Editors: Fortner, Kimberly B.; Szymanski, Linda M.; Fox, Harold E.

; Wallach,
Edward E.
Title: J ohns Hopki ns Manual of Gynecol ogy and Obst et r i cs, The, 3r d Edi t i on
Copyright 2007 Lippincott Williams & Wilkins
> Tabl e of Contents > V - Gynecol ogi c Oncol ogy > 42 - Cervi cal Cancer
42
Cervical Cancer
Katherine Goodrich
Teresa P. Daz-Montes
I. Epidemiology
A. Introduction. Cervical cancer is the most common gynecologi c mali gnancy i n the
worl d, and the second most frequentl y diagnosed cancer in women worldwide after
breast cancer (1). The majority of cases occur i n devel oping countri es. In the United
States, cervical cancer is the third most common gynecologic mal ignancy and the third
most common cause of gynecol ogi c cancer death (2). Mortality and incidence rates for
cervical cancer have decli ned in most devel oped countries. This decrease is mostly
attributed to the introduction of routine Papanicol aou smear (pap test) screening
(Chapter 34). Approximately 60% of women who devel op cervi cal cancer i n developed
countri es have either never been screened or have not been screened i n the preceding
5 years (3). The mean age for cervi cal cancer i s 52.2 years, and the distri bution of
cases is bimodal, with peaks at 35 to 39 years and 60 to 64 years (4).
B. Risk Factors
1. Race and Socioeconomic Status. The i nci dence rate of cervi cal cancer among
African Americans in the Uni ted States is higher than that among whi te women,
with approximately 11 new cases per 100,000 blacks and 8 cases per 100,000
whites per year (5). The i nci dence is even higher i n the Nati ve Ameri can
populations and Hispanics, i n whi ch there are approximately 14 new cases per
100,000 women each year (5). Asian groups experience rates similar to or lower
than those of whi tes. These differences, at l east, are parti all y accounted for by
the strong i nverse associati on between cervi cal cancer i nci dence and
socioeconomi c factors. When socioeconomic differences are controlled for, the
excess ri sk of cervical cancer among African Ameri cans decreases. Raci al
differences are also apparent in survival; 58% of all African Americans wi th
cervical cancer survive 5 years, compared with 72% of all whites wi th the disease
(2).
2. Sexual and Reproductive History. Ri sk factors for cervi cal cancer are
essenti all y rel ated to exposure to human papil loma virus (HPV), smoki ng, and
i mmunosuppression.
a. HPV. HPV infection is present in 99.7% of all cervical cancers (12). Thus,
tradi tional ri sk factors for cervical cancer include early age at first coi tus,
multipl e sexual partners, mul ti pari ty, lack of barri er contraception, and
history or sexual transmi tted infections (6,7,8). Hi gh-risk HPV types 16, 18,
31, 33, 35, 45, 52, and 58 are associated with 95% of squamous cell
carcinomas of the cervix (12). HPV 16 is most commonly linked with
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squamous cell cervical cancer; HPV 18 is most commonly present i n
adenocarci noma. Most HPV infections are transient, resul ti ng i n ei ther no
change in the cervi cal epitheli um or low-grade intraepitheli al l esions that are
often spontaneously cl eared. The progressi on from hi gh-grade lesi on to
i nvasi ve cancer takes approximately 8 to 12 years, yieldi ng a long
prei nvasive state with multipl e opportuniti es for detecti on (5).
b. Cigarette smoking has been found to be an i ndependent ri sk factor i n the
development of cervical disease. Brock et al demonstrated that smokers have
a 4.5-fol d increased ri sk of carcinoma in situ (CIS) compared with matched
controls (17). Additionall y, an i ncreased risk of cervi cal cancer has been
noted in women exposed passi vely to tobacco smoke (18). The potenti al
effect of smoki ng appears to be li mi ted to squamous cell carci noma of the
cervix (18).
c. Immunosuppression. Immunocompromised women may be at higher ri sk of
developi ng cervical cancer and may demonstrate more rapid progressi on
from preinvasive to invasive lesions. Pati ents who test posi tive for human
i mmunodefici ency virus (HIV) infection appear to present wi th invasive
cervical cancer earlier than pati ents testi ng negative for the vi rus, and wi th
more advanced di sease at the ti me of diagnosis when CD4 cell counts are
reduced (below 200/mm
3
) (20). The CDC has descri bed cervi cal cancer as an
AIDS defining illness in those infected with HIV (21).
II. Detection
Cervical neoplasi a is presumed to be a continuum from dysplasi a to carcinoma i n si tu to
i nvasi ve carci noma. See Chapter 41 on CIN. Screeni ng for cervical cancer with the use of
exfol iati ve cytol ogi c study (pap smear exami nation) has si gni ficant effects on the i nci dence,
morbidity, and mortality of invasive disease by faci li tati ng the di scovery of precursor
l esi ons.
III. Clinical Presentation
A. Symptoms. The most common presenti ng symptom of i nvasive cervical cancer i s
abnormal vaginal bl eedi ng and discharge. Abnormal vaginal bl eedi ng may take the form
of postcoital bleeding, i ntermenstrual, or postmenopausal bleeding. It coul d be
asymptomati c, especi all y i n sexuall y inacti ve women, when the disease i s qui te
advanced. Serosangui neous or yel lowish vagi nal discharge, at ti mes foul smel ling, may
occur parti cul arly in large tumors. Premenopausal patients may develop hematometra
due to occlusion of the endocervical canal by a cancer. Other pati ents may present with
symptomati c anemi a or pel vic pai n. Sciati c and back pain can be rel ated to si dewall
extension, hydronephrosis, or metastasis. Bladder or rectal invasion by advanced-stage
di sease may produce urinary or rectal symptoms (e.g., vaginal passage of stool or
uri ne, hematuria, urinary frequency, hematochezi a). Advanced di sease may al so cause
l ower extremi ty swel li ng from occl usi on of pelvic lymphatics or thrombosis of the
external il iac vein.
B. Signs. Most women with cervical cancer have a vi sibl e cervi cal l esi on. On specul um
exami nation, cervical cancer may appear as an exophyti c cervi cal mass (Fig. 42.1)
that characteri stically bleeds on contact. Endophytic tumors develop entirely withi n the
endocervi cal canal, and the external cervix may appear normal . In these cases,
P.481
P.482
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bi manual examinati on may reveal a firm, indurated, and often barrel-shaped cervi x.
The vagina should be i nspected for extension of di sease. Rectal exam provi des
i nformation regarding the nodulari ty of the uterosacral li gaments and hel ps determi ne
extension of disease into the parametrium.
On general physi cal exami nation, advanced cervi cal cancer may present with pl eural
effusi ons, ascites, and/or lower extremi ty edema. Unil ateral l ower extremi ty edema
may be i ndi cati ve of cancerous i nvolvement of the pel vic si dewall . Groi n and
supracl avi cul ar l ymph nodes may be i ndurated or enlarged, i ndi cating spread of
di sease.
IV. Diagnosis
With obvious exophyti c lesions, cervical biopsy i s usually al l that is needed for histologic
confirmation. In patients with a grossly normal appeari ng cervix and with abnormal cytology
on pap smear, colposcopi c examinati on with di rected biopsi es and endocervi cal curettage
(ECC) i s necessary (Chapter 41). If a defi ni te diagnosi s of cervi cal cancer cannot be made
on the basi s of offi ce bi opsies, di agnostic cervical coni zati on may be necessary.
V. Spread of Disease
A. Direct Extension. Cervi cal cancer usual ly spreads by direct extensi on into the
parametria, vagina, uterine corpus, peritoneal cavi ty, bladder, or rectum.
1. Parametrial Extension. The lateral spread of cervical cancer occurs through the
cardinal l igament l ymphatics and vessel s, and signifi cant invol vement of the
medial porti on of thi s li gament may result in ureteral obstruction.
2. Vaginal Extension. The upper vagina is frequently i nvolved (50% of cases) when
the primary tumor has extended beyond the confi nes of the cervi x.
3. Bladder and Rectal Involvement. Anterior and posteri or spread of cervical
Figure 42.1. Photograph of the cervix demonstrati ng an exophytic cervical
carcinoma. (Courtesy of Dr. Robert Gi untol i, The Johns Hopkins Hospi tal ,
Department of Gynecology and Obstetrics, Divisi on of Gynecol ogic Oncol ogy.)
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cancer to the bladder and rectum is uncommon in the absence of l ateral
parametrial disease.
B. Lymphatic Spread (Fig. 42.2). The cervix is drained by preureteral, postureteral, and
uterosacral lymphati c channel s. The fol lowing are considered first stati on nodes:
obturator, external iliac, hypogastric, parametrial, presacral, and common iliac. Para-
aorti c nodes are second stati on, are rarely i nvolved in the absence of primary nodal
di sease, and are considered metastases (23). The percentage of invol ved lymph nodes
i ncreases di rectl y wi th pri mary tumor vol ume.
C. Blood-Borne Metastasis. Bl ood-borne metastases from cervical carci nomas occur but
are less frequent and are usual ly seen late i n the course of the disease.
VI. Staging
A. Clinical Staging. Staging of cervi cal cancer i s based on clinical , rather than surgical ,
evaluation. Please refer to Tables 42.1 for FIGO staging and Table 42.2 for
permitted staging examinations. In addition to the stagi ng procedures menti oned,
routine laboratory studi es should i ncl ude a CBC, electrolyte and chemistry panel, l iver
function tests, and urinalysis. No tumor marker has achi eved widespread acceptance.
Inspection and palpation shoul d begi n with the cervi x, vagi na, and pel vis and continue
wi th examinati on of extrapel vi c areas, specifi call y the abdomen and supraclavicular
l ymph nodes (23).
1. Lymphangiograms, arteriograms, computer tomography (CT), magneti c resonance
i maging (MRI), positron emissi on tomography (PET), l aparoscopy, or l aparotomy
fi ndi ngs shoul d not be used for cli ni cal stagi ng, but thei r resul ts may be valuable
for planning treatment (11). Imaging studies beyond the chest x-ray should be
obtained only when the findings will have an impact on treatment. Other than the
chest x-ray, a CT of the abdomen and pel vis i s the most important study in the
early di agnosi s of cervical cancer.
2. Cervi cal cancer i s staged accordi ng to the International Federation of Gynecology
and Obstetrics (FIGO) system that was last revi ewed in 1995 (Table 42.1;
Figs. 42.3 and 42.4). During this last revision, stage IA included al l microscopic
di sease, and any cli ni call y apparent case wi ll be i ncl uded on stage IB. Stage IA is
further divi ded in IA1 (i nvasion no greater than 3 mm in depth and no wider than
7 mm) and IA2 (invasi on between 3 to 5 mm in depth and no wider than 7 mm).
Lymph vascular i nvolvement does not al ter the cl assifi cation.
P.483
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3. When doubt exists concerning the stage to which a tumor should be assigned, the
earli er stage is chosen. Once a cl inical stage has been determined and treatment
has begun, subsequent findi ngs on ei ther extended cl inical stagi ng or surgi cal
exploration shoul d not alter the assi gned stage. Overstaging and understagi ng of
the parametria is the most problematic i ssue and the most li kely to affect
therapeutic decisi ons. Nevertheless, FIGO stage correlates with prognosi s, and
strict adherence to the rules of cl inical staging i s necessary for compari son of
results between insti tutions.
4. The di stribution of patients by cli ni cal stage is as follows: 38% stage I, 32% stage
II, 25% stage III, 4% stage IV (9). Cli ni cal stage of di sease at the ti me of
presentati on i s the most important determinant of subsequent survival regardl ess
of treatment modality. Five-year survival decl ines as FIGO stage at di agnosis
i ncreases from stage IA (95%) to stage IV (14%) (2).
Fi gure 42.2. Possibl e si tes of direct extensi on of cervi cal cancer to adjoini ng
organs or metastases to regional l ymph nodes. The uterus, cervi x, and vagi na
are depicted bi sected and opened to reveal the possible si tes of tumor
implantation. (From Scott JR, DiSaia PJ, Hammond CB, et al. Danforth's
Obstetrics and Gynecology, 7th Ed. Phil adel phia: Li ppincottRaven
Publishers, 1997:909, with permission.)
P.484
P.485
P.486
Table 42.1 Staging for Carcinoma of the Cervix
Uteri. (International Federation of Gynecology
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and Obstetrics, 1995)
Stage Description Comments
0 Carcinoma in situ,
intraepithelial
carcinoma.
I The carcinoma i s
stri ctly confi ned to the
cervix.
The di agnosi s of both stage IA1 and
IA2 cases shoul d be based on
mi croscopi c examinati on of removed
ti ssue, preferabl y a cone, whi ch must
include the entire lesion. The depth
of invasion should not be more than
5 mm taken from the base of the
epitheli um, either surface or
glandular, from which it originates.
The second di mensi on, the horizontal
spread, must not exceed 7 mm.
Vascul ar space invol vement, either
venous or l ymphatic, should not al ter
the staging but should be speci fi call y
recorded, because it may affect
treatment deci sions in the future.
IA Invasi ve cancer
identi fied only
mi croscopically. Al l
gross lesions, even
wi th superfici al
i nvasi on, are stage IB
cancers. Invasion is
l imi ted to measured
stromal invasi on with
maximum depth of 5
mm and wi dth of 7
mm.
IA1 Measured invasion of
stroma no greater than
3 mm in depth and no
wider than 7 mm.
IA2 Measured invasion of
stroma greater than 3
mm and no greater
than 5 mm in depth,
and no wider than 7
Lesions of larger size shoul d be
classi fied as stage IB.
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mm.
IB Clinical lesions
confined to the cervi x
or precl ini cal l esi ons
higher than stage IA.
As a rule, estimating clinically
whether a cancer of the cervi x has
extended to the corpus or not i s
impossible. Extension to the corpus
shoul d therefore be disregarded.
IB1 Clinical lesions no
larger than 4 cm.
IB2 Clinical lesions larger
than 4 cm.
II The carcinoma extends
beyond the cervix but
has not extended to
the pelvic wall . The
carcinoma i nvolves the
vagi na but not as far
as the lower one-thi rd.
A patient wi th a growth fixed to the
pelvi c wal l by a short and indurated
but not nodul ar parametri um should
be assi gned to stage IIB. At cl inical
exami nation, to decide whether a
smooth and indurated parametrium i s
truly cancerous or only inflammatory
is i mpossible. Therefore, the case
should be placed in stage III only if
the parametrium is nodular on the
pelvic wall or if the growth itself
extends to the pelvic wall.
IIA No obvious parametrial
involvement.
IIB Obvious parametrial
involvement.
III The carcinoma has
extended to the pelvic
wall. On rectal
exami nation, no
cancer-free space is
found between the
tumor and the pelvic
wall. The tumor
i nvolves the lower one-
third of the vagina.
All cases with a
hydronephrosis or
nonfunctioni ng ki dney
The presence of hydronephrosis or
nonfunctioning kidney due to
stenosi s of the ureter by cancer
permits a case to be allotted to stage
III even if, accordi ng to the other
findi ngs, the case should be assigned
to stage I or stage II.
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are included unless
they are known to be
due to other causes.
IIIA No extension to the
pelvic wal l.
IIIB Extension to the pelvic
wall and/or
hydronephrosis or
nonfunctioni ng ki dney.
IV The carcinoma has
extended beyond the
true pelvis or has
cl inical ly involved the
mucosa of the bladder
or rectum. A bullous
edema as such does
not permit a case to be
allotted to stage IV.
The presence of bullous edema, as
such, should not permit a case to be
assigned to stage IV. Ri dges and
furrows i n the bl adder wal l should be
interpreted as signs of submucous
invol vement of the bl adder i f they
remain fixed to the growth during
palpation (i .e., exami nation from the
vagi na or the rectum during
cystoscopy). A finding of mal ignant
cell s in cytol ogic washi ngs from the
uri nary bl adder requi res further
exami nation and bi opsy of the wall of
the bladder.
IVA Spread of the growth
to adjacent organs.
IVB Spread to distant
organs.
Modified from Shingleton HM, Orr JW. Cervical Cancer. Phil adelphia: JB
Lippincott, 1995, with permission.
Table 42.2 Staging Procedures
Physi cal
examinati on
a
Palpation of lymph nodes
Exami nati on of vagi na
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Bi manual rectovaginal examinati on (under
anesthesia recommended)
Radiologic studies
a
IVP
Bari um enema
Chest
Skeletal radi ograph
Procedures
a
Bi opsy
Coni zati on
Hysteroscopy
Colposcopy
Endocervical curettage
Cystoscopy
Proctoscopy
Opti onal studies
b
CT scan
Lymphangiography
Ul trasonography
MRI
Radi onucleoti de scanning
Laparoscopy
a
All owed by International Federation of Gynecology and Obstetrics
(FIGO).
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B. Surgical Staging. As described in the previous section, the 1995 FIGO staging
classi fication for cervi cal cancer i s based on pretherapy cli nical findings. Onl y the
subcl assifi cati ons of stage I (IA1, IA2) requi re pathol ogic assessment. Vast
di screpanci es can exist between cli ni cal staging and surgi copathologic fi ndi ngs, such
that cl inical staging fai ls to identify extension of disease to the para-aortic nodes in 7%
of patients with stage IB disease, 18% with stage IIB, and 28% wi th stage III (9).
Thus, some cl inici ans emphasize surgi cal staging in women with l ocall y advanced
cervical carcinoma to identi fy occult tumor spread and allow treatment of metastatic
di sease beyond the traditional pel vic radi ati on fi eld.
VII. Prognostic variables
Prognostic variables include age, race, soci oeconomic status, and immune status, as
outl ined i n the epidemi ology secti on. Prognosti c variabl es are directl y rel ated to tumor
characteristics: (a) histologic subtype, (b) histol ogic grade, (c) FIGO stage, (d) lymph node
status, (e) tumor volume, (f) depth of invasion, and (g) lymph vascular space involvement
(Table 42.3).
b
Information that is not allowed by FIGO to change the cl inical stage.
Adapted from Berek JS, Hacker NF, eds. Practi cal Gynecol ogic Oncol ogy,
2nd Ed. Baltimore: Williams & Wilkins, 1994.
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Fi gure 42.3. FIGO classi ficati on of carci noma of the cervix. (From Chi DS, Abu-Rustum
NR, Hoskins WJ. Cancer of the cervix. In Rock JA, Jones HW III, eds. TeLinde's
Operative Gynecol ogy, 9th Ed. Philadelphia: Lippi ncott Williams & Wilkins,
2003:13781379, with permission.)
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A. Histologic Subtype. Confli cti ng data exi st on the i nfluence of histol ogic subtype on
tumor behavior, prognosis, and survival . Invasive squamous cell carcinoma is the
most common hi stol ogic type of cervi cal cancer, compri sing about 80% of cases (11).
Squamous cell carci nomas are al so subcl assifi ed accordi ng to cel l type: large cell
keratinizing, large cell nonkeratinizing, and small cell types. Rarer types i ncl ude
verrucous carcinoma (wel l-di fferenti ated squamous cel l carci noma appearing
exophyti c and hyperkeratotic and lacking fibrovascular cores). Papillary squamous
cell carcinoma is another rare variant of squamous carci noma,
resembl ing hi gh-grade squamous i ntraepi thel ial lesion, looking simi lar to a transi tional
cell carcinoma of the urinary bladder.
1. Adenocarcinomas comprise 15% of i nvasive cervical carci nomas (11). Grossl y,
cervical adenocarcinoma may appear as a pol ypoid or papill ary exophyti c mass.
However, in nearly 15% of adenocarcinomas, the l esion is l ocated enti rel y wi thin
the endocervical canal and escapes visual i nspecti on (2). Mucinous
adenocarcinoma is the most common type and is well differentiated with
pl enti ful muci n producti on. Endometrioid carcinoma, 30% of cervical
adenocarci nomas, unfortunatel y, resembles those typical of the uterine corpus.
Clear cell carcinomas, approximately 4% of adenocarci nomas, are nodular,
reddi sh lesions wi th punctate ul cers and cel ls with abundant, cl ear cytoplasm.
Diethylstilbestrol exposure is a ri sk factor. Minimal deviation adenocarcinoma,
or adenoma mali gnum, is reported to represent 1% of cervical adenocarcinomas.
2. Primary cervical carci noma wi th both mali gnant-appearing glandul ar and
Fi gure 42.4. Cli ni cal stages of carcinoma of the cervix. In stage I, onl y the cervi x i s
invol ved. In stage II, the parametrium or upper two-thirds of the vagina is involved. In
stage III, the mal ignancy extends to the pelvic side walls or involves the lower one-
thi rd of the vagina. In stage IV, areas beyond the true pel vi s are i nvolved. (From Scott
JR, DiSaia PJ, Hammond CB, et al. Danforth's Obstetrics and Gynecology, 7th Ed.
Philadelphia: LippincottRaven Publishers, 1997:909, with permission.)
P.487
P.488
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squamous el ements is referred to as adenosquamous carcinoma. The cl inical
behavior of these tumors is controversial , with some studies that suggest l ower
survival rates and others hi gher survival rates than with the more common
squamous tumors.
3. Small cell carcinomas of the uteri ne cervix are simil ar to small cell
neuroendocrine tumors of the lung and other anatomic locations. These
tumors are cl inical ly aggressive, with a marked propensi ty to metastasize l ocal ly
and to di stant sites. At di agnosi s, di sease is often disseminated, with bone, brain,
and li ver bei ng the most common si tes. Because of high metastatic potential, local
therapy alone (surgery, radiati on, or both) rarel y results in long-term survi val .
Multi agent chemotherapy, in combi nation with external-beam and intracavitary
radiation therapy, is the standard therapeuti c approach.
Table 42.3 Prognostic Variables: Tumor
Characteristics
Characteristic Five-Year Survival (%)
Stage
a
IA 97.0
IB 78.9
IIA 54.9
IIB 51.6
IIIA 40.5
IIIB 27.0
IV 12.4
Histologic findings
a
Squamous 67.2
Adenocarci noma 67.7
Adenosquamous 54.9
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Grade
a
Wel l-di fferentiated 74.5
Moderatel y differenti ated 63.7
Poorly differentiated 51.4
Lymph node status
a
Negati ve 75.2
Posi ti ve pelvic 45.6
Posi ti ve para-aortic 15.4
Tumor volume
b
<2 cm 90
>2cm 60
>4 cm 40
Depth of invasion
c
,
d
<10 mm 8694
1120 mm 7175
>20 mm 60
a
From Kosary CL. FIGO stage, histology, histologic grade, age and race as
prognosti c factors in determi ning survival for cancers of the female
gynecol ogical system: an anal ysis of 197387 SEER cases of cancers of
the endometrium, cervix, ovary, vulva, and vagina. Semi n Surg Oncol
1994;10:3146, wi th permission.
b
From Hatch KD. Cervical cancer. In Berek JS, Hacker NF, eds. Practi cal
Gynecol ogic Oncology, 2nd Ed. Baltimore: Wi ll iams & Wi lki ns, 1994.
c
From Delgado G, Bundy BN, Fowler WC Jr, et al. A prospective surgical
pathological study of stage I squamous carcinoma of the cervix: a
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4. Histologic Grade. Histologic differentiation of cervical carcinomas includes three
grades.
a. Grade 1 tumors are well differentiated with mature squamous cell s, often
formi ng kerati ni zed pearl s of epitheli al cells. Mitotic activity is low.
b. Grade 2. Moderately well-differentiated carcinomas, have higher mi totic
acti vity and less cel lular maturati on accompani ed by more nuclear
pl eomorphism.
c. Grade 3 tumors are composed of poorly differentiated smal ler cel ls wi th
l ess cytoplasm and often bizarre nuclei. Mitotic activity is hi gh.
The more poorly differenti ated tumors have l ower 5-year survival rates.
B. Stage. The most important factor in the prognosis for cervical cancer is cl inical stage
(2). Results from a study by Pecorell i et al demonstrate the rel ati onship between 5-
year survi val and stage i n approxi mately 12,000 patients treated worl dwi de between
1990 and 1992 (8).
C. Node Status. Among surgically treated patients, survival is related to the number and
location of involved lymph nodes. When pelvic nodes alone are invol ved, the 5-year
survival rate is about 65% (9). Five-year survival drops to 25% when common il iac
l ymph nodes are posi ti ve (9), and invol vement of para-aortic nodes further l owers
survival . Bil ateral pelvi c lymph node invol vement has a worse prognosis than uni lateral
di sease.
D. Tumor Volume. Lesi on si ze is an i mportant predi ctor of survival, independent of other
factors. Greater tumor vol ume i s associ ated wi th hi gher rates of parametri al
i nvolvement and decreased survi val . Pati ents wi th lesions <2 cm have approxi mately a
90% survi val rate, whereas patients with lesions >2 cm have closer to a 60% survival
rate (9). Survival is about 40% in patients with lesions >4 cm (9).
E. Depth of Invasion. Survival i s also correlated with depth of tumor i nvasion into the
stroma, with survival rates being inversely correlated with depth of invasion.
F. Lymph-Vascular Space Invasion (LVSI). No clear relati onship exists between lymph
vascular space invol vement and survi val . Some reports have shown l ower survival rates
wi th LVSI; however, other studies have found no si gni ficant di fference i n survival if
data are adjusted for other risk factors (9).
Gynecol ogic Oncology Group study. Gynecol Oncol 1989;35:314320,
with permissi on.
d
Three-year survival.
P.489
P.490
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VIII. Treatment
Surgery and radi ation therapy are the two therapeuti c modaliti es most commonly used to
treat i nvasi ve cervi cal carcinoma.
A. Surgical Management. In general, pri mary surgi cal management i s li mi ted to disease
of stages I through IIA. Several advantages to surgical therapy make i t an attracti ve
opti on, parti cul arl y for younger women. Surgery all ows for thorough pelvic and
abdomi nal exploration, whi ch can identify patients with a disparity between the cl inical
and surgicopathol ogi c stages. These patients can be offered an individuali zed treatment
pl an based on thei r di sease status. Surgery al so permi ts conservati on of the ovaries
with their transposition out of subsequent radiation treatment fi elds. Radical
hysterectomy results in vaginal shortening; however, with sexual acti vity, gradual
l engthening wi ll occur. Fi stul a formati on (urinary or bowel ) and i nci sional compli cations
related to surgical treatment tend to occur earl y in the postoperative period and are
usual ly amenable to surgical repai r. Other indications for the selecti on of radi cal
surgery over radiati on include concomi tant infl ammatory bowel disease, previous
radiation for other di sease, and the presence of a simul taneous adnexal neopl asm.
1. The abdomen is opened through either a low transverse incision using the Maylard
or Cherney method, or through a mi dli ne i nci sion. Once inside the peri toneal
cavi ty, a thorough abdominal explorati on should be performed to evaluate for
vi sual or palpabl e metastases. Parti cular attention should be paid to the
vesicouterine peritoneum for signs of tumor extensi on or i mpl antation and
pal pation of the cardinal l igaments and the cervix. The para-aortic nodes should
be palpated transperi toneal ly.
2. Five di stinct vari ations or classes of hysterectomy are used in the treatment of
cervical cancer. (See Table 42.4 and Fi g. 42.5 for a brief compari son. See a more
definitive text for further i nformation.) Of note, Class I hysterectomy refers to
the standard extrafascial total abdominal hysterectomy. This procedure
ensures compl ete removal of the cervi x wi th mini mal di srupti on to surroundi ng
structures (bladder, ureters). This procedure may be performed in patients wi th
stage IA1. Class II hysterectomy is also referred to as a modified radical
hysterectomy or Wertheim's hysterectomy and is well suited for pati ents with
stage IA2 and smal l lesi ons that do not distort the anatomy. A class III
hysterectomy, al so known as radical abdominal or Meigs' hysterectomy, i s
recommended for stages IB and IIA. A class IV or extended radical
hysterectomy includes removal of the superior vesi cal artery, periureteral tissue,
and up to three-fourths of the vagina. In a class V or partial
exenteration operation, the distal ureters and porti on of the bl adder are
resected. Class IV and cl ass V procedures are rarel y performed today, because
pati ents with disease extensi ve enough to requi re these operati ons can be more
adequatel y treated usi ng pri mary radiati on therapy.
P.491
Table 42.4 Types of Abdominal Hysterectomy
Type of
surgery Intrafascial
Extrafascial
class I
Modified
radical
class II
Radical
class III
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B. Primary radiation therapy can be used for all stages of di sease and for most
pati ents, regardless of age, body habitus, or coexistent medical condi tions. Radiati on
therapy should not be used in patients with diverti culosis, tubo-ovarian abscess, and
pelvic ki dney. Radiati on therapy has evolved to include concurrent chemotherapy as a
radiosensiti zer, which results in improved disease-free progressi on and overall survi val
compared with radi ation therapy alone (24). Preservation of sexual functi on is
Cervical
fascia
Parti all y
removed
Completely
removed
Completely
removed
Compl etely
removed
Vagi nal
cuff
None
removed
Small rim
removed
Proximal
12 cm
removed
Upper one-
third to
one-half
removed
Bl adder Parti all y
mobilized
Partial ly
mobi li zed
Mobi li zed Mobil ized
Rectum Not
mobilized
Rectovagi nal
septum
partiall y
mobi li zed
Mobi li zed Mobil ized
Ureters Not
mobilized
Not
mobi li zed
Unroofed
i n ureteral
tunnel
Compl etely
dissected
to bladder
entry
Cardi nal
li gaments
Resected
medial to
ureters
Resected
medial to
ureters
Resected
at level of
ureter
Resected
at pelvi c
si de wall
Uterosacral
li gaments
Resected
at level of
cervi x
Resected at
level of
cervix
Partially
resected
Resected
at
postpel vi c
inserti on
Uterus Removed Removed Removed Removed
Cervix Parti all y
removed
Completely
removed
Completely
removed
Compl etely
removed
From Perez CA. Uterine cervi x. In Perez CA, Brady LW, eds. Pri nciples and
Practi ce of Radiati on Oncology, 2nd Ed. Phi ladelphia: JB Lippi ncott, 1992,
with permissi on.
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significantly related to the mode of primary therapy. Pel vic radiati on produces
persi stent vaginal fibrosis and atrophy, with loss of both vaginal l ength and cali ber. In
addition, ovarian functi on is lost in vi rtually all patients who undergo tolerance-dose
radiation therapy to the pel vis. Fi stulous compli cati ons associ ated with radiation
therapy tend to occur late and are more difficult to repai r because of radi ati on fibrosis,
vasculi ti s, and poorl y vasculari zed tissues.
1. The two main methods of radiation therapy del ivery are external photon beam
radiation and brachytherapy. External photon beam radiation is usual ly
deli vered from a l inear accelerator. Mi croscopic or occul t tumor deposits from
epitheli al cancers requi re 4,000 to 5,000 cGy for l ocal control . A cli ni call y obvious
tumor requires in excess of 6,000 cGy.
2. Two reference poi nts are commonl y used to describe the dose prescri ption for
cervical cancer: (a) Point A i s 2 cm lateral and 2 cm superior to the external
cervical os and, theoreti cal ly, represents the area where the uteri ne artery
crosses the ureter; and (b) Point B is 3 cm lateral to point A and corresponds to
the pelvic sidewall and to the location of the obturator lymph nodes (25). The
summated dose to poi nt A, regardless of method, i s bel ieved to be adequate for
central control and is usually between 7,500 and 8,500 cGy. The prescribed dose
to point B is 4,500 to 6,500 cGy, depending on the bulk of parametrial and
sidewal l disease. See more defi nitive text for further discussion.
3. Once external therapy has been completed, brachytherapy can be deli vered
using various intracavi tary techniques, i ncl udi ng i ntrauterine tandem and vagi nal
col postats, vaginal cyli nders, or interstitial needle impl ants. Brachytherapy is a
form of radi ation therapy in which the source is placed close to the tumor. The
Fi gure 42.5. Diagram of pel vic anatomy and types of hysterectomy. (From
Berek JS, Hacker NF. Practical Gynecologic Oncol ogy, 4th Ed. Philadelphia:
Lippi ncott Williams & Wilkins, 2005:356, with permission.)
P.492
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radiation may be in the form of interstitial therapy i n which needl es are implanted
into the tumor, or in the form of intracavitary therapy in which intrauteri ne
tandem and vaginal ovoids, also known as colpostats, are used. The tandem i s
pl aced through the cervi x into the uterus, and the ovoids are placed in the lateral
vagi nal fornices (Fi g. 42.6). Brachytherapy can be deli vered as l ow dose rates
(LDR) or high dose treatments. LDR treatments are inpatient over 3 to 4 days and
receive 40 to 70 cGy per hour. HDR treatments may be deli vered as an outpatient
over five visits.
C. Chemotherapy. Singl e-agent chemotherapy is used to treat pati ents wi th extrapel vi c
metastases as well as those with recurrent tumor who have been previously treated
wi th surgery or radi ati on and are not candidates for exenterati on procedures. The best
candidates for chemotherapy are those wi th an excell ent performance
status and disease that are both outside of the fiel d of radi ati on and not amenable to
surgi cal resection. Cispl atin has been the most extensivel y studied agent and has
demonstrated the most consistent clinical response rates (20% to 25%) (5). Tumors
that responded best were those that recurred in nonradi ated sites (2).
1. The most active combination chemotherapy regimens used to treat cervical
cancer contain cispl ati n. The agents most commonly used in combinati on with
cispl ati n are bleomyci n, 5-fl uorouracil , mi tomyci n C, methotrexate,
cycl ophosphami de, and doxorubici n. A limited number of fairly well-powered
randomized tri als compari ng dual agent regimens with either triplet regimens or
P.493
Fi gure 42.6. Brachytherapy: tandems and ovoi ds. (Image courtesy of Dr. Robert
Giuntoli , The Johns Hopki ns Hospital, Department of Gynecology and Obstetri cs,
Di vi sion of Gynecologi c Oncology.)
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singl e agent regi mens have demonstrated that combi nation therapy leads to a
slightly hi gher response rate and a longer progression-free survi val ; however, no
di fference was found between the regimens i n terms of overal l survival.
D. Combined Modalities
1. Postoperative adjuvant radiation therapy has been advocated for patients with
mi croscopi c parametrial invasion, pel vic lymph node metastases, deep cervi cal
i nvasi on, and positi ve or close surgi cal margi ns. Postoperati ve radi ati on therapy
has been shown to reduce the rate of pel vic recurrence after radi cal hysterectomy
i n high-risk patients.
2. Neoadjuvant chemotherapy is referred to the administration of
chemotherapeutic agents before or after radical hysterectomy. No randomized
tri als demonstrating the effecti veness of preoperati ve chemotherapy have been
reported (9).
3. Chemoradiation. The use of chemoradi ati on has become widely recognized as
provi ding survi val benefit over radiation alone in the treatment of cervical cancer.
The use of combined chemotherapy and radiation therapy is based on the theory
of synergi sti c cel l ki llthe therapeutic effect of two treatment modaliti es used in
combi nation is greater than if the i ndi vidual effects of the two modaliti es were
simply added together. When combined with radiation, weekly cisplati n
admi ni strati on reduces the ri sk of progressi on for stage IIB through stage IVA
cervical cancer (9). Cispl ati n appears to act as a radiosensiti zer, yielding a l arge
reducti on in the rate of l ocal recurrence and a more modest reducti on in the rate
of distant metastases.
IX. Management by Stage of Disease
A. Stage IA1. Stage IA1 (mi croinvasive cervical cancer 3 mm or l ess depth of i nvasi on
and 7 mm width or less) wi thout l ymph-vascular invasi on is managed with conservative
surgery, such as exci sional conizati on or extrafasci al hysterectomy. Conization may be
used selecti vely i f preservati on of ferti lity is desired, provided that the surgi cal
margins are free of disease. Patients treated with conization should be followed closely
wi th pap smear, colposcopy, and ECC every 3 months for the fi rst year. For medi call y
i noperable pati ents, stage IA carci noma can be effectively treated with chemoradi ati on
as previously described.
B. Stage IA2. Mi croi nvasive carcinoma wi th stromal invasion of 3.1 to 5.0 mm is
associated with posi tive pelvic lymph nodes in 5% of cases (5). The preferred
treatment of these l esi ons i s modi fied radical (class II) hysterectomy wi th pel vic
l ymphadenectomy. In patients who desi re preservation of fertil ity, radi cal
trachel ectomy wi th laparoscopi c or extraperitoneal lymphadenectomy has been
performed with success.
In a radical trachelectomy, cervical and vagi nal branches of the uterine artery are
l igated, whi le the main trunk of the uteri ne artery is preserved. Once the blood supply
has been control led, the cervix i s amputated at a poi nt approximatel y 5 mm caudal to
the uterine isthmus. The uterus is then suspended from the lateral stumps of the
transected paracervical li gaments. Once the uterus has been suspended, isthmi c
cercl age is performed, using a techni que simil ar to that used as prophylaxis agai nst
mi scarri age. Subsequently, the vaginal and isthmi c mucosa are reapproxi mated.
Although the risk of miscarriage is i ncreased after radical trachel ectomy, numerous
P.494
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successful pregnancies have been reported after such surgery.
C. Stages IB1, IB2, IIA. Radical hysterectomy (cl ass III hysterectomy) and adequate
radiation are equall y effective i n treati ng stages IB and IIA carcinoma of the cervix.
Five-year survi val and di sease-free survival were 83% in the pri mary surgi cal group
and 74% i n the radiati on group, whi ch was not a stati stical ly si gnifi cant di fference
(28).
1. Management of patients with bulky stage I disease (IB2) is controversial. The
di scussion i s between offeri ng surgery vi a a class III hysterectomy or radi ati on.
Often surgery i s first performed wi th postoperative radi ation. Alternati vely, a
Gynecologi c Oncology Group study showed that weekly cisplatin 40 mg/m
2
(six
doses) with external radiation and a single implant to give 55 Gy at point B,
fol lowed by extrafasci al hysterectomy, gave the best outcome (30).
D. Stages IIB, III, IVA, IVB. Radiation therapy is the treatment of choice for pati ents
wi th stage IIB and more advanced disease. Long-term survival rates wi th radiation
therapy alone are approxi mately 70% for stage I di sease, 60% for stage II disease,
45% for stage III disease, and 18% for stage IV di sease (9). With the routi ne use of
chemoradiati on, long-term survival and disease-free progressi on are expected to
i ncrease for al l stages of di sease (9). Patients with stage IVB disease are usuall y
treated with chemotherapy al one or chemotherapy i n combination with local radiation.
These pati ents have a uniformly poor prognosis regardl ess of treatment modali ty.
X. Treatment-Related Complications
A. Surgical Complications. Modern surgical techniques and anesthesia have reduced the
operative mortali ty rate. Febri le morbi dity is common after radical hysterectomy due to
typical postoperative reasons. Major causes of morbidi ty i ncl ude lower extremi ty
venous thrombosi s, vesicovaginal fi stulas (<1%) (2), ureteral fistulas, permanent
ureteral stenosis, bladder of voi ding dysfuncti on (due to parti al denervati on of the
detrusor), and pelvic lymphocyst formati on.
B. Radiation-Related Complications
1. Acute compl ications of radiation therapy that occur duri ng or i mmediatel y after
therapy include uterine perforation, proctosigmoiditis (secondary to i oni zi ng
radiation), and acute hemorrhagic cystitis.
2. Chronic complications of radiation therapy that occur months to years after
completing therapy incl ude vaginal stenosis (very common), rectovaginal and
vesicovaginal fistulas (complicate fewer than 2% of cases), small bowel
obstruction, and radiation-induced second cancers.
XI. Posttreatment Surveillance
Abdominal exam, l eg and groin exam, specul um exam, bi manual rectovaginal exami nation
and evaluation of l ymph nodes, including ingui nal and supraclavicular nodes, should be
performed every 3 months for 3 years foll owi ng a di agnosi s of cervical cancer. After the first
3 years, exami nations shoul d be done every 6 months for an additional 2 years, and every 6
months to 1 year thereafter (2). More frequent examinati ons are warranted i f abnormal
signs or symptoms devel op. Pap smears should be obtained at every vi si t, with consideration
for annual chest x-ray and IVP or abdominal pelvic CT.
P.495
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A. Recurrent Disease. Cervical cancer detected within the first 6 months after therapy i s
often termed persistent cancer. Disease di agnosed >6 months l ater i s usually
referred to as recurrent disease. Treatment of recurrent cervi cal cancer i s di ctated by
the site of recurrence and by the primary mode of therapy. In patients with recurrence
after primary surgery, radi ati on therapy is considered. Conversel y, surgical treatment
shoul d be considered for patients who initial ly received radiation. Onl y pati ents with
central recurrence and no evi dence of disease outside the pel vis are candi dates for
pelvic exenterati on. See other contraindications in Table 42.5.
Table 42.5 Preoperative Contraindications to
Exenteration in Patients with Recurrent Cervical
Cancer
Absolute
Extrapel vi c di sease
Tri ad of uni lateral leg edema, sciati ca, and ureteral obstruction
Tumor-related pelvic sidewal l fixation
Bi lateral ureteral obstruction (if secondary to recurrence)
Severe, li fe-li miting medical il lness
Psychosis or the inability of the pati ent to care for herself
Rel igi ous or other beli efs that prohibi t the pati ent from accepting transfusi on
Inabil ity of physici an or consul tants to manage any or all intraoperative and
postoperative compl ications
Inadequate hospital facili ties
Relative
Age ol der than 75 years
Large tumor volume (>4 cm)
Uni lateral ureteral obstruction
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XII. Special Problems
A. Cervical Cancer in Pregnancy. Cervical cancer is the most common mali gnancy i n
pregnancy, ranging from 1 in 1,200 to 1 in 2,200 pregnancies (32). Cervical cancer
coi nci dent wi th pregnancy requires complex di agnosti c and therapeuti c deci sions that
may jeopardize both mother and fetus.
1. The symptoms of cervical cancer are the same i n pregnant patients and
nonpregnant pati ents. Diagnosis can be made during cervi cal cytologi c screeni ng
that should be part of routine antenatal care. Pregnant women are at ri sk of delay
of di agnosi s of cervical cancer. Reasons for a delayed di agnosi s include (a) young
age of pati ent, (b) low level of suspici on by physi cian, (c) di fficulty of performing
col poscopy in pregnant pati ents, (d) attributi on of vaginal bl eedi ng to pregnancy
compl icati ons, not neopl asm, (e) tendency of cervix in pregnancy to look
abnormal, and (f) reluctance of physicians to perform cervical biopsies on
pregnant women. Directed cervical punch biopsi es can be performed safely during
pregnancy when high-grade i ntraepitheli al lesions or microi nvasion is suspected.
Endocervical curettage shoul d be avoided due to the ri sk of rupturing the amni oti c
membranes. Cervical coni zati on should be performed only if i t i s strictl y indi cated
and between 12 and 20 weeks of gestati on.
2. Pregnant women with cervical cancer should undergo the same pretreatment
metastatic eval uati on as nonpregnant women. Because the bimanual examination
may be difficult in pregnancy, MRI may be useful to deli neate extracervical
di sease.
3. In patients with carcinoma in situ or microinvasi ve disease stages IA1 and IA2,
there appears to be no harm in delaying defi ni ti ve therapy until after fetal
maturity has been attained. Pati ents with less than 3 mm of invasion and no
l ymph vascul ar space i nvolvement may be followed to term and deli vered
vagi nal ly. The major ri sk to the pati ent duri ng del ivery through a cervix that
contains invasi ve carci noma is the risk of hemorrhage due to tearing of the tumor
duri ng cervi cal di lati on and deli very (8). Recurrences of cervical cancer have been
reported at the episi otomy site i n women who deli ver vaginall y (34). Foll owi ng
vagi nal deli very, these women shoul d be re-evaluated and treated at 6 weeks
postpartum. If deli very is by cesarean section, extrafasci al hysterectomy can be
performed at the ti me of deli very or after a delay of 4 to 6 weeks if further
Metastasis to the distal vagina
Adapted from Shingleton HM, Orr JW. Cancer of the Cervix: Di agnosi s and
Treatment. New York: Churchill Livingstone, 1995:265, with permission.
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chil dbeari ng i s not desi red. Pati ents with 3 to 5 mm of invasion or lymph vascular
invasion can also be safely followed until fetal maturity has been reached. In
these cases, however, surgical treatment should i ncl ude a modi fied radical
hysterectomy wi th pel vic l ymph node di ssecti on, performed either at the time of
cesarean delivery or at 4 to 6 weeks postpartum. Radiati on therapy i s associated
wi th survival rates comparabl e to those after surgi cal treatment.
4. In patients with stages IB1, IB2, and IIA a delay in therapy i n excess of 6 weeks
may be detrimental to the mother' s chance of survival. If the diagnosis i s made
after 20 weeks' gestation, consideration may be gi ven to postponing therapy until
fetal viability, because neonatal intensive care allows salvage rates of
approximately 75% for infants born at 28 weeks (9). Standard treatment consists
of cl assic cesarean del ivery fol lowed by radi cal hysterectomy and pelvi c and para-
aorti c lymph node dissection; however, this procedure i s associated with longer
operative time and greater blood loss than in nonpregnant pati ents. Lower
segment transverse cesarean section is not recommended because of the
i ncreased risk of cervi cal extension wi th thi s procedure that may increase i ntra-
operative bl eedi ng. Radiation therapy resul ts in equi val ent survival rates and may
be preferable for pati ents who are poor surgical candi dates.
5. Cli ni cal stage of cervical cancer remains the most important prognostic factor for
pregnant and nonpregnant women ali ke (9). Because most pati ents di agnosed wi th
cervical cancer during pregnancy have stage I disease (11), overal l survival is
slightly better for patients with cervical cancer during pregnancy (9). Di agnosi s at
a l ate gestational age or postpartum, however, i s associated wi th more advanced
clinical stage and correspondingly poor long-term survival rates (9).
B. Cervical Hemorrhage. Profuse vaginal bl eedi ng from l arge cervical mal ignanci es i s a
challenging therapeutic situation. Generally, conservative measures to control cervical
hemorrhage are preferable to emergency l aparotomy and vascular (hypogastric artery)
l igati on. Attention must first be di rected toward the stabilizati on of the patient with
appropriate i ntravenous fluid and blood product repl acement. Immedi ate control of
cervical hemorrhage can usuall y be accompli shed wi th a vaginal pack soaked in
Monsel 's sol ution (ferri c subsul fate). Topical acetone (dimethyl ketone) appl ied wi th a
vagi nal pack pl aced fi rmly against the bl eedi ng tumor bed has al so been used
successful ly to control vaginal hemorrhage from cervical malignancy. Definitive control
of cervical hemorrhage can be accompli shed with external radiation therapy of 180 to
200 cGy per day if the pati ent has not previously received tolerance doses of pelvic
i rradi ation. Al ternati vely, arteri ography can be used to identify the bleeding vessel (s),
and Gelfoam or steel coil embolizati on can then be performed. Vascul ar emboli zati on
has the di sadvantage of producing a hypoxic local tumor envi ronment and potenti all y
compromi sing the effi cacy of subsequent radiation therapy.
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2003:13731444.
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