24 CANCER CERVIX

and CIN
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OVERVIEW
Cancer of the cervix is the second most commonly occurring cancer of the female genital tract and is
also recognized as the most preventable gynaecologic cancer. Since the introduction of the Papanicolaou
screening test (Pap smear), invasive cancers of the cervix showed a significant decline in their occurrence
being now less common than endometrial carcinoma (EC).
acial, ethnic, geographic and socioeconomic factors play important roles in the prevalence of this
disease. Social, sexual and hygienic habits are also important factors.
!ervical cancers are "nown to progress slowly from precancerous lesions (CIN), to preinvasive
disease (carcinoma in situ - CIS), to invasive cancer. #his slow progression provided the rationale for the
preventive and early treatment strategies that have caused the decline of invasive cervical cancer, and the
rise in the incidence of preinvasive disease, and premalignant lesions, over the last few decades.
RISK FACTORS:
$. %arly age at the first sexual intercourse (the transformation zone being near to external os).
&. 'ultiple sexual partners (sub(ects cervical epithelium to variable foreign protein).
). *iral sexually transmitted diseases (+P* $,-$--)$-)) . +S* type //).
0. 1ow socioeconomic standards and poor hygiene (chronic irritation).
2. !igarette smo"ing. (3y-products in cigarettes may concentrate in cervical epithelium, with depletion of
1angerhan4s cells that assist in cell mediated immunity).
,. /mmunosuppression (e.g. from +/* infection, or immunosuppressant drugs used in organ transplant).
INFECTIOUS ASSOCIATIONS
A) Human Papilloma Viu! "HPV):
- 5enital forms of HPV can be transmitted by sexual contact and may result in premalignant changes in
cervical tissues that may eventually lead to cancer.
- #he virus may provide the genetic material for cells at the s6uamo-columnar (unction within the
transformation zone of the ectocervix, which will later provide malignant epithelium.
- +P* is detected in 7 89: of cervical cancers and precancers. /t is also detected in vaginal, vulval,
penile, and anal cancers and precancers.
- #here are more than $99 types of +P* virus, of these only $2-&9 types are considered oncogenic, most
important of which are types $,-$--)$-))-)2-)8-02-2$-2& . 2-.
- /n almost ;9--9: of women exposed to genital HPV, the infection is transient, and cleared by the
immune system in $-& years. /f the virus remains present for several years, with low immunity and
repeated exposures, precancerous changes may occur in cervical cells resulting in cervical
intraepithelial neoplasia (CIN).
- /f left untreated, CIN may develop to preinvasive then invasive cancer however in many cases it may
remain stationary or even spontaneously regress.
#) H$p$! !impl$% &iu! '(p$ II "HSV)2)
$
- +S*-& <=> and messenger => se6uences have been found in cervical cancer cells. #hey may also
increase the li"elihood of +P* infection
N.B.: /t is important to note that many cases, which will develop cervical cancers, have never been exposed
to +P*, +S* //, or other ris" factors. Such cases are genetically determined and are not much affected by
many of the above-mentioned ris" factors.
#$ni*n !+uamou! m$'apla!ia:
>t puberty under the influence of oestrogen, reserve cells at the transformation zone (!), in the
s6uamo-columnar (unction undergoes a process of benign metaplasia (change of growth), in which mucous
secreting glandular cells are continuously transformed to non-mucous secreting s6uamous cells .
!ontinuous exposure of reserve cells at the #? to carcinogenic factors, as viral <=> may lead to the
production of atypical metaplasia or dysplasia (disordered growth) which might progress to carcinoma in
situ and later to invasive cancer.
CERVICA, INTRAEPITHE,IA, NEOP,ASIA "CIN)
#he term CIN describes a spectrum of intraepithelial changes occurring within the s6uamous epithelium
of the ectocervix that carry a premalignant potential. #hese changes include@ increased cellular
proliferation, increased amount of immature cells, disparity in the shape of cells (pleomorphism), and 1oss
of polarity. +istologically !/= is graded into ) grades according to its premalignant potentialA
CIN 1: dysplastic cells occupy the basal one third (1!) of the thic"ness of the s6uamous epithelium.
!ells of the upper &B) show normal stratification and maturation.
CIN II: dysplastic cells occupy one hal" (1#) of the thic"ness of s6uamous epithelium. !ells of the
upper $B& show normal stratification and maturation
CIN III: dysplastic cells occupy the "ull thic$ness of the s6uamous epithelium, "ithout invasion of
the basement membrane# !/= /// . in situ carcinoma are grouped in one category.
CIN, if untreated, may slowly progress through grades /, //, ///, and finally to preinvasive or invasive
cervical cancer. #his progression may ta"e ;-$9 years before invasive cancer will occur
-IA.NOSIS OF CIN:
CIN usually affects women in younger age groups (&2-02 years). /t is usually asymptomatic,
accidentally diagnosed through screening of high ris" women by the $ap smear test, and confirmed by
performing colposcopy and biopsies in women with abnormal smears.
/) C$&i0al !m$a! "Pap !m$a '$!'):
#he Pap smear test is based on cytologic examination of cells shed from the ectocervix. /t is performed
using a c%to&rush to wipe cells from the endocervical canal, and an '%re wooden spatula to wipe cells
from the surface of the ectocervix. !ells obtained are spread on a glass slide fixed by ethyl alcohol and
stained by $apanicolaou stain. #he test is done as an office procedure with an accuracy rate 7 -9:,
however it carries a small percentage of both false positive and false negative results ($2-&2:).
In'$p$'a'ion o1 a Pap !m$a will include either;
a) Benign changes
&) (eactive changes:
- 1ow grade intraepithelial changes 1/S1s (!/= /)
&
- +igh grade intraepithelial lesions +/S1s (!/= //-///).
c) )alignant cells present
2) Colpo!0op(:
- !olposcopy allows inspection of the #? with a magnification up to &9 times after applying ):-2:
acetic acid solution.
- Colposcopic directed &iopsies are performed from areas of abnormal epithelium (aceto-white areas,
punctuation, mosaicism, leu"opla"ia, and Schiller4s iodine negative areas) with accuracy of -2:- 82:.
- *ndocervical curettage is performed to rule out dysplasia when the #? in the cervical canal is not
properly visualized in presence of an abnormal pap smear.
F$+u$n0( o1 0$&i0al 0('olo*( !0$$nin*
- +igh ris" population should be screened annually within ) years from onset of sexual activity
- Comen above the age of )9, with low ris" factors and ) consecutive annual negative pap smears
should be screened every ) years
- Comen over the age of ;9 with ) negative Pap smears in the last decade, can consider discontinuation
of Pap testing at the physician4s advice
TREAT2ENT OF CIN:
#reatment of !/= is based on colposcopic obtained biopsiesA
/3 ,o4 *ad$ l$!ion! ",IS,! ) CIN I):
a) Conservative treat+ent, (treat infection and repeat smear within $& wee"s) as ;9: will show
spontaneous regression while only $2: may progress to high grade abnormality.
&) -estruction o" a&nor+al cells at #? if the lesion persists in repeated smearsA
- Ablation using CO2 laser
- Cauterization by heat or electro-cautery
- Freezing by cryotherapy
23 Hi*5 *ad$ l$!ion! "HIS,! ) CIN II)III): %xcision of abnormal cells in #? viaA
a) Cold $ni"e coni.ation: is the gold standard as it yields a pathologic specimen with clean margins
&) /oop *lectrosurgical *0cision Procedure (/**P) or large loop e0cision 12 (//*12): a hot
metal wire loop is used to excise a wedge of cervical tissue. Dields a smaller pathologic specimen
with charred margins.
c) 1otal a&do+inal h%sterecto+% (1'H) in older patients and those not desiring fertility.
3ollow 4p '"ter 1reat+ent: <espite the efficacy of the above mentioned techni6ues in treating !/= yet
recurrence is still common and follow up by annual Pap smears is recommended for around $9 years.
PREINVASIVE CARCINO2A OF THE CERVIX (carcino+a in situ5C6I):
/n carcinoma in situ (stage 9)A malignant changes occur in cervical s6uamous epithelium without
invasion of basement membrane. #he condition is asymptomatic diagnosed through histopathologic
examination of biopsies obtained from cases with abnormal $ap smear.
)anage+ent o" C6I
)
- %& is the treatment of choice which will include removal of the whole cervical tissue.
- Cold 'nife conization with wide safety marginA has a limited place only in the young infertile patient.
INVASIVE CARCINO2A OF THE CERVIX

INCI-ENCE AN- AETIO,O.6:
Invasive cervical cancer has significantly declined in the last ) decades in comparison to the increase
in CIN lesions. #hese changes are attributed to the effective screening programs, using the Pap smear test,
1he age incidence for cancer cervix is most commonly between 02-22 years which is almost $9 years
younger than that for endometrial carcinoma, and $9 years older than that for !/= lesions.
High ris$ "actors are same as for !/= includingA early exposure to first intercourse, multiple sexual
partners, viral agents as +P* . +S* //, and cigarette smo"ing. Entreated !/= cases especially high grade
lesions may gradually progress to invasive cancer in a period ranging ;-$9 years
PATHO,O.6:
A) S+uamou! 0$ll 0a0inoma o1 '5$ E0'o0$&i% "789):
5 >rise from s6uamous epithelium covering the ectocervix (rarely metaplasia of glandular epithelium.
3eing at the portio vaginalis it is usually easily visualized by na"ed eye examination.
5 Presents either asA a friable necrotic mass easily bleeding on touch, a deep ulcer with everted and
indurated edges, or as an indurated nodule that may brea" forming an ulcer
#) Ad$no0a0inoma o1 '5$ Endo0$&i% "/:9):
- #hey arise from the columnar epithelium lining the endocervix. 3eing within the endocervix, it is more
difficult to be detected by na"ed eye.
- #hey may distend the cervix giving it a barrel-shaped appearance. 3y the time it appears at the
external os, the carcinoma has often spread extensively outside the cervix.
C) O'5$ a$ '(p$! ":9) includeA small cell carcinomas, sarcomas, and lymphomas
Hi!'olo*i0al .adin* o1 Can0$ C$&i%:
a) 7ell di""erentiated (grade I), the ma(ority of cells resemble the normal s6uamous epithelium of the
cervix. #hey grow slowly and are less li"ely for early spread.
;) )oderate and poorl% di""erentiated (grade # 8 !), cervical carcinoma is predominantly of the
moderate or poorly differentiated type. >bnormal cells predominateA they are more li"ely for rapid
growth and early spread.
SPREA- OF CANCER CERVIX: !ancer cervix is famous for its early direct and lymphatic spread.
1. -irect spread: #o ad(acent tissues including the body of the uterus, the parametrium, upper and
lower vagina, and uterosacral ligaments. 1ater spread may involve the bladder and rectum.
#. /%+phatic spread: Esually follows direct spread, but may coincide with it. /t involvesA
- $rimary groups: include spread from the cervical lymphatics along the paracervical lymph
tract, to the external iliac nodes, and occasionally bac"wards to the internal iliac group.
- Secondary groups@ involve drainage into the common iliac and lateral sacral groups.
Eltimately the common iliac group drains into the para-aortic lymph nodes.
0
!. Blood strea+ spread: 1east common, usually in late or advanced cases. 'etastases may occur to
distant organs as to the liver, lungs, brain and bone.
S62PTO2S
- Contact bleeding( is the commonest presentation (postcoital bleeding or bleeding on touch)
- )etrorrhagia* or postmenopausal bleeding, is the second most common presentation
- +aginal discharge which is excessive bloody or malodorous.
- $ain( deep pelvic pain and loin pain may be associated with advanced disease
C,INICA, SI.NS:
1. ,eneral examination-
- %arly stages do not affect the patient4s general condition.
- >dvanced stages are associated withA chronic blood loss, urinary manifestations and ureteric
obstruction which may lead to severe anaemia, uraemia and cachexia.
#. Inspection via a speculum vaginal examination:
- %arly stages may show a small friable warty mass, nodule or an ulcer that bleeds on touch.
- 1ater on, the mass or ulcer will extend to the vaginal walls obliterating the vaginal fornices.
!. $alpation by digital vaginal examination ($+):
- %arly stages show a mass or ulcer that bleeds profusely when touched by the finger.
- >s the disease progresses, the cervix loses its mobility, becomes fixed, and the surrounding
parametrium becomes tender and indurated.
9. .imanual pelvic examination: #he uterus is usually normal in size, except if pyometra develops
causing symmetrical uterine enlargement.
:. $er rectum examination ($/): #o evaluate possible parametrial extension and uterosacral
involvement.
-IA.NOSIS
+istopathologic examination of cervical tissue biopsies containing the abnormal epithelium is the
gold standard for diagnosis of cervical cancer. 3iopsies are obtained as followsA
1. ;ni"e Biopsies, obtained from suspicious lesions seen by the na"ed eye such as an ulcer, mass, polyp,
or nodule. /t is done under general anaesthesia.
#. Colposcopic -irected Biopsies, /ndicated when a Pap smear reveals positive malignant cells in
absence of a suspicious =% lesion on the cervix. 3iopsies are obtained from aceto-white positive
areas or Schiller4s iodine negative areas. /t is an office procedure performed without anaesthesia.
!. Cone Biops%: emoval of a cone shaped piece of the cervix with the apex including the #? is done
when a Pap smear is positive for malignant cells while the extent of the lesion cannot be delineated
colposcopically. !ervical conization can be performed through cold "nife, laser conization, 11%#?,
or 1%%P procedures. #he latter two are associated with less blood loss, but may be associated with
charring at the edge of specimen limiting reliability of its histopathologic evaluation
9. 3ractional Curettage (3C): to obtain tissue from the endocervix thus diagnosing high endocervical
lesions together with obtaining separate endometrial biopsies to exclude spread of cervical cancer to
the endometrium and body of uterus. (See the procedure of F! in gynaecologic operation).
2
C,INICA, STA.IN. AN- PREOPERATIVE PREPARATION:
3efore starting treatment, clinical staging of the disease should be complete. Staging re6uiresA
Examination under anaesthesia (E0%)- done during performing cervical biopsies to test for cervical
mobility and to define the presence and extent of parametrial infiltration through P* and P
examination.
Cystoscopy- to exclude bladder wall invasion which if present will shift staging from stages / . //, in
which treatment is curable, to stage /* in which treatment is palliative.
Intravenous pyelography (I+$)- to exclude ureteric compression if parametrial infiltration is present.
Chest 1 ray 2 %bdominal 0#S#: to exclude distant metastases in advanced cases.
STA.IN. OF CERVICA, CARCINO2A:
3oth, staging and grading, help to decide on the most appropriate treatment, and to predict the
possible prognosis of the case. #he F/5G clinical staging classification is based on findings on %E>, /*P,
cystoscopy, and cervical biopsies. Staging does not change after surgery.
Clini0al S'a*in* o1 In&a!i&$ Can0$ C$&i% "FI.O 0la!!i1i0a'ion):
S'a*$ I: Ca0inoma 0on1in$d 'o '5$ 0$&i%
- Stage I %- Microinvasive cancer, microscopic tumour (invasion depth !." mm # $idth %." mm&
- Stage I .- 'nvasive cancer con(ined to the cervi) (depth * !." mm # $idth * %." mm&
S'a*$ II: Ca0inoma $%'$nd! ou'!id$ '5$ 0$&i% 'o '5$ &a*ina ;u' no' 'o '5$ lo4$ /<=> 'o '5$
paam$'ium ;u' no' 'o '5$ p$l&i0 !id$4all
- Stage II %- +o obvious parametrial involvement.
- Stage II .- Obvious parametrial involvement not reaching the lateral pelvic side $all
S'a*$ III: Ca0inoma $%'$ndin* 'o lo4$ /<= &a*ina o on'o p$l&i0 !id$4all
- Stage III %- ,umour e)tending to lo$er -./ o( the vagina
- Stage III .- 0)tension to parametrium reaching the pelvic side $all
S'a*$ IV: Ca0inoma in&ol&$! mu0o!a o1 ;ladd$ o $0'um> o $%'$nd! ;$(ond '5$ p$l&i!
- Stage I+ %- ,umour involving the bladder or rectum (direct spread&
- Stage I+ .- 0)trapelvic spread, e.g. liver or lung metastases (blood borne spread)
T$a'm$n' o1 Ca0inoma in !i'u "S'a*$ 8)
1. otal abdominal hysterectomy "ith bilateral salpingo-oophorectomy (%& .S3)( is the mainstay of
therapy especially in the elderly perimenopausal patients.
- Pelvic lymphadenectomy is not re6uired as there is no invasion of the basement membrane.
- #>+ without 3SG is acceptable in middle age patients to preserve ovarian hormonal function.
#. Cervical Conization- has a limited place only in young patients with low-grade tumours and wide
free surgical margin after excision. #he aim is to preserve the uterus for fertility.
,
T$a'm$n' o1 2i0oin&a!i&$ Ca0inoma "!'a*$ IA)
%&-.S3 is the gold standard treatment. Selective lymph node sampling may be offered to detect
lymph node extension and to minimize the extent and morbidity of complete lymphadenectomy.
!ure rate in stage /> may reach up to 82: in most cases.
TREAT2ENT OF INVASIVE CANCER
- Choice o" treat+ent, whether surgery, radiotherapy or both, and the extent of each of them is based
namely on the stage of the disease, grade of the tumour, age and general condition of the patient.
- Early invasive cancer cervix, %ither surger% or radiotherap% can be used with comparable results,
however surgery is more preferred as it allows for complete resection of the tumour and provides a
specimen available for ensuring the extent of the disease. Che+otherap% may be also used as a
radiation sensitizer.
- In more advanced stages( the high morbidity of extensive surgery and possible distant spread of the
disease are in favour of choosing the option of radiotherap%.

/) SUR.ER6 in Can0$ C$&i%
Surgery is usually the "irst line o" treat+ent whenever the disease is con"ined to the
cervi0 (stage />-/3). /f the disease has reached the upper vagina without parametrial
involvement (stage //>) surgery will be as effective as radiotherapy but with less side
effects and morbidity. Surgery is superior to radiotherapy in providing a specimen for
histopathologic examination that allows evaluation of the safety margin and detects the
extent of nodal affection if present.
- 7erthei+<s radical h%sterecto+% is the standard surgical procedure for invasive carcinoma of the
cervix. /t involves a %&-.S3 4 pelvic lymphadenectomy 1 removal o( paracervical tissue and 2-/
cm (rom the upper vaginal cuff.
- Pelvic lymphadenectomy include removal ofA the external, internal, and common iliac nodes, together
with obturator and presacral nodes.
- /f surgery results in removal of the whole tumour, with a (ree sa(ety margin of healthy tissue and
negative lymph nodes, there will be usually no further need for postoperative radiotherapy.
- Patients with positive nodal affection or non free safety margin are best offered ad=uvant
radiotherap% treat+ent.
- #he ovaries may be preserved in younger women to benefit fro their hormonal function.
- SchautaHs vaginal hysterectomy and lymphadenectomy is rarely resorted to owing to the limited access
to pelvic nodes via such procedure ending in incomplete lymphadenectomy.
- #he principal complication seen with surgery is related to some degree of bladder dysfunction due to
division of the parasympathetic nerve supply to the bladder that runs within the uterosacral ligaments.
- 3ive %ears survival rates a"ter surger% alone ranges ;2:-$99: in stages from /> to //>.
Postoperative radiotherapy with or without chemotherapy may improve survival in some cases.
2) RA-IOTHERAP6 in Can0$ C$&i%:
;
adiotherapy can be used in all stages of cervical cancer either for curative or palliative intent.
- In earl% stages (I5II') cure rates are comparable to those for surgery.
- In +ore advanced stages (IIB5III) cancer will not be curable by surgery alone, and
radiotherapy becomes the preferred first line of treatment. /t may be given alone, or in
combination with surgery or chemotherapy.
a) Pri+ar% therap%, usually involves external beam radiotherapy (*B(1) to the pelvis
followed by intracavitary treatment or brachytherapy.
&) 'd=uvant therap%, administered after radical hysterectomy to high ris" cases (positive safety
margins, and or positive nodal involvement)
5 1he "ive %ears survival rates "or radiotherap% alone are comparable for survival with surgery alone
for stages />-//> disease.
5 For advanced stages localized within the pelvis, 2- years survival ranges from 29:--9:. For
metastatic disease outside the pelvis, survival is less than $2:.
5 Co+plications o" radiotherap% include, diarrhoea, radiation induced menopause, and variable
degrees of vaginal narrowing and fibrosis, few wee"s after treatment is completed. arely radiation
vesico-vaginal fistulas may occur and are difficult to deal with.
=) C5$mo'5$ap( in 0an0$ 0$&i%:
- !hemotherapy has proved to play a role as a radiation sensitizer in cases of cancer cervix
(e.g.A wee"ly /.*. !isplatin), with a nearly $9: increase in cure rates.
Po*no!i! in 0an0$ 0$&i%
- Stage />@ cure rates may reach up to 82:
- Stage /3A 2 year survival rates may reach up to -2: whether surgery or radiotherapy were used.
- Stage //A drops sharply to a 2 years survival of 29:.
- Sages /// and /*, 2 years survival may be as low as &2: and 2: respectively. #he treatment in these
stages is therefore only palliative.
PREVENTION o1 0an0$ 0$&i%:
/nvasive cancer cervix is the most preventable female genital cancer. Prevention is achieved viaA
a) Secondary prevention-
- egular screening for asymptomatic high ris" patients using the Pap smear test. !olposcopy and
directed biopsies should be done for all cases with abnormal Pap smears.
- #reatment of !/= lesions by ablation or excision, and regular follow up after treatment.
- egular Pap smear screening resulted in a significant decrease in the incidence of invasive cancer
cervix, and a $9 fold decrease in mortality compared to unscreened population.
b) $rimary prevention-
- >n +P* vaccine has been approved for prevention of +P* infection especially types ,, $$, $, .
$- which account for ;9: of all cervical cancers, and almost 89: of cases of genital warts.
- #he vaccine appears to be over 82: effective in preventing +P* $,, $-, related cervical cancers.
- #he vaccine is effective when given in age groups from 8-&, years, in non-previously infected
population. /t is not effective in treatment of already pre-existing infections.
-
CARCINO2A OF THE CERVICA, STU2P a1'$ !u;'o'al 5(!'$$0'om(
!ancer cervix may develop in the stump of the cervix left after subtotal hysterectomy performed for
benign indications as leiomyomata, and <E3. Prognosis is worse and treatment is more difficult.
6urger% (radical cervicecto+% and l%+phadenecto+%) is complicated by presence of adhesions and
abnormal anatomic relations induced by the previous hysterectomy.
(adiotherap%: *B(1 may be the best option as internal irradiation is compromised by the absence of
the uterus as a container for intrauterine applicators, while vaginal irradiation may not deliver the sufficient
dose without ris" of damage to the bladder and rectum.
RECURRENT CERVICA, CANCER
') (ecurrence a"ter pri+ar% surger% (more than , months)A is treated palliatively by external beam
irradiation. #he aim is to controlA bleeding, pain, and infection. Prognosis is poor in all conditions.
B) (ecurrence a"ter radiotherap%A Palliative surgery through pelvic exentration may be considered, in
order to control pain, bleeding, and infection. %xentration may be anterior (involving the uterus, vagina and
bladder, or posterior involving the rectum, or total involving both). #he operation carries very high
morbidity and mortality, and is rarely resorted to.
Key Points
- Cervical cancer is highly correlated $ith 234 in(ection and less commonly 254 type ''
- 6egular 3A3 smears done annually (or young se)ually active (emales and those $ith previous 1ve
C'+ smears $ill allo$ prevention and early detection o( most lesions.
- A positive smear $arrants repetition and Colposcopic guided biopsies i( con(irmed.
- On average C'+ ' may undergo spontaneous regression, or $ill advance to C'+ '' in 7 years.
- 3rogression o( C'+ to invasive cancer is slo$ and may ta8e about % years to occur.
- C'+ '' lesions may be treated by destruction o( the lesion by cauterization, cryo or laser therapy
- C'+ ''' is best surgically removed by conization using the 9003 procedure or cold 8ni(e.
2ysterectomy is another option in the elderly patient.
- Contact bleeding is the most common presenting symptom (or invasive cancers
- :iopsy (rom a suspicious cervical lesion (ulcer, or a (riable mass& is the gold standard (or diagnosis.
- ,reatment o( 5tage O is surgical by conization in the young patient and ,A2 in the elderly.
- 5tage 'A is best treated by ,A2, $ith or $ithout :5O, $ith no need to lymphadenectomy.
- More advanced stages are either treated by ;ertheim<s hysterectomy or radiotherapy.
- 6adiotherapy $hether as a primary treatment or as ad=uvant therapy has an important role in cancer
cervi), and is used as curative, palliative, or ad=uvant therapy.
8