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1059

Chapter 22 - The Female Genital Tract

Christopher P. Crum MD

Chapter 22 - The Female Genital Tract Normal

Embryology Anatomy

Pathology Infections of the Female Genital Tract

INFECTI!N" C!NFINE# T! T$E %!&E'GENITA% T'ACT

INFECTI!N" IN(!%(ING T$E %!&E' AN#)PPE' GENITA% T'ACT

Pel*ic Inflammatory #isease +PI#, orphology.

(/l*a 0artholin Cyst (/l*ar (estib/litis Non-Neoplastic Epithelial #isor1ers

%IC$EN "C%E'!")" %IC$EN "IP%E C$'!NIC)"

Neoplasms 0ENIGN T)!'"

Papillary $i1ra1enoma

Con1yloma Ac/minat/m P'EA%IGNANT AN# A%IGNANT

NE!P%A"" Carcinoma an1 (/l*ar Intraepithelial

Neoplasia orphology. E3tramammary Paget #isease orphology.

alignant elanoma (agina

Congenital Anomalies

Premalignant an1 alignant Neoplasms (AGINA% INT'AEPIT$E%IA% NE!P%A"IA

AN# "4)A!)" CE%% CA'CIN!A orphology.

A#EN!CA'CIN!A orphology.

E0'5!NA% '$A0#!5!"A'C!A orphology

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Cer*i3 Inflammations

AC)TE AN# C$'!NIC CE'(ICITI" orphology.

EN#!CE'(ICA% P!%5P"

Intraepithelial an1 In*asi*e "6/amo/s Neoplasia Pathogenesis. CE'(ICA% INT'AEPIT$E%IA% NE!P%A"IA

orphology. "4)A!)" CE%% CA'CIN!A

orphology. Clinical Co/rse an1 anagement.

0o1y of )ter/s an1 En1ometri/m En1ometrial $istology in the enstr/al Cycle F/nctional En1ometrial #isor1ers +#ysf/nctional )terine

0lee1ing,

AN!()%AT!'5 C5C%E INA#E4)ATE %)TEA% P$A"E EN#!ET'IA% C$ANGE" IN#)CE# 05

!'A% C!NT'ACEPTI(E" EN!PA)"A% AN# P!"TEN!PA)"A%

C$ANGE" Inflammation

C$'!NIC EN#!ET'ITI" En1ometriosis an1 A1enomyosis

orphology. Clinical Co/rse.

En1ometrial Polyps En1ometrial $yperplasia +En1ometrial Intraepithelial

Neoplasia, orphology.

alignant T/mors of the En1ometri/m CA'CIN!A !F T$E EN#!ET'I)

Inci1ence an1 Pathogenesis. orphology. Clinical Co/rse.

T/mors of the En1ometri/m 7ith "tromal #ifferentiation CA'CIN!"A'C!A"

orphology. A#EN!"A'C!A" "T'!A% T)!'"

orphology. T/mors of the yometri/m

%EI!5!A" orphology.

%EI!5!"A'C!A"

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orphology. Fallopian T/bes

Inflammations T/mors an1 Cysts

!*aries

Non-Neoplastic an1 F/nctional Cysts F!%%IC)%A' AN# %)TEA% C5"T" orphology.

P!%5C5"TIC !(A'IE" AN# "T'!A%$5PE'T$EC!"I"

orphology. !*arian T/mors

Pathogenesis. Classification. T)!'" !F 8%%E'IAN EPIT$E%I)

"ero/s T/mors

orphology. /cino/s T/mors orphology.

En1ometrioi1 T/mors orphology.

Clear Cell A1enocarcinoma Cysta1enofibroma 0renner T/mor

orphology. Clinical Co/rse9 #etection9 an1 Pre*ention

of "/rface Epithelial T/mors GE' CE%% T)!'"

Teratomas at/re +0enign, Teratomas.

orphology. ono1ermal or "peciali:e1 Teratomas. Immat/re alignant Teratomas.

orphology. #ysgerminoma

orphology. En1o1ermal "in/s +5ol; "ac, T/mor Choriocarcinoma !ther Germ Cell T/mors

"E C!'#-"T'!A% T)!'" Gran/losa-Theca Cell T/mors

orphology. Fibroma-Thecomas "ertoli-%ey1ig Cell T/mors

+An1roblastomas, orphology.

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!ther "e3 Cor1-"tromal T/mors etastatic T/mors

Gestational an1 Placental #isor1ers #isor1ers of Early Pregnancy

"P!NTANE!)" A0!'TI!N

ECT!PIC P'EGNANC5 orphology. #isor1ers of %ate Pregnancy

P%ACENTA% A0N!'A%ITIE" AN# T&INP%ACENTA"

P%ACENTA% INF%AATI!N" AN#INFECTI!N"

T!EIA !F P'EGNANC5 +P'EEC%AP"IAAN# EC%AP"IA,

Pathogenesis. orphology.

Clinical Co/rse. INT'A)TE'INE G'!&T$ 'E"T'ICTI!N Gestational Trophoblastic #isease

$5#ATI#IF!' !%E +C!P%ETE AN#PA'TIA%,

Types an1 Pathogenesis. orphology. Clinical Co/rse.

IN(A"I(E !%E C$!'I!CA'CIN!A

Inci1ence. orphology. Clinical Co/rse.

P%ACENTA% "ITE T'!P$!0%A"TIC T)!'

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Normal

m!r"olo#"

The embryology of the female genital tract is rele*ant to both anomalies in this region

an1 the histogenesis of *ario/s t/mors. The primor1ial germ cells arise in the 7all of theyol; sac by the fo/rth 7ee; of gestation< by the fifth or si3th 7ee;9 they migrate into the/rogenital ri1ge. The meso1ermal epitheli/m of the /rogenital ri1ge then proliferates9e*ent/ally to pro1/ce the epitheli/m an1 stroma of the gona1. The 1i*i1ing germ cells=of en1o1ermal origin=are incorporate1 into these proliferating epithelial cells to formthe o*ary.>?@Fail/re of germ cells to 1e*elop may res/lt in either absence of o*aries orpremat/re o*arian fail/re. #isr/ption of normal migration may acco/nt for e3tragona1al
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1istrib/tion of germ cell mi1line str/ct/res +retroperitone/m9 me1iastin/m9 an1 e*enpineal glan1, an1 may rarely lea1 to t/mors in these sites.

A secon1 component of female genital 1e*elopment is the mllerian 1/ct. At abo/t thesi3th 7ee;9 in*agination an1 s/bse6/ent f/sion of the coelomic lining epitheli/m form

the lateral mllerian +or paramesonephric, 1/cts. llerian 1/cts progressi*ely gro7ca/1ally to enter the pel*is9 7here they s7ing me1ially to f/se 7ith the /rogenital sin/sat the mllerian t/bercle +Fig. 22-?A,. F/rther ca/1al gro7th brings these f/se1 1/ctsinto contact 7ith the /rogenital sin/s9 forme1 7hen the cloaca is s/b1i*i1e1 by the/rorectal sept/m. The /rogenital sin/s e*ent/ally becomes the *estib/le of the e3ternalgenitalia +Fig. 22-?B ,. Normally9 the /nf/se1 portions mat/re into the fallopian t/bes9the f/se1 ca/1al portion 1e*eloping into the /ter/s an1 /pper *agina an1 the /rogenitalsin/s forming the lo7er *agina an1 *estib/le +Fig. 22-?C ,. Conse6/ently9 the entirelining of the /ter/s an1 t/bes as 7ell as the o*arian s/rface is /ltimately 1eri*e1 fromcoelomic epitheli/m +mesotheli/m,. This close embryologic relationship bet7een themesotheli/m an1 mllerian system may be reflecte1 in a1/lt life in the form of benign

+en1ometriosis, an1 malignant +en1ometrioi1 an1 sero/s neoplasia, lesions9 7hich mayarise in both the s/rface mesotheli/m of the o*aries an1 the peritoneal s/rfaces.

The epitheli/m of the *agina9 cer*i39 an1 /rinary tract is forme1 by in1/ction of basalcells from the /n1erlying stroma9 7hich /n1ergo s6/amo/s an1 /rothelial 1ifferentiation.>2@A portion of these cells remains /ncommitte19 forming the reser*e cells of the cer*i3.The latter are capable of both s6/amo/s an1 col/mnar cell 1ifferentiation. >B@

In males9 mllerian inhibitory s/bstance >@from the 1e*eloping testis ca/ses regression ofthe mllerian 1/cts9 an1 the paire1 7olffian +or mesonephric, 1/cts form the epi1i1ymisan1 the *as 1eferens. Normally9 the mesonephric 1/ct regresses in the female9 b/t

remnants may persist into a1/lt life as epithelial incl/sions a1Dacent to the o*aries9 t/bes9an1 /ter/s. In the cer*i3 an1 *agina9 these rests may be cystic an1 are terme1 Gartner1/ct cysts. any of the e*ents in the

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Fi#ure 22-1Embryology an1 anatomy of the female genital tract.A9 Early in 1e*elopment the mesonephric+red, an1 mllerian +blue, 1/cts merge at the /rogenital sin/s to form the mllerian t/bercle.B9 0y birththe mllerian 1/cts ha*e f/se1 to form the fallopian t/bes9 /ter/s an1 en1ocer*i3 +blue, merging 7ith the*aginal s6/amo/s m/cosa. The mesonephric 1/cts regress b/t may be fo/n1 as a remnant in the o*ary9a1ne3a an1 cer*i3 +Gartner 1/ct,. (Adapted from Langman J: Medical Embryology. Baltimore, Williamsand Wilins, !"#!.$C9 Normal a1/lt genital tract9 7ith cer*i39 /ter/s9 fallopian t/bes9 an1 o*aries. A small

parat/bal cyst is present on the right.

formation of the internal an1 e3ternal genitalia an1 their epithelial co*erings res/lt fromreciprocal epithelial-stromal signaling9 lea1ing to mesenchymal remo1eling an1 changesin epithelial cell fate.>2@>@

$natom"

#/ring acti*e repro1/cti*e life9 the o*aries meas/re abo/t 2. ?. cm in 1imension.The o*ary is 1i*i1e1 into a corte3 an1 a me1/lla. The corte3 consists of a layer of closelypac;e1 stromal cells an1 a thin co*ering of relati*ely acell/lar collageno/s connecti*etiss/e. Follicles in *arying stages of mat/ration are fo/n1 7ithin the o/ter corte3. &itheach menstr/al cycle9 one follicle 1e*elops into a graafian follicle9 7hich is transforme1
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into a corp/s l/te/m follo7ing o*/lation. Corpora l/tea ranging from recent to senescent+corpora albicantia, may be fo/n1 in the corte3 of the a1/lt o*ary.

The me1/lla of the o*ary consists of loosely arrange1 mesenchymal tiss/e an1 containsremnants of both 7olffian 1/ct +rete o*arii, an1 small cl/sters of ro/n1 to polygonal9

epithelioi1 cells aro/n1 *essels an1 ner*es. These hil/s cells are *estigial remains ofthe gona1 from its primiti*e ambise3/al phase9 are steroi1 pro1/cing9 an1 resemble theinterstitial cells of the testis. 'arely9 these cells gi*e rise to masc/lini:ing t/mors +hilarcell t/mors,.

The fallopian t/be m/cosa is compose1 of n/mero/s 1elicate papillary fol1s +plica,consisting of three cell typesH ciliate1 col/mnar cells< nonciliate19 col/mnar secretorycells< an1 so-calle1 intercalate1 cells9 7hich may simply represent inacti*e secretorycells.

The /ter/s *aries in si:e 1epen1ing on the age an1 parity of the in1i*i1/al. It 7eighs

abo/t gm an1 meas/res abo/t J. K. B. cm in n/lliparo/s repro1/cti*e age7omen. Follo7ing pregnancies9 /teri are slightly larger +/p to L gm in 7eight,9 then1iminish to half their 7eight an1 1imension follo7ing menopa/se.

The /ter/s has three 1istincti*e anatomic an1 f/nctional regionsH the cer*i39 the lo7er/terine segment9 an1 the corp/s. The cer*i3 is f/rther 1i*i1e1 into the *aginal portio+ectocer*i3, an1 the en1ocer*i3. The portio is *isible to the na;e1 eye on *aginale3amination an1 is co*ere1 by a stratifie1 non;eratini:ing s6/amo/s epitheli/mcontin/o/s 7ith the *aginal *a/lt. The s6/amo/s epitheli/m con*erges centrally at asmall opening terme1 the e%ternal os. In the n/lliparo/s 7oman9 this os is *irt/allyclose1. M/st cephala1 to the os is the en1ocer*i39 7hich is line1 by col/mnar9 m/c/s-

secreting epitheli/m that 1ips 1o7n into the /n1erlying stroma to pro1/ce crypts+en1ocer*ical glan1s,. The point at 7hich the s6/amo/s an1 mllerian col/mnarepitheli/m meet is the s6/amocol/mnar D/nction +Fig. 22-2,. The position of theD/nction is *ariable 1/e to both the cer*ical anatomy an1 the 1istrib/tion of the basal an1s/bcol/mnar reser*e cells that e3ist D/st cephala1 of this D/nction. It is the progressi*e1ifferentiation of these basalreser*e cells that go*erns the microanatomy of this region9/ltimately res/lting in the

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Fi#ure 22-2"chematic of the 1e*elopment of the cer*ical transformation :one.

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cephala1 migration of the s6/amocol/mnar D/nction. The portion of the col/mnarepitheli/m that is /ltimately replace1 by s6/amo/s epitheli/m is terme1 thetransformation &one +Fig. 22-2an1 Fig. 22-B,. As 7e shall see9 it is in thistransformation :one9 incl/1ing the s6/amocol/mnar D/nction9 7here precancero/s lesionsan1 s6/amo/s carcinomas 1e*elop.>K@

The en1ometrial changes that occ/r 1/ring the menstr/al cycle are ;eye1 to the rise an1fall in the le*els of o*arian hormones9 an1 the rea1er sho/l1 be familiar 7ith the comple3b/t fascinating interactions among hypothalamic9 pit/itary9 an1 o*arian factors/n1erlying mat/ration of o*arian follicles9 o*/lation9 an1 the menstr/al cycle. It is alsoimportant to ;no7 that the hormonal patterns of most 7omen 1iffer from the stan1ar1as 1epicte1 1iagrammatically +1isc/sse1 later< seeFig. 22-2,. >L@)n1er the infl/ence ofthe pit/itary follicle-stim/lating hormone an1 l/teini:ing hormone9 1e*elopment an1ripening of a single o*/m occ/r9 an1 estrogen pro1/ction by the enlarging o*arian follicleprogressi*ely rises 1/ring the first 2 7ee;s of the /s/al 2J-1ay menstr/al cycle. Itreaches a pea;9 pres/mably D/st before o*/lation9 an1 then falls. After o*/lation9 the

estrogen le*els again begin to rise to a platea/ at abo/t the en1 of the thir1 7ee;9 b/tthese le*els are ne*er as high as the preo*/latory pea;. The le*el of this hormone thenprogressi*ely falls9 beginning B to 1ays before the onset of menstr/ation. Progesterone9pro1/ce1 by the corp/s l/te/m9 rises thro/gho/t the last half of the menstr/al cycle an1falls to basal le*els D/st before the onset of menstr/al blee1ing. The histology of thenormal an1 abnormal en1ometrial cycle is 1isc/sse1 later in the section on theen1ometri/m.

Patholo#"

#iseases of the female genital tract are e3tremely common in clinical an1 pathology

practice an1 incl/1e complications of pregnancy9 inflammations9 t/mors9 an1 hormonallyin1/ce1 effects. The follo7ing 1isc/ssion presents the pathology of the maDority ofclinical problems. #etails can be fo/n1 in c/rrent boo;s of obstetric an1 gynecologicpathology an1 me1icine.>J@>O@>?@>??@The pathologic con1itions pec/liar to each segment ofthe female genital tract are 1isc/sse1 separately9 b/t first 7e briefly re*ie7 pel*icinflammatory 1isease +PI#, an1 other infections beca/se they can affect many of thesegments concomitantly.

%n&ections o& the Female Genital Tract

A large *ariety of organisms can infect the female genital tract an19 in total9 acco/nt forconsi1erable s/ffering an1 morbi1ity +Table 22-?,. "ome9 s/ch as Candidainfections9trichomoniasis9 an1 'ardnerellainfections9 are e3tremely common an1 may ca/sesignificant 1iscomfort 7ith no serio/s se6/elae. !thers9 s/ch as gonorrhea an1Clamydiainfection9 are maDor ca/ses of female infertility9 an1 others still9 s/ch asMycoplasmainfections9 are implicate1 in spontaneo/s abortions. (ir/ses9 principally theh/man papilloma*ir/ses +$P(,9 appear to be in*ol*e1 in the pathogenesis of */l*ar an1cer*ical cancer.
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any of these infections are se3/ally transmitte19 incl/1ing trichomoniasis9 gonorrhea9chancroi19 gran/loma ing/inale9 lymphogran/loma *enere/m9 syphilis9 mycoplasmalinfection9 chlamy1ial infection9 herpes9 an1 $P( infection. >?2@ost of these con1itionsha*e been consi1ere1 inChapter Kan1 Chapter J. $ere 7e to/ch only on selecte1aspects rele*ant to the female genital tract9 incl/1ing pathogens confine1 to the lo7er

genital tract +*/l*a9 *agina9 an1 cer*i3, an1 those that in*ol*e the entire genital tract an1are implicate1 in PI#. Papilloma*ir/ses are 1isc/sse1 s/bse6/ently /n1er t/mors.

%NFCT%'N( C'NF%ND T' T) *'+, GN%T$* T,$CT

)erpes simple% infectionis common an1 /s/ally in*ol*es the */l*a9 *agina9 an1 cer*i3. >?2@In se3/ally transmitte1 1isease clinics9 appro3imately half of patients ha*e c/rrent orprior

106

Fi#ure 22-A9 Colposcopic *ie7 of the cer*i3 in a repro1/cti*e age 7oman. The portio epitheli/m+peripheral, merges 7ith +at 1otte1 bo/n1ary, an1 e*ent/ally replaces the en1ocer*ical col/mnarepitheli/m +re1 an1 grapeli;e, to form the transformation :one. The os is in the center.B9 The

postmenopa/sal cer*i3. The epithelial s/rface is smooth an1 completely co*ere1 by s6/amo/s epitheli/m.The s6/amocol/mnar D/nction is not *isible an1 is insi1e the en1ocer*ical canal. (A and B, courtesy of *r.

Ale% +erenc&y, Mc'ill ni-ersity, Montreal, uebec.$

e*i1ence of infection compare1 to less than ? of /nselecte1 7omen. >?B@The fre6/encyof genital herpes has increase1 1ramatically in the past t7o 1eca1es9 partic/larly inteenagers an1 yo/ng 7omen. $erpes simple3 *ir/s type 2 +$"(-2, infection is no7 oneof the maDor se3/ally transmitte1 1iseases. Clinical symptoms are seen in abo/t one thir1of infecte1 in1i*i1/als.>?B@The lesions begin B to L 1ays after se3/al relations an1 consistof painf/l re1 pap/les in the */l*a that progress to *esicles an1 then to coalescent /lcers.Cer*ical or *aginal in*ol*ement ca/ses se*ere le/;orrhea +genital 1ischarge,9 an1 theinitial infection pro1/ces systemic symptoms s/ch as fe*er9 malaise9 an1 ten1er ing/inallymph no1es. The *esicles an1 /lcers contain n/mero/s *ir/s particles9 acco/nting for the
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high transmission rate 1/ring acti*e infection. The lesions heal spontaneo/sly in ? to B7ee;s9 b/t as 7ith herpetic infections else7here9 latent infection of regional ner*eganglia persists. Abo/t t7o thir1s of affecte1 7omen s/ffer rec/rrences9 7hich are lesspainf/l. Transmission may occ/r 1/ring acti*e or inacti*e +latent, phases9 altho/gh it ism/ch less li;ely in asymptomatic carriers. The gra*est conse6/ence of $"( infection is

transmission to the neonate 1/ring birth. ThisT$* 22-1-- Anatomic #istrib/tion of Common Female Genital Infections

*ocation an/ Mani&estations o& %n&ection

'r#anism (ource Vulva Vagina Cervix Corpus Adnexa

$erpes*ir/s "T# $erpetic/lcers

oll/sc/mcontagios/m

"T# oll/sc/mlesions

$P( "T# Genital 7arts9 intrapeithelial neoplasia9 in*asi*e carcinoma

Clamydia

tracomatis

"T# Follic/lar cer*icitis9 en1ometritis9 salpingo-oophoritis

/eisseria

gonorroeae

"T# ";ene glan1a1enitis

(aginitis inchil1ren

Ac/tecer*icitis

Ac/teen1ometritis an1

salpingitis

Candida En1ogeno/s (/l*o*aginitis

0ricomonas "T# Cer*ico*aginitis

$P(9 h/man papilloma*ir/s< "T#9 se3/ally transmitte1 1isease.

ris; is highest if the infection is acti*e 1/ring 1eli*ery an1 partic/larly if it is a primary+initial, infection in the mother.>?@

Mycotican1yeast (Candida$ infectionsare common< abo/t ? of 7omen are tho/ght tobe carriers of */l*o*aginal f/ngi. #iabetes mellit/s9 oral contracepti*es9 an1 pregnancymay enhance the 1e*elopment of infection9 7hich manifests as small 7hite s/rfacepatches similar to monilial lesions else7here. It is accompanie1 by le/;orrhea an1pr/rit/s. The 1iagnosis is ma1e by fin1ing the organism in 7et mo/nts of the lesions.

0ricomonas -aginalisis a large9 flagellate1 o*oi1 proto:oan that can be rea1ilyi1entifie1 in 7et mo/nts of *aginal 1ischarge in infecte1 patients +Fig. 22-,. Infectionsmay occ/r at any age an1 are seen in abo/t ? of 7omen in se3/ally transmitte11isease clinics.>?@They are associate1 7ith a p/r/lent *aginal 1ischarge an1 1iscomfort2?@

Because licen simple% cronicus is secondary to pruritus, it is, by definition, non3

specific.Its ca/ses incl/1e specific infections +tinea9 can1i1a9 etc.,9 m/cosal irritationssecon1ary to chemical e3pos/res9 an1 /n;no7n ca/ses of pr/rit/s. 0eca/se the lesionsmay present as 7hite */l*ar pla6/es9 they may be in1isting/ishable clinically from moreserio/s 1isor1ers. Th/s9 biopsy is in1icate1 in all lesions9 e*en those that are remotelys/spicio/s. #ist/rbances in cell/lar 1ifferentiation9 n/clear atypia9 an1 *err/co/s gro7th

may signify the onset of s6/amo/s neoplasia.

Neoplasms

T/mors of the */l*a are the most important lesions to affect this region. any types ha*ebeen recor1e19 both benign an1 malignant9 incl/1ing neoplasms of the a1ne3al glan1s9epitheli/m9 an1 /n1erlying soft tiss/e. any of these t/mors are /ncommon an1 arehistologically similar to t/mors occ/rring else7here in the bo1y. Attention 7ill befoc/se1 on the more common t/mors /ni6/e to the */l*a.

N%GN TM',(

1067

Papillar" )i/ra/enoma

%i;e the breast9 the */l*a contains mo1ifie1 apocrine s7eat glan1s. In fact9 the */l*a maycontain tiss/e closely resembling breast +ectopic breast, an1 1e*elop t7o t/mors 7ithco/nterparts in the breast. !ne of these9 papillary hi1ra1enoma9 is i1entical in appearance
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to intra1/ctal papillomas of the breast. The other9 Paget 1isease9 is 1isc/sse1 later.$i1ra1enoma presents as a sharply circ/mscribe1 no1/le9 most commonly on the labiamaDora or interlabial fol1s9 an1 may be conf/se1 clinically 7ith carcinoma beca/se of itsten1ency to /lcerate. !n histologic e3amination9 hi1ra1enomas consist of t/b/lar 1/ctsline1 by a single or 1o/ble layer of nonciliate1 col/mnar cells9 7ith a layer of flattene1

myoepithelial cells /n1erlying the epitheli/m. These myoepithelial elements arecharacteristic of s7eat glan1s an1 s7eat glan1 t/mors.

Con/"loma $cuminatum

0enign raise1 or 7artli;e +*err/co/s, con1itions of the */l*a occ/r in three formsH +?,Con1yloma ac/minat/m9 a papilloma*ir/s-in1/ce1 s6/amo/s lesion also calle1 *enereal7art9 is9 by far9 the most common< +2, m/cosal polyps9 7hich are benign stromalproliferations co*ere1 7ith s6/amo/s epitheli/m< an1 +B, syphilitic con1yloma lat/m91escribe1 in Chapter J.

Con1ylomata ac/minata are se3/ally transmitte19 benign t/mors that ha*e a 1istinctly

*err/co/s gross appearance>22@+Fig. 22-JA ,. Altho/gh they may be solitary9 they aremore fre6/ently m/ltiple an1 often coalesce< they in*ol*e perineal9 */l*ar9 an1 perianalregions as 7ell as the *agina an19 less commonly9 the cer*i3. The lesions are i1entical tothose fo/n1 on the penis an1 aro/n1 the an/s in males + Chapter 2?,. !n histologice3amination9 they consist of a branching9 treeli;e proliferation of stratifie1 s6/amo/sepitheli/m s/pporte1 by a fibro/s stroma +Fig. 22-JB ,. Acanthosis9 para;eratosis9hyper;eratosis9 an19 most specifically9 n/clear atypia in the s/rface cells 7ith perin/clear*ac/oli:ation +calle1 oilocytosis, are present. Con1ylomata are ca/se1 by $P(9principally types K an1 ??9 >2B@7hich are associate1 7ith benign genital lesions an1replicate in the s6/amo/s epitheli/m. The *ir/s life cycle is complete1 in the mat/res/perficial cells of the epitheli/m. This 1epen1ence of *iral gro7th on s6/amo/s

Fi#ure 22-A9 N/mero/s con1ylomas of the */l*a encircling the introit/s. (Courtesy of *r. Ale%+erenc&y, Mc'ill ni-ersity, Montreal, uebec.$B9 $istopathology of con1yloma ac/minat/m sho7ingacanthosis9 hyper;eratosis9 an1 cytoplasmic *ac/olation +;oilocytosis9 center,.
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mat/ration is typical of $P( an1 pro1/ces a 1istinct cytologic change in the mat/re cells=oilocytotic atypia+n/clear atypia an1 perin/clear *ac/oli:ation,=that is consi1ere1 a*iral cytopathic effect. E3cept in imm/nos/ppresse1 in1i*i1/als9 con1ylomataac/minata fre6/ently regress spontaneo/sly9 an1 are not consi1ere1 to be precancero/slesions. They are9 ho7e*er9 a mar;er for se3/ally transmitte1 1isease.>2B@

P,M$*%GN$NT $ND M$*%GN$NT N'P*$(M(

Carcinoma an/ ul3ar %ntraepithelial Neoplasia

Carcinoma of the */l*a is an /ncommon malignant neoplasm +appro3imately one eighthas fre6/ent as cer*ical cancer, representing abo/t B of all genital cancers in the female2@Eigty3fi-e per cent oftese malignant tumors are s2uamous cell carcinomas9 the remain1er being basal cellcarcinomas9 melanomas9 or a1enocarcinomas. In terms of etiology9 pathogenesis9 an1clinical presentation9 */l*ar s6/amo/s cell carcinomas may be 1i*i1e1 into t7o generalgro/ps.

0e first group is associated 1it cancer3related (ig3ris$ )459 an1 fre6/ently coe3ists7ith or is prece1e1 by a classic an1 easily recogni:e1 precancero/s change calle1 */l*arintraepithelial neoplasia +(IN,. This form of (IN incl/1es lesions classifie1 as carcinomain sit/ or 0o7en 1isease.>2@(IN is characteri:e1 by n/clear atypia in the epithelial cells9increase1 mitoses9 an1 lac; of s/rface 1ifferentiation +Fig. 22-OA ,. It is analogo/s tohigh-gra1e s6/amo/s intraepithelial lesions of the cer*i3 +see /n1er cer*i3,. Theselesions /s/ally present as 7hite or pigmente1 pla6/es on the */l*a. (IN is appearing7ith increasing fre6/ency in 7omen yo/nger than years of age. &ith or 7itho/tassociate1 in*asi*e carcinoma9 56/ is fre2uently multicentric9 an1 ? to B areassociate1 7ith another primary s6/amo/s neoplasm in the *agina or cer*i3. This

association in1icates a common etiologic agent. In1ee19 O of cases of (IN an1associate1 cancers contain $P( #NA9 specifically types ?K9 ?J9 an1 other cancer-associate1 +high-ris;, types.>2@"pontaneo/s regression of (IN lesions has been reporte19/s/ally in yo/nger 7omen< the ris; of progression to in*asi*e cancer increases in ol1er+ol1er than years of age, or imm/nos/ppresse1 7omen.>2@

106
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Fi#ure 22-9A9 $istopathology of classic +$P( positi*e, */l*ar intraepithelial neoplasia 7ith 1iff/secell/lar atypia9 n/clear cro71ing9 an1 increase1 mitotic in1e3.B9 1ifferentiate1 +$P( negati*e, (IN9sho7ing mat/ration9 hyper;eratosis an1 basal cell atypia +arro1,.

0e second group of s2uamous cell carcinomas is associated 1it s2uamous cell

yperplasia and licen sclerosus.The etiology of this gro/p of carcinomas is /nclear9an1 they are not typically associate1 7ith $P(. In one scenario9 genetic alterations arise

in lichen scleros/s or hyperplasia9 lea1ing 1irectly to in*asion9 or by an interme1iate stepin 7hich atypia 1e*elops 7ithin hyperplasia or lichen scleros/s9 lea1ing to an /n/s/alform of (IN terme1 1ifferentiate1 +simple3, (IN +Fig. 22-OB ,.>2K@>2L@These t/mors ha*ealso been associate1 7ith increase1 acc/m/lation of pB protein. >2L@+/tations of thep78gene increase its half-life an1 hence it is possible to 1etect the m/tant pB protein rea1ilyby imm/nohistochemistry., A *ariety of chromosome abnormalities are lin;e1 toin*asi*e */l*ar cancer9 some of 7hich may be specific for $P(-positi*e t/mors. >2J@

Morpholo#".

$P(-associate1 */l*ar s6/amo/s cell carcinomas begin as classic (IN lesions9 7hich

present as 1iscrete flesh-colore1 or pigmente19 slightly raise1 lesions that may behyper;eratotic. Coe3isting carcinomas may be e3ophytic or in1/rate19 fre6/ently 7ith/lceration. Carcinomas associate1 7ith lichen scleros/s9 lichen simple3 chronic/s9 an11ifferentiate1 (IN may 1e*elop 6/ic;ly as no1/les in a bac;gro/n1 of */l*arinflammation. The often s/btle emergence of the latter may be misinterprete1 as1ermatitis9 ec:ema9 or le/;opla;ia for long perio1s. The clinical manifestations arechiefly non-specific9 incl/1ing local 1iscomfort9 itching9 an1 e3/1ation beca/se of
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s/perficial secon1ary infection9 an1 /n1erscore the importance of repeate1 e3aminationin 7omen 7ith */l*ar inflammatory 1isor1ers.

!n histologic e3amination9 t/mors associate1 7ith $P( or (IN fre6/ently e3hibitin*asi*e gro7th patterns that mimic intraepithelial neoplasia. These intraepithelial-li;e

patterns may be 7ell 1ifferentiate1 +7arty, or poorly 1ifferentiate1 +basaloi1,>2@

>2O@

+Fig.22-?A ,. $P(-negati*e t/mors9 7hich at times arise from lichen scleros/s or s6/amo/shyperplasia9 typically e3hibit an in*asi*e pattern 7ith prominent ;eratini:ation +Fig. 22-?B ,.

'is; of cancer 1e*elopment in (IN is principally a f/nction of age9 e3tent of t/mor9 an1imm/ne stat/s.>B@>B?@!nce in*asi*e cancer 1e*elops9 metastatic sprea1 is lin;e1 to the si:eof t/mor9 1epth of in*asion9 an1 in*ol*ement of lymphatic *essels. The ing/inal9 pel*ic9iliac9 an1 periaortic lymph no1es are most commonly in*ol*e1. )ltimately9lymphohematogeno/s 1issemination in*ol*es the l/ngs9 li*er9 an1 other internal organs.Patients 7ith lesions less than 2 cm in 1iameter ha*e a K to J -year s/r*i*al rate

after treatment 7ith one-stage */l*ectomy an1 lympha1enectomy< larger lesions 7ithlymph no1e in*ol*ement yiel1 a less than ? -year s/r*i*al rate.

'are *ariants of s6/amo/s cell carcinoma incl/1e -errucous carcinomas9 7hich aref/ngating t/mors resembling con1yloma ac/minat/m9 an1 basal cell carcinomas9 7hichare i1entical to their co/nterparts on the s;in +Fig. 22-??,. Neither t/mor is associate17ith papilloma*ir/ses. 0oth t/mors rarely metastasi:e an1 can /s/ally be c/re1 by 7i1ee3cision.>B2@>BB@

tramammar" Pa#et Disease

This c/rio/s an1 rare lesion of the */l*a9 an1 sometimes the perianal region9 is similar in

its s;in manifestations to Paget 1isease of the breast >2@+Chapter 2B,. As a */l*arneoplasm9 it manifests as a pr/ritic9 re19 cr/ste19 sharply 1emarcate19 mapli;e area9occ/rring /s/ally on the labia maDora. It may be accompanie1 by a palpable s/bm/cosalthic;ening or t/mor.

1069
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Fi#ure 22-10A9 Poorly 1ifferentiate1 */l*ar carcinoma associate1 7ith h/man papilloma*ir/ses +$P(,.B9&ell-1ifferentiate1 ;eratini:ing */l*ar carcinoma9 typically $P( negati*e.

Fi#ure 22-11A9 (err/co/s carcinoma of the */l*a.B9 0asal cell carcinoma of the */l*a.

Morpholo#".

The 1iagnostic microscopic feat/re of this lesion is the presence of large t/mor cells lyingsingly or in small cl/sters 7ithin the epi1ermis an1 its appen1ages. These cells are

1isting/ishe1 by a clear separation +halo, from the s/rro/n1ing epithelial cells + Fig.22-?2, an1 a finely gran/lar cytoplasm containing m/copolysacchari1e that stains 7ithperio1ic aci1-"chiff9 Alcian bl/e or m/cicarmine. )ltrastr/ct/rally9 Paget cells 1isplayapocrine9 eccrine9 an1 ;eratinocyte 1ifferentiation an1 pres/mably arise from primiti*eepithelial progenitor cells.

In contrast to Paget 1isease of the nipple9 in 7hich ? of patients sho7 an /n1erlying1/ctal breast carcinoma9 */l*ar lesions are most fre6/ently confine1 to the epi1ermis ofthe s;in an1 a1Dacent hair follicles an1 s7eat glan1s. The prognosis of Paget 1isease ispoor in the /ncommon cases 7ith associate1 carcinoma9 b/t intraepi1ermal Paget 1iseasemay persist for many years9 e*en 1eca1es9 7itho/t the 1e*elopment of in*asion.

$o7e*er9 beca/se Paget cells may e3ten1 beyon1 the confines of the grossly *isiblelesion9 often into s;in appen1ages9 they are prone to rec/rrence.
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Fi#ure 22-12Paget 1isease of the */l*a 7ith a cl/ster of large clear t/mor cells 7ithin the s6/amo/sepitheli/m.

1070

Fi#ure 22-1A9 alignant melanoma in*ol*ing the *aginal introit/s an1 labia minora.B9 $istology ofin*asi*e melanoma 7ith melanin pro1/ction +inset,.

Mali#nant Melanoma

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elanomas of the */l*a are rare9 representing less than of all */l*ar cancers an1 2of all melanomas in 7omen. Their pea; inci1ence is in the si3th or se*enth 1eca1e< theyten1 to ha*e the same biologic an1 histologic characteristics as melanomas occ/rringelse7here an1 are capable of 7i1esprea1 metastatic 1issemination +Fig. 22-?B,. The -year s/r*i*al rate is less than B29 pres/mably o7ing to 1elays in 1etection an1 the fact

that the maDority of these t/mors rapi1ly enter a *ertical gro7th phase follo7inginception +Chapter 2,. Prognosis is lin;e1 principally to 1epth of in*asion9 7ith greaterthan K mortality for lesions in*a1ing 1eeper than ? mm. >B@0eca/se it is initiallyconfine1 to the epitheli/m9 melanoma may resemble Paget 1isease9 both grossly an1histologically. It can /s/ally be 1ifferentiate1 by its /niform reacti*ity 7ith antibo1ies to"? protein9 absence of reacti*ity 7ith antibo1ies to carcinoembryonic antigen9 an1 lac;of m/copolysacchari1es9 both of 7hich are present in Paget 1isease.

Vagina

The *agina is a portion of the female genital tract that is remar;ably free from primary

1isease. In the a1/lt9 inflammations often affect the */l*a an1 peri*/l*ar str/ct/res an1sprea1 to the cer*i3 7itho/t significant in*ol*ement of the *agina. The maDor serio/sprimary lesion of this str/ct/re is the /ncommon primary carcinoma. The remainingentities can therefore be cite1 briefly.

Con#enital $nomalies

Atresia an1 total absence of the *agina are both e3tremely /ncommon. The latter /s/allyocc/rs only 7hen there are se*ere malformations of the entire genital tract. "eptate9 or1o/ble9 *agina is also an /ncommon anomaly that arises from fail/re of total f/sion ofthe mllerian 1/cts an1 accompanies 1o/ble /ter/s +/ter/s 1i1elphys,. These an1 otheranomalies of the e3ternal genitalia9 incl/1ing genital hypoplasia9 may be themanifestations of genetic syn1romes or other 1ist/rbances associate1 7ith abnormalitiesin reciprocal epithelial-stromal signaling 1/ring fetal 1e*elopment. >@>B@

Gartner 1/ct cysts are relati*ely common lesions fo/n1 along the lateral 7alls of the*agina an1 1eri*e1 from 7olffian 1/ct rests. They are ?- to 2-cm fl/i1-fille1 cysts thatocc/r s/bm/cosally. !ther cysts incl/1e m/co/s cysts9 7hich occ/r in the pro3imal*agina9 are 1eri*e1 from mllerian epitheli/m9 an1 often contain s6/amo/s metaplasia.Another mllerian-1eri*e1

1071

lesion +en1ometriosis9 1escribe1 later, may occ/r in the *agina an1 sim/late a neoplasm.

Premali#nant an/ Mali#nant Neoplasms
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ost benign t/mors of the *agina occ/r in repro1/cti*e-age 7omen an1 are s;eletalm/scle t/mors +rhab1omyomas, or stromal t/mors +stromal polyps,. The latter maye3hibit cell/lar atypia b/t are benign9 locali:e19 an1 self-limite1. !thers incl/1e benignleiomyomas9 hemangiomas9 an1 rare mi3e1 t/mors. >BK@Clinically important malignantt/mors in terms of fre6/ency an1 biologic beha*ior are carcinoma an1 embryonal

rhab1omyosarcoma +sarcoma botryoi1es,.$G%N$* %NT,$P%T)*%$* N'P*$(%$ $ND (:$M'( C** C$,C%N'M$

Primary carcinoma of the *agina is an e3tremely /ncommon cancer +abo/t .K per?9 7omen yearly, acco/nting for abo/t ? of malignant neoplasms in the femalegenital tract9 an1 of these9 O are s6/amo/s cell carcinomas. ost are associate1 7ith$P(. The greatest ris; factor is a pre*io/s carcinoma of the cer*i3 or */l*a< ? to 2 ofpatients 7ith an in*asi*e cer*ical carcinoma e*ent/ally 1e*elop a *aginal s6/amo/scarcinoma.

Morpholo#".

ost often9 the t/mor affects the /pper posterior *agina9 partic/larly along the posterior7all at the D/nction 7ith the ectocer*i3. It begins as a foc/s of epithelial thic;ening9 oftenin association 7ith 1ysplastic changes9 progressing to a pla6/eli;e mass that e3ten1scentrif/gally an1 in*a1es9 by 1irect contin/ity9 the cer*i3 an1 peri*aginal str/ct/res. Thelesions in the lo7er t7o-thir1s metastasi:e to the ing/inal no1es9 7hereas /pper lesionsten1 to in*ol*e the regional iliac no1es.

These t/mors first come to the patientQs attention by the appearance of irreg/lar spottingor the 1e*elopment of a fran; *aginal 1ischarge +le/;orrhea,. At other times9 they remaintotally silent an1 become clinically manifest only 7ith the onset of /rinary or rectal

fist/las.$DN'C$,C%N'M$

A1enocarcinomas are rare b/t ha*e recei*e1 attention beca/se of the increase1 fre6/encyof clear cell a1enocarcinomas in yo/ng 7omen 7hose mothers ha1 been treate1 7ith1iethylstilbestrol +#E", 1/ring pregnancy +for a threatene1 abortion,.>BL@Fort/nately9 lessthan .? of s/ch #E"-e3pose1 yo/ng 7omen 1e*elop a1enocarcinoma.

Morpholo#".

The t/mors are most often locate1 on the anterior 7all of the *agina9 /s/ally in the /pper

thir19 an1 *ary in si:e from .2 to ? cm in greatest 1iameter. They are /s/ally1isco*ere1 bet7een the

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Fi#ure 22-1Clear cell a1enocarcinoma of the *agina sho7ing *ac/olate1 t/mor cells in cl/sters an1glan1li;e str/ct/res.

ages of ? an1 2 years an1 are often compose1 of *ac/olate19 glycogen-containing cells9hence the term clear cell carcinoma +Fig. 22-?,. These cancers can also arise in thecer*i3. A probable prec/rsor of the t/mor is 3a#inal a/enosis9 a con1ition in 7hichglan1/lar col/mnar epitheli/m of mllerian type either appears beneath the s6/amo/sepitheli/m or replaces it.>BJ@A1enosis presents clinically as re19 gran/lar foci contrasting7ith the normal pale pin;9 opa6/e *aginal m/cosa. !n microscopic e3amination9 theglan1/lar epitheli/m may be either m/c/s secreting9 resembling en1ocer*ical m/cosa9 orsocalle1 t/boen1ometrial9 often containing cilia. A1enosis has been reporte1 in B toO of the offspring of estrogen-treate1 mothers9 b/t as mentione1 earlier9 malignanttransformation is e3tremely rare.

0eca/se of its insi1io/s9 in*asi*e gro7th9 *aginal cancer +s6/amo/s an1a1enocarcinomato/s, is 1iffic/lt to c/re. Th/s9 early 1etection by caref/l follo7-/p isman1atory in #E"-e3pose1 7omen. "/rgery an1 irra1iation ha*e s/ccessf/lly era1icate1#E"-relate1 t/mors in /p to J of patients. E3tension of cer*ical carcinoma to the*agina is m/ch more common than are primary malignant neoplasms of the *agina.Accor1ingly9 before a 1iagnosis of primary *aginal carcinoma can be ma1e9 a pree3istingcer*ical lesion m/st be r/le1 o/t.

M,;'N$* ,)$D'M;'($,C'M$

Also calle1sarcoma botryoides9 this is an interesting b/t /ncommon *aginal t/mor mostfre6/ently fo/n1 in infants an1 in chil1ren yo/nger than years of age. The t/morconsists pre1ominantly of malignant embryonal rhab1omyoblasts an1 is th/s a type ofrhab1omyosarcoma. >BO@

1072

Morpholo#"
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These t/mors ten1 to gro7 as polypoi19 ro/n1e19 b/l;y masses that sometimes fill an1proDect o/t of the *agina< they ha*e the appearance an1 consistency of grapeli;e cl/sters+hence the 1esignation botryoi1es9 meaning grapeli;e, +Fig. 22-?,. !n histologice3amination9 the t/mor cells are small an1 ha*e o*al n/clei9 7ith small protr/sions ofcytoplasm from one en19 so they resemble a tennis rac;et. 'arely9 striations can be seen

7ithin the cytoplasm. 0eneath the *aginal epitheli/m9 the t/mor cells are cro71e1 in aso-calle1 cambi/m layer< b/t in the 1eep regions9 they lie 7ithin a loosefibromy3omato/s stroma that is e1emato/s an1 may contain many inflammatory cells.For this reason9 the lesions can be mista;en for benign inflammatory polyps9 lea1ing to/nfort/nate 1elays in 1iagnosis an1 treatment. These t/mors ten1 to in*a1e locally an1ca/se 1eath by penetration into the peritoneal ca*ity or by obstr/ction of the /rinary tract.

Conser*ati*e s/rgery9 co/ple1 7ith chemotherapy9 appears to offer the best res/lts incases 1iagnose1 s/fficiently early.>@

Fi#ure 22-15"arcoma botryoi1es +embryonal rhab1omyosarcoma, of the *agina appearing as a polypoi1mass protr/1ing from the *agina. (Courtesy of *r. Micael *ono-an, Cildren9s )ospital, Boston, MA.$

Cervix

The cer*i3 is both a sentinel for potentially serio/s /pper genital tract infections an1 atarget for *iral an1 other carcinogens9 7hich may lea1 to in*asi*e carcinoma. Infectionconstit/tes one of the most common clinical complaints in gynecologic practice an1fre6/ently *e3es both patient an1 clinician. The potential threat of cancer9 ho7e*er9 iscentral to Papanicolao/ smear screening programs an1 histologic interpretation of biopsyspecimens by the pathologist. &orl17i1e9 cer*ical carcinoma alone is responsible forabo/t of all cancer 1eaths in 7omen.

%n&lammations
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$CT $ND C),'N%C C,%C%T%(

At the onset of menarche9 the pro1/ction of estrogens by the o*ary stim/lates mat/ration+glycogen /pta;e, of cer*ical an1 *aginal s6/amo/s m/cosa. As these cells are she19 theglycogen pro*i1es a s/bstrate for en1ogeno/s *aginal aerobes an1 anaerobes9streptococci9 enterococci9Escericia coli9 an1 staphylococci. The bacterial gro7thpro1/ces a 1rop in *aginal p$. The e3pose1 en1ocer*i3 is sensiti*e to these changes inchemical en*ironment an1 bacterial flora an1 respon1s by /n1ergoing a *ariety ofchanges incl/1ing proliferation of reser*e cells lea1ing to s6/amo/s metaplasia. Thisprocess of transformation from a col/mnar to a s6/amo/s lining is also hastene1 bytra/ma an1 other infections occ/rring in the repro1/cti*e years. As the s6/amo/sepitheli/m o*ergro7s an1 obliterates the s/rface col/mnar papillae9 it co*ers an1obstr/cts crypt openings9 7ith the acc/m/lation of m/c/s in 1eeper crypts +glan1s, toform m/co/s +nabothian, cysts. This process is in*ariably associate1 7ith aninflammatory infiltrate compose1 of a mi3t/re of polymorphon/clear le/;ocytes an1monon/clear cells9 an1 if the inflammation is se*ere9 it may be associate1 7ith loss of theepithelial lining +erosion or /lceration, an1 epithelial repair +reparati*e atypia or

anaplasia of repair,. All of these components characteri:e 7hat is ;no7n as croniccer-icitis+Fig. 22-?K,.

"ome 1egree of cer*ical inflammation may be fo/n1 in *irt/ally all m/ltiparo/s an1 inmany n/lliparo/s a1/lt 7omen9 an1 it is /s/ally of little clinical conse6/ence. Principalconcerns incl/1e the potential presence of organisms9 7hich may be clinically important."pecific infections by gonococci9 chlamy1iae9 mycoplasmas9 an1 herpes simple3 *ir/s+mostly type 2, may pro1/ce significant ac/te or chronic cer*icitis an1 sho/l1 bei1entifie1 for their rele*ance to /pper genital tract 1isease9 pregnancy complications9 orse3/al transmission.

Morpholo#".

The pathologic correlates of ac/te an1 chronic cer*icitis incl/1e epithelial spongiosis+intercell/lar e1ema,9 s/bm/cosal e1ema9 an1 a combination of epithelial an1 stromalchanges. Ac/te cer*icitis is characteri:e1 by ac/te inflammatory cells9

107
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Fi#ure 22-16In the 1iagram +upper,9 reser*e cells in the transformation :one are contin/o/s 7ith the basalcells of the ectocer*i3 +rigt, an1 may /n1ergo col/mnar an1 s6/amo/s 1ifferentiation +metaplasia,.Photomicrographs at bottom 1epict +from left to rigt, 6/iescent s/bcol/mnar reser*e cells9 reser*e cells/n1ergoing col/mnar 1ifferentiation +second from left,9 reser*e cells /n1ergoing s6/amo/s metaplasia+second from rigt, an1 ectocer*ical s6/amo/s epitheli/m +rigt,.

erosion9 an1 reacti*e or reparati*e epithelial change. Chronic cer*icitis incl/1esinflammation9 /s/ally monon/clear9 7ith lymphocytes9 macrophages9 an1 plasma cells.Necrosis an1 gran/lation tiss/e may also be present. Altho/gh the inflammation alone isnot specific9 some patterns are associate1 7ith certain organisms. $"( is most stronglyassociate1 7ith epithelial /lcers +often 7ith intran/clear incl/sions in epithelial cells, an1a lymphocytic infiltrate9 an1 C. tracomatis7ith lymphoi1 germinal centers an1 aprominent plasmacytic infiltrate.>?@Epithelial spongiosis is associate1 7ith 0. -aginalisinfection.>2@

All the aforementione1 changes are more prono/nce1 in patients 7ith clinical symptoms

+m/cop/r/lent cer*icitis, or in 7hom specific organisms can be i1entifie1. Thesechanges9 ho7e*er9 may be obser*e1 in c/lt/re-negati*e or asymptomatic 7omen9/n1erscoring the importance of combine1 c/lt/re9 clinical e*al/ation9 an1 Papanicolao/smear e3amination. "e*ere reparati*e changes may she1 atypical-appearing s6/amo/scells that mimic precancero/s lesions9 beca/se cells /n1ergoing repair are 1eplete1 oftheir normal content of glycogen an1 may ha*e n/clear atypia.

ND'C,%C$* P'*;P(

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En1ocer*ical polyps are relati*ely innoc/o/s9 inflammatory t/mors that occ/r in 2 to of a1/lt 7omen. Perhaps the maDor significance of polyps lies in their pro1/ction ofirreg/lar *aginal spotting or blee1ing that aro/ses s/spicion of some more omino/slesion. ost polyps arise 7ithin the en1ocer*ical canal an1 *ary from small an1 sessile tolarge9 -cm masses that may protr/1e thro/gh the cer*ical os. All are soft9 almost

m/coi19 an1 are compose1 of a loose fibromy3omato/s stroma harboring 1ilate19 m/c/s-secreting en1ocer*ical glan1s9 often accompanie1 by inflammation an1 s6/amo/smetaplasia +Fig. 22-?L,. In almost all instances9 simple c/rettage or s/rgical e3cisioneffects a c/re.

%ntraepithelial an/ %n3asi3e (

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potentially c/rable cancers an1 the 1etection an1 era1ication of prein*asi*e lesions9 someof 7hich 7o/l1 progress to cancer if not 1isco*ere1.

Patho#enesis.

To /n1erstan1 the pathogenesis of cer*ical cancer9 it is important to ;no7 the factorsin*ol*e1 in its 1e*elopment9 7hich ha*e been i1entifie1 from a series of clinical9epi1emiologic9 pathologic9 an1 molec/lar st/1ies. Epi1emiologic 1ata ha*e longimplicate1 a se3/ally transmitte1 agent9 7hich is no7 establishe1 to be the h/manpapilloma*ir/s. $P( is c/rrently consi1ere1 to be the most important agent in cer*icaloncogenesis. As note1 earlier9 this *ir/s is the ;no7n ca/se of the se3/ally transmitte1*/l*ar con1yloma ac/minat/m an1 has been isolate1 from */l*ar an1 *aginal s6/amo/scell carcinomas< it is also s/specte1 of being an oncogenic agent in a *ariety of others6/amo/s t/mors or proliferati*e lesions of s;in an1 m/co/s membranes9 as 1etaile1 inChapter L.>B@

A 7ealth of molec/lar epi1emiologic 1ata has establishe1 the follo7ing ris; factors for

cer*ical neoplasia9 all of 7hich in1icate a comple3 interaction bet7een host an1 *ir/s. >B@>@

Early age at first interco/rse /ltiple se3/al partners Increase1 parity A male partner 7ith m/ltiple pre*io/s se3/al partners The presence of a cancer-associate1 $P( The persistent 1etection of a high-ris; $P(9 partic/larly in high concentration+*iral loa1, Certain $%A an1 *iral s/btypes E3pos/re to oral contracepti*es an1 nicotine

Genital infections +chlamy1ia,
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Fi#ure 22-1A9 Post/late1 steps in the pathogenesis of cer*ical neoplasia. Con1itions infl/encingprogression are liste1 at the lo7er center of the 1iagram.B9 Appro3imate lifetime ris;s of ac6/iring $P(infection +left, an1 1ying of cer*ical cancer +rigt,. The interme1iate steps incl/1e ris;s of infection 7ithhigh-ris; $P( types9 1e*elopment of a1*ance1 cer*ical intraepithelial neoplasia +CIN,9 an1 progression toin*asi*e carcinoma.

There is mo/nting molec/lar e*i1ence lin;ing $P( to cancer in general an1 cer*icalcancer in partic/lar.

?. $P( #NA is 1etecte1 by hybri1i:ation techni6/es in o*er O of cer*icalcancers.>2B@

2. "pecific $P( types are associate1 7ith cer*ical cancer +high ris;, *ers/scon1ylomata +lo7 ris;,< lo7 +incl/1e types K9 ??9 29 9 B9 9 K29 an1 KK, an1high-ris; types +incl/1e types ?K9 ?J9 B?9 BB9 B9 BO9 9 ?9 29 K9 J9 O9 an1KJ, +Fig. 22-?JA ,. >2B@

B. E3perimental 1ata in1icate that *iral +Ean1E;, genes of high ris; $P(s can

1isr/pt the cell cycle *ia bin1ing to '0 7ith /p-reg/lation of Cyclin E +EL, an1p?KINR< interr/pt cell 1eath path7ays by bin1ing to pB +EK,< in1/cecentrosome 1/plication an1 genomic instability +EK9 EL,< an1 pre*ent replicati*esenescence by /p-reg/lation of telomerase +EK, +Chapter L,.>@>K@>L@>J@$P( EKin1/ces rapi1 1egra1ation of pB *ia /bi6/itin-1epen1ent proteolysis9 re1/cingpB le*els by t7o- to three-fol1. EL comple3es 7ith the hypophosphorylate1+acti*e, form of '09 promoting its proteolysis *ia the proteosome path7ay.0eca/se hypophosphorylate1 '0 normally inhibits "-phase entry *ia bin1ing tothe E2F transcription factor9 the t7o *iral oncogenes cooperate to promote #NAsynthesis 7hile interr/pting pB-me1iate1 gro7th arrest an1 apoptosis ofgenetically altere1 cells. Th/s9 the *iral oncogenes are critical

1075

in e3ten1ing the life span of genital epithelial cells=a necessary component oft/mor 1e*elopment.>@

. The physical state of the *ir/s 1iffers in 1ifferent lesions9 being integrate1 into thehost #NA in cancers9 an1 present as free +episomal, *iral #NA in con1ylomataan1 most precancero/s lesions.>@

. Certain chromosome abnormalities9 incl/1ing 1eletions at Bp an1 amplificationsof B69 ha*e been associate1 7ith cancers containing specific +$P(-?K,papilloma*ir/ses. >J@>O@

K. ost compelling9 recent 1ata in1icate that *accines 1irecte1 againstpapilloma*ir/ses can pre*ent infection an1 the 1e*elopment of precancero/s1isor1ers.>@>?@

)o1e-er, te e-idence does not implicate )45 as te only factor.A high percentage ofyo/ng 7omen are infecte1 7ith one or more $P( types 1/ring their repro1/cti*e years9
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an1 only a fe7 1e*elop cancer. !ther cocarcinogens9 the imm/ne stat/s of the in1i*i1/al9n/trition9 an1 many other factors infl/ence 7hether the $P( infection remainss/bclinical +latent,9 t/rns into a precancer9 or e*ent/ally progresses to cancer.Fig/re 22-?Jpresents an attempt to e3plain the role of $P( in cer*ical carcinogenesis an1 itsimpact on the pop/lation in the )nite1 "tates.

C,%C$* %NT,$P%T)*%$* N'P*$(%$

The reason that Papanicolao/ smear screening is so effecti*e in pre*enting cer*icalcancer is that the maDority of cancers are prece1e1 by a precancero/s lesion. This lesionmay e3ist in the nonin*asi*e stage for as long as 2 years an1 she1 abnormal cells thatcan be 1etecte1 on cytologic e3amination.>2@These precancero/s changes sho/l1 be*ie7e1 7ith the follo7ing in min1H +?, they represent a contin//m of morphologicchange 7ith in1istinct bo/n1aries< +2, they 1o not in*ariably progress to cancer an1 mayspontaneo/sly regress9 7ith the ris; of persistence or progression to cancer increasing7ith the se*erity of the precancero/s change< +B, they are associate1 7ithpapilloma*ir/ses9 an1 high-ris; $P( types are fo/n1 in increasing fre6/ency in the

higher-gra1e prec/rsors.>B@

Fi#ure 22-19"pectr/m of cer*ical intraepithelial neoplasiaH normal s6/amo/s epitheli/m for comparisonO@>K@At some point in the f/t/re9 $P( testing may be /se1 forprimary screening of 7omen o*er the age of B.

1079

$o7e*er9 the specificity of the test in the general pop/lation is lo79 an1 it nee1s to be/se1 in conD/nction 7ith the Papanicolao/ smear. >K?@

0eca/se most Papanicolao/ smear abnormalities 1o not signify a serio/s precancero/s orcancero/s con1ition9 treatment re6/ires first that the abnormalities be *is/ali:e1 bycolposcopic e3amination of the cer*i3. CIN lesions are characteri:e1 on colposcopice3am by 7hite patches on the cer*i3 after the application of acetic aci1. >K2@In a11ition91istinct *asc/lar mosaic or p/nct/ation patterns can be obser*e1. $ighly abnormal*asc/lar patterns reg/larly accompany in*asi*e cer*ical cancer. If abnormalities are*is/ali:e19 they m/st be confirme1 by histologic e3amination of a p/nch biopsy. This isfacilitate1 by both the application of morphologic criteria an1 also9 recently9 theimm/nohistochemical i1entification of increase1 e3pression of host cell biomar;ers +s/chasp!6/=>9 cyclin E9 an1 Ri-KL,.>KB@These mar;ers are e3presse1 in a greater proportionof cells in precancero/s lesions +1/e to cell cycle 1ist/rbances, an1 7ill fre6/ently1isting/ish these from non-neoplastic epithelial changes.

!nce CIN is confirme1 histologically9 mo1es of treatment 1epen1 on the stage of theneoplasm< treatment of prec/rsor lesions incl/1es Papanicolao/ smear follo7-/p for CINI9 an1 cryotherapy9 laser9 loop electrical e3cision proce1/res +%EEP,9 an1 cone biopsy for

CIN II or CIN III. 'arely +appro3imately ? in , a patient 7ith a treate1 CIN IIIe*ent/ally 1e*elops an in*asi*e cancer. The ris; is minimi:e1 by follo7-/p pap smears.Altho/gh *ery early in*asi*e cancers +microin*asi*e carcinomas, may be treate1 by conebiopsy alone9 most in*asi*e cancers are manage1 by hysterectomy 7ith lymph no1e1issection an19 for a1*ance1 lesions9 ra1iation. The prognosis an1 s/r*i*al for in*asi*ecarcinomas 1epen1 largely on the stage at 7hich cancer is first 1isco*ere1 an1 to some1egree on the cell type9 7ith small cell ne/roen1ocrine t/mors ha*ing a poor prognosis.Appro3imately one half of cer*ical cancers 1e*elop in 7omen 7ho 7ere not screene1.
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&ith c/rrent metho1s of treatment9 there is a -year s/r*i*al rate of at least O for stageIA +incl/1ing microin*asi*e, carcinomas9 abo/t J to O 7ith stage I09 L 7ithstage II9 an1 less than for stage III an1 higher. ost patients 7ith stage I( cancer1ie as a conse6/ence of local e3tension of the t/mor +e.g.9 into an1 abo/t the /rinarybla11er an1 /reters9 lea1ing to /reteral obstr/ction9

Fi#ure 22-2Electron micrograph of *ir/s-li;e papilloma*ir/s particles +(%Ps, pro1/ce1 in e/;aryoticcells by e3pression of the late region an1 /se1 as *accines. (Courtesy of lan +ra&er, M*, 4rincess

Ale%andra )ospital, ni-ersity of ueensland, Australia.$

pyelonephritis9 an1 /remia, rather than 1istant metastases. $o7e*er9 as mentione1 abo*e9early 1etection has re1/ce1 the n/mber of patients 7ith stage I( cancer by o*er t7o-thir1s in the past years.

0eginning in ?OO? a series of p/blications 1escribe1 the pro1/ction in *itro ofpapilloma*ir/s-li;e particles +(%Ps, by transfecting e/;aryotic cells 7ith *ector-1ri*en$P( #NA +Fig. 22-2,. >@This 1isco*ery pro*i1e1 the /ni6/e opport/nity tomanip/late the *iral genome to pro1/ce reagents that co/l1 be /se1 to st/1y=an1/ltimately generate=host imm/nity to $P(s. "t/1ies ha*e sho7n that *accination 7ith(%Ps an1 similar reagents generates protecti*e imm/nity in animals an1 strong hostresponse in h/mans. 'ecent p/blications ha*e sho7n that $P( *accines may pre*entcer*ical $P( infection an19 by inference9 cer*ical cancer.>?@Ass/ming *accination trialsagainst cer*ical papilloma*ir/ses bear fr/it9 it is concei*able that the ne3t 2 years 7ill7itness the beginning of a significant an1 s/staine1 re1/ction in not only cer*ical cancer

inci1ence b/t also of other papilloma*ir/s-relate1 1iseases in both men an1 7omen.

Body of Uterus and Endometrium

The /ter/s is compose1 principally of smooth m/scle +myometri/m,9 7hich encases theen1ometrial ca*ity. The latter is compose1 of a m/cosa ma1e /p of en1ometrial glan1san1 s/rro/n1ing stroma. The /ter/s is stim/late1 contin/ally by hormones9 1en/1e1monthly of its en1ometrial m/cosa9 an1 transiently inhabite1 by fet/ses. It is s/bDect to a
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*ariety of 1isor1ers9 the most common of 7hich res/lt from en1ocrine imbalances9complications of pregnancy9 an1 neoplastic proliferation. Together 7ith the lesions thataffect the cer*i3 +ca/sing abnormal pap smears,9 the lesions of the corp/s of the /ter/san1 the en1ometri/m +ca/sing abnormal *aginal blee1ing, acco/nt for most patient *isitsto gynecologic practices.

100

n/ometrial )istolo#" in the Menstrual C"cle

#ating the en1ometri/m by its histologic appearance is helpf/l clinically to assesshormonal stat/s9 1oc/ment o*/lation9 an1 1etermine ca/ses of en1ometrial blee1ing an1infertility. &e can begin 7ith the she11ing of the /pper half to t7o-thir1s of theen1ometri/m 1/ring the menstr/al perio1 +Fig. 22-2,. The basal thir1 1oes not respon1to o*arian steroi1s an1 is retaine1 at the concl/sion of the menstr/al flo7. From the basalthir1 of this preo*/latory proliferati*e
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Fi#ure 22-25Appro3imate 6/antitati*e changes in se*en morphologic criteria fo/n1 to be most /sef/l in1ating h/man en1ometri/m. (Modified from /oyes W: /ormal pases of te endometrium. 6n /orris )J,et al (eds$: 0e terus. Baltimore, Williams ? Wilins, !";8.$

phase of the cycle9 there is e3tremely rapi1 gro7th of both glan1s an1 stroma+proliferati-e pase,. The glan1s are straight9 t/b/lar str/ct/res line1 by reg/lar9 tall9pse/1ostratifie1 col/mnar cells. itotic fig/res are n/mero/s9 an1 there is no e*i1ence ofm/c/s secretion or *ac/olation +Fig. 22-2KA ,. The en1ometrial stroma is compose1 ofthic;ly compacte1 spin1le cells that ha*e scant cytoplasm b/t ab/n1ant mitotic acti*ity.

At the time of o*/lation9 the en1ometri/m slo7s in its gro7th9 an1 it ceases apparentmitotic acti*ity 7ithin 1ays after o*/lation. The posto*/latory en1ometri/m is initiallymar;e1 by basal secretory *ac/oles beneath the n/clei in the

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101

Fi#ure 22-26$istology of the menstr/al cycle9 incl/1ing the proliferati*e phase 7ith mitoses +A,9 the earlysecretory phase 7ith s/bn/clear *ac/oles +B, follo7e1 by secretory e3ha/stion +C,9 pre1eci1/al changes+*,9 stromal gran/locytes +E,9 an1 stromal brea;1o7n at the onset of menses ++, +see te3t,.

glan1/lar epitheli/m +Fig. 22-2KB ,. Thissecretory acti-ityis most prominent 1/ring thethir1 7ee; of the menstr/al cycle9 7hen the basal *ac/oles progressi*ely p/sh past then/clei. 0y the fo/rth 7ee;9 the secretions are 1ischarge1 into the glan1 l/mens. &hensecretion is ma3imal9 bet7een ?J an1 2 1ays9 the glan1s are 1ilate1. 0y the fo/rth 7ee;9the glan1s are tort/o/s9 pro1/cing a serrate1 appearance 7hen they are c/t in their longa3is. This serrate1 or sa7-toothe1 appearance is accent/ate1 by secretory e3ha/stionan1 shrin;ing of the glan1s.

The stromal changes in late secretory phase are important for 1ating the en1ometri/m an1consist of the 1e*elopment of prominent spiral arterioles by 1ays 2? to 22. Aconsi1erable increase in gro/n1 s/bstance an1 e1ema bet7een the stromal cells occ/rs+Fig. 22-2KC , an1 is follo7e1 in 1ays 2B to 2 by stromal cell hypertrophy 7ithacc/m/lation of cytoplasmic eosinophilia +pre1eci1/al change, an1 res/rgence of stromalmitoses +Fig. 22-2K* ,. Pre1eci1/al changes sprea1 thro/gho/t the f/nctionalis +thehormonally responsi*e /pper :one, 1/ring 1ays 2 to 2J an1 are accompanie1 byscattere1 ne/trophils an1 occasional lymphocytes +Fig. 22-2KE ,9 7hich here 1o notimply inflammation. This is follo7e1 by 1isintegration of the f/nctionalis an1 escape ofbloo1 into the stroma9 7hich mar;s the beginning of menstr/al she11ing +Fig. 22-2K+ ,.

The proliferati*e phase e3hibits mitotic acti*ity in glan1/lar an1 stromal cells< o*/lationis confirme1 by prominent basal *ac/olation of glan1/lar epithelial cells9 secretorye3ha/stion9 or pre1eci1/al changes. !b*io/sly9 o*/lation cannot be confirme1 1/ring theproliferati*e phase or in the late stages of en1ometrial she11ing 7hen only the basalis ispresent.>K@

Functional n/ometrial Disor/ers 4D"s&unctional terine lee/in#

#/ring acti*e repro1/cti*e life9 the en1ometri/m is constantly engage1 in the 1ynamicsof she11ing an1 regro7th. It is controlle1 by the rise an1 fall of pit/itary an1 o*arianhormones9 an1 this control is e3ec/te1 by proper timing of hormonal release in bothabsol/te an1 relati*e amo/nts. Alterations in this fine-t/ning mechanism may res/lt in a
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spectr/m of 1ist/rbances9 incl/1ing atrophy9 abnormal proliferati*e or secretory patterns9an1 hyperplasia.>K@

0y far the most common problem is the occ/rrence of e3cessi*e blee1ing 1/ring orbet7een menstr/al perio1s. The ca/ses of abnormal blee1ing from the /ter/s are many

an1 *ary among 7omen of 1ifferent age gro/ps +Table 22-2,. In some instances9blee1ing is the res/lt of a 7ell-1efine1 organic abnormality9 s/ch as chronic en1ometritis9s/bm/cosal leiomyomas9 en1ometrial polyp9 or en1ometrial neoplasms. $o7e*er9 thelargest single gro/p encompasses f/nctional 1ist/rbances +so-calle1 1ysf/nctional /terineblee1ing, 1/e to abnormalities in the menstr/al cycle or systemic 1iseases.>K@

$N'*$T',; C;C*

In most instances9 1ysf/nctional blee1ing is 1/e to the occ/rrence of an ano*/latorycycle9 7hich res/lts in e3cessi*e an1 prolonge1 estrogenic stim/lation 7itho/t the1e*elopment of the progestational phase that reg/larly follo7s o*/lation. %esscommonly9 lac; of o*/lation is the res/lt of +?, an en1ocrine 1isor1er9 s/ch as thyroi1

1isease9 a1renal 1isease9 or

T$* 22-2-- Ca/ses of Abnormal )terine 0lee1ing by Age Gro/p

$#e Group Causes

Prep/berty Precocio/s p/berty +hypothalamic9 pit/itary9 or o*arian origin,

A1olescence Ano*/latory cycle9 coag/lation 1isor1ers

'epro1/cti*e age Complications of pregnancy +abortion9 trophoblastic 1isease9ectopic pregnancy,

!rganic lesions +leiomyoma9 a1enomyosis9 polyps9en1ometrial hyperplasia9 carcinoma,

Ano*/latory cycle

!*/latory 1ysf/nctional blee1ing +e.g.9 ina1e6/ate l/tealphase,

Perimenopa/sal Ano*/latory cycle

Irreg/lar she11ing

!rganic lesions +carcinoma9 hyperplasia9 polyps,

Postmenopa/sal !rganic lesions +carcinoma9 hyperplasia9 polyps,

En1ometrial atrophy

102
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pit/itary t/mors< +2, a primary lesion of the o*ary9 s/ch as a f/nctioning o*arian t/mor+gran/lose-theca cell t/mors, or polycystic o*aries +see section on o*aries,< or +B, agenerali:e1 metabolic 1ist/rbance9 s/ch as mar;e1 obesity9 se*ere maln/trition9 or anychronic systemic 1isease. In most patients9 ho7e*er9 ano*/latory cycles are/ne3plainable9 probably occ/rring beca/se of s/btle hormonal imbalances. Ano*/latory

cycles are most common at menarche an1 the perimenopa/sal perio1.

Fail/re of o*/lation res/lts in prolonge19 e3cessi*e en1ometrial stim/lation by estrogens.)n1er these circ/mstances9 the en1ometrial glan1s /n1ergo mil1 architect/ral changes9incl/1ing cystic 1ilation +persistent proliferati*e en1ometri/m,. )nsche1/le1 brea;1o7nof the stroma may also occ/r +ano*/latory menstr/ation,9 7ith no e*i1ence ofen1ometrial secretory acti*ity +Fig. 22-2LA ,. ore se*ere conse6/ences of ano*/lationare 1isc/sse1 /n1er en1ometrial hyperplasia.

%N$D:$T *T$* P)$(

This term refers to the occ/rrence of ina1e6/ate corp/s l/te/m f/nction an1 lo7

progesterone o/tp/t9 7ith an irreg/lar o*/latory cycle. The con1ition often manifestsclinically as infertility9 7ith either increase1 blee1ing or amenorrhea. En1ometrial

Fi#ure 22-27Common ca/ses of abnormal /terine blee1ing.A9 The most common is 1ysf/nctional /terineblee1ing9 seen here as ano*/latory en1ometri/m 7ith stromal brea;1o7n. Note brea;1o7n associate1 7ithproliferati*e glan1s.B9 Chronic en1ometritis. C9 En1ometrial polyp.*9 "/bm/cosal leiomyoma +lo1er,

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7ith atten/ation of the en1ometrial lining +arro1,.

biopsy performe1 at an estimate1 posto*/latory 1ate sho7s secretory en1ometri/m97hich9 ho7e*er9 lags in its secretory characteristics 7ith respect to the e3pecte1 1ate.

ND'MT,%$* C)$NG( %NDCD ; ',$* C'NT,$CPT%(

As might be s/specte19 oral contracepti*es containing synthetic or 1eri*ati*e o*ariansteroi1s in1/ce a 7i1e *ariety of en1ometrial changes9 1epen1ing on the stero

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