yet cl ear. Many angi ogeni c mol ecul es al so
sti mul ate NOS acti vi ty; endothel i al NOS has been shown to pl ay an
essenti al r ol e i n VEG F -i nduced angi ogenesi s.
PPAR Ligands
A member of the ster oi d hor mone r eceptor super fami l y, PPAR, i s
acti vated by ei cosanoi ds, i ncl udi ng the natural l i gand 15-deoxydel ta12, 14-pr ostagl andi n J2 (15D-PG J2), a pr ostanoi d der i ved fr om
the cycl ooxygenase pr oduct PG D2, and by anti di abeti c agents such
as thi azol i di nedi ones. PPAR i s a key transcr i pti on factor i nvol ved i n
adi pogenesi s and monocyte di ffer enti ati on. The r ol e of PPARs i n
cancer chemopr eventi on has r ecentl y been r evi ewed. PPAR,
acti vated by 15D-PG J2 or by new anti di abeti c agents (BRL49653 and
ci gl i tazone), showed a potent anti angi ogeni c acti vi ty by i nhi bi ti ng
di ffer enti ati on of HUVEC cel l s i nto tubel i ke str uctur es i n a
tr i di mensi onal col l agen matr i x. In addi ti on, 15D-PG J2 and
cycl opentenone pr ostagl andi ns have been shown to i nhi bi t the NF Bdependent transcr i pti on of tar get genes, i ncl udi ng COX-2, by
di r ectl y bl ocki ng IB ki nase i n a PPAR-i ndependent manner. Agai n,
bl ockade of NF -B si gnal i ng i nhi bi ts angi ogenesi s of ovar i an cancer
by suppr essi ng the expr essi on of VEG F and IL-8. Because the NF -B
si gnal i ng
pathway appear s to be a key r egul ator y pathway i n i nfl ammati on
and angi ogenesi s, thi s novel mechani sm coul d enhance the
anti angi ogeni c acti vi ty of COX-2 i nhi bi tor s.
Protease Inhibitors
Because an al ter ed equi l i br i um of the pr otease/pr otease i nhi bi tor
acti vi ty rati o i s at the base of tumor i nvasi on and extravasati on and
i s associ ated wi th other di seases character i zed by excessi ve
angi ogenesi s, an i ncr easi ng number of sel ecti ve pr otease i nhi bi tor s,
i ncl udi ng syntheti c MMP i nhi bi tor s, ar e cur r entl y under cl i ni cal
i nvesti gati on.
Exper i mental evi dence suggests that MMP-7 (matr i l ysi n) pl ays an
essenti al r ol e i n much ear l i er stages of i ntesti nal tumor i genesi s.
Matr i l ysi n i s detected i n a hi gh per centage of pr ei nvasi ve l esi ons, i n

contrast to i ts absence i n most nor mal ti ssues, and i s expr essed by
the epi thel i al -der i ved tumor cel l s. Mani pul ati ng l evel s of thi s
enz yme i n vi tr o r esul ts i n cel l l i nes wi th enhanced tumor i geni c
potenti al , whi l e abl ati ng the gene i n vi vo l eads to a si gni fi cant
r educti on i n tumor number i n two di ffer ent ani mal model s of
i ntesti nal tumor i genesi s. In addi ti on, r egul ati on of matr i l ysi n gene
expr essi on appear s to be under the contr ol of geneti c pathways that
ar e acti vated ear l y i n the tumor devel opment sequence. Al though
the pr eci se mechani sm by whi ch matr i l ysi n acti vi ty contr i butes to
tumor for mati on i s not yet cl ear, i t has been pr oposed that MMP
i nhi bi tor s may be of benefi t as chemopr eventi ve agents, i n addi ti on
to thei r therapeuti c potenti al for metastati c di sease.
Pr otease i nhi bi tor s wi th potenti al use i n angi ogenesi s/tumor
chemopr eventi on i ncl ude the fr ee oxygen radi cal scavenger Nacetyl -L-cystei ne and fl avonoi ds, such as EG CG . N-acetyl -L-cystei ne
i s abl e to r educe the i nvasi ve and metastati c potenti al of mel anoma
cel l s and to i nhi bi t endothel i al cel l i nvasi on by di r ect i nhi bi ti on of
MMP acti vi ty. EG CG , a fl avonoi d fr om gr een tea that possesses
chemopr eventi ve acti vi ty i n exper i mental and epi demi ol ogi c studi es,
i s a potent i nhi bi tor of MMP-2 and MMP-9.
Miscellaneous
Other chemopr eventi ve agents not menti oned i n thi s chapter,
i ncl udi ng natural or syntheti c r eti noi ds, ster oi d hor mone
antagoni sts, per oxi some pr ol i ferator-acti vated r eceptor, and vi tami n
D, mi ght al so have anti angi ogenesi s as an i mpor tant mechani sm of
acti on, a novel concept ter med angi opr eventi on. The angi ogeni c
swi tch i s an ear l y event i n car ci nogenesi s, maki ng angi opr eventi on
an opti mal tar get for cancer pr eventi on.
Antiangiogenic Agents: Trials and

Tribulations
Pr esentl y, a mul ti tude of cl i ni cal tr i al s exi st that test the effi cacy of
anti angi ogeni c agents (Tabl es 22.1 and 22.2). Most of these agents
ar e i n phase I or II tr i al s. At l east 12 anti angi ogeni c agents have
enter ed or compl eted phase III tr i al s. The gr owi ng i nter est i n the
use of anti angi ogeni c agents i n the tr eatment of cancer l i es i n the
theor eti cal advantages of thi s mol ecul ar l y tar geted modal i ty of
chemotherapy. Del i ver y of anti angi ogeni c agents i s not compl i cated
by havi ng to penetrate l ar ge bul ky masses but, i nstead, have easy
access to tumoral endothel i al cel l s. Anti angi ogeni c

dr ugs may not cause cytopeni as and thus wi l l avoi d many of the
unwar ranted toxi ci ti es of standar d chemotherapeuti c agents.
Because they act di r ectl y on nascent endothel i al cel l s,
anti angi ogeni c agents may avoi d tumor r esi stance mechani sms. If
anti angi ogeni c agents ar e successful , they mi ght be appl i cabl e to
many tumor types and not be dependent on cel l type or gr owth
fracti on of cel l s wi thi n a tumor. However, ther e r emai n several
i mpor tant obstacl es wi th r egar d to usi ng anti angi ogeni c dr ugs i n
cl i ni cal tr i al s wi th whi ch we must contend i n or der to accuratel y
deter mi ne the effi cacy of these agents.
Dosage
Because these agents do not r esul t i n the usual toxi ci ti es seen wi th
chemotherapy agents (i .e., bone mar r ow or gastr oi ntesti nal tract),
the appr opr i ate dose that confer s opti mal anti angi ogeni c acti vi ty
may be di ffi cul t to deter mi ne. A dose-l i mi ti ng toxi ci ty may not be
r eached wi th these agents. It i s l i kel y that the opti mal bi ol ogi cal
dose i s not the maxi mal l y tol erated dose. The best way to deter mi ne
appr opr i ate bi ol ogi cal doses i s to have r el i abl e bi ol ogi cal cor r el ates.
Because these have yet to be opti mal l y di scer ned, the dosi ng
pr obl em r emai ns a chal l enge. Many cl i ni cal tr i al s have been
di sconti nued because tumor s have not decr eased i n si ze by
radi ol ogi c measur ements. However, thi s appr oach may not be
accurate because many of these agents i nduce di sease stabi l i z ati on.
Ther e i s al so evi dence i n pr ecl i ni cal studi es wi th angi ostati n and
endostati n that the onset of the anti angi ogeni c effect may take days
to weeks. It may be r easonabl e to conti nue therapy for months
unl ess a bi ol ogi cal cor r el ate demonstrates that the dr ug has no
anti angi ogeni c acti vi ty i n vi vo befor e thi s ti me per i od.
Scheduling of Drugs
Because anti angi ogeni c therapy i s consi der ed to be l ong-ter m,
chr oni c therapy for suppr essi on of pr i mar y tumor gr owth and
metastases, the opti mal schedul i ng of these dr ugs needs to be
deter mi ned. However, many of these studi es l ack phar macoki neti c
i nfor mati on. It i s necessar y to measur e l evel s of the dr ug or i ts
metabol i tes i n the bl ood and to deter mi ne the best r oute and for m
of del i ver y based on chr oni c mai ntenance of effecti ve therapeuti c
concentrati ons. Thi s i nfor mati on may var y fr om pati ent to pati ent,
as wel l as fr om one di sease state to another. Ther efor e, mor e
phar macoki neti c data of new anti angi ogeni c dr ugs fr om pr ecl i ni cal
studi es i s necessar y on entr y to cl i ni cal tr i al s. Desi gn of phase I
tr i al s shoul d i ncl ude measur ement of dr ug l evel s i n the bl ood
because i t i s so cr i ti cal for these agents to mai ntai n a consi stent
therapeuti c dr ug l evel for chr oni c suppr essi on of angi ogenesi s and
tumor gr owth.
Biological End Points

The bi ol ogi cal end poi nts for anti angi ogeni c therapy r emai n
contr over si al . Deter mi ni ng the anti angi ogeni c acti vi ty of i nhi bi tor s
i n pati ents i s chal l engi ng, i n par t, because tumor ti ssue may not be
easi l y avai l abl e for i mmunohi stochemi cal and gene expr essi on
studi es. Some i nvesti gator s ar e now studyi ng endothel i al cel l
sheddi ng fr om tumor vascul atur e as a cor r el ate for
anti angi ogeni c acti vi ty of dr ugs. Methods ar e cur r entl y bei ng
devel oped to detect endothel i al cel l s i n the ci r cul ati on of pati ents.
Other methods to deter mi ne angi ogenesi s i n vi vo i ncl ude i magi ng
strategi es to eval uate per fusi on, angi ography, sonography, and
magneti c r esonance vi sual i z ati on of tumor vascul atur e. The use of
fl uor odeoxygl ucose and posi tr on emi ssi on tomography i magi ng was
used to moni tor r egi onal bl ood fl ow i n tumor s of pati ents
par ti ci pati ng i n a r ecent phase I tr i al of endostati n. Eval uati on of
tumor-fr ee pr ogr essi on, ti me to pr ogr essi on, and di sease
stabi l i z ati on may be the best way to assess new i nhi bi tor s i n cl i ni cal
tr i al . Because most of these i nhi bi tor s may be bl ocki ng new
angi ogeni c gr owth of tumor s, r egr essi on of di sease may be di ffi cul t
to achi eve. The goal of thi s type of tr eatment i s to pr event any
fur ther gr owth of tumor s.
Optimal Clinical Settings

How best to use anti angi ogeni c agents i n cancer therapy i s not
known. Many phase I tr i al s have enter ed pati ents wi th metastati c
di sease after fai l ur e of standar d therapi es. However, i t may not be
the best way to i ncor porate these dr ugs i nto cl i ni cal tr i al s. To gai n
i nsi ght i nto the effecti veness of these agents on i nhi bi ti on of
angi ogenesi s i n vi vo, i t may be best to i ncor porate them i ni ti al l y i n
pati ents who have been successful l y tr eated and deemed fr ee of
di sease (i .e., the adjuvant setti ng). The natur e of the neovessel s i n
advanced di sease may be heter ogeneous and mor e di ffi cul t to tr eat
wi th anti angi ogeni c agents compar ed wi th mi cr oscopi c or ear l ystage di sease, wher e ther e may be a mor e uni for m nascent
vascul atur e. Thi s appr oach may pr event a useful anti angi ogeni c
dr ug fr om bei ng pr ematur el y di scar ded, especi al l y i f i t does not
show acti vi ty i n advanced di sease.
Combination Therapy
How to use these anti angi ogeni c agents wi th other modal i ti es or
other bi ol ogi cal agents has not been deter mi ned. Because some
chemotherapeuti c dr ugs have anti angi ogeni c acti vi ty, per haps ther e
may be syner gi sti c anti tumor effects. Wi th r egar d to combi ni ng
angi ogenesi s i nhi bi tor s wi th radi ati on, per haps they may wor k as
radi ati on sensi ti zer s. In mouse model s, Par i s et al . showed that
mi cr ovascul ar endothel i al cel l s ar e a pr i mar y tar get of radi ati on
damage. Ther e i s al so evi dence that radi ati on therapy del i ver ed to
tumor s i n mi ce can be enhanced i f mi ce ar e tr eated wi th
angi ostati n. Ther efor e, angi ogenesi s i nhi bi tor s coul d be used for
enhanci ng the l ocal effects of radi otherapy and per haps l eadi ng to
l ower r egi onal r ecur r ence rates. The use of anti angi ogeni c agents
can al so be envi si oned i n combi nati on therapi es wi th bi ol ogi cal
agents that have al r eady been appr oved for cancer.
Individualized Therapies
It has been shown that ear l y i n tumor devel opment, one or several
angi ogeni c factor s ar e secr eted by a tumor. Wi th fur ther pr ogr ess of
the tumor, ther e ar e other angi ogeni c factor s that ar e added. Wi th
thi s knowl edge, i t may be envi si oned that anti angi ogeni c therapy
coul d be customi zed, dependi ng on the angi ogeni c pr ofi l e of a
pati ent's tumor and bl ood. Ther efor e, i t may be that anti -VEG F
monocl onal anti body coul d be effecti ve i n ear l y stages, but
that i n advanced stages, i t may be best to combi ne thi s anti body
wi th a tyr osi ne ki nase i nhi bi tor that coul d i nter fer e wi th si gnal i ng
medi ated by other gr owth factor s. G enomi c and pr oteomi c ar rays of
tumor ti ssue coul d hel p i denti fy var i ous hi ghl y expr essed angi ogeni c
factor s and l ead to customi zed therapy.
Future Directions
Molecular Profiling: Treatment Tailored to
the Individual Patient
The concept of empl oyi ng tumor character i sti cs, such as hi stol ogi c
featur es, to pr edi ct the best tr eatment for an i ndi vi dual pati ent has
l ong been par t of the practi ce of oncol ogy. A si gni fi cant r efi nement
of thi s hi stol ogy-based appr oach to sel ecti on of tr eatment has been
the appl i cati on of mol ecul ar mar ker s, an appr oach best exempl i fi ed
i n the use of mar ker s i n the tr eatment of human l eukemi as. For
sol i d tumor s, the devel opment of tumor mar ker s for the pr edi cti on
of therapeuti c r esponse has general l y been much sl ower. However,
the HER2/neu gene i s an i mpr essi ve posi ti ve exampl e of a tumor
mar ker useful i n sol i d tumor s. The HER2/neu gene encodes a 185kD pr otei n bel ongi ng to the transmembrane type I tyr osi ne ki nase
r eceptor fami l y, whi ch al so i ncl udes the EG F r eceptor, HER3, and
HER4. Cl i ni cal studi es demonstrated that HER2 ampl i fi cati on or
over expr essi on i s a mar ker of poor pr ognosi s for pati ents wi th
l ymph node-posi ti ve br east cancer. A major questi on, however, has
been whether thi s poor pr ognosi s i s i r r evocabl e or can be bypassed
by some i nter venti on. In 1994, the Cancer and Leukemi a G r oup B
(CALG B) demonstrated that the poor cl i ni cal outcome of pati ents
wi th l ymph node-posi ti ve br east cancer wi th HER2 over expr essi on
can be over come by adequate dose-i ntensi ve r egi mens of
cycl ophosphami de, doxor ubi ci n, and 5-F U. The HER2-negati ve
gr oup, however, exper i enced no benefi t fr om the dose escal ati on.
These data rai sed the possi bi l i ty that the adver se effects of HER2
over expr essi on can be speci fi cal l y over come by effecti ve doses of
doxor ubi ci n. The most defi ni ti ve test of the HER2doxor ubi ci n
i nteracti on was seen i n two studi es: the r eanal ysi s of the Nati onal
Sur gi cal Adjuvant Br east and Bowel Pr oject tr i al B-11, and the 10year fol l ow-up of the anal ysi s of the compl ete cohor t i n CALG B tr i al
8541. Impor tant i n the anal ysi s was that the HER2 deter mi nati on
was r i gor ousl y val i dated thr ough concur r ent anal ysi s by
i mmunohi stochemi str y, di ffer enti al pol ymerase chai n r eacti on
(PCR), and fl uor escent i n si tu hybr i di z ati on. Pati ents wi th HER2posi ti ve tumor s r esponded wi th i mpr oved overal l sur vi val when
tr eated wi th dose-i ntensi ve cycl ophosphami de, doxor ubi ci n, and 5F U chemotherapy, wher eas HER2-negati ve pati ents showed no
benefi t wi th dose escal ati on. Al though the mechani sm of thi s
i nteracti on and putati ve r esi stance i s uncl ear, ther e i s evi dence that
i nhi bi ti on of HER2 si gnal i ng i s associ ated wi th a decr eased abi l i ty of
the cel l to r epai r DNA damage such as i s seen after exposur e to
chemotherapy.
HER2 i s an exampl e of how the mol ecul ar pr ofi l e of a cancer may
al l ow pr edi cti on of i ts r esponse to standar d chemotherapeuti c
agents. In most cases, the mechani sm for oncogene-associ ated
r el ati ve r esi stance or sensi ti vi ty of a tumor to chemotherapy i s
uncer tai n. However, many mar ker s may themsel ves be sui tabl e
tar gets for mol ecul ar l y based therapeuti cs. G i ven the sur face
l ocati on of HER2 on cel l s and the over expr essi on that occur s mai nl y
i n cancer ous states, the HER2 oncopr otei n r epr esented one such
attracti ve tar get for Ab-di r ected therapi es. One such Ab, 4D5,
suppr essed cancer cel l gr owth i n both i n vi tr o and i n vi vo ani mal
studi es. When coupl ed wi th standar d chemotherapeuti c agents, 4D5
showed addi ti ve and potenti al l y syner gi sti c anti pr ol i ferati ve effects.
The humani zed for m of the mur i ne 4D5 Ab (Her cepti n) was
devel oped for cl i ni cal appl i cati ons. Based on a phase II cl i ni cal tr i al
that showed i mpr ovement i n r esponse rates i n pati ents r ecei vi ng
Her cepti n, a phase III study was conducted i n whi ch i ndi vi dual s wi th
metastati c br east cancer wer e randoml y assi gned to chemotherapy
al one or chemotherapy pl us weekl y Her cepti n. The r esul ts showed
that pati ents tr eated wi th chemotherapy and Her cepti n exhi bi ted an
i mpr ovement i n al l measur es: r esponse rate (49% vs. 32% wi th
chemotherapy al one), medi an durati on of r esponse (9.3 vs. 5.9
months wi th chemotherapy al one), and ti me to pr ogr essi on (7.6
months vs. 4.6 months wi th chemotherapy al one). Thus, as
pr edi cted i n the i n vi tr o i nvesti gati ons, the combi nati on of
chemotherapy and Her cepti n l ed to a mor e favorabl e outcome.
Because oncogenes ar e si gnal i ng mol ecul es that r el y on pr otei n
pr otei n i nteracti ons to conduct thei r si gnal s, i nter r upti on of these
i nteracti ons was pr edi cted to di sr upt cr i ti cal pathways that mai ntai n
the cancer ous state. Inhi bi ti on of the enz ymati c acti vi ty of cer tai n
oncogenes, such as the genes encodi ng ras pr otei ns and ki nases,
wi th smal l chemi cal l y der i ved mol ecul es has been both an attracti ve
and ul ti matel y successful appr oach. Some of the most notabl e
cl i ni cal successes have been i n the tr eatment of l eukemi as. Ther e i s
cur r entl y a r i ch devel opmental pi pel i ne for these ki nase i nhi bi tor s,
wi th many potenti al agents bei ng tested (or soon to be r eady for
testi ng) i n the cl i ni cal setti ng. The tar gets i ncl ude the ras pr otei ns
PDG F and EG F and the VEG F r eceptor s. The number and di ver si ty of
tar gets make mol ecul ar pr ofi l i ng a necessar y adjunct to therapeuti c
deci si on maki ng. Thus, a compr ehensi ve appr oach for tar get
detecti on wi l l no l onger r emai n sol el y of academi c i nter est but i s
pr edi cted to become a cl i ni cal necessi ty.
Postgenome Challenge for Molecular Medicine

The r ecentl y compl eted sequenci ng of the enti r e human genome wi l l
have i ncal cul abl e effects on sci ence and soci ety. The data on gene
expr essi on and putati ve gene functi ons i nfer r ed fr om sequence

si mi l ar i ti es and moti f anal ysi s wi l l pr ovi de a power ful means of
assessi ng the transcr i pti onal acti vi ty of the genome i n the cel l s and
ti ssue befor e, dur i ng, and after the devel opment of di sease.
However, compl eti on of the human genome sequence i s just the
begi nni ng. The cur r ent chal l enge i s to generate a compr ehensi ve
under standi ng of the softwar e and the har dwar e of the cel l and the
or gani sm. Less than 2% of the noni nfecti ous human di sease bur den
i s monogeni c i n natur e. The r est (98% ) i s pol ygeni c (caused by
mul ti pl e genes at once) or epi geni c (caused by nongeneti c or
postgeneti c al terati ons i n cel l ul ar mol ecul es). Consequentl y, ful l y
el uci dati ng the causal mechani sms dr i vi ng
car ci nogenesi s and cancer pr ogr essi on wi l l r equi r e anal ysi s tool s
rangi ng fr om di r ect DNA sequenci ng, to mRNA expr essi on
moni tor i ng, to pr otei n sequenci ng and pr otei n l ocal i z ati on studi es,
to metabol i c or physi ol ogi cal pr ofi l i ng.
A fur ther essenti al phase wi l l be a descr i pti on of the nor mal range
of human pol ymor phi sms (base var i ati ons i n the genome), whi ch
may pr ovi de a star ti ng poi nt for cor r el ati ng geneti c var i ance wi th
di sease states. The fi nal physi ol ogi cal state i s fur ther compl i cated
because bi ol ogi cal di ver si ty causal l y associ ated wi th di sease may be
due to posttransl ati onal pr ocesses r egul ated by the cel l ul ar
envi r onment. These changes cannot be i nfer r ed fr om known DNA
var i ance. Thus, a compl ete under standi ng of the mol ecul ar basi s of
cancer wi l l depend on a mul ti di sci pl i nar y appr oach combi ni ng
geneti cs, pathol ogy, pr otei n str uctur e and functi on anal ysi s, cel l
bi ol ogy, and cl i ni cal medi ci ne.
F i ndi ng the expr essed human genes i s a di ffer ent task fr om
sequenci ng the genome i tsel f. Thi s i s because the actual expr essed
genes and thei r r egul ator y el ements compr i se onl y a smal l
pr opor ti on of the genome. The number of expr essed human genes
may be 100,000. However, at any poi nt i n ti me, for any i ndi vi dual
cel l i n any gi ven ti ssue, the number of genes i n use may be as few
as 10,000. Of thi s 10,000, onl y a pr opor ti on may be suscepti bl e to
the i nfl uence of car ci nogeni c events. Thus, an i mpor tant goal for
mol ecul ar pr ofi l i ng of cancer i s to i denti fy a subset of expr essed
genes that i s cor r el ated wi th or causal l y r el ated to the devel opment
and pr ogr essi on of cancer. Setti ng asi de her edi tar y suscepti bi l i ty, i t
i s l i kel y that the major i ty of cancer s or i gi nate i n ti ssue that star ts
wi th a compl etel y nor mal genome and that car ci nogeni c events
pr oduce her i tabl e geneti c al terati ons that expand i n mi cr oscopi c
pr emal i gnant states, such as hyper pl asi a and dyspl asi a, befor e frank
mal i gnant cancer ensues. Identi fi cati on of the i mpor tant geneti c
derangements and the causal l y i mpor tant genes and pr otei ns wi l l
depend on di r ect anal ysi s of actual human cancer ti ssues, combi ned
wi th i nsi ghts gai ned usi ng ani mal and cel l cul tur e methods. The
massi ve pr ofi l i ng of genes associ ated wi th cancer pr ogr essi on i s now
possi bl e usi ng new technol ogy for mi cr odi ssecti on and ar ray
hybr i di z ati on.
In r esponse to thi s chal l enge, i nvesti gator s i n both the publ i c and
the pr i vate sector s have been per fecti ng compl ementar y DNA
(cDNA) ar rays (so-cal l ed gene chi ps) that can be used to sur vey
patter ns of gene expr essi on. Changes i n the patter n can then be
cor r el ated wi th hi stomor phol ogy, cl i ni cal behavi or, or r esponse to
tr eatment. Typi cal l y, the cDNA ar rays take the for m of r ows and
r ows of ol i gonucl eoti de strands l i ned up i n dots on a mi ni atur e
si l i con chi p, gl ass sl i de, or sheet of ni tr ocel l ul ose. The mi cr oar rays
wor k as fol l ows. F i r st, the RNA i s extracted fr om the tumor ti ssue,
ampl i fi ed, and l abel ed wi th a fl uor escent or radi oacti ve pr obe. Thi s
of cour se assumes that the hi ghl y l abi l e RNA i s pr eser ved when the
ti ssue i s extracted. The l abel ed total RNA, contai ni ng the mRNA of
the expr essed genes, i s appl i ed to the sur face of the chi p or sheet.
After appr opr i ate hybr i di z ati on, the r el ati ve i ntensi ty of the si gnal
for each spot on the chi p cor r esponds to the abundance of i ts
matchi ng mRNA speci es and hence r efl ects the expr essi on l evel for
i ts gene. Wi th appr opr i ate patter n r ecogni ti on softwar e, i t i s
possi bl e to assembl e a gl obal scor e for
the gene study set r epr esented on the substratum. Tr emendous
pr ogr ess has been made i n the use of cDNA ar rays to anal yze gene
expr essi on patter ns i n human cancer cel l l i nes and human cancer
ti ssue.
Once a putati ve mar ker (or set of mar ker s) i s i denti fi ed by cDNA
ar ray anal ysi s of cancer ti ssue sampl es, the next step i s to val i date
these mar ker s i n a l ar ge popul ati on of human tumor s. Thi s
exhausti ve pr ocess has now been tel escoped i nto a hi gh-thr oughput
mi ni atur i zed ti ssue ar ray. The ar ray consi sts of 1,000 cyl i ndr i cal
ti ssue bi opsi es, each fr om a di ffer ent pati ent, al l di str i buted on a
si ngl e gl ass sl i de. Tumor ar rays ar e i deal for compar i ng l ar ge
number s of sol i d tumor sampl es. F ul l automati on of tumor ar ray
cr eati on and scr eeni ng i s envi si oned as a means to expedi ti ousl y
cor r el ate mar ker l evel s over l ar ge study sets of tumor s.
Mol ecul ar anal ysi s of pur e cel l popul ati ons i n thei r nati ve ti ssue
envi r onment wi l l be an i mpor tant component of the next generati on

of medi cal geneti cs. Accompl i shi ng thi s goal i s much mor e di ffi cul t
than just gr i ndi ng up a pi ece of ti ssue and appl yi ng the extracted
mol ecul es to a panel of assays. Thi s i s because ti ssues ar e
compl i cated thr ee-di mensi onal str uctur es composed of l ar ge
number s of di ffer ent types of i nteracti ng cel l popul ati ons. The cel l
subpopul ati on of i nter est may consti tute a ti ny fracti on of the total
ti ssue vol umefor exampl e, one goal may be to anal yze the geneti c
changes i n the pr emal i gnant cel l s or mal i gnant cel l s, but these
subpopul ati ons ar e fr equentl y l ocated i n mi cr oscopi c r egi ons
occupyi ng l ess than 5% of the ti ssue vol ume. Cul tur i ng cel l
popul ati ons fr om fr esh ti ssue i s one means of r educi ng
contami nati on. However, cul tur ed cel l s may not accuratel y r epr esent
the mol ecul ar events taki ng pl ace i n the actual ti ssue fr om whi ch
they wer e der i ved. Assumi ng the ti ssue cel l s of i nter est can be
successful l y i sol ated and gr own i n cul tur e, the gene expr essi on
patter n of the cul tur ed cel l s wi l l be i nfl uenced by the cul tur e
envi r onment and may be qui te di ffer ent fr om the gene expr essi on
patter n i n the nati ve ti ssue state. Thi s i s because the cul tur ed cel l s
ar e separated fr om the ti ssue el ements that r egul ate gene
expr essi on, such as sol ubl e factor s, extracel l ul ar matr i x mol ecul es,
and cel l cel l communi cati on. Thus, the pr obl em of cel l ul ar
heter ogenei ty has been a si gni fi cant bar r i er to the mol ecul ar
anal ysi s of nor mal and di seased ti ssue. Thi s pr obl em can now be
over come by new devel opments i n the fi el d of ti ssue
mi cr odi ssecti on. Laser-captur e mi cr odi ssecti on (LCM) has been
devel oped to pr ovi de sci enti sts wi th a fast and dependabl e method
of captur i ng and pr eser vi ng speci fi c cel l s fr om ti ssue, under di r ect
mi cr oscopi c vi sual i z ati on. Wi th the ease of pr ocur i ng a
homogeneous popul ati on of cel l s fr om a compl ex ti ssue usi ng LCM,
the appr oaches to mol ecul ar anal ysi s of pathol ogi cal pr ocesses ar e
si gni fi cantl y enhanced. The mRNA fr om mi cr odi ssected tumor s has
been used as the star ti ng mater i al to pr oduce cDNA l i brar i es,
mi cr oar rays, di ffer enti al di spl ay, and other techni ques used to fi nd
new genes or mutati ons. The devel opment of LCM al l ows
i nvesti gator s to deter mi ne speci fi c gene expr essi on patter ns fr om
ti ssues of i ndi vi dual pati ents. Pur e popul ati ons of cel l s can be
obtai ned, and RNA can be extracted, copi ed to cDNA, and hybr i di zed
to thousands of genes on a cDNA mi cr oar ray. In thi s manner, an
i ndi vi dual i zed mol ecul ar
pr ofi l e can be obtai ned for each hi stol ogi cal l y i denti fi ed pathol ogi cal
subtype. Usi ng such mul ti pl ex anal ysi s, i nvesti gator s wi l l be abl e to
cor r el ate the patter n of expr essed genes wi th eti ol ogy, pr emal i gnant
pr ogr essi on, and r esponse to tr eatment. A pati ent's r i sk for di sease
and appr opr i ate choi ce of tr eatment coul d, i n the futur e, be
per sonal i zed based on the pr ofi l e. A gr owi ng cl i ni cal database of
such r esul ts coul d be used to devel op a mi ni mal subset of key
mar ker s that wi l l l ead to a r evol uti onar y appr oach for ear l y
detecti on and accurate di agnosi s of di sease.
Beyond Functional Genomics to Cancer

Proteomics
Al though DNA i s an i nfor mati on ar chi ve, pr otei ns do al l the wor k of
the cel l . The exi stence of a gi ven DNA sequence does not guarantee
the synthesi s of a cor r espondi ng pr otei n. The DNA sequence i s al so
not suffi ci ent to descr i be pr otei n str uctur e, functi on, and cel l ul ar
l ocati on. Thi s i s because pr otei n compl exi ty and ver sati l i ty stems
fr om context-dependent posttransl ati onal pr ocesses such as
phosphor yl ati on, sul fati on, and gl ycosyl ati on. Mor eover, the DNA
code does not pr ovi de i nfor mati on about how pr otei ns l i nk together
i nto networ ks and functi onal machi nes i n the cel l . In fact, the
acti vati on of a pr otei n si gnal pathway causi ng a cel l to mi grate, di e,
or i ni ti ate di vi si on can occur i mmedi atel y, befor e any changes occur
i n DNA/RNA gene expr essi on. Consequentl y, the technol ogy to dr i ve
the mol ecul ar medi ci ne r evol uti on i nto the thi r d phase i s emer gi ng
fr om pr otei n anal yti cal methods. An i mpor tant goal wi l l be to appl y
thi s knowl edge at the l evel of human ti ssue i tsel f.
The ter m pr oteome denotes the pr otei ns expr essed by a genome.
Pr oteomi cs i s pr ocl ai med as the next step after genomi cs. A goal of
i nvesti gator s i n thi s exci ti ng fi el d i s to assembl e a compl ete l i brar y
of al l human pr otei ns. Onl y a smal l per centage of the pr oteome has
been catal ogued i n 2002. Because PCR for pr otei ns does not exi st,
sequenci ng the or der of the up to 20 possi bl e ami no aci ds i n a gi ven
pr otei n r emai ns r el ati vel y sl ow and l abor-i ntensi ve wor k compar ed
wi th nucl eoti de sequenci ng. Al though a number of new technol ogi es
ar e bei ng i ntr oduced for hi gh-thr oughput pr otei n character i z ati on
and di scover y, the mai nstay of pr otei n i denti fi cati on conti nues to be
two-di mensi onal gel el ectr ophor esi s. When a mi xtur e of pr otei ns i s
appl i ed to the two-di mensi onal gel , i ndi vi dual pr otei ns i n the
mi xtur e ar e separated out i nto si gnatur e l ocati ons on the di spl ay,
dependi ng on thei r i ndi vi dual si ze and char ge. Each si gnatur e i s a
spot on the gel that can consti tute a uni que si ngl e-pr otei n speci es.
The pr otei n spot can be pr ocur ed fr om the gel , and a par ti al ami no
aci d sequence can be r ead. In thi s manner, known pr otei ns can be
moni tor ed for changes i n abundance wi th tr eatment, or new

pr otei ns can be i denti fi ed. An exper i mental two-di mensi onal gel
i mage can be captur ed and over l ai d di gi tal l y wi th known ar chi ved
two-di mensi onal gel s. In thi s way, i t i s possi bl e to i mmedi atel y
hi ghl i ght pr otei ns that ar e di ffer enti al l y abundant i n one state
ver sus another (e.g., tumor vs. nor mal or befor e and after hor mone
tr eatment). The use of LCM i n combi nati on wi th pr oteomi cs al l ows
for studyi ng pr otei n expr essi on of speci fi c subpopul ati ons of cel l s
wi thi n a tumor. Thi s appr oach al l ows for studyi ng these
cel l s i n thei r nor mal mi cr oenvi r onment and avoi ds the pr obl ems of
ti ssue heter ogenei ty and contami nati on.
Usi ng a pr otei n bi ochi p that cl assi fi ed pr otei n popul ati ons i nto
mol ecul ar wei ght cl asses, Pawel etz et al . showed di sti nct pr otei n
patter ns of nor mal , pr emal i gnant, and mal i gnant cancer cel l s
mi cr odi ssected fr om human ti ssue. F ur ther mor e, they r epor ted that
di ffer ent hi stol ogi c types of cancer and nor mal ti ssue (ovar i an,
esophageal , pr ostate, br east, and hepati c) exhi bi ted di sti nct pr otei n
pr ofi l es. Such a means to rapi dl y di spl ay a patter n of expr essed
pr otei ns fr om mi cr oscopi c ti ssue cel l ul ar popul ati ons wi l l potenti al l y
be an i mpor tant enabl i ng technol ogy for phar macopr oteomi cs,
mol ecul ar pathol ogy, and dr ug i nter venti on. Pr oteomi c ar ray
technol ogi es of the futur e wi l l be used to rapi dl y generate di spl ays
of si gnal pathway pr ofi l es. Investi gator s wi l l be abl e to assess the
status of defi ned pathways that contr ol mi togenesi s, apoptosi s,
sur vi val , and a host of other physi ol ogi cal states. The i nfor mati on
fl ow thr ough these ci r cui ts, separatel y or thr ough cr oss-tal k, may
di ctate cl i ni cal behavi or and suscepti bi l i ty to therapy.
Conclusion
Bi ol ogi cal cancer therapi es hol d enor mous pr omi se; many di ffer ent
for ms of bi ol ogi cal therapy, fr om cytoki nes to vacci nes, have been
shown to i nduce tumor r egr essi on i n many human cl i ni cal tr i al s.
Al though the r esponse rates ar e not hi gh, they ar e encouragi ng
because the best r esul ts i n tr i al s i n ani mal s have been i n smal l vol ume di sease and pr eventi on, not i n the tr eatment of establ i shed
l ar ge cancer s. Because most bi ol ogi cal therapi es r el y on the
i nducti on of host i mmune r esponses, pati ents wi th end-stage, bul ky
di sease and poor nutr i ti onal status may not r espond opti mal l y.
Ther efor e, most bi ol ogi cal modal i ti es may not have been adequatel y
tested cl i ni cal l y to date. F ur ther mor e, mor e speci fi c and possi bl y
mor e potent therapi es ar e just now enter i ng cl i ni cal tr i al s. Advances
i n bi otechnol ogy offer the pr omi se of even mor e sophi sti cated
therapeuti cs. The next generati on of bi ol ogi cal therapi es wi l l most
l i kel y consi st of mul ti modal i ty bi ol ogi cal tr eatments tar geti ng both
humoral and cel l ul ar i mmuni ty agai nst mul ti pl e tumor anti gens.
Angi ogenesi s pl ays a cr uci al r ol e i n tumor devel opment and tumor
pr ogr essi on. Therapi es tar geti ng tumor angi ogenesi s ar e rapi dl y
emer gi ng and hol d gr eat pr omi se. These tumor-di r ected therapi es
tar get endothel i al cel l s, a mor e phenotypi cal l y stabl e tar get than
rapi dl y mutati ng tumor cel l s. Toxi ci ty pr ofi l es ar e mor e favorabl e
than standar d chemotherapeuti c r egi mens. Mor eover, anti angi ogeni c
therapy shows gr eat potenti al i n combi nati on wi th chemotherapy
and radi ati on therapy. Anti angi ogeni c therapy, however, has not
pr ovi ded the magi c bul l et for cancer tr eatment that many have
pr edi cted i t woul d be. Issues about tr i al desi gn, schedul i ng and
mode of del i ver y of dr ugs, pr oper bi ol ogi cal end poi nts, and
adequate sur r ogate mar ker s for effi cacy of therapy, among other s,
need to be fur ther del i neated. Cl ear l y, mor e wor k i s necessar y to
fur ther advance thi s fi el d and tap i nto i ts enor mous potenti al .
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M.
Edition
> Ta ble o f C o nt e nt s > 2 3 - P ha rm a c o t he ra py o f C a nc e r
23
Pharmacotherapy of Cancer
Judy L. Chase
Chad M. Barnett
A basi c under standi ng of cancer phar macotherapy and r el ated
toxi ci ti es i s mandator y for the ful l i ntegrati on of the sur gi cal
oncol ogi st i nto a mul ti di sci pl i nar y cancer car e pr ogram. To
i ntel l i gentl y di scuss sur gi cal opti ons wi th pati ents, knowl edge of the
avai l abl e tr eatment r egi mens and thei r potenti al for toxi ci ty i s
essenti al .
Thi s chapter i ncl udes a di scussi on of basi c pr i nci pl es of
chemotherapy, an over vi ew of the mechani sms of dr ug acti on and
dr ug r esi stance, a tabul ar l i sti ng of the dr ugs avai l abl e and thei r
common toxi ci ti es, and a tabul ar l i sti ng of appr oved bi ol ogi cal
agents used i n oncol ogy. F i nal l y, a summar y of cancer pai n
management and the tr eatment of chemotherapy-i nduced emesi s
(CIE) i s i ncl uded.
The r eader shoul d be awar e that a compl ete di scussi on of cancer
chemotherapy i s beyond the scope of thi s br i ef over vi ew. The dr ug
and dosage r egi mens l i sted ar e r epr esentati ve exampl es onl y and do
not consti tute a l i sti ng of al l avai l abl e pr otocol s. For speci fi c
pr escr i bi ng i nfor mati on, the practi ti oner i s advi sed to consul t
i ndi vi dual manufactur er package i nser ts or one of the r efer enced
texts.
Basic Principles of Chemotherapy

Cancer chemotherapeuti c agents ar e the r esul t of dr ug desi gn and,
l ar gel y, empi r i ci sm. Thei r use has devel oped based on an
under standi ng of tumor gr owth character i sti cs, the cel l cycl e, dr ug
mechani sms of acti on, and dr ug r esi stance. It i s hoped that new
techni ques and advances i n mol ecul ar bi ol ogy wi l l al l ow

i mpr ovements i n dr ug desi gn to extend the possi bi l i ty of compl ete
chemotherapeuti c r esponse and possi bl y the cur e of pati ents
cur r entl y deemed beyond sal vage.
Tumor Growth and Kinetics

Ki neti c aspects of tumor gr owth have been wel l descr i bed. Two
concepts that under scor e our knowl edge of the ki neti cs of tumor
gr owth ar e Ski pper 's l aws and G omper tz i an gr owth. Ski pper 's l aws
appl y to cel l s i n the pr ol i ferati ng compar tment of a tumor. F i r st, the
doubl i ng ti me of pr ol i ferati ng cel l s i s constant, cr eati ng a strai ght
l i ne on a semi l og pl ot. Second, cel l ki l l by a par ti cul ar dr ug at a
gi ven dose i s constant, i r r especti ve of body bur den. In most sol i d
tumor s, however, onl y a por ti on of cel l s wi thi n the tumorthe
gr owth fracti oni s pr ol i ferati ng at any gi ven ti me. Thi s par ti al l y
accounts for the r efractor y natur e of many sol i d tumor s to
chemotherapy.
Human tumor s fol l ow a patter n of G omper tz i an, rather than strai ght
l i ne, gr owth. G omper tz i an gr owth descr i bes a cel l popul ati on
decr easi ng as a r esul t of cel l death and i ncr easi ng because of
pr ol i ferati on. Al so, cel l subpopul ati ons may have ceased to
pr ol i ferate but have not di ed, fur ther swayi ng the gr owth cur ve
fr om a strai ght semi l og pl ot. The nor mal G omper tz i an gr owth cur ve
i s si gmoi d i n shape. Maxi mum tumor gr owth rate occur s at
appr oxi matel y 30% of maxi mum tumor vol ume, wher e nutr i ent and
oxygen suppl y to the gr eatest number of tumor cel l s i s opti mi zed.
Thi s por ti on of the cur ve i s al so wher e dr ug effi cacy agai nst a
par ti cul ar tumor may best be esti mated.
The cel l cycl e i s an i mpor tant fundamental concept to under stand
when desi gni ng chemotherapeuti c agents and tr eatment r egi mens.
The cel l cycl e i s di vi ded i nto fi ve components. The r esti ng or
nonpr ol i ferati ng cel l i s i n the G 0 phase. Upon enter i ng the acti ve
por ti on of the cycl e fol l owi ng sti mul ati on, DNA synthesi s occur s
dur i ng the S phase and i s fol l owed by the postsyntheti c G 2 phase.
Mi tosi s occur s dur i ng the M phase, whi ch pr ecedes the postmi toti c
G 1 phase.
The cel l cycl e becomes i mpor tant i n dr ug sel ecti on because cel l s i n
the gr owth fracti on ar e mor e suscepti bl e to cer tai n agents. In a
br oad sense, anti neopl asti c agents may be cl assi fi ed on the basi s of
thei r acti vi ty i n r el ati on to the cel l cycl e. Most anti metabol i tes,
etoposi de, hydr oxyur ea, vi nca al kal oi ds, and bl eomyci n ar e cel l
cycl e-speci fi c agents that ar e most effecti ve agai nst tumor s wi th a
hi gh gr owth fracti on. In contrast, al kyl ati ng agents, anti neopl asti c
anti bi oti cs, fl uor ouraci l , fl oxur i di ne, and pr ocar baz i ne exer t thei r
effect i ndependent of the cel l cycl e, and general l y show mor e
acti vi ty agai nst sl ow-gr owi ng tumor s.
Drug Mechanisms and Therapeutics

Knowl edge of the basi c mechani sms of acti on of chemotherapeuti c
agents i s cr i ti cal i n sel ecti ng dr ugs for an effecti ve chemotherapy
combi nati on r egi men, mi ni mi z i ng toxi ci ty and dr ug i nteracti ons, and
pr eventi ng emer gence of dr ug-r esi stant cl ones. Agents may damage
the DNA templ ate by al kyl ati on, cr oss-l i nki ng, doubl e-strand
cl eavage by topoi somerase II, i nter cal ati on, and bl ockage of RNA
synthesi s. Spi ndl e poi sons may ar r est mi tosi s. Anti metabol i tes bl ock
enz ymes necessar y for DNA synthesi s. Hor monal agents and thei r
antagoni sts may i nfl uence cel l ul ar si gnal transducti on, and
bi ol ogi cal r esponse modi fi er s may i nfl uence the host's i mmune
r esponse to the tumor al one or i n the context of concomi tantl y
admi ni ster ed dr ugs. Anti body-based therapeuti cs have
r evol uti oni zed the car e of some cancer pati ents, i ncl udi ng those
wi th col on cancer, br east cancer, and cer tai n l eukemi as and
l ymphomas. These therapi es expl i ci tl y tar get cancer cel l s based on
str uctural and bi ol ogi cal pr oper ti es that di ffer fr om nor mal cel l s.
They i ncl ude unconjugated anti bodi es or anti bodi es that have toxi c
mater i al s attached that can del i ver radi ati on or i mmunotoxi ns
di r ectl y to cancer cel l s. Unconjugated anti bodi es, such as r i tuxi mab
and trastuz umab, exer t thei r cytotoxi ci ty by i nvoki ng i mmune
r esponses agai nst the tar geted cel l s. Conjugated anti bodi es, such as
Zeval i n and Bexxar, del i ver toxi c compounds di r ectl y to tumor si tes,
thus r esul ti ng i n cel l death. In addi ti on to anti body-based therapi es,
oral l y avai l abl e smal l mol ecul e tar geted therapi es have been
cr eated, such as i mati ni b mesyl ate, gefi ti ni b, and er l oti ni b. Imati ni b
mesyl ate i s a pr otei n tyr osi ne ki nase i nhi bi tor of bcr /abl , an
abnor mal i ty found i n some pati ents wi th chr oni c myel ogenous
l eukemi a. G efi ti ni b and
er l oti ni b ar e smal l mol ecul e tyr osi ne ki nase i nhi bi tor s that tar get
the epi der mal gr owth factor r eceptor.
Combi nati on chemotherapy i s fr equentl y used i n an effor t to
for estal l the devel opment of dr ug r esi stance to anti neopl asti c
agents and to achi eve syner gi sm wi th r educed toxi ci ty. The G ol di e-
Col dman hypothesi s assumes that at the ti me of di agnosi s, most

tumor s possess r esi stant cl ones. Mul ti pl e mechani sms of dr ug
r esi stance devel op dur i ng cancer pr ogr essi on. The most wel l studi ed
of these i nvol ves the mdr gene, whi ch codes for membrane-bound Pgl ycopr otei n. P-gl ycopr otei n ser ves as a channel thr ough whi ch
cel l ul ar toxi ns (i .e., chemotherapeuti c agents) may be excr eted
fr om the cel l . Addi ti onal mechani sms of dr ug r esi stance ar e
decr eased dr ug transpor t i nto cel l s, r educti on of dr ug acti vati on,
dr ug metabol i sm enhancement, devel opment of al ter nati ve
metabol i c pathways, dr ug i nhi bi ti on of enz yme tar gets over come by
gene ampl i fi cati on, and i mpai r ment of dr ug bi ndi ng to a tar get. A
si ngl e dr ug may be subject to one or mor e mechani sms.
Inter esti ngl y, nor mal human cel l s never devel op dr ug r esi stance. As
a r esul t, several caveats of combi nati on chemotherapy have
emer ged. Dr ugs shown to be acti ve as si ngl e agents shoul d be
chosen, and dr ugs sel ected for combi ned use shoul d have di ffer ent
mechani sms of acti on. Ideal l y, dr ugs wi th di ffer ent dose-l i mi ti ng
toxi ci ti es shoul d be admi ni ster ed together, al though toxi ci ty over l ap
may necessi tate dose r educti on, as wi th myel osuppr essi on. F i nal l y,
dr ug combi nati ons wi th si mi l ar patter ns of r esi stance shoul d be
avoi ded.
Di ffer ent patter ns of chemotherapy admi ni strati on ar e used i n
par ti cul ar setti ngs wi th speci fi c goal s. Inducti on chemotherapy i s
usual l y hi gh dose and gi ven i n combi nati on to i nduce compl ete
r emi ssi on. Consol i dati on i s a r epeti ti on of an i nducti on r egi men i n a
compl ete r esponder to pr ol ong r emi ssi on or i ncr ease the cur e rate.
Chemotherapy gi ven wi th an i ntent si mi l ar to that of consol i dati on
but wi th hi gher doses than i nducti on or wi th di ffer ent agents at
hi gh doses i s known as i ntensi fi cati on. Mai ntenance r egi mens ar e
l ow-dose, l ong-ter m pr otocol s i ntended to del ay tumor cel l r egr owth
after compl ete r emi ssi on. Inducti on, consol i dati on, i ntensi fi cati on,
and mai ntenance usual l y appl y to hematol ogi c mal i gnanci es but may
al so descr i be sol i d tumor r egi mens.
Neoadjuvant tr eatment i n the pr eoperati ve or per i operati ve per i od
i s used mor e commonl y wi th sol i d tumor s, such as l ocal l y advanced
br east car ci noma, soft-ti ssue sar comas of the extr emi ti es, and,
mor e r ecentl y, r ectal car ci noma and squamous cel l car ci noma of the
head and neck. It i s often gi ven i n combi nati on wi th radi ati on
therapy to i mpr ove sur vi val , r esectabi l i ty, and or gan pr eser vati on.
Pal l i ati ve chemotherapy may be gi ven to contr ol symptoms or, i f the
toxi ci ty pr ofi l e i s favorabl e, pr ol ong l i fe for i ncurabl e pati ents.
Sal vage chemotherapy i nvol ves the use of a potenti al l y curati ve,
hi gh-dose pr otocol i n pati ents fai l i ng or r ecur r i ng after di ffer ent
standar d tr eatment pl ans have been attempted.
Adjuvant chemotherapy i s admi ni ster ed fol l owi ng curati ve sur ger y
or radi ati on therapy as a shor t-cour se, hi gh-dose r egi men to
destr oy a l ow number of r esi dual tumor cel l s. Several factor s
deter mi ne the effecti veness of adjuvant r egi mens, i ncl udi ng
tumor bur den, dr ug dose and schedul e, combi nati on chemotherapy,
and dr ug r esi stance. The dr ug(s) must be acti ve l ocal l y agai nst
r esi dual cel l s and di stantl y agai nst cl i ni cal l y occul t metastati c
deposi ts. Extensi ve l i teratur e suppor ts the use of adjuvant
chemotherapy for br east, col on, r ectal , and anal car ci nomas and for
ovar i an ger m cel l tumor s, osteosar coma, and pedi atr i c sol i d tumor s.
No defi ni ti ve benefi t has been r epor ted yet for pancr eati c, gastr i c,
and testi cul ar car ci nomas or for cer vi cal cancer and mel anoma,
al though i nvesti gati ve adjuvant therapy pr otocol s ar e ongoi ng and
open for pati ent enr ol l ment i n these di sease si tes.
Most chemotherapeuti c agents exhi bi t ver y steep doser esponse
pr ofi l es and have l ow therapeuti c i ndi ces, maki ng a hi gh-dose,
shor t-ter m admi ni strati on desi rabl e. Thi s can be accompl i shed
thr ough r egi onal dose i ntensi fi cati on. One exampl e i s
i ntraper i toneal chemotherapy for ovar i an cancer wi th hi gh r i sk of
per i toneal r ecur r ence or for pr i mar y tumor s that mani fest as
i ntraper i toneal di sease, such as pseudomyxoma per i tonei and
per i toneal mesothel i oma. Another type of r egi onal dose
i ntensi fi cati on i s i ntra-ar ter i al therapy, whi ch r equi r es r egi onal
tumor confi nement and a uni que tumor bl ood suppl y and i s most
commonl y used i n hepati c ar ter y i nfusi on for pr i mar y or metastati c
l i ver tumor s that ar e sur gi cal l y unr esectabl e. Intra-ar ter i al
chemotherapy has al so been used for gl i omas of the brai n and some
head and neck tumor s. Isol ated per fusi on of a speci fi c anatomi cal
si te, usual l y the extr emi ti es, i s one mor e type of r egi onal dose
i ntensi fi cati on that al l ows for the del i ver y of ver y hi gh doses of
chemotherapy to the i nvol ved si te wi th l i ttl e systemi c toxi ci ty; i t i s
often combi ned wi th hyper ther mi a. The l ar gest body of l i teratur e
di scusses i ts use i n al l stages of mel anoma, al though l i mb per fusi on
for extr emi ty sar coma has been r epor ted.
Chemotherapeutic Agents
F undamental knowl edge of the dr ugs avai l abl e for cancer tr eatment,
thei r mechani sms of acti on, general dose ranges, domi nant
toxi ci ti es, and i ndi cati ons for use i s i mpor tant to the general
sur geon car i ng for cancer pati ents. Tabl e 23.1 l i sts the avai l abl e
agents and thei r mechani sms of acti on, doses, and toxi ci ti es. Tabl e
23.2 l i sts the avai l abl e bi ol ogi cal agents, as wel l as thei r U.S. Food
and Dr ug Admi ni strati on (F DA) i ndi cati ons and dosages. Tabl e 23.3
l i sts commonl y used combi nati on chemotherapeuti c r egi mens.
Management of Cancer Pain

The vast major i ty of pati ents wi th advanced cancer, and as many as
60% of pati ents wi th any stage of di sease, exper i ence si gni fi cant
pai n. However, cancer pai n i s fr equentl y under tr eated for a
mul ti tude of r easons and fear s that ar e l ar gel y unfounded. Effecti ve
management of cancer pai n i s achi eved best wi th a mul ti di sci pl i nar y
appr oach, i ncl udi ng pai n speci al i sts, oncol ogi sts, nur ses,
phar maci sts, physi atr i sts, physi cal and occupati onal therapi sts,
psychol ogi sts, psychi atr i sts, pr i mar y car e physi ci ans, soci al wor ker s,
cl er gy, and hospi ce car egi ver s. Open l i nes of communi cati on ar e of
paramount i mpor tance to the successful management of cancer
pai n.
Table 23.1. Cancer chemotherapeutic age

Mechanisms, doses, and toxicities
Drug
Alkylating agents
Dose and
Schedule
Toxicity
260 mg/m2
PO in
divided
doses
1421 d
Nausea and
vomiting,
myelosuppre
paresthesias
toxicity
Busulfan (Myleran)
48 mg PO
daily
Myelosuppre
pulmonary f
aplastic anem
skin
hyperpigmen
Carmustine (BCNU,
BiCNU)
150200
mg/m 2 IV
every 68
wk
Delayed
myelosuppre
nausea and
vomiting,
hepatotoxici
Chlorambucil
(Leukeran)
0.10.2
mg/kg/d PO
36 wk
(average
410 mg/d)
Myelosuppre
pulmonary f
hepatotoxici
Altretamine
(hexamethylmelamine,
Hexalen)
Carboplatin
(Paraplatin)
300360
mg/m 2 IV
every 4 wk
or
Target area
under the
curve
(AUC) of 4
Myelosuppre
nausea and
vomiting, pe
neuropathy,
ototoxicity
6 mg/dL
every 4 wk
Cisplatin (Platinol,
Platinol-AQ)
40120
mg/m 2 IV
every 34
wk
20
mg/m 2 /d IV
5 d every
34 wk
Nephrotoxici
nausea and
vomiting, pe
neuropathy,
myelosuppre
ototoxicity
Cyclophosphamide
(Cytoxan, Neosar)
4050
mg/kg IV in
divided
doses over
25 d
15
mg/kg/d PO
Myelosuppre
hemorrhagic
cystitis,
immunosupp
alopecia, sto
SIADH
Dacarbazine (DTICDome)
2.04.5
mg/kg/d IV
10 d
250
mg/m 2 /d IV
5 d
(melanoma)
150
mg/m 2 /d IV
5 d
375 mg/m2
Myelosuppre
nausea and
vomiting, flu
syndrome,
hepatoxicity,
alopecia, sei
IV every 15
d (Hodgkin
disease)
1.2 g/m2 IV
daily 5 d
every 3 wk
Myelosuppre
hemorrhagic
cystitis,
somnolence,
confusion
Lomustine (CCNU,
CeeNU)
130 mg/m2
PO every 6
wk
Delayed
myelosuppre
nausea and
vomiting,
hepatotoxici
neurotoxicity
nephrotoxici
Mechlorethamine
(Nitrogen mustard,
Mustargen)
0.4 mg/kg
IV single
dose or in
divided
doses of
0.10.2
mg/kg/d
Myelosuppre
nausea and
vomiting, ph
gonadal dysf
Ifosfamide (Ifex)
Melphalan (Alkeran)
26 mg PO
daily 14
21 d
10 mg PO
daily 7
10 d
Myelosuppre
stomatitis, n
and vomiting
16 mg/m2
IV every 2
wk
gonadal dysf
Procarbazine
(Matulane)
16
mg/kg/d PO
daily
100
mg/m 2 /d
PO 14 d
Myelosuppre
nausea and
vomiting, let
depression,
paresthesias
headache, fl
syndrome
Streptozocin
(Zanosar)
500
mg/m 2 /d IV
5 d
1,000
1,500
mg/m 2 IV
weekly
Renal toxicit
nausea and
vomiting, dia
altered gluco
metabolism,
dysfunction
Thiotepa (Thioplex)
0.30.4
mg/kg IV
every 14
wk
Myelosuppre
nausea and
vomiting, mu
skin rashes
75100
mg/m 2 SC
7 d every
Nausea and
vomiting,
myelosuppre
pyrexia, diar
Antimetabolites
Azacitidine (Vidaza)
4 wk
constipation
fatigue, ecch
Capecitabine (Xeloda)
2,000
2,500
mg/m 2 /d
PO 14 d
every 21 d
Diarrhea,
stomatitis, n
and vomiting
foot syndrom
myelosuppre
Cladribine (Leustatin)
0.090.1
mg/kg/d IV
continuous
infusion
7 d every 4
wk
Myelosuppre
fever, rash
Clofarabine (Clolar)
52 mg/m2
IV 5 d
every 26
wk
Nausea and
vomiting, dia
myelosuppre
pruritis, rigo
dermatitis,
abdominal p
infection
Cytarabine (Ara-C,
Cytosar, DepoCyt)
100200
mg/m 2 /d IV
infusion
57 d
3 g/m2 IV
every 12 h
412
doses
Myelosuppre
nausea and
vomiting, dia
hepatotoxici
fever, conjun
CNS toxicity
Fludarabine (Fludara)
25
mg/m 2 /d IV
5 d every
4 wk
Myelosuppre
nausea and
vomiting, fe
malaise, pul
infiltrates
Floxuridine (FUDR)
0.10.6
mg/kg/d
514 d
continuous
arterial
infusion
Hepatotoxici
gastritis, na
and vomiting
diarrhea
5-Fluorouracil (5-FU,
Adrucil)
300500
mg/m 2 /d IV
35 d
1015
mg/kg IV
weekly
200300
mg/m 2 /d IV
continuous
infusion
Stomatitis,
myelosuppre
diarrhea, na
and vomiting
cerebellar at
Gemcitabine (Gemzar)
1,000
1,250
mg/m 2 IV
weekly
Myelosuppre
fever, flulike
syndrome, r
mild nausea
vomiting
80 mg/kg
PO every 3
d
2030
mg/kg PO
daily
Myelosuppre
nausea and
vomiting, ra
6-Mercaptopurine (6MP, Purinethol)
1.52.5
mg/kg/d PO
(average
100200
mg/d)
Myelosuppre
nausea and
vomiting, an
diarrhea,
hepatotoxici
Methotrexate (MTX,
Mexate, Rheumatrex)
2.55.0 mg
PO daily
(low dose)
50 mg/m2
IV every 2
3 wk (low
dose)
112 g/m2
IV every 1
3 wk (high
dose)
510
mg/m 2
(max 15
mg)
intrathecal
every 37
d
Mucositis,
myelosuppre
pulmonary f
hepatotoxici
nephrotoxici
diarrhea, sk
erythema
Hydroxyurea (Hydrea)
Myelosuppre
500600
mg/m 2 IV
every 21 d
fatigue, nau
vomiting, dia
rash, infecti
Pentostatin (Nipent)
4 mg/m2 IV
every other
wk
Nephrotoxici
depression,
myelosuppre
nausea and
vomiting,
conjunctiviti
6-Thioguanine (6-TG,
Tabloid)
2 mg/kg PO
daily
Myelosuppre
hepatotoxici
stomatitis
1020
U/m 2 IV,
IM, or SC
oncetwice
weekly
Pneumonitis
pulmonary f
fever,
hypersensiti
hyperpigmen
alopecia
Pemetrexed (Alimta)
Natural products
Antitumor antibiotics
Bleomycin
(Blenoxane)
Dactinomycin
(Actinomycin D,
Cosmegen)
0.5 mg/day
IV 5 d
max
0.012
0.015
Stomatitis,
myelosuppre
anorexia, na
and vomiting
mg/kg/d IV
5 d max
(children)
diarrhea, alo
Daunorubicin
(Cerubidine)
3045
mg/m 2 /d IV
3 d
40 mg/m2
IV every 2
wk
(liposomal)
Myelosuppre
cardiotoxicit
mucositis, a
nausea and
vomiting
Doxorubicin
(Adriamycin PFS,
Adriamycin RDF)
4075
mg/m 2 IV
every 21 d
2030
mg/m 2 /d IV
3 d,
every 34
wk
2050
mg/m 2 IV
every 34
wk
(liposomal)
Myelosuppre
cardiotoxicit
stomatitis, a
nausea and
vomiting
Epirubicin (Ellence)
100120
mg/m 2 IV
every 34
wk
Myelosuppre
nausea and
vomiting,
cardiotoxicit
alopecia
Idarubicin (Idamycin)
12
mg/m 2 /d IV
3 d every
3 wk
Myelosuppre
nausea and
vomiting,
stomatitis, a
cardiotoxicit
Mitomycin C
(Mutamycin)
20 mg/m2
IV every 6
8 wk
Myelosuppre
nausea and
vomiting, an
alopecia, sto
Mitoxantrone
(Novantrone)
12
mg/m 2 /d IV
3 d
1214
mg/m 2 IV
every 3 wk
Myelosuppre
cardiotoxicit
alopecia, sto
nausea and
vomiting
1016
mg/kg PO
daily
Myelosuppre
ischemic hea
disease,
thrombophle
hepatotoxici
nausea and
vomiting
Mitotic inhibitors
Estramustine (Emcyt)
Docetaxel (Taxotere)
60100
mg/m 2 IV
Myelosuppre
fluid retentio
hypersensiti
peripheral
every 21 d
neuropathy,
onycholysis,
alopecia
Paclitaxel (Taxol)
135175
mg/m 2 /d IV
infusion
every 3 wk
80 mg/m2
IV infusion
weekly
Myelosuppre
peripheral
neuropathy,
alopecia, mu
anaphylaxis,
onycholysis
Vinblastine (Velban)
318.5
mg/m 2 IV
every 12
wk
Myelosuppre
paralytic ileu
alopecia, na
stomatitis
Vincristine (Vincasar)
0.031.4
mg/m 2 IV
weekly (2.0
mg/wk
max)
Peripheral
neuropathy,
paralytic ileu
SIADH,
myelosuppre
2530
mg/m 2 IV
weekly
Peripheral
neuropathy,
myelosuppre
nausea and
vomiting, he
dysfunction
Vinorelbine
(Navelbine)
Topoisomerase inhibitors
Etoposide (VP16,
VePesid)
35100
mg/m 2 /d IV
35 d
100
mg/m 2 /d
PO 5 d
Myelosuppre
nausea and
vomiting, dia
fever, hypot
with infusion
alopecia
Irinotecan (CPT-11,
Camptosar)
125 mg/m2
IV weekly
350 mg/m2
IV every 3
wk
Myelosuppre
diarrhea, na
and vomiting
anorexia
Teniposide (Vumon)
60
mg/m 2 /d IV
5 d every
3 wk
50100
mg/m 2 IV
once
weekly
Myelosuppre
nausea and
vomiting, alo
hepatotoxici
hypotension
infusion
Topotecan (Hycamtin)
1.251.5
mg/m 2 /d IV
5 d
Myelosuppre
fever, flulike
syndrome, n
and vomiting
6,000
IU/m 2 IM 3
Allergic reac
nausea and
Enzymes
Asparaginase
wk
1,000
IU/kg/d IV
10 d
vomiting, liv
dysfunction,
depression,
hyperglycem
2,500
IU/m 2 IM
every 14 d
Hypersensiti
reactions,
hepatotoxici
fever, nause
vomiting
Dexamethasone
(Decadron)
0.54.0 mg
PO, IV, IM
daily
Fluid retenti
hyperglycem
hypertension
infection
Methylprednisolone
(Depo-Medrol, Medrol,
Solu-Medrol)
4200
mg/d PO,
IV daily
Fluid retenti
hyperglycem
hypertension
infection
Prednisone
(Deltasone)
5100
mg/d PO
Same as abo
Pegaspargase
(Oncaspar)
Hormonal agents
Adrenocorticoids
Estrogens
Fluid retenti
feminization
Diethylstilbestrol
(DES)
115 mg/d
PO
uterine blee
nausea and
vomiting,
thromboemb
Estradiol (Climara,
Estrace)
0.630 mg
PO daily
Same as abo
Medroxyprogesterone
(Provera, DepoProvera)
4001,000
mg IM
weekly
Weight gain,
retention,
feminization
cardiovascul
effects
Megestrol (Megace)
40320
mg/d PO
Same as abo
Tamoxifen (Nolvadex)
2040
mg/d PO
Hot flashes,
and vomiting
altered men
Toremifene (Fareston)
60 mg PO
daily
Same as abo
Progestins
Antiestrogens
Fulvestrant (Faslodex)
250 mg IM
monthly
Nausea and
vomiting,
constipation
diarrhea, he
back pain, h
flushes, pha
Aromatase inhibitors
Aminoglutethimide
(Cytadren)
250 mg PO
bidqid
Rash, hot flu

fever, drows
nausea, ano
Anastrozole
(Arimidex)
1 mg PO
daily
Same as abo
Exemestane
(Aromasin)
25 mg PO
daily
Same as abo
Letrozole (Femara)
2.5 mg PO
daily
Same as abo
Testosterone
(Androderm, DepoTestosterone)
200400
mg IM
every 24
wk (long
acting)
Masculinizat
amenorrhea,
gynecomasti
nausea, wat
retention, ch
in libido, ski
hypersensiti
hepatotoxici
Methyltestosterone
(Android, Testred)
50200 mg
PO daily
Same as abo
Androgens
Fluoxymesterone
(Halotestin)
1040 mg
PO daily
Same as abo
Bicalutamide
(Casodex)
50 mg PO
daily
Hot flashes,
decreased li
impotence,
diarrhea, na
and vomiting
gynecomasti
hepatotoxici
Flutamide (Eulexin)
250 mg PO
tid
Same as abo
Nilutamide (Nilandron)
150300
mg PO
daily
Same as abo
Antiandrogens
LHRH analogs
Leuprolide (Lupron
Depot)
1 mg SC
daily
7.5 mg IM
monthly,
22.5 mg IM
every 3
mo,
or 30 mg
IM every 4
mo
Hot flashes,
menstrual
irregularity,
dysfunction,
22.5 mg IM
every 3 mo
Goserelin (Zoladex)
3.610.8
mg implant
SC every
13 mo
Same as abo
Triptorelin (Trelstar
Depot, Trelstar LA)
3.75 mg IM
monthly
(Depot) or
11.75 mg
IM every
84 d (LA)
Same as abo
Abarelix (Plenaxis)
100 mg IM
on days 1,
15, 29, and
every 4 wk
thereafter
Same as abo
PO, orally; CNS, central nervous system; IV,

intravenously; SIADH, syndrome of inappropriate
antidiuretic secretion; SC, subcutaneously; IM,
intramuscularly; bid, twice daily; qid, four times da
three times daily; LHRH, luteinizing hormone-releas
hormone.
Table 23.2. Biological agents used

Cytokine
Indications
Dose and
Schedule
Interferon-alfa
(Roferon-A,
Intron A)
Melanoma, hairycell leukemia,

Kaposi sarcoma,
chronic hepatitis
B and C
250 millio
IU/m 2 /d or
per wk
Interleukin-2
(Aldesleukin,
Proleukin)
Renal cell
carcinoma,
metastatic
melanoma
600,000
720,000
IU/kg ever
h 14 dos
Interleukin-11
(Oprelvekin,
Neumega)
Thrombocytopenia
50 g/kg S
once daily
Filgrastim (GCSF, Neupogen)
Nonmyeloid
malignancy,
neutropenia
510 g/kg
IV or SC da
Pegfilgrastim
(pegylated GCSF, Neulasta)
Nonmyeloid
malignancy,
neutropenia
6 mg SC on
per
chemother
cycle 24 h
after
chemother
Sargramostim
(GM-CSF)
(Leukine)
Acceleration of
myeloid recovery
BMT failure or
engraftment
delay
Induction for
acute
myelogenous
leukemia
Mobilization after
autologous
peripheral blood
progenitor cells
250 g/m2
IV or SC
Epoetin alfa
(Erythropoietin;
Epogen, Procrit)
Anemia
associated with
chronic renal
failure, cancer
chemotherapy, or
AIDS treatments
Reduction of
Initial dose
50300 U/k
IV or SC 3
per wk or
40,000
blood transfusions
in surgery
patients
Darbepoetin
(Aranesp)
Anemia
associated with
chronic renal
failure and cancer
chemotherapy
60,000 U S
weekly
Initial dose
2.254.5
g/kg SC
weekly or
200300
SC every 2
wk
Monoclonal antibody
Bevacizumab
(Avastin)
Bortezomib
(Velcade)
Colorectal cancer
Multiple myeloma
510 mg/k
IV infusion
every 2 wk
1.3 mg/m2
twice week
for 2 wk
followed by
10 d rest
period (21
cycle)
Cetuximab
(Erbitux)
Rituximab
(Rituxan)
Trastuzumab
(Herceptin)
Colorectal cancer
400 mg/m
infusion
(loading
dose), then
250 mg/m
infusion
weekly
Non-Hodgkin
lymphoma
375 mg/m
infusion
weekly 4
doses
Breast cancer
Initial dose
mg/kg IV
infusion
Maintenanc
dose: 2
mg/kg IV
infusion
weekly
Initial dose
mg/d IV
Alemtuzumab
(Campath)
Gemtuzumab
ozogamicin
(Mylotarg)
B-cell chronic
lymphocytic
leukemia
infusion, if
tolerated
increase to
10 mg/d IV
tolerated
increase to
30 mg/d IV
per wk
Acute myeloid
leukemia
9 mg/m2 IV
infusion
every 14 d
2 doses
Cutaneous T-cell
lymphoma
9 or 18
g/kg/d IV
5 d, repeat
every 21 d
Immunotoxin
Denileukin
diftitox (Ontak)
Radiopharmaceutical
Tositumomab and
Iodine
131/Tositumomab
(Bexxar)
Non-Hodgkin
lymphoma
Dosimetric
step:
Tositumom
450 mg IV
followed by
iodine I-13
tositumoma
(5 mCi iodi
I-131, 35 m
tositumoma
IV
Therapeuti
step:
Tositumom
450 mg IV
followed by
iodine I-13
tositumoma
(iodine I-1
to deliver 7
cGy and 35
mg
tositumoma
IV
Dosimetric
step:
Rituximab
250 mg/m
followed by
Indium-111
ibritumoma
Ibritumomab
tiuxetan
(Zevalin)
Non-Hodgkin
lymphoma
tiuxetan (5
mCi) IV
Therapeuti
step:
Rituximab
250 mg/m
followed by
yttrium-90
ibritumoma
tiuxetan 0.
mCi/kg
(maximum
mCi) IV
Growth factor receptor inhibitors
Erlotinib
(Tarceva)
Nonsmall-cell
lung cancer
150 mg PO
daily
Gefitinib (Iressa)
Nonsmall-cell
lung cancer
250 mg PO
daily
Imatinib
(Gleevec)
Chronic myeloid
leukemia,
gastrointestinal
stromal tumors
400800 m
PO daily
SC, subcutaneously; IV, intravenously; BMT, bone m
Table 23.3. Commonly used combination

chemotherapeutic regimens
Acronym
Cancer Use
Agents
ABH
Melanoma
Dactinomycin,
carmustine,
hydroxyurea
ABV
Hodgkin
lymphoma
Doxorubicin,
bleomycin,
vinblastine
ABVD
Hodgkin
lymphoma
Doxorubicin,
bleomycin,
vinblastine,
dacarbazine
AC
Breast,
sarcoma,
neuroblastoma
Doxorubicin,
cyclophosphamide
ACE, CAE
Small-cell lung
Cyclophosphamide,
doxorubicin,
etoposide
AP
Ovarian,
endometrial
Doxorubicin,
cisplatin
Hodgkin
lymphoma
Bleomycin,
etoposide,
doxorubicin,
cyclophosphamide,
vincristine,
procarbazine,
prednisone,
filgrastim
BEAM
Bone marrow
transplant
Carmustine,
etoposide,
cytarabine,
melphalan
BEP
Testicular
Bleomycin,
etoposide, cisplatin
BEACOPP
Melanoma
Carmustine,
hydroxyurea,
dacarbazine
Melanoma
Bleomycin,
vincristine,
lomustine,
dacarbazine,
interferon alfa 2b
BOP
Testicular
Bleomycin,
vincristine,
cisplatin
BuCy
Bone marrow
transplant
Busulfan,
cyclophosphamide
Head and neck
Cisplatin,
methotrexate,
bleomycin,
vincristine
Breast
Cyclophosphamide,
doxorubicin,
fluorouracil
Nonsmall-cell
lung
Cyclophosphamide,
doxorubicin,
methotrexate,
procarbazine
BHD
Bold-IFN
CABO
CAF
CAMP
Nonsmall-cell
lung
Cyclophosphamide,
doxorubicin,
cisplatin
Small-cell lung
Cyclophosphamide,
doxorubicin,
vincristine,
etoposide
CEF
Breast
Cyclophosphamide,
epirubicin,
fluorouracil
CF
Head and neck
Cisplatin,
fluorouracil
Bladder
Cisplatin,
gemcitabine,
ifosfamide
Non-Hodgkin
lymphoma
Cyclophosphamide,
doxorubicin,
vincristine,
prednisone
Non-Hodgkin
lymphoma
Cyclophosphamide,
doxorubicin,
vincristine,
prednisone,
bleomycin
CAP
CAVE
CGI
CHOP
CHOP-Bleo
Methotrexate,
CMF
COMLA
COPE
COPP
CVD
CVD
CVD + IL21
Breast
fluorouracil,
cyclophosphamide
Non-Hodgkin
lymphoma
Cyclophosphamide,
vincristine,
methotrexate,
leucovorin,
cytarabine
Small-cell lung
Cyclophosphamide,
vincristine,
cisplatin, etoposide
Hodgkin
lymphoma
Cyclophosphamide,
vincristine,
prednisone,
procarbazine
Prostate
Cyclophosphamide,
vincristine,
dexamethasone
Melanoma
Cyclophosphamide,
vincristine,
dacarbazine
Malignant
melanoma
Cisplatin,
vinblastine,
dacarbazine,
aldesleukin,
interferon-
CYVADIC
Sarcoma (bone
or soft tissue)
Cyclophosphamide,
vincristine,
doxorubicin,
dacarbazine
Cy-TBI
Bone marrow
transplant
Cyclophosphamide,
total body
irradiation
DCTER
Acute
myelogenous
leukemia,
myelodysplastic
syndrome
Daunorubicin,
cytarabine,
thioguanine,
etoposide
DI
Soft-tissue
sarcoma
Doxorubicin,
ifosfamide
EAP
Gastric, small
bowel
Etoposide,
doxorubicin,
cisplatin
EC
Lung
Etoposide,
carboplatin
ECF
Esophageal
Epirubicin,
cisplatin,
fluorouracil
EFP
Gastric, small
bowel
Etoposide,
fluorouracil,
cisplatin
Gastric
Etoposide,
leucovorin,
fluorouracil
EOX
Esophageal
Epirubicin,
oxaliplatin,
capecitabine
EP
Testicular, lung
Etoposide, cisplatin
Non-Hodgkin
lymphoma
Methylprednisolone
etoposide,
cytarabine,
cisplatin
FAC
Breast
Fluorouracil,
doxorubicin,
cyclophosphamide
FAM
Gastric,
pancreas
Fluorouracil,
doxorubicin,
mitomycin
Gastric
Methotrexate,
fluorouracil,
leucovorin,
doxorubicin
Gastric
Fluorouracil,
doxorubicin,
cisplatin
ELF
ESHAP
FAMTX
FAP
Breast
Fluorouracil,
epirubicin,
cyclophosphamide
Colorectal
Irinotecan,
fluorouracil,
leucovorin
FOLFOX
Colorectal
Oxaliplatin,
fluorouracil,
leucovorin
FU/LV
Colorectal
Fluorouracil,
leucovorin
GTX
Pancreatic
Gemcitabine,
docetaxel,
capecitabine
HyperCVAD
Acute
lymphocytic
leukemia
Cyclophosphamide,
doxorubicin,
vincristine,
dexamethasone
IFL
Colorectal
Irinotecan,
fluorouracil,
leucovorin
ITP
Bladder
Ifosfamide,
paclitaxel, cisplatin
FEC
FOLFIRI
Prostate
Ketoconazole,
doxorubicin,
vincristine,
estramustine
MACOP-B
Non-Hodgkin
lymphoma
Methotrexate,
leucovorin,
doxorubicin,
prednisone,
cyclophosphamide,
vincristine,
bleomycin
MAID
Soft-tissue
sarcoma
Mesna, doxorubicin
ifosfamide,
dacarbazine
Non-Hodgkin
lymphoma
Methotrexate,
leucovorin,
doxorubicin,
cyclophosphamide,
vincristine,
bleomycin,
dexamethasone
MICE (ICE)
Sarcoma, lung
Ifosfamide,
carboplatin,
etoposide, mesna
MBC
Head and neck
Methotrexate,
bleomycin, cisplatin
KAVE
m-BACOD
MOPP
Hodgkin
lymphoma
Mechlorethamine,
vincristine,
procarbazine,
prednisone
MP
Multiple
myeloma
Melphalan,
prednisone
MP
Prostate gland
Mitoxantrone,
prednisone
M-VAC
Bladder
Methotrexate,
vinblastine,
doxorubicin,
cisplatin
PAC
Ovarian,
endometrial
Cisplatin,
doxorubicin,
cyclophosphamide
PVB
Testicular,
adenocarcinoma
Cisplatin,
vinblastine,
bleomycin
Non-Hodgkin
lymphoma
Rituximab,
cyclophosphamide,
doxorubicin,
vincristine,
prednisone
R-CHOP
SMF
Pancreas
Streptozocin,
mitomycin,
fluorouracil
TAC
Breast
Docetaxel,
doxorubicin,
cyclophosphamide
TCF
Esophageal
Paclitaxel, cisplatin,
fluorouracil
TIP
Head and neck,

esophageal,
testicular
Paclitaxel,
ifosfamide, mesna,
cisplatin
Prostate
Paclitaxel,
estramustine,
carboplatin
Prostate
Paclitaxel,
estramustine,
etoposide
Bladder
Paclitaxel,
methotrexate,
cisplatin
Sarcoma
Vincristine,
dactinomycin,
cyclophosphamide
Multiple
myeloma, acute
lymphocytic
Vincristine,
doxorubicin,
TEC
TEE
TMP
VAC
VAD
leukemia
dexamethasone
VB
Testicular
Vinblastine,
bleomycin
VC
Nonsmall-cell
lung
Vinorelbine,
cisplatin
VIP
Testicular,
genitourinary,
lung
Etoposide,
cisplatin,
ifosfamide, mesna
XELIRI
Colorectal
Irinotecan,
capecitabine
XELOX
Colorectal
Oxaliplatin,
capecitabine
5 + 2
Acute
myelocytic
leukemia
Cytarabine,
daunorubicin or
mitoxantrone
7 + 3
Acute
myelocytic
leukemia
Cytarabine,
daunorubicin or
mitoxantrone
Cancer pai n may be due to di r ect tumor i nvol vement of bone,

ner ves, vi scera, bl ood vessel s, or mucous membranes and can occur
postoperati vel y, after radi ati on therapy, or after chemotherapy.
Nar coti c use shoul d fol l ow the basi c pr i nci pl es of cancer pai n
management, begi nni ng wi th an agent that has the potenti al to
pr ovi de r el i ef; i ndi vi dual i z ati on of the agent, r oute, dose, and
schedul e; ti trati on to effi cacy; and pr ovi si on of r el i ef for

br eakthr ough pai n. Si de effects shoul d be anti ci pated and tr eated.
Change fr om one r oute of admi ni strati on to another shoul d be done
wi th equi anal gesi c doses, and the oral r oute shoul d be used
whenever possi bl e. In cancer pati ents r ecei vi ng chemotherapy,
combi nati on anal gesi cs empl oyi ng an acetami nophen component
may not be the best choi ce for tr eatment of chr oni c pai n secondar y
to the r i sk of maski ng a neutr openi c fever and the r i sk of
acetami nophen toxi ci ty i f l ar ge doses ar e r equi r ed. In addi ti on,
combi nati on pr oducts usi ng an aspi r i n component ar e di scouraged
secondar y to the anti pl atel et and anti pyr eti c effects. The
nonster oi dal anti -i nfl ammator y agents ar e a useful adjunct to the
tr eatment of cancer pai n but must be used wi th cauti on secondar y
to the anti pl atel et effects. The practi ti oner shoul d be awar e of
var i ous adjuncts to pai n management, i ncl udi ng ster oi ds,
anti depr essants, anxi ol yti cs, and neur ol epti cs, as wel l as
neur oabl ati ve, neur osti mul ator y, and anestheti c pr ocedur es.
Tabl e 23.4 i s a compi l ati on of var i ous nonnar coti c and nar coti c
anal gesi c agents for tr eati ng cancer pai n and i ncl udes dose ranges
and expected toxi ci ti es.
Management of Chemotherapy-Induced
Emesis
Because many sur gi cal pati ents r ecei ve neoadjuvant and adjuvant
chemotherapy, the sur geon may be cal l ed on to tr eat CIE, whi ch i s
often a dose-l i mi ti ng toxi ci ty that may l ead pati ents to r efuse
fur ther therapy. Thr ee physi ol ogi cal ar eas ar e i ncl uded i n the
pathogenesi s of CIE: (a) the emeti c center i n the l ateral r eti cul ar
for mati on of the medul l a, (b) vagal and spl anchni c affer ents fr om
the gastr oi ntesti nal tract to the central ner vous system, and (c) the
chemor eceptor tr i gger zone i n the ar ea postr ema of the medul l a.
Chemotherapeuti c agents and thei r metabol i tes may tr i gger the
l atter two di r ectl y.
Thr ee patter ns of emesi s tend to occur i n associ ati on wi th
chemotherapy. Acute emesi s occur s wi thi n 24 hour s of
chemotherapy. Del ayed emesi s occur s mor e than 24 hour s after the
cessati on of chemotherapy admi ni strati on and i s pr edi sposed by
femal e gender, hi gh-dose ci spl ati n, and pr i or epi sodes of acute
emesi s. Anti ci pator y emesi s may occur befor e r etr eatment i n
pati ents whose pr i or epi sodes of emesi s wer e poor l y contr ol l ed,
occur r i ng i n up to 25% of pati ents who r ecei ved pr i or
chemotherapy. Younger age and hi stor y of moti on si ckness al so

pr edi spose to CIE.
Tabl e 23.5 l i sts the emetogeni c potenti al of many of the i ndi vi dual
chemotherapeuti c agents. As chemotherapeuti c agents ar e
combi ned, the combi nati on wi l l have a hi gher emetogeni c potenti al
than the i ndi vi dual agents, and appr opr i ate pr eventi on of nausea
and vomi ti ng wi l l be r equi r ed. It i s often hel pful to i denti fy the
overal l emetogeni ci ty of mul ti pl e chemotherapy agents gi ven
concomi tantl y. The fi r st step i s to i denti fy the emetogeni ci ty l evel
of each agent i n the r egi men (Tabl e 23.5). Identi fy the most
emetogeni c agent i n the r egi men, and assess the r el ati ve
contr i buti on of the other agents. Level 1 agents do not contr i bute
the emetogeni ci ty of the r egi men. Addi ng one or mor e l evel 2
agent(s) i ncr eases the emetogeni ci ty of the r egi men by one l evel
gr eater than the most emetogeni c agent i n the combi nati on. Addi ng
a l evel 3 or 4 agent i ncr eases the emetogeni ci ty of the combi nati on
by one l evel per agent. Once the total l evel of emetogeni ci ty i s
deter mi ned, the r ecommended agents for pr eventi on of acute and
del ayed emesi s for the chemotherapy combi nati on can be
ascer tai ned fr om avai l abl e anti emeti c gui del i nes (Tabl e 23.6). The
emetogeni c potenti al of many agents i s dose dependent. Ther efor e,
addi ti onal anti emeti c pr ophyl axi s/tr eatment may be r equi r ed wi th
hi gher chemotherapy dosages.
Table 23.4. Nonnarcotic and narcotic analge

used for treating cancer pain
Drug
How Supplied
Dose
and
To
Schedule
Nonnarcotics
650
Acetaminophen
(Tylenol)
Various tablets,
liquid, and
suppository
strengths
1,000
mg PO
every 6
h
He
ren
im
Celecoxib
(Celebrex)
Capsules: 100
and 200 mg
100400
mg PO
daily
Dy
he
na
ga
ble
dy
Ibuprofen
(Advil, Motrin)
Tablets: 50, 100,

200, 400, 600,
and 800 mg
Suspension: 100
mg/5 mL
200400
mg PO
every 4
6 h
Sa
Injection: 15
and 30 mg/mL
Tablets: 10 mg
1530
mg
IV/IM
every 6
h
10 mg
PO every
6 h
(limit
therapy
to 5 d)
Sa
Ketorolac
(Toradol)
100
Nabumetone
(Relafen)
Tablets: 500 and

750 mg
2,000
mg PO
daily
Sa
Naproxen
(Naprosyn)
Tablets: 125,
220, 250, 275,
375, 500, and
750 mg
Suspension: 125
mg/5 mL
250500
mg PO
twice
daily
Sa
Tramadol
(Ultram,
Ultracet)
Tablets: 50 mg
Tablets: 37.5 mg
with
acetaminophen
50100
mg PO
every 4
6 h
Diz
na
con
he
Tablets: 15, 30,

and 60 mg
Oral solution: 15
mg/5 mL
Tablets: 15, 30,
and 60 mg with
acetaminophen
1560
mg PO,
IM, IV,
or SC
every 4
6 h
Se
con
na
res
de
occ
na
an
Injection: 30
and 60 mg
50100 mcg I
12 h
Lozenges: 200,
200400
mcg PO
Narcotics
Codeine
300, 400, 600,

800, 1,200, and
1,600 mcg
Transdermal
patch: 25, 50,
75, and 100
g/h
Injection: 50
mcg/5 mL
every 2
3 h
Apply
one
patch
(25300
mcg/h)
every 72
h
Levorphanol
(LevoDromoran)
Tablets: 2 mg
Injection: 2
mg/mL
24 mg
PO/IV/IM
every 4
6 h
Sa
Hydrocodone
(Lortab,
Vicodin)
Tablets: 5, 7.5,
and 10 mg with
acetaminophen
Oral elixir: 2.5
mg with
acetaminophen/5
mL
510 mg
PO every
46 h
Sa
24 mg
PO every
34 h
0.52
mg
IV/IM
every 3
4 h
Sa
Fentanyl
(Duragesic,
Sublimaze)
Hydromorphone
(Dilaudid)
Tablets: 1, 2, 4,
and 8 mg
Injection: 1, 2,
4, and 10
mg/mL
Oral liquid: 5
mg/5 mL
Suppository: 3
Sa
mg
Methadone
(Dolophine)
Meperidine
(Demerol)
Morphine
(MSIR, MS
Tablets: 5, 10,
and 40 mg
Oral solution: 1,
2, and 10
mg/mL
Injection: 10
mg/mL
2.520
mg PO
every 3
4 h
515 mg
IV/IM
every 3
4 h
As
De
tox
acc
Tablets: 50 and
100 mg
Oral syrup: 50
mg/5 mL
Injection: 25,
50, 75, and 100
mg/mL
50150
mg PO
every 3
4 h
25100
mg
IV/IM
every 3
4 h
As
Se
no
me
acc
Tablets: 10, 15,

and 30 mg
Oral solution:
10, 20, and 100
mg/5 mL
1030
mg PO
every 3
4 h
As
Extendedrelease
tablets/capsules:
15, 20, 30, 60,
30200 mg PO
h
Contin)
Oxycodone
(Percocet,
Tylox,
OxyContin)
Propoxyphene
(Darvon,
Darvocet N100)
90, 100, 120,

and 200 mg
Injection: 0.5,
1, 2, 4, 8, 10,
15, 25, and 50
mg/mL
Suppositories: 5,
10, 20, and 30
mg
210 mg IV/IM
h
Tablet/capsule:
5, 15, 30 mg
Oral solution: 1
and 20 mg/mL
Tablets: 2.5, 5,
7.5, and 10 mg
with
acetaminophen
510 mg
PO every
46 h
Controlledrelease tablets:
10, 20, 40, 80,
and 160 mg
20160 mg PO
h
Tablets: 65 mg
(as HCl)
Tablets: 50 and
100 mg with
acetaminophen
65 mg
PO every
4 h
50100
mg PO
every 4
h
As
As
PO, orally; IM, intramuscularly; IV, intravenously; S

subcutaneously.
Table 23.5. Emetogenic potential of individua

chemotherapeutic agents
Frequency
of Emesisa
Agents
High
emetic
risk, Level
5 (>90%
frequency
of emesis)
Altretamine (oral)
Carmustine > 250
mg/m 2
Cisplatin 50
mg/m 2
Cyclophosphamide
> 1,500 mg/m2
Dacarbazine
Dactinomycin
Mechlorethamine
Melphalan (lV)
Procarbazine
(oral)
Streptozocin
Moderate
emetogenic
risk, Level
4 (60%
90%
frequency
of emesis)
Carboplatin
Carmustine 250
mg/m 2
Cisplatin < 50
mg/m 2
Cyclophosphamide
7501,500 mg/m2
Cytarabine > 1
g/m 2
Doxorubicin >
60 mg/m2
Methotrexate >
1,000 mg/m2
Arsenic trioxide
Cyclophosphamide
Moderate
emetogenic
risk, Level
3 (30%
60%
frequency
of emesis)
Low
emetogenic
risk, Level
2 (10%
30%
frequency
of emesis)
Minimal
emetogenic
risk, Level
1 (<10%
frequency
of emesis)
750 mg/m2
Cyclophosphamide
(oral)
Daunorubicin
Doxorubicin 20
60 mg/m2
Epirubicin 90
mg/m 2
Gemcitabine
Anastrozole
Capecitabine
Cetuximab
Docetaxel
Etoposide
5-Fluorouracil
Irinotecan
Methotrexate 50
250 mg/m2
Alemtuzumab
Asparaginase
Bicalutamide
Bleomycin
Busulfan
Chlorambucil
(oral)
Cladribine
Denileukin diftitox
Erlotinib
Fludarabine
Idarubicin
Ifosfamide
Methotrexate
2501,000
mg/m 2
Mitoxantrone
Oxaliplatin
Topotecan
Mitomycin
Paclitaxel
Pemetrexed
Pentostatin
Temozolomide
Teniposide
Thiotepa
Trastuzumab
Hydroxyurea
Interferon Alfa
lnterleukin-2
6Mercaptopurine
Melphalan (oral)
Methotrexate
50 mg/m2
Rituximab
Tamoxifen
Thioguanine
Gemtuzumab
ozogamicin
Imatinib mesylate
(oral)
Vinblastine
Vincristine
Vinorelbine
a Proportion
of patients who experience emesis in

the absence of effective antiemetic prophylaxis.
Adapted from: Ettinger DS, Bieman PJ, Bradbury
B, et al. NCCN Antiemesis Clinical Practice
Guidelines in Oncology. Version 1.2006, National
Comprehensive Cancer Network, 2006. The
University of Texas M.D. Anderson Cancer Center.
Antiemetic Guidelines for Chemotherapy-Induced
Nausea and Vomiting (CINV). 2006.
Table 23.6. General recommendations for

treatment of acute and delayed chemotherap
induced emesis
Emetogenicity
Acute Emesis
Level
Level 5
5-HT3
antagonist +
corticosteroids
aprepitant
lorazepam
Delayed Emes
5-HT3
antagonist +
corticosteroids
aprepitant
lorazepam
5-HT3
antagonist OR
metoclopramid
diphenhydrami
OR
corticosteroids
lorazepam
aprepitant
Levels 3 and 4
5-HT3
antagonist +
corticosteroids
lorazepam
aprepitant
Level 2
Corticosteroids
OR
prochlorperazine
OR
metoclopramide
diphenhydramine
lorazepam
No prophylaxis
recommended
Level 1
No prophylaxis
recommended
No prophylaxis
recommended
Adapted from: Ettinger DS, Bieman PJ, Bradbury B

et al. NCCN Antiemesis Clinical Practice Guidelines
Oncology. Version 1.2006, National Comprehensive
Cancer Network, 2006. The University of Texas M.D
Anderson Cancer Center. Antiemetic Guidelines for
Chemotherapy-Induced Nausea and Vomiting (CINV
2006.
The tr eatment of CIE under went a ver i tabl e r evol uti on wi th the
i ntr oducti on of the fi r st sel ecti ve ser otoni n antagoni st,
ondansetr on. Cur r entl y, ther e ar e four F DA-appr oved sel ecti ve
ser otoni n antagoni sts avai l abl e for the tr eatment and pr eventi on of
CIE (ondansetr on, dol asetr on, grani setr on, and pal onosetr on).
Pal onosetr on i s the onl y sel ecti ve ser otoni n antagoni st F DA
appr oved for the pr eventi on of acute and del ayed nausea and
vomi ti ng. These agents have al so found gr eat uti l i ty i n the
pr eventi on
of postoperati ve nausea and vomi ti ng and radi ati on therapy-i nduced

nausea and vomi ti ng. Intravenous (IV) admi ni strati on i s not
necessar y i n most cases of nonci spl ati n-i nduced emesi s because
effi cacy by oral admi ni strati on i s comparabl e. The excepti on to thi s
i s pal onosetr on, whi ch i s onl y avai l abl e by IV admi ni strati on. They
al so have the advantage of not causi ng sedati on, and ther efor e can
be safel y admi ni ster ed i n combi nati on wi th other agents. Hi gh-dose
IV metocl oprami de has been found effecti ve i n tr eati ng CIE,
al though l ess so than ondansetr on, but i ts extrapyrami dal si de
effects can be a si gni fi cant pr obl em. These extrapyrami dal si de
effects may occur wi th any of the anti dopami ner gi c agents,
i ncl udi ng metocl oprami de, hal oper i dol , dr oper i dol , and the
phenothi az i nes. The extrapyrami dal si de effects can be
tr eated/pr evented by coadmi ni strati on or pr etr eatment wi th an
anti chol i ner gi c such as benz tr opi ne or di phenhydrami ne. Standar d
phenothi az i nes ar e l ess effecti ve but ser ve as useful adjuncts i n the
tr eatment of CIE. Cor ti coster oi ds, especi al l y dexamethasone and
methyl pr edni sol one, act vi a a mechani sm that i s sti l l uncl ear. In
combi nati on wi th other agents, cor ti coster oi ds dramati cal l y i mpr ove
anti emeti c effi cacy and may r educe the i nci dence of unwanted si de
effects by per mi tti ng dosage r educti on. Cor ti coster oi ds ar e
especi al l y useful i n tr eati ng/pr eventi ng del ayed emesi s. Apr epi tant
i s an oral l y admi ni ster ed substance P/neur oki ni n (NK) 1 r eceptor
antagoni st. It i s F DA-appr oved for pr eventi on of acute and del ayed
CIE wi th i ni ti al and r epeated cour ses of hi ghl y emetogeni c
chemotherapy, and must be used i n combi nati on wi th a ser otoni n
r eceptor antagoni st and a cor ti coster oi d. Apr epi tant i s not i ndi cated
as tr eatment for br eakthr ough nausea or emesi s. Due to
i nteracti ons wi th the CYP450 system, apr epi tant has a potenti al to
i nteract wi th many medi cati ons, i ncl udi ng chemotherapy.
Lorazepam, a benzodi azepi ne, i s useful i n the pr eventi on of
anti ci pator y emesi s and may r educe the i nci dence of dystoni c
r eacti ons to metocl oprami de. Most i mpor tant, combi nati ons of these
agents, speci fi cal l y ondansetr on, dexamethasone, l orazepam, and
metocl oprami de, i ncr ease anti emeti c effi cacy and r educe
tr oubl esome si de effects thr ough pr esumed syner gi sti c acti vi ty.
Table 23.7. Antiemetic agents for chemo

Drug
Class/Mechanism
Ondansetron
(Zofran)
Selective serotonin receptor

antagonist
Granisetron
(Kytril)

antagonist
Dolasetron
(Anzemet)

antagonist
Palonosetron
(Aloxi)

antagonist
Aprepitant
(Emend)
Substance P/Neurokinin 1
receptor antagonist
Metoclopramide
(Reglan)
Otherdopamine antagonist
Haloperidol
(Haldol)
Droperidol
(Inapsine)
Prochlorperazine
(Compazine)
Phenothiazinedopamine
antagonist
Chlorpromazine
(Thorazine)
Phenothiazinedopamine
antagonist
Dexamethasone
(Decadron)
Othercorticosteroid
Methylprednisolone
(Depo-Medrol,
Medrol, SoluMedrol)
Othercorticosteroid
Lorazepam
(Ativan)
Otherbenzodiazepine
Diphenhydramine
(Benadryl)
Antihistamine/anticholinergic
Dronabinol
(Marinol)
Othercannabinoid
IV, intravenously; PO, orally; ECG, electrocardiogra

sublingually.
Tabl e 23.7 l i sts avai l abl e and commonl y used anti emeti c agents wi th
thei r dose ranges and the known major si de effects.
Recommended Reading
Abramowi cz M, ed. Dr ugs of choi ce for cancer chemotherapy. Med
Lett Dr ugs Ther 1993;35:43.
Bur nham T, ed. Dr ug F acts and Compar isons. 55th ed. St. Loui s,
Mo: Facts and Compar i sons, Wol ter s Kl uwer ; 2001.
Chang HM. Pai n and i ts management i n pati ents wi th cancer.
Cancer Invest 2004;22(5):799809.
DeVi ta V, Hel l man S, Rosenber g S, eds. Cancer : Pr inciples and
Pr actice of Oncology. 7th ed. Phi l adel phi a, Pa: Li ppi ncott; 2004.
Etti nger DS, Bi eman PJ, Bradbur y B et al . NCCN Antiemesis
Clinical Pr actice G uidelines in Oncology. Ver si on 1. 2006. Nati onal
Compr ehensi ve Cancer Networ k, 2006. Avai l abl e at: URL:
http://www.nccn.or g.
Krakoff I. Cancer chemotherapeuti c and bi ol ogi c agents. CA

Cancer J Clin 1991;41:264.
McEvoy G , ed. AHF S Dr ug Infor mation. Easton, Md: Amer i can
Soci ety of Hospi tal Phar maci sts; 2001.
Pazdur R, ed. Cancer Management: A Multidisciplinar y Appr oach.
8th ed. Mel vi l l e, NY: PRR, Inc.; 2004.
Per r y M, ed. The Chemother apy Sour ce Book. 3r d ed.
Phi l adel phi a, Pa: Li ppi ncott Wi l l i ams & Wi l ki ns; 2001.

M.
Edition
> Ta ble o f C o nt e nt s > 2 4 - Re c o ns t ruc t iv e Surge ry in t he C a nc e r Pa t ie nt
24
Reconstructive Surgery in the Cancer
Patient
Jules A . Feledy Jr.
Matthew M. Hanasono
Geoffrey L. Robb
Introduction
Reconstr ucti ve sur ger y i n the cancer pati ent endeavor s to r estor e
for m and functi on fol l owi ng abl ati ve sur ger y. The par ti ti on of
oncol ogi c abl ati on fr om pl asti c sur ger y r econstr ucti on faci l i tates
r esecti on of a cancer l esi on i ndependent of the steps r equi r ed for
r estorati on. Reconstr ucti ve strategi es bal ance the r equi r ements of
the r esul ti ng wound defect, i ncl udi ng the overal l si ze, functi onal
pr i or i ti es, and consti tuti ve vi tal r equi si tes of the pati ent wi th the
avai l abl e donor sour ces and the consequent addi ti onal mor bi di ti es
associ ated wi th ti ssue har vest. Successful r econstr ucti ve sur ger y
achi eves r estorati on of functi on and for m wi th mi ni mal donor si te
defor mi ty and consequent enhancement of qual i ty of l i fe.
General Principles
Wound defects ar e assessed based on si ze, l ocati on, physi cal
components, and functi onal r equi r ements. The defect may or i gi nate
fol l owi ng tumor r esecti on or as a r esul t of tumor necr osi s, and may
be compl i cated by i nfecti on or exposur e of vi tal str uctur es. The
physi ol ogi cal functi on of a bodi l y r egi on may be i mpai r ed and the
qual i ty of l i fe compr omi sed. An eval uati on for the components of
ti ssue that wi l l be r equi r ed to r epai r a r egi on i s made, i ncl udi ng
components of ski n, mucosa, muscl e, ner ves, fasci a, and bone. For
exampl e, an anter i or base of skul l defect may r equi r e coverage of
dura, crani um, and exposed bl ood vessel s, i n addi ti on to cl osur e of

the oral mucosa and exter nal ski n, whi l e a per i neal wound may
r equi r e r econstr ucti on of the pel vi c fl oor, geni tal str uctur es, and
coverage of the exter nal ski n.
Sel ecti on of the appr opr i ate r econstr ucti ve techni que i s based on
several factor s. The pati ent's medi cal and functi onal condi ti on must
be assessed r el ati ve to the anti ci pated r econstr ucti ve goal s. The
abi l i ty to tol erate a l engthy operati ve pr ocedur e and the
postoperati ve physi ol ogi cal str esses ar e i mpor tant pr eoperati ve
consi derati ons. In addi ti on, the r ol e of r econstr ucti on i n the overal l
oncol ogi c tr eatment pl an must be deter mi ned. Reconstr ucti ve
sur ger y opti mal l y does not i nter fer e wi th the admi ni strati on of
adjuvant therapy. F ur ther mor e, the l i festyl e and per sonal
consi derati ons of the pati ent often factor i nto the deci si on to
pr oceed wi th speci fi c r econstr ucti ve opti ons. F i nal l y, l ocal wound
defect consi derati ons, such as pr evi ous radi ati on therapy and
i nci si onal scar patter ns, may i nfl uence the choi ce of pr ocedur e.
Reconstr ucti ve sur ger y can be per for med i n the i mmedi ate or
del ayed setti ng. The ti mi ng of r econstr ucti ve sur ger y i s i nfl uenced
by the tumor pathol ogy, extent of r esecti on, adjuvant
therapy, sur gi cal exper ti se, and pati ent pr efer ence. Immedi ate
defect wound coverage i s necessi tated for coverage of vi tal
str uctur es, i ncl udi ng brai n and dura, major or gan and vascul ar
str uctur es, and spi ne and joi nts. Immedi ate r econstr ucti on i s
general l y pr efer r ed fol l owi ng tumor exti r pati on because di ssected
ti ssue pl anes ar e avai l abl e, pl i abl e ski n and soft-ti ssue coverage ar e
maxi mal l y pr eser ved, and nonfi br osed ti ssues ar e accessi bl e. Scar
ti ssue for mati on and contractur e may pr ecl ude l ater r estorati on of
anatomi cal l y cr i ti cal str uctur es, and pr eser vati on of these
str uctur es may necessi tate i mmedi ate r econstr ucti on.
Del ayed r econstr ucti on, i n contrast, necessi tates exposur e thr ough
fi br osed and often i r radi ated ti ssue fi el ds. Ther e i s general l y a
gr eater r equi r ement for the r epl acement of over l yi ng ski n and
subcutaneous ti ssues. Donor ti ssue for transfer and thei r
accompanyi ng vessel s ar e l i kel y to have r educed capaci ty for
del ayed transfer, and potenti al r eci pi ent vessel di ssecti on for
mi cr ovascul ar transfer may be compl i cated by ci r cumfer enti al
encasement i n scar ti ssue and vessel wal l fr i abi l i ty. Del ayed
r econstr ucti on i s i ndi cated when the oncol ogi c sur gi cal team i s
unabl e to deter mi ne the extent of sur gi cal r esecti on based on
sur gi cal tumor mar gi ns, when extensi ve necr osi s i s compl i cated by
i nfecti on, or i n ci r cumstances when i mmedi ate r econstr ucti on wi l l

del ay adjuvant chemotherapy.
The choi ce of a r econstr ucti ve pr ocedur e bal ances r econstr ucti on of
a speci fi c wound defect wi th the avai l abl e donor sour ces and
consequent addi ti onal mor bi di ti es associ ated wi th ti ssue har vest. A
fl exi bl e paradi gm of a r econstr ucti ve l adder pr ovi des a star ti ng
poi nt fr om whi ch to consi der the var i ous opti ons avai l abl e for wound
cl osur e. Opti ons ar e consi der ed i n i ncr easi ng or der of compl exi ty for
a speci fi c defect: Pr i mar y cl osur e i s general l y consi der ed as the fi r st
choi ce, when possi bl e, fol l owed by ski n grafts, l ocal fl aps, r egi onal
fl aps, and di stant fl aps. Mul ti pl e di ffer ent opti ons may exi st for a
defect, and sur gi cal opti ons ar e often based on the qual i ty of the
anti ci pated r econstr ucti on. A compl ex mi cr ovascul ar pr ocedur e may
be sel ected over a si mpl er pr ocedur e when i t wi l l pr oduce a super i or
r econstr ucti ve r esul t. Mor eover, al ter nati ve therapi es, i ncl udi ng
ti ssue expansi on and vacuum-assi sted coverage, may r epr esent
vi abl e opti ons. The r estorati on of functi on and for m often r equi r es
i ntegrati on of mul ti pl e steps i n a compl ex r econstr ucti ve strategy.
Reconstructive Options
The r econstr ucti on of wound defects, asi de fr om pr i mar y cl osur e, i s
fundamental l y dependent on ti ssue transfer fr om one bodi l y r egi on
to another. A br oad ar mamentar i um has been establ i shed consi sti ng
of di ffer ent ti ssue categor i es, and opti mal r econstr ucti on depends
on r el i abl e desi gn and transfer of these ti ssues.
G r afts consi st of nonvascul ar i zed ti ssue that i s separated fr om a
donor si te and depends on the gr owth of new vessel s at the
r eci pi ent si te. G rafts under go r egul ated stages of maturati on, whi ch
begi n wi th the di ffusi on of oxygen and nutr i ents acr oss a wound
i nter face fol l owed by an i nter medi ate phase of neovascul ar i z ati on
and then l ater matr i x r emodel i ng and stabi l i z ati on. The most
common grafts used for r econstr ucti on i ncl ude par ti al - or ful l thi ckness ski n, car ti l age, ner ve, and cor ti cal or cancel l ous
bone. The success of the grafti ng pr ocedur e depends on ther e bei ng
vascul ar i zed r eci pi ent wound ti ssue, whi ch i s often devi tal i zed
because of hypoxi a, i nfecti on, or pr evi ous radi ati on therapy.
F laps ar e ti ssues that ar e transfer r ed wi th an i ntact bl ood suppl y
and r epr esent the fundamental method of ti ssue transfer used i n
r econstr ucti on. The pr eser vati on and i ncor porati on of the bl ood
suppl y i s the sal i ent featur e of fl aps, al l owi ng for transfer of
composi te ti ssues. Each fl ap has di sti nct featur es based on i ts

i nher ent anatomi cal character i sti cs, i ncl udi ng patter n of ci r cul ati on,
bl ood suppl y, component ti ssues, thi ckness, and functi on. Compl ex
r econstr ucti on i s based on mani pul ati on of the pr oper ti es of
di ffer ent fl aps to achi eve an engi neer ed r esul t.
The most useful cl assi fi cati ons of fl aps ar e those based on the
vascul ar anatomy, component par ts, and pr oxi mi ty to the wound
defects. The vascul ar patter n for each fl ap i s di vi ded i nto random
patter n, i ndi cati ng ci r cul ati on that depends on the tr i butar i es of the
pl exus at the attached base, or axi al patter n, speci fyi ng the
pr esence of a domi nant central bl ood suppl y. A compl ex
cl assi fi cati on based on the bl ood suppl y to each fl ap i s used to
har vest and i nset donor ti ssues. F l aps ar e al so cl assi fi ed by the
ti ssue components i ncor porated i n the fl ap; thus, ther e ar e ski n,
fasci ocutaneous, muscl e, muscul ocutaneous, osseous,
osteocutaneous, and osteomyocutaneous fl aps. The attr i butes of the
var i ous fl aps enabl e the sur geon to sel ect the best fl ap to match the
wound defect to achi eve compl ex r econstr ucti on. The di stance fr om
the wound defect i s character i zed as l ocal , i ndi cati ng transfer fr om
an adjacent ar ea; r egi onal , speci fyi ng fl aps that or i gi nate fr om a
separate par t of the body but that have a suffi ci ent ar c of r otati on
to r each a wound defect wi thout di vi si on of the bl ood suppl y; and
di stant, i mpl yi ng that the fl ap exi sts beyond the r each of the wound
defect.
Tissue expansion i s a common fl ap modi fi cati on based on staged
expansi on of r egi onal ti ssue and del ayed transfer. It opti mi zes the
use of l ocal ti ssues but r equi r es pl acement of a pr ostheti c devi ce.
Micr ovascular tissue tr ansfer i s a speci fi c appl i cati on of fl ap transfer.
Thi s techni que entai l s el evati on of a composi te ti ssue fl ap fol l owed
by di vi si on of the bl ood suppl y and r e-establ i shment of the
ci r cul ati on to a r eci pi ent bl ood suppl y wi thi n pr oxi mi ty to the wound
defect. Anastomosi s i s usual l y per for med wi th the assi stance of a
mi cr oscope or l oupe magni fi cati on. F l ap choi ce i s based on the
vascul ar pedi cl e l ength, ti ssue components, and abi l i ty to pr ovi de a
stabl e r econstr ucti ve r esul t. The mai n advantage of thi s appr oach i s
the r ecr ui tment of ti ssues fr om another r egi on of the body.
Head and Neck Reconstruction

The goal s of head and neck r econstr ucti on ar e to pr otect vi tal
str uctur es, pr eser ve functi on, r estor e contour, and maxi mi ze
aestheti c appearance. The chal l enge i s achi evi ng these
r equi r ements i n thi s compl ex r egi on.
Scalp
Reconstr ucti ve opti ons for the scal p must be consi der ed i n the
context of the cause of the defect. The r estorati on of abl ati ve
defects i nvol ves matchi ng the defect wi th the avai l abl e ti ssue. Local
r otati on fl aps ar e pr efer r ed for smal l defects; mul ti pl e br oadl y
based fl aps, augmented wi th gal eal scor i ng, can often cl ose most
smal l (<3 cm) defects. For l ar ger defects, l ar ge r otati on fl ap
advancement wi th ski n grafti ng of the exposed donor si te or
mi cr ovascul ar fl ap coverage can be per for med. Abl ati ve contr ol
often necessi tates composi te r esecti on of i nvol ved cal var i al bone, so
r econstr ucti on may al so r equi r e the use of al l opl asti c mater i al s,
such as ti tani um mesh or methyl methacr yl ate, or of vascul ar i zed
bone fl aps, such as vascul ar i zed r i b fl aps. Scal p defects r esul ti ng
fr om i r radi ati on i njur y, however, pr ecl ude the use of l ocal fl aps, and
r econstr ucti on i n such cases i nstead i nvol ves the debr i dement of
devi tal i zed ti ssues and then autol ogous fl ap coverage.
Facial Skin
Al though most faci al defects ar e smal l , they tend to be l ocated i n
aestheti cal l y and functi onal l y di ffi cul t r egi ons, such as the nasal ti p
or i n pr oxi mi ty to the eyel i d. Smal l super fi ci al defects of the faci al
ski n ar e tr eated pr i mar i l y wi th ski n grafts and l ocal fl aps. If l ocal
ti ssue can be mobi l i zed, then l ocal ti ssue cl osur e i s pr eferabl e. For
exampl e, smal l random fl aps or r egi onal axi al fl aps can be r otated
i nto a defect. Al ter nati vel y, ful l -thi ckness ski n grafts can be
har vested fr om ar eas wi th ski n of si mi l ar thi ckness, col or, and
qual i ty as that of the face. Pr eaur i cul ar, postaur i cul ar, and cer vi cal
ski n si tes pr ovi de super i or matches for faci al ski n defects. Lar ger
defects, however, may r equi r e advanced pr ocedur es wi th compl ex
r otati on fl aps or, i n rar e cases, mi cr ovascul ar fl ap transfer.
Neck
The neck i s often tr eated wi th radi ati on for potenti al or cl i ni cal l y
detectabl e nodal di sease i n cancer. Fol l owi ng neck di ssecti on,
i r radi ated neck ski n may be unabl e to pr ovi de suffi ci ent coverage of
the major vessel s of the neck, r esul ti ng i n thei r pr ol onged exposur e
and the r i sk of hemor r hage. In some ci r cumstances, the
ster nocl ei domastoi d muscl e can be r otated to cover the vessel s;
however, the muscl e i s l i mi ted by a segmental bl ood suppl y.

Ther efor e, noni r radi ated autol ogous ti ssue i s general l y r ecr ui ted,
whi ch wi l l enabl e mi ni mal l y r estr i cted neck movement. The most
commonl y used fl ap i s a pedi cl ed pectoral i s major muscl e fl ap
r otated on the thoracoacr omi al axi s and cover ed wi th an over l yi ng
ski n graft. Al ter nati ve opti ons for neck coverage i ncl ude fr ee ti ssue
transfer wi th muscul ocutaneous fl aps, such as a l ati ssi mus dor si fl ap
suppl i ed by the thoracodor sal vessel s, or wi th fasci ocutaneous fl aps,
such as a radi al for ear m fl ap suppl i ed by the radi al ar ter y, an
anter ol ateral thi gh fl ap based on the descendi ng branch of the
l ateral ci r cumfl ex femoral ar ter y, or a scapul ar fl ap suppl i ed by the
ci r cumfl ex scapul ar vessel s to avai l abl e neck vessel s.
Nose
The nose i s typi cal l y r econstr ucted wi th l ocal and r egi onal fl aps. In
general , such fl aps r esul t i n cosmeti c r esul ts super i or to those
attai nabl e by ski n grafts. F ul l -thi ckness defects must be r epai r ed
wi th an i nner l i ni ng, a framewor k, and an exter i or cover. The nasal
l i ni ng i s usual l y r epl aced wi th l ocal fl aps taken fr om the nasal
mucosa. Car ti l age grafts fr om the ear or r i b can be used
to r epl ace the car ti l agi nous framewor k. When possi bl e, enti r e
subuni ts of the nose, i ncl udi ng the dor sum, si dewal l s, al a, ti p,
col umel l a, and soft tr i angl es, ar e r epl aced for the best aestheti c
r esul ts. For l ar ger defects, the nasol abi al fl ap, whi ch may be based
on the angul ar ar ter y i nfer i or l y or the dor sal branch of the
ophthal mi c ar ter y super i or l y, or the paramedi an for ehead fl ap,
whi ch i s based on the supratr ochl ear ar ter y, ar e used. The
paramedi an for ehead fl ap may be used to r esur face the enti r e
exter i or nasal ski n. Note that the pedi cl es of the nasol abi al and
paramedi an for ehead fl aps ar e l eft i ntact for appr oxi matel y 2 weeks
befor e di vi si on.
Lips
Defects i nvol vi ng appr oxi matel y one-thi r d or l ess of the wi dth of the
upper or l ower l i p can be r epai r ed by pr i mar y cl osur e. For ful l thi ckness defects wi der than thi s, l ocal fl aps ar e needed. Li p swi tch
fl aps, i n whi ch pedi cl ed ti ssue i s transfer r ed fr om the upper l i p to
the l ower l i p or vi ce ver sa, ar e used for defects that ar e
appr oxi matel y one-thi r d to two-thi r ds of the wi dth of the upper or
l ower l i p. Lar ger defects r equi r e bi l ateral r otati on or advancement
fl aps. In addi ti on, total l i p defects can be r econstr ucted wi th
fasci ocutaneous fr ee fl aps, such as the radi al for ear m fl ap, fol ded on
themsel ves to r e-cr eate the i nner and outer sur faces of the l i p.
Ear
Most par ti al ear r econstr ucti ons can be per for med by usi ng l ocal
ti ssues, as i n pr i mar y cl osur e of wedge-type r esecti ons,
r ear rangement of the r emai ni ng aur i cl e, and coverage by pedi cl ed
ski n fl aps fr om the postaur i cul ar ar ea. For l ar ger defects, the
car ti l agi nous framewor k of the aur i cl e can be r e-cr eated by usi ng
car ti l age grafts obtai ned fr om the r i bs and cover ed wi th the
super fi ci al temporal fasci a, al so known as the tempor opar i etal
fasci a, whi ch der i ves i ts bl ood suppl y fr om the super fi ci al temporal
ar ter y. Spl i t-thi ckness ski n grafts wi l l sur vi ve on the super fi ci al
temporal fasci a. Some sur geons have al so had success wi th
al l opl asti c framewor ks cover ed by the super fi ci al temporal fasci a
and a ski n graft. Al ter natel y, pr ostheti c ear s can be manufactur ed
for total or near-total defects and secur ed wi th osteoi ntegrated
i mpl ants.
Oral Cavity
The oral cavi ty i ncl udes the tongue, fl oor of mouth, al veol ar r i dges,
r etr omol ar tr i gone, pal ate, and buccal mucosa. Defects i n any of
these str uctur es can compr omi se speech, chewi ng, swal l owi ng, and
br eathi ng, and mul ti pl e si tes may be i nvol ved. In addi ti on, r esecti on
of hi gher-stage cancer s that i nvade maxi l l ar y or mandi bul ar bone
can r esul t i n composi te defects. The pedi cl ed pectoral i s major fl ap
has l ong been used for such si tuati ons. However, i n many cases, the
pectoral i s fl ap's bul k, l ack of pl i abi l i ty, and l i mi ted r each sti l l make
i t a second choi ce behi nd fr ee fl aps i n oral cavi ty r econstr ucti on.
The radi al for ear m fr ee fl ap i s an excel l ent opti on for r econstr ucti ng
thi n mucosal defects, such as those i n the fl oor of mouth, buccal
ar ea, and pal ate, and for r econstr ucti ng par ti al
gl ossectomy defects. The l ateral ar m fl ap, whi ch i s suppl i ed by the
poster i or radi al col l ateral vessel s, and the anter ol ateral thi gh fl ap
may al so be appr opr i ate choi ces for pati ents wi th a thi n l ayer of
suffi ci ent subcutaneous fat i n the extr emi ti es. In ful l -thi ckness
cheek defects, the radi al for ear m fl ap or other fasci ocutaneous fl aps
can be fol ded on themsel ves to pr ovi de an i nter nal and exter nal
l i ni ng. Total and near-total gl ossectomi es r equi r e bul ky fl aps to
potenti al l y r estor e swal l owi ng; for exampl e, the r ectus abdomi nus
and anter ol ateral thi gh fl aps can pr ovi de adequate bul k for
r econstr ucti ng l ar ge defects of the tongue.
Mandible
The most common i ndi cati on for mandi bul ar r econstr ucti on r emai ns
abl ati ve sur ger y for neopl asti c pr ocesses of the oral cavi ty and
or ophar ynx. The functi onal l osses and aestheti c defor mi ty that
occur wi th mandi bul ar defects depend on the si ze and l ocati on of
the segmental mandi bul ar defect. Defects i n the poster i or body or
ramus ar e better tol erated, whi l e anter i or defects ar e associ ated
wi th si gni fi cant defor mi ty and l oss of functi on. Masti cati on and
degl uti ti on ar e compr omi sed as str uctural suppor t for the tongue
and l ar ynx i s l ost. Ai r way compr omi se necessi tati ng tracheostomy
may r esul t fr om the l oss of ai r way stabi l i ty and tongue suppor t.
Mal occl usi on may devel op fr om mandi bul ar shi fts fr om r esecti on.
F uncti onal and aestheti c goal s ar e i mpor tant consi derati ons, and
r econstr ucti on fol l owi ng abl ati ve sur ger y opti mal l y pr eser ves these
functi ons, r estor es l ower faci al aestheti cs, and al l ows for l ater
dental r ehabi l i tati on.
The functi onal and aestheti c r esul ts obtai ned wi th mi cr ovascul ar
ti ssue transfer ar e super i or to those obtai ned wi th nonvascul ar i zed
bone grafts or pedi cl ed ti ssue transfer s. Al though smal l er bony
defects may be r econstr ucted wi th nonvascul ar i zed grafts and metal
pl ates, these defects r epr esent onl y a smal l per centage of cases.
Most cases i nvol ve ei ther a l ar ger segmental bony r esecti on or the
i nvol vement of i nter nal oral l i ni ng or exter nal ski n. F r ee ti ssue
transfer al l ows for suffi ci ent bony and soft-ti ssue transfer wi th a
r el i abl e vascul ar suppl y. In general , vascul ar i zed bone fl aps ar e
used to r econstr uct mandi bul ar defects gr eater than 5 to 6 cm or
composi te defects. Bone uni on rates ar e hi gh for vascul ar i zed bone
fl aps because they heal by pr i mar y bone heal i ng, si mi l ar l y to
fractur es, i n contrast to nonvascul ar i zed bone grafts, whi ch heal by
osteoconducti on.
The mai nstay of mandi bul ar r econstr ucti on i s the fi bul a fl ap. Up to
25 cm of bone can be har vested, whi ch pr ovi des suffi ci ent l ength to
r econstr uct any defect fr om mandi bul ar angl e to mandi bul ar angl e.
The bony shape i s r el ati vel y consi stent, and osteotomi es can be
made at i nter val s to confor m the bone to a l ocki ng r econstr ucti on
pl ate model ed after the r esected mandi bl e. A ski n paddl e can be
har vested to pr ovi de soft-ti ssue coverage. Har vest of the central
fi bul a i s wel l tol erated i f 5 cm of pr oxi mal and di stal fi bul a ar e
pr eser ved i n si tu for ti bi al stabi l i ty. The pedi cl e l ength and cal i ber
ar e suffi ci ent for r eanastomosi s i n the neck. The fi bul a fl ap i s based

on the per oneal ar ter y and vei n; ther efor e, i ts use r equi r es
adequate di stal l ower l i mb per fusi on by ei ther the anter i or or the
poster i or ti bi al vessel s. If di stal per fusi on i s i n doubt, an angi ogram
shoul d be obtai ned pr eoperati vel y.
Secondar y fl ap sour ces for mandi bl e r econstr ucti on i ncl ude the i l i ac
cr est fl ap, the scapul a fl ap, and the radi al for ear m fl ap.
Maxilla
The maxi l l a i s the pr edomi nant bony str uctur e i n the mi dface and
contai ns or contr i butes to the pal ate, super i or al veol ar r i dge, l ateral
nasal wal l , or bi tal fl oor, and mal ar emi nence. Pr evi ousl y, many
maxi l l ar y defects wer e not r econstr ucted. Instead, defects r esul ti ng
fr om a maxi l l ectomy wer e l i ned wi th ski n grafts or al l owed to r eepi thel i al i ze spontaneousl y so they coul d be better moni tor ed for
tumor r ecur r ence. Hi stor i cal l y, pr ostheti c obturator s wer e used i n
l i eu of autol ogous ti ssue to i sol ate the oral cavi ty fr om the
maxi l l ar y cavi ty and someti mes to r estor e contour to the mi dface.
Pr i or to the i ntr oducti on of contemporar y i magi ng modal i ti es, ther e
was concer n that autol ogous ti ssue transfer coul d make the
detecti on of ear l y r ecur r ences di ffi cul t. Now, wi th the i mpr oved
abi l i ty to detect tumor r ecur r ence by i magi ng studi es, the pl asti c
sur geon can per for m autol ogous r econstr ucti on, whi ch pr ovi des
mi dfaci al contour, or onasal competence, and suppor t for the or bi t.
However, the opti mal ti ssue to use for r econstr ucti on i n thi s ar ea i s
contr over si al and depends on the speci fi c defect. Muscl e or
muscul ocutaneous fr ee fl aps such as the r ectus abdomi ni s,
fasci ocutaneous fr ee fl aps such as the anter ol ateral thi gh fl ap and
the radi al for ear m fl ap, and osseous or osteocutaneous fr ee fl aps
such as the fi bul a and i l i ac fr ee fl aps have al l been used for
r econstr ucti on of thi s ar ea.
Pharynx and Esophagus

Reconstr ucti on of the phar ynx and pr oxi mal esophagus i s
chal l engi ng. The goal i s to r estor e swal l owi ng and speech functi ons.
F ur ther compl i cati ng r econstr ucti ve effor ts i s that most pati ents wi l l
r ecei ve radi ati on therapy.
Tradi ti onal methods of r econstr ucti on, i ncl udi ng tubed del topectoral
fl aps, gastr i c pul l -up pr ocedur es, and col oni c i nter posi ti on
pl acement, have gi ven way to cur r ent mi cr ovascul ar transfer s wi th
jejunal segment, radi al for ear m, and anter ol ateral thi gh fl aps.
Mi cr ovascul ar fl aps ar e associ ated wi th gr eater success i n
r estorati on of swal l owi ng and speech functi ons. A tracheoesophageal
punctur e for speech i s general l y per for med after the i mmedi ate
r econstr ucti on. Abdomi nal pr ocedur es i nvol ve an addi ti onal
l apar otomy and bowel anastomosi s. Mi cr ovascul ar transfer wi th the
anter ol ateral thi gh fl ap has been shown to have a sl i ghtl y better
functi onal outcome than the jejunal fl ap. Al though the fr ee jejunum
fl ap offer s the benefi t of a secr etor y sur face, whi ch can hel p r educe
symptoms of xer ostomi a, swal l owi ng i s often i nter r upted fr om
di sor der ed per i stal si s wi thi n the fl ap, and speech tends to be l ess
r obust and under standabl e. The rates of str i ctur e for mati on and
fi stul a for mati on ar e si mi l ar, both bei ng super i or to
nonmi cr ovascul ar al ter nati ves.
Breast Reconstruction
The goal s of br east r econstr ucti on ar e the r estorati on of the for m
and contour of the femal e br east and symmetr y wi th the
contral ateral br east. Sal i ent chal l enges i ncl ude matchi ng the
appr opr i ate techni que wi th the par ti cul ar needs of the pati ent and
i ncor porati ng the r econstr ucti ve appr oach chosen i nto the overal l
tr eatment pl an.
Ini ti al consi derati ons for deci di ng whi ch r econstr ucti ve method to
use i ncl ude the type of br east defect, the status of the contral ateral
br east, the overal l heal th of the pati ent, any hi stor y of pr evi ous
i r radi ati on or smoki ng, and the pr efer ences of the pati ent.
Pati ents wi th par ti al mastectomy defects as a r esul t of br east
conser vati on therapy tend to be r econstr ucted based on the r el ati ve
si ze of the par ti al defect i n r el ati on to the overal l br east si ze.
Opti ons for r econstr ucti on i ncl ude l ocal ti ssue r ear rangement,
br east r educti on, and pedi cl ed fl ap transposi ti on. Our pr efer ence i s
for i mmedi ate r econstr ucti on when possi bl e.
Impl ant-based r econstr ucti on techni ques use an i nter nal pr osthesi s
to pr ovi de br east vol ume and for m. Br east i mpl ants contai n a
si l i cone-el astomer shel l fi l l ed wi th ei ther sal i ne or si l i cone gel .
Common i ndi cati ons for the use of i mpl ants i ncl ude a thi n habi tus
woman wi th i nsuffi ci ent donor ti ssue for autol ogous r econstr ucti on,
a smal l br east vol ume, and mi ni mal ptosi s. Pr evi ous radi ati on
tr eatment of the br east r epr esents a r el ati ve contrai ndi cati on to
expander /i mpl ant r econstr ucti on.
A staged r econstr ucti on consi sti ng of ti ssue expansi on fol l owed by

per manent i mpl ant pl acement i s most commonl y per for med. Thi s
pr ocedur e i nvol ves pl aci ng an expander under the mastectomy ski n
i n the subpectoral i s muscl e ei ther i mmedi atel y after mastectomy or
as a del ayed pr ocedur e. After al l owi ng the over l yi ng i nci si ons to
heal , al i quots of sal i ne ar e i njected transcutaneousl y on an i nter val
basi s unti l the desi r ed fi nal vol ume si ze i s achi eved. A second-stage
operati on i s then per for med to r emove the br east expander s and
pl ace the per manent br east i mpl ant. The advantages of thi s method
of r econstr ucti on i ncl ude i ts si mpl i ci ty, i ts r equi r ement of l ess
operati ng r oom ti me, and i ts sui tabi l i ty for women who ar e not abl e
to under go autol ogous r econstr ucti on. The di sadvantages i ncl ude
potenti al l ocal compl i cati ons, devel opment of capsul ar contractur e,
and r uptur e of the i mpl ant.
A second i mpl ant-based techni que uses a l ati ssi mus dor si fl ap wi th
an i mpl ant. A pedi cl ed muscul ocutaneous fl ap based on the
thoracodor sal vascul ar suppl y i s r otated anter i or l y to the br east and
i s used to cover the i mpl ant. The i mpl ants used ar e general l y the
same as those used after ti ssue expansi on. The ski n paddl e may be
i ncl uded wi th the muscl e to faci l i tate coverage of the mastectomy
wound. The pr i mar y advantage of the l ati ssi mus dor si fl ap pr ocedur e
i s that suffi ci ent ti ssue for coverage of the i mpl ant i s avai l abl e
wi thout ti ssue expansi on and a staged appr oach i s not r equi r ed.
Another key advantage i s that vascul ar i zed ti ssue can be
transfer r ed to the br east i n a pr edi ctabl e manner. Two major
drawbacks ar e that a donor si te scar i s cr eated and that some
r esul tant weakness of upper tor so str ength may be r eal i zed. Thi s
appr oach does, however, r epr esent a vi abl e opti on for women wi th a
thi n habi tus or i nsuffi ci ent pannus who ar e not candi dates for an
abdomi nal fl ap or for women who have pr evi ousl y fai l ed other types
of r econstr ucti on.
Reconstr ucti ve techni ques that use autol ogous ti ssue transfer ski n,
fat, and muscl e fr om one ar ea of the body to the chest and
general l y el i mi nate the need for a suppl emental pr osthesi s. The
transver se r ectus abdomi nus myocutaneous (TRAM) fl ap pr ocedur e
i s the most common techni que for autol ogous r econstr ucti on and
uses the l ower abdomi nal fat suppl i ed by epi gastr i c vascul ar
per forator s thr ough the r ectus abdomi ni s muscl e. A l ar ge vol ume of
wel l -vascul ar i zed ski n and subcutaneous ti ssue can be transfer r ed
to the chest to r econstr uct the mastectomy si te. A pedi cl ed TRAM
fl ap pr ocedur e i nvol ves r otati on of the l ower abdomi nal pannus
thr ough a subcutaneous tunnel fr om the abdomen to the chest al ong

the ar c of the upper r ectus muscl e that pr otects the super i or
epi gastr i c bl ood suppl y.
A var i ati on of thi s method uses a mi cr ovascul ar fr ee TRAM fl ap. The
fr ee TRAM fl ap maxi mi zes the bl ood suppl y to the l ower abdomi nal
pannus by usi ng the deep i nfer i or epi gastr i c bl ood vessel s, whi ch
pr ovi de gr eater bl ood fl ow than do the super i or epi gastr i c vessel s.
The deep i nfer i or epi gastr i c vessel s ar e di vi ded fr om the i l i ac bl ood
vessel s and then anastomosed i n the chest under mi cr oscopi c
magni fi cati on to, most commonl y, the i nter nal mammar y or
thoracodor sal bl ood vessel s. The advantages of the TRAM ar e the
r el ati vel y l ar ge ski n and fi l l vol umes avai l abl e for r econstr ucti on of
a pr ojecti ng br east. Some r efi nements to thi s techni que i ncl ude the
muscl e-spar i ng TRAM fl ap pr ocedur e, i n whi ch a sel ecti ve bl ood
suppl y fr om ei ther the medi al or the l ateral r ow of deep i nfer i or
epi gastr i c per forator s (DIEPs) to the fl ap i s har vested al ong wi th a
str i p of muscl e, whi l e a por ti on of the r ectus muscl e and i ts
cor r espondi ng fasci a and the per forator fl aps i s pr eser ved. Wi th the
DIEP fl aps, for exampl e, one or several per forator s to the fl ap ar e
di ssected away fr om the muscl e i n a way that pr eser ves the enti r e
muscl e and fasci a.
Al ter nati ve autol ogous fl aps can be har vested fr om other si tes,
i ncl udi ng the buttocks, wi th ei ther a super i or gl uteal or i nfer i or
gl uteal bl ood suppl y, and the fl ank wi th a deep ci r cumfl ex i l i ac bl ood
suppl y (Rubens fl ap). These al ter nati ve fl aps ar e r eser ved for
ci r cumstances i n whi ch the abdomen i s not avai l abl e as a donor si te.
Overal l , autol ogous ti ssue r econstr ucti on pr oduces the best l ongter m r esul ts. These operati ons ar e of gr eater magni tude, have
l onger postoperati ve r ecuperati on ti mes, and have a smal l but
defi ni ti ve r i sk of fai l ur e.
Ni ppl e-ar eol ar r econstr ucti on i s per for med as a separate pr ocedur e
after the r econstr ucted br east has had ti me to attai n i ts fi nal shape
and posi ti on. A ni ppl e posi ti on on the br east mound i s deter mi ned,
and a ni ppl e i s constr ucted fr om l ocal fl aps. An ar eol a i s tattooed
ar ound the central ni ppl e fl ap.
Trunk and Perineum Reconstruction

Chest Wall and Sternum
The pr i nci pl es of chest wal l r econstr ucti on ar e to r estor e the
dynami c stabi l i ty of the chest, pr otect the thoraci c vi scera, and
mai ntai n the r espi rator y and car di ac physi ol ogi cal functi ons.
Contour consi derati ons ar e addr essed after functi onal r equi r ements
ar e met. Lar ge defects can r esul t fr om tumor r esecti on for l ocal or
metastati c contr ol and ar e often compl i cated by radi ati on i njur y or
the devel opment of i nfecti on, i nvar i abl y i n compr omi sed ti ssue
fi el ds. Skel etal stabi l i z ati on wi th pr ostheti c mater i al s i s per for med
for r esecti ons i nvol vi ng ei ther four or mor e r i b
segments or chest wal l cavi ti es gr eater than 6 cm i n di ameter to
r educe the r i sk of fl ai l chest.
The major i ty of these defects can be r epai r ed wi th l ocal and
r egi onal muscul ocutaneous fl aps. Muscl e fl ap opti ons for ster nal
wound coverage i ncl ude the pectoral i s major muscl e, ei ther as a
pedi cl ed fl ap based on the thoracoacr omi al vessel s or as a tur nover
fl ap based on per forator s fr om the i nter nal mammar y vessel s, and
the r ectus abdomi ni s muscl e based on the super i or epi gastr i c
vessel s. Opti ons for axi l l ar y coverage i ncl ude the pectoral i s major
and the l ati ssi mus dor si fl aps. Coverage of the poster i or thorax can
be pr ovi ded by the l ati ssi mus dor si fl ap, the trapez i us fl ap,
paraspi nous muscl e fl aps, or di ffer ent l ar ge desi gn fl aps, such as a
hemi back r otati on advancement fl ap, dependi ng on the speci fi c
l ocati on of the defect. In rar e ci r cumstances, the omentum can be
transfer r ed outsi de the abdomen thr ough a tunnel to pr ovi de
vascul ar i zed wound coverage. In the absence of l ocal ti ssue opti ons,
mi cr ovascul ar transfer of di stant ti ssues may be r equi r ed to pr ovi de
coverage.
Abdomen
After oncol ogi c sur ger y of the abdomen, abdomi nal wal l
r econstr ucti on i s r equi r ed to pr otect the abdomi nal vi scera and
r estor e abdomi nal fasci al conti nui ty. Local ti ssue techni ques i ncl ude
component separati on, i n whi ch the l ayer s of the abdomi nal wal l
muscul atur e ar e separated and advanced; fasci al par ti ti on r el ease,
whi ch consi sts of paral l el parasagi ttal r el axi ng i nci si ons i nto the
abdomi nal wal l muscul atur e; and ti ssue expansi on. Fasci al i ntegr i ty
can be r estor ed wi th fasci al sheet grafts fr om the tensor fasci a l ata,
pr ostheti c mesh, or fl ap r ecr ui tment. Pedi cl ed muscul ocutaneous
fl aps fr om the hi p and thi gh can be r otated to the l ower abdomen.
Mi cr ovascul ar transfer of di stant ti ssue i s r equi r ed to r econstr uct
l ar ge defects.
Perineum
The pr i nci pl es of per i neal r econstr ucti on ar e to maxi mi ze wound
heal i ng, pr ovi de durabl e coverage when possi bl e, and faci l i tate
ear l y pati ent r ehabi l i tati on. Most pati ents wi th per i neal defects
after oncol ogi c sur ger y have r ecei ved radi ati on tr eatment. Our
exper i ence has shown that i mmedi ate r econstr ucti on substanti al l y
r educes postoperati ve compl i cati ons, such as i nfecti on, fi stul a
for mati on, smal l bowel obstr ucti on, and del ayed wound heal i ng.
Myocutaneous fl aps pr ovi de both wel l -vascul ar i zed ti ssues to fi l l the
l ower pel vi c space and heal thy ti ssues for wound cl osur e. Local
pedi cl ed fl aps can often be r otated fr om the abdomen or the thi gh.
Peni l e and scr otal sur face coverage or vagi nal r econstr ucti on i s
fr equentl y r equi r ed wi th per i neal r econstr ucti on. The r equi r ements
of mobi l i ty and durabi l i ty must be bal anced wi th consi derati ons of
coi tal abi l i ty and body habi tus. For super fi ci al defects of the peni s
and scr otum, par ti al - and ful l -thi ckness ski n grafts may pr ovi de
adequate coverage, al though l ar ger defects may r equi r e r otati onal
muscl e fl aps. Testi cul ar pr eser vati on may necessi tate temporar y
coverage i n the subcutaneous anter i or thi gh r egi on. Par ti al vagi nal
defects can be r estor ed wi th l ocal random fl aps
fr om the vul var r egi on or smal l er pedi cl ed fl aps fr om the thi gh,
such as the graci l i s or anter ol ateral thi gh, whi l e l ar ger defects
usual l y r equi r e fl ap r otati on fr om the thi gh or abdomen.
Ci r cumfer enti al neovagi nal r econstr ucti on i s a compl ex pr ocedur e
r equi r i ng a pedi cl ed fl ap wi th a l ar ge ski n paddl ed for r ol l i ng on
i tsel f such as pr ovi ded by a r ectus abdomi ni s or anter ol ateral thi gh
fl ap, or a combi nati on of two smal l er fl aps to pr ovi de the l ar ge ski n
sur face ar ea fr om ei ther bi l ateral poster i or thi gh fl aps or graci l i s
fl aps.
Extremities
The goal of extr emi ty r econstr ucti on i s l i mb sal vage rather than
amputati on. Reconstr ucti ve sur ger y after exti r pati ve sur ger y to
manage cutaneous mal i gnanci es i n the extr emi ti es general l y
i nvol ves pr i mar y cl osur e, ski n grafts, and l ocal or r egi onal
cutaneous and muscul ocutaneous fl aps. Soft-ti ssue and bony
neopl asms ar e much l ess common but general l y r equi r e
r econstr ucti on wi th mi cr ovascul ar fr ee fl aps. Adjuvant therapy often
r esul ts i n decr eased tumor si ze and faci l i tates spar i ng of the l i mb;
however, the use of adjuvant modal i ti es may have a str ong negati ve
i mpact on wound heal i ng and may necessi tate cover i ng the wound
wi th noni r radi ated ti ssue to faci l i tate heal i ng and pr ovi de coverage
of the ner ves, vessel s, and bone r equi r ed to mai ntai n a useful l i mb.
The need to r epl ace var i ous ti ssues, i ncl udi ng bone, ner ves, muscl e,
soft ti ssues, and ski n, must be anti ci pated befor e r econstr ucti on.
Bony defects can be cor r ected by l i mb shor teni ng, wi th or wi thout
l ater bone transpor t for l engtheni ng, al l ografts, bone grafts, or
vascul ar i zed bone fl aps. F r ee and pedi cl ed muscl e transfer s not onl y
can pr ovi de wel l -vascul ar i zed wound coverage, but can al so be
neur oti zed and used for functi onal muscl e transfer. Fasci ocutaneous
fl aps, muscul ocutaneous fl aps, and muscl e fl aps cover ed wi th spl i tthi ckness ski n grafts ar e used for r epl acement of soft ti ssue and
ski n. Ner ve r epai r can be per for med by usi ng mi cr osur gi cal
techni ques to r estor e motor and sensor y functi ons. Pr i mar y ner ve
r epai r per for med at the ti me of tumor r esecti on r esul ts i n the best
functi onal outcome. If the ner ve defi ci t i s too l ar ge to per for m a
tensi on-fr ee r epai r, ner ve grafti ng can be used. The sural ner ve,
whi ch pr ovi des sensati on to the l ateral foot, i s typi cal l y chosen as
the donor ner ve and can pr ovi de as much as 30 to 40 cm of ner ve
fr om one l eg wi th mi ni mal mor bi di ty.
Li mb spar i ng, however, must be wei ghed agai nst per for mi ng an
adequate oncol ogi c r esecti on. Al so, l eavi ng a pati ent wi th a l i mb
that i s nonfuncti onal , i nsensate, or pai nful pr ovi des l i ttl e i f any
benefi t over amputati on. Indi cati ons for amputati on i ncl ude major
neur ovascul ar or extensi ve muscl e i nvol vement of the l i mb by the
tumor, whi ch woul d r esul t i n a nonfuncti onal l i mb; i nfecti on and
fractur es, whi ch coul d compr omi se r econstr ucti on and del ay
adjuvant therapy; poor nutr i ti on and other ser i ous medi cal
condi ti ons; a l ack of pati ent moti vati on for r ehabi l i tati on; and the
need for mul ti pl e sur ger i es. Pati ents must be war ned befor e
r econstr ucti ve sur ger y that poor functi onal outcomes, i nfecti ons
and other wound compl i cati ons, and tumor r ecur r ence may
ul ti matel y l ead to amputati on.
Upper Extremity
As i n other l ocati ons, fl ap coverage i s i ndi cated for upper-extr emi ty
defects to r econstr uct wounds wi th extensi ve ti ssue l oss or to
pr otect exposed vi tal str uctur es, such as bone, tendons, ner ves, or
major vessel s, when ski n grafts woul d be unl i kel y to adher e or
pr ovi de durabl e coverage or woul d l ead to si gni fi cant scar r i ng and
decr eased functi on. For exampl e, scar contractur e of i nci si ons
pl aced paral l el to the axi s of the l i mb acr oss joi nts can r esul t i n a
decr eased range of moti on and may r equi r e l engtheni ng wi th zpl asty pr ocedur es or i nter posi ti on of a pl i abl e fl ap. Si mi l ar l y, not
onl y ar e tendons str i pped bar e of paratenon-poor r eci pi ents for ski n
grafts, but thei r functi on can al so be compr omi sed, i f adher ence
occur s, by the pr eventi on of fr ee gl i di ng movement.
Ther e ar e several l ocal fl aps used i n hand sur ger y, i ncl udi ng
advancement, r otati on, transposi ti on, and cr oss-fi nger fl aps. In the
case of an amputati on of a di gi t or l i mb, fi l l et fl aps, i n whi ch the
bone has been par ti al l y or total l y r emoved, can be used to cover the
di stal stump wi th wel l -vascul ar i zed ti ssue.
A pedi cl ed radi al for ear m fl ap based on the radi al ar ter y and i ts
venae comi tantes (i .e., pai r ed vei ns i nti matel y associ ated wi th the
ar ter y) i s the mai n fl ap used to pr ovi de fasci ocutaneous ti ssue to
the for ear m and el bow. An Al l en's test shoul d be per for med pr i or to
sur ger y to document patent ul nar and radi al bl ood fl ow to the hand.
If si ngl e vessel fl ow i s i nadequate to per fuse the hand, vei n grafti ng
can be per for med to r e-establ i sh bl ood fl ow, as needed. A l ateral
ar m fl ap can be used i n the upper ar m and can r each the acr omi on
and poster i or axi l l a.
Upper l i mb wounds can al so be cover ed wi th pedi cl ed fl aps fr om the
tr unk and pel vi s. After neovascul ar i z ati on of the fl ap at i ts r eci pi ent
si te, the donor pedi cl e i s di vi ded. These fl aps general l y r equi r e 2 to
3 weeks (or mor e) of i mmobi l i z ati on. Such di stant pedi cl ed fl aps
i ncl ude the gr oi n fl ap, suppl i ed by the super fi ci al ci r cumfl ex i l i ac
vessel s; the anter i or chest wal l fl ap, suppl i ed by the i nter costal or
thoracoepi gastr i c vessel s; and the epi gastr i c or abdomi nal fl aps,
suppl i ed by the super fi ci al i nfer i or epi gastr i c vessel s or a randompatter n bl ood fl ow. The pectoral i s major fl ap, based on the
thoracoacr omi al vessel s, i s used for anter i or shoul der wounds or
amputati on coverage. The l ati ssi mus dor si fl ap, based on the
thoracodor sal vessel s, i s used for shoul der, axi l l ar y, and upper ar m
wounds; thi s fl ap can r each beyond the ol ecranon or antecubi tal
fossa i n many cases and can be used for functi onal muscl e transfer
to r estor e el bow fl exi on or extensi on.
Many fr ee muscl e, muscul ocutaneous, and fasci ocutaneous fl aps
used el sewher e for r econstr ucti on ar e al so useful i n the upper
extr emi ty. Speci fi cal l y, the r ectus abdomi nus, l ati ssi mus dor si ,
ser ratus anter i or, and graci l i s (often the fl ap of choi ce for
i nner vated functi onal r econstr ucti on) muscl e fl aps and the radi al
for ear m, ul nar for ear m, l ateral ar m, anter ol ateral thi gh, dor sal i s
pedi s, and scapul ar /parascapul ar fasci ocutaneous fl aps have al l
been successful l y used for upper-extr emi ty r econstr ucti on. The
tempor opar i etal fasci a fl ap, based on the super fi ci al temporal ar ter y
and cover ed by a ski n graft, can r econstr uct the dor sal
hand and pr ovi de a sui tabl e gl i di ng sur face for under l yi ng tendons.
In addi ti on, the fi r st and second toes have been successful l y
transfer r ed to r epl ace the thumb, and the fi bul a and i l i ac cr est
osseous fl aps have been used to r econstr uct the l ong bones of the
upper l i mb. Angi ography may be i ndi cated befor e the har vesti ng of
a fi bul ar fl ap i f di stal per fusi on to the foot i s i n questi on.
Adequate sensor y and motor functi on of the l i mb, hand, or di gi t i n
questi on must be pr esent, or r econstr ucti on may be mor e of a
hi ndrance than a benefi t to the pati ent's qual i ty of l i fe. Pr i mar y or
ner ve graft r epai r s ar e often needed to pr eser ve adequate functi on.
Epi neural or i nter fasci cul ar r epai r s ar e typi cal l y per for med,
dependi ng on the ner ve and l ocati on. Tendon transfer s i n whi ch
functi onal l y expendabl e muscl e/tendon uni ts ar e r er outed to r epl ace
functi onal l y cr i ti cal uni ts can al so be per for med. At a mi ni mum, the
goal of functi onal upper l i mb r econstr ucti on r equi r es havi ng a stabl e
shoul der joi nt, r estor i ng el bow fl exi on, and ensur i ng medi an ner ve
sensi bi l i ty.
Lower Extremity
Defects i n the gr oi n and pr oxi mal medi al or anter i or thi gh can often
be cl osed by usi ng a pedi cl ed r ectus abdomi nus fl ap suppl i ed by the
deep i nfer i or epi gastr i c vessel s. Lar ge defects i n other ar eas of the
thi gh ar e typi cal l y r econstr ucted wi th adjacent muscl es, i ncl udi ng
the r ectus abdomi nus or l ati ssi mus dor si muscl e, or fr ee ti ssue
transfer wi th muscul ocutaneous fl aps. The femoral and deep femoral
vessel s ar e usual l y good r eci pi ents for these fl aps. End-to-si de
anastomoses ar e commonl y per for med i n the l ower extr emi ty to
pr eser ve the di stal bl ood fl ow.
Tumor s of the knee, di stal femur, or pr oxi mal ti bi a usual l y r equi r e
r econstr ucti on wi th an al l ograft or endopr osthesi s. The medi al or
l ateral heads of the gastr ocnemi us can be separated and used as
pedi cl ed muscl e fl aps, or both heads can be used to pr ovi de muscl e
fl ap coverage of the knee, the upper thi r d of the l ower l eg, or the
fi r st 15 cm of the thi gh above the knee. Thi s pedi cl ed fl ap r ecei ves
i ts bl ood suppl y fr om the sural ar ter y and vei n, whi ch ar e branches
of the popl i teal vessel s. If both heads ar e used, the sol eus muscl e
must be l eft i ntact to pr eser ve pl antar fl exi on of the foot. F l aps
fr om the sol eus muscl e can al so be used to r el i abl y cover defects of
the mi ddl e thi r d of the l eg. As wi th the gastr ocnemi us, the sol eus
can be spl i t down i ts medi an raphe, and the medi al and l ateral
heads can be used separatel y. If the sol eus i s used for
r econstr ucti on, then the gastr ocnemi us must be l eft i ntact to
pr eser ve pl antar fl exi on. Al ter nati vel y, one head of the sol eus and
one head of the gastr ocnemi us can be used for r econstr ucti on,
whi ch spar es pl antar fl exi on of the foot. F i nal l y, r econstr ucti ng the
di stal thi r d of the l eg wi th l ocal or r egi onal muscl e fl aps i s, for the
most par t, not an opti on. G eneral l y, al l but the smal l est wounds i n
thi s r egi on r equi r e fr ee fasci ocutaneous or
muscl e/muscul ocutaneous fl ap coverage because l ocal ti ssues l ack
l axi ty.
Reconstr ucti on opti ons for smal l defects of the foot i ncl ude the use
of ski n grafts and l ocal fl aps. Lar ger defects r equi r e mi cr ovascul ar
fr ee ti ssue transfer r econstr ucti on. F r ee muscl e fl aps, such as
graci l i s muscl e or ser ratus anter i or muscl e fl aps cover ed by a ski n
graft, pr ovi de coverage that confor ms wel l to many defects.
The l ar gest defects may r equi r e r ectus abdomi nus or l ati ssi mus
dor si fl aps cover ed by a ski n graft. The desi gn of muscl e fl aps used
for foot r econstr ucti on must take i nto account the expected atr ophy
of the muscl e wi th ti me; too much fl ap bul k i s usual l y unfavorabl e
for ambul ati on and may necessi tate r evi si on, speci al or thoti c
footwear, or both. Fasci ocutaneous fl aps, such as a radi al for ear m
fl ap, ar e al so used for foot r econstr ucti on and can be desi gned to
i ncl ude sensor y i nner vati on. Muscl e and fasci ocutaneous fl aps ar e
suscepti bl e to pr essur e ul cerati on and so must be vi gi l antl y
moni tor ed for the br eakdown of ski n and soft ti ssue.
Re-establ i shi ng pl antar sensati on after ner ve r esecti on i s cr i ti cal i n
l ower l i mb r econstr ucti on. Wi thout pr otecti ve sensati on, the l ower
l i mb i s pr one to ul cerati on and i njur y that can l ead to i nfecti on and,
ul ti matel y, the need for amputati on. G ood extr emi ty management
may al l ow a pati ent to other wi se mai ntai n a bi opr osthesi s.
Pr oxi mal ner ve r esecti on and r epai r yi el d poor er functi onal
r estorati on than does di stal r econstr ucti on. In addi ti on,
postoperati ve i mmobi l i z ati on after ner ve r epai r i s necessar y for
appr oxi matel y 7 to 10 days. Rei nner vati on usual l y occur s no faster
than 1 mm per day and can be detected by testi ng for advanci ng
Ti nel si gn and per for mi ng ner ve conducti on studi es. Muscl e
sti mul ati on to mai ntai n motor end-pl ate functi on can be attempted
when r ei nner vati on i s expected to take l onger than 12 to 18
months.
F r ee ti ssue transfer and bony r econstr ucti on of the l ower extr emi ty
usual l y r equi r e a per i od of bedr est wi th el evati on of the extr emi ty.
The pr eventi on of deep venous thr ombosi s i s i mpor tant dur i ng thi s
ti me. After 5 to 7 days, the pati ent can dangl e the extr emi ty for
shor t per i ods of 15 to 30 mi nutes at a ti me. Standi ng and cr utchassi sted ambul ati on wi th gradual wei ght bear i ng i s then al l owed
wi th the fl ap gentl y wrapped wi th an el asti c bandage to pr event
venous pool i ng and to hel p contour the fl ap.
Recommended Reading
Head and Neck
Ar i yan S. The pectoral i s major myocutaneous fl ap for
r econstr ucti on i n the head and neck. Plast Reconstr Sur g
1979;63:7381.
Bur get G C, Meni ck F J. Nasal r econstr ucti on: seeki ng a four th
di mensi on. Plast Reconstr Sur g 1986;78:145157.
Hi dal go DA. F i bul a fr ee fl ap: a new method of mandi bl e
r econstr ucti on. Plast Reconstr Sur g 1989;87:7178.
Newman MI, Hanasono MM, Di sa JJ, et al . Scal p r econstr ucti on: a
fi fteen-year exper i ence. Ann Plast Sur g 2004;52:501506.
Robb G L, Lewi n JS, Deschl er DG , et al . Speech and swal l owi ng
outcomes i n r econstr ucti ons of the phar ynx and cer vi cal
esophagus. Head Neck 2003;25:232244.
Breast
Bostwi ck J. Plastic and Reconstr uctive Br east Sur ger y. 2nd ed. St.
Loui s, Mo: Qual i ty Medi cal Publ i shi ng; 2000.
Kr ol l SS, Reece G P. The Well-infor med Patient's G uide to Br east
Reconstr uction. Houston, Tex: The Uni ver si ty of Texas M. D.
Ander son Cancer Center ; 2002.

Kr ol l SS, Schuster man MA, Reece G P, et al . Choi ce of fl ap and
i nci dence of fr ee fl ap success. Plast Reconstr Sur g 1996;98:459
463.
Kr onowi tz SJ, Robb G L, Youssef A, et al . Opti mi z i ng autol ogous

br east r econstr ucti on i n thi n pati ents. Plast Reconstr Sur g
2003;112:17681778.
Mi l l er MJ, Rock CS, Robb G L. Aestheti c br east r econstr ucti on
usi ng a combi nati on of fr ee transver se r ectus abdomi ni s
muscul ocutaneous fl aps and br east i mpl ants. Ann Plast Sur g
1996;37:258264.
Tran NV, Evans G R, Kr ol l SS, et al . Postoperati ve adjuvant
i r radi ati on: effects on transver se r ectus abdomi ni s muscl e fl ap
br east r econstr ucti on. Plast Reconstr Sur g 2000;106:313317.
Trunk and Perineum

Ar nol d PG , Pai r ol er o PC. Chest wal l r econstr ucti on: an account of
500 consecuti ve pati ents. Plastic Reconstr Sur g 1996;98:804
810.
Buchel EW, F i ni cal S, Johnson C. Pel vi c r econstr ucti on usi ng
ver ti cal r ectus abdomi ni s muscul ocutaneous fl aps. Ann Plast Sur g
2004;52:2226
Chang RR, Mehrara BJ, Hu QY, et al . Reconstr ucti on of compl ex
oncol ogi c chest wal l defects: a 10-year exper i ence. Plastic
Reconstr Sur g 2004;52:471479.
McCraw JB, Papp C, Ye Z, et al . Reconstr ucti on of the per i neum
after tumor sur ger y. Sur g Oncol Clin N Am 1997;6:177189.
Extremity
Bar wi ck WJ, G ol dber g JA, Scul l y SP, Har r el son JM. Vascul ar i zed
ti ssue transfer for cl osur e of i r radi ated wounds after soft ti ssue
sar coma r esecti on. Ann Sur g 1992: 216;591595.
Br ennan MF. Management of extr emi ty soft-ti ssue sar coma. Am J
Sur g 1989;158:7178.
Cor dei r o PG , Neves RI, Hi dal go DA. The r ol e of fr ee ti ssue
transfer fol l owi ng oncol ogi c r esecti on i n the l ower extr emi ty. Ann
Plast Sur g 1994;33:916.
Evans G RD, G ol dber g DP. Pr i nci pl es of extr emi ty mi cr ovascul ar
r econstr ucti on. In: Schuster man MA, ed. Micr osur gical
Reconstr uction of the Cancer Patient. Phi l adel phi a, Pa: Li ppi ncottRaven; 1997: 233247.
G i dumal R, Wood MB, Si m F H, Shi ves TC. Vascul ar i zed bone
transfer of l i mb sal vage and r econstr ucti on after r esecti on of
aggr essi ve bone l esi ons. J Reconstr Micr osur g 1987;3:183188.
Hi dal go DA, Car rasqui l l o IM. The tr eatment of l ower extr emi ty
sar comas wi th wi de exci si on, radi otherapy, and fr ee-fl ap
r econstr ucti on. Plast Reconstr Sur g 1992;89:96101.
Reece G P, Schuster man MA, Pol l ock RE, et al . Immedi ate ver sus
del ayed fr ee-ti ssue transfer sal vage of the l ower extr emi ty i n soft
ti ssue sar coma pati ents. Ann Sur g Oncol 1994;1:1117.
Robb G L, Reece G P. Lower extr emi ty r econstr ucti on. In:
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MD Anderson Surgical Oncology Handbook, The, 4th Edition PDF

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Editors: Feig, Barry W .; Berger, David H.

Secondary Edi tor

R.R. Donnelley, Craw fordsville

Ander son Cancer Center , Houston, Texas

Depar tment of Sur gical Oncology, The Univer sity of Texas M. D.

Univer sity of Texas M. D. Ander son Cancer Center , Houston, Texas

Assi stant Pr ofessor

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

of use as a r eady r efer ence as wel l , i n much the same manner as

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

Thi s handbook i s not meant to encompass al l aspects of oncol ogy i n

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

Ductal Carcinoma in Situ

Classification of Ductal Carcinoma In Situ

based on thei r l i kel i hood of r ecur r ence. Lagi os et al . (1989)

i n pati ents wi th i nvasi ve ductal car ci noma than i n pati ents wi th

al so demonstrated that the mammographi c fi ndi ngs si gni fi cantl y

Other Imaging Modalities

document the sampl i ng of suspi ci ous mi cr ocal ci fi cati ons. Car e

Mastectomy Versus Breast-conserving

Tradi ti onal l y, DCIS has been tr eated wi th mastectomy. However,

Technique of Breast-conserving Surgery

mar gi n-negati ve r esecti ons. At a fol l ow-up ti me of 12 year s,

As i ndi cated by the USC/VNPI scor e, mar gi n wi dth i s an i ndependent

br east-conser vi ng sur ger y choose to under go a mastectomy because

adjuvant tr eatment of i nvasi ve br east cancer i n postmenopausal

Axillary Node Staging

Predictors of Local Relapse

Treatment and Outcome of Local Recurrence

Current Management of Ductal Carcinoma In

mastectomy, mastectomy i s often pr efer r ed for pati ents wi th l ar ge

F i gur e 1.1. Management of l obul ar car ci noma i n si tu (LCIS) and

the pati ent i s fol l owed wi th an annual di agnosti c contral ateral

Lobular Carcinoma in Situ

i ncr ease i n i nci dence i n women 40 to 49 year s ol d conti nued to the

mammographi c abnor mal i ti es. Ul trasound i s al so useful i n

Endocrine Therapy and Chemoprevention

Current Treatment of Lobular Carcinoma In

exami nati ons and bi l ateral di agnosti c mammography. Fol l owi ng a

F i sher B, Di gnam J, Wol mar k N, et al . Tamoxi fen i n tr eatment of

conser vi ng tr eatment for ductal car ci noma i n si tu: fi r st r esul ts of

r ecur r ence i n pati ents wi th ductal car ci noma i n si tu of the br east.

Editors: Feig, Barry W .; Berger, David H.; Fuhrman, George

Table 2.1. Risk factors for breast cancer

Singletary SE. Rating the risk factors for breast

Table 2.2. Autosomal dominant conditions

lung, and bladder;

A per sonal hi stor y of br east cancer i s a si gni fi cant r i sk factor for

1:13 between ages 60 and 79.

heter ogeneous tumor s. The vast major i ty of these tumor s ar e

ductal components wi l l have pr ognoses si mi l ar to i nvasi ve ductal

Table 2.3. Current AJCC TNM classification

Primary tumor cannot be

No evidence of primary tumor

Ductal carcinoma in situ

Lobular carcinoma in situ

Paget disease of the nipple

Tumor 2 cm or less in greatest

not more than 0.5 cm in

Tumor more than 0.5 cm but

Tumor more than 1 cm but not

Tumor more than 2 cm but not