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 "I-P%E2 C$'!NIC)" Neoplasms 0ENIGN T)-!'" Papillary $i1ra1enoma Con1yloma Ac/minat/m P'E-A%IGNANT AN# -A%IGNANT NE!P%A"-" Carcinoma an1 (/l*ar Intraepithelial Neoplasia -orphology. E3tramammary Paget #isease -orphology. -alignant -elanoma (agina Congenital Anomalies Premalignant an1 -alignant Neoplasms (AGINA% INT'AEPIT$E%IA% NE!P%A"IA AN# "4)A-!)" CE%% CA'CIN!-A -orphology. A#EN!CA'CIN!-A -orphology. E-0'5!NA% '$A0#!-5!"A'C!-A -orphology

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$ANGE" IN#)CE# 05 !'A% C!NT'ACEPTI(E" -EN!PA)"A% AN# P!"T-EN!PA)"A% C$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"

-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 "E2 C!'#-"T'!-A% T)-!'" Gran/losa-Theca Cell T/mors -orphology. Fibroma-Thecomas "ertoli-%ey1ig Cell T/mors +An1roblastomas, -orphology.

!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&IN P%ACENTA" P%ACENTA% INF%A--ATI!N" AN# INFECTI!N" T!2E-IA !F P'EGNANC5 +P'EEC%A-P"IA AN# EC%A-P"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 the yol; 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 proliferates9 e*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 form the o*ary. Fail/re of germ cells to 1e*elop may res/lt in either absence of o*aries or premat/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*en pineal glan1, an1 may rarely lea1 to t/mors in these sites. A secon1 component of female genital 1e*elopment is the mAllerian 1/ct. At abo/t the si3th 7ee;9 in*agination an1 s/bse6/ent f/sion of the coelomic lining epitheli/m form the lateral mAllerian +or paramesonephric, 1/cts. -Allerian 1/cts progressi*ely gro7 ca/1ally to enter the pel*is9 7here they s7ing me1ially to f/se 7ith the /rogenital sin/s at the mAllerian t/bercle + Fig. 22-?A ,. F/rther ca/1al gro7th brings these f/se1 1/cts into 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 e3ternal genitalia + Fig. 22-?B ,. Normally9 the /nf/se1 portions mat/re into the fallopian t/bes9 the f/se1 ca/1al portion 1e*eloping into the /ter/s an1 /pper *agina an1 the /rogenital sin/s forming the lo7er *agina an1 *estib/le + Fig. 22-?C ,. Conse6/ently9 the entire lining of the /ter/s an1 t/bes as 7ell as the o*arian s/rface is /ltimately 1eri*e1 from coelomic epitheli/m +mesotheli/m,. This close embryologic relationship bet7een the mesotheli/m an1 mAllerian system may be reflecte1 in a1/lt life in the form of benign +en1ometriosis, an1 malignant +en1ometrioi1 an1 sero/s neoplasia, lesions9 7hich may arise 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 basal cells from the /n1erlying stroma9 7hich /n1ergo s6/amo/s an1 /rothelial 1ifferentiation. 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.
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In males9 mAllerian inhibitory s/bstance from the 1e*eloping testis ca/ses regression of the mAllerian 1/cts9 an1 the paire1 7olffian +or mesonephric, 1/cts form the epi1i1ymis an1 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/bes9 an1 /ter/s. In the cer*i3 an1 *agina9 these rests may be cystic an1 are terme1 Gartner 1/ct cysts. -any of the e*ents in the
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1061

Fi#ure 22-1 Embryology an1 anatomy of the female genital tract. A9 Early in 1e*elopment the mesonephric +red, an1 mAllerian +blue, 1/cts merge at the /rogenital sin/s to form the mAllerian t/bercle. B9 0y birth the mAllerian 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*ary9 a1ne3a an1 cer*i3 +Gartner 1/ct,. (Adapted from Langman J: Medical Embryology. Baltimore, Williams and Wil ins, !"#!.$ 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 from reciprocal epithelial-stromal signaling9 lea1ing to mesenchymal remo1eling an1 changes in epithelial cell fate.
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$natom"

#/ring acti*e repro1/cti*e life9 the o*aries meas/re abo/t C F 2.E F ?.E cm in 1imension. The o*ary is 1i*i1e1 into a corte3 an1 a me1/lla. The corte3 consists of a layer of closely pac;e1 stromal cells an1 a thin co*ering of relati*ely acell/lar collageno/s connecti*e tiss/e. Follicles in *arying stages of mat/ration are fo/n1 7ithin the o/ter corte3. &ith each menstr/al cycle9 one follicle 1e*elops into a graafian follicle9 7hich is transforme1

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 contains remnants 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 Ghil/sG cells are *estigial remains of the gona1 from its primiti*e Gambise3/alG phase9 are steroi1 pro1/cing9 an1 resemble the interstitial cells of the testis. 'arely9 these cells gi*e rise to masc/lini:ing t/mors +hilar cell 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 secretory cells< an1 so-calle1 intercalate1 cells9 7hich may simply represent inacti*e secretory cells. The /ter/s *aries in si:e 1epen1ing on the age an1 parity of the in1i*i1/al. It 7eighs abo/t EI gm an1 meas/res abo/t J.I F K.I F B.I cm in n/lliparo/s repro1/cti*e age 7omen. Follo7ing pregnancies9 /teri are slightly larger +/p to LI gm in 7eight,9 then 1iminish 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 *aginal e3amination an1 is co*ere1 by a stratifie1 non;eratini:ing s6/amo/s epitheli/m contin/o/s 7ith the *aginal *a/lt. The s6/amo/s epitheli/m con*erges centrally at a small opening terme1 the e%ternal os. In the n/lliparo/s 7oman9 this os is *irt/ally close1. M/st cephala1 to the os is the en1ocer*i39 7hich is line1 by col/mnar9 m/c/ssecreting epitheli/m that 1ips 1o7n into the /n1erlying stroma to pro1/ce crypts +en1ocer*ical Gglan1sG,. The point at 7hich the s6/amo/s an1 mAllerian col/mnar epitheli/m meet is the s6/amocol/mnar D/nction + Fig. 22-2 ,. The position of the D/nction is *ariable 1/e to both the cer*ical anatomy an1 the 1istrib/tion of the basal an1 s/bcol/mnar reser*e cells that e3ist D/st cephala1 of this D/nction. It is the progressi*e 1ifferentiation of these basalNreser*e cells that go*erns the microanatomy of this region9 /ltimately res/lting in the
1062

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

cephala1 migration of the s6/amocol/mnar D/nction. The portion of the col/mnar epitheli/m that is /ltimately replace1 by s6/amo/s epitheli/m is terme1 the Gtransformation &oneG + Fig. 22-2 an1 Fig. 22-B ,. As 7e shall see9 it is in this transformation :one9 incl/1ing the s6/amocol/mnar D/nction9 7here precancero/s lesions an1 s6/amo/s carcinomas 1e*elop.
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The en1ometrial changes that occ/r 1/ring the menstr/al cycle are ;eye1 to the rise an1 fall in the le*els of o*arian hormones9 an1 the rea1er sho/l1 be familiar 7ith the comple3 b/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 also important to ;no7 that the hormonal patterns of most 7omen 1iffer from the Gstan1ar1G as 1epicte1 1iagrammatically +1isc/sse1 later< see Fig. 22-2E ,. )n1er the infl/ence of the pit/itary follicle-stim/lating hormone an1 l/teini:ing hormone9 1e*elopment an1 ripening of a single o*/m occ/r9 an1 estrogen pro1/ction by the enlarging o*arian follicle progressi*ely rises 1/ring the first 2 7ee;s of the /s/al 2J-1ay menstr/al cycle. It reaches 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/t these le*els are ne*er as high as the preo*/latory pea;. The le*el of this hormone then progressi*ely falls9 beginning B to C 1ays before the onset of menstr/ation. Progesterone9 pro1/ce1 by the corp/s l/te/m9 rises thro/gho/t the last half of the menstr/al cycle an1 falls to basal le*els D/st before the onset of menstr/al blee1ing. The histology of the normal an1 abnormal en1ometrial cycle is 1isc/sse1 later in the section on the en1ometri/m.
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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 hormonally in1/ce1 effects. The follo7ing 1isc/ssion presents the pathology of the maDority of clinical problems. #etails can be fo/n1 in c/rrent boo;s of obstetric an1 gynecologic pathology an1 me1icine. The pathologic con1itions pec/liar to each segment of the female genital tract are 1isc/sse1 separately9 b/t first 7e briefly re*ie7 pel*ic inflammatory 1isease +PI#, an1 other infections beca/se they can affect many of the segments concomitantly.
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%n&ections o& the Female Genital Tract

A large *ariety of organisms can infect the female genital tract an19 in total9 acco/nt for consi1erable s/ffering an1 morbi1ity + Table 22-? ,. "ome9 s/ch as Candida infections9 trichomoniasis9 an1 'ardnerella infections9 are e3tremely common an1 may ca/se significant 1iscomfort 7ith no serio/s se6/elae. !thers9 s/ch as gonorrhea an1 C(lamydia infection9 are maDor ca/ses of female infertility9 an1 others still9 s/ch as Mycoplasma infections9 are implicate1 in spontaneo/s abortions. (ir/ses9 principally the h/man papilloma*ir/ses +$P(,9 appear to be in*ol*e1 in the pathogenesis of */l*ar an1 cer*ical cancer.

-any of these infections are se3/ally transmitte19 incl/1ing trichomoniasis9 gonorrhea9 chancroi19 gran/loma ing/inale9 lymphogran/loma *enere/m9 syphilis9 mycoplasmal infection9 chlamy1ial infection9 herpes9 an1 $P( infection. -ost of these con1itions ha*e been consi1ere1 in Chapter K an1 Chapter J . $ere 7e to/ch only on selecte1 aspects rele*ant to the female genital tract9 incl/1ing pathogens confine1 to the lo7er genital tract +*/l*a9 *agina9 an1 cer*i3, an1 those that in*ol*e the entire genital tract an1 are implicate1 in PI#. Papilloma*ir/ses are 1isc/sse1 s/bse6/ently /n1er t/mors.
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%NF CT%'N( C'NF%N D T' T) *'+ , G N%T$* T,$CT

)erpes simple% infection is common an1 /s/ally in*ol*es the */l*a9 *agina9 an1 cer*i3. In se3/ally transmitte1 1isease clinics9 appro3imately half of patients ha*e c/rrent or prior
106-

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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/mnar epitheli/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 ?IP of /nselecte1 7omen. The fre6/ency of genital herpes has increase1 1ramatically in the past t7o 1eca1es9 partic/larly in teenagers an1 yo/ng 7omen. $erpes simple3 *ir/s type 2 +$"(-2, infection is no7 one of the maDor se3/ally transmitte1 1iseases. Clinical symptoms are seen in abo/t one thir1 of infecte1 in1i*i1/als. The lesions begin B to L 1ays after se3/al relations an1 consist of 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 the initial infection pro1/ces systemic symptoms s/ch as fe*er9 malaise9 an1 ten1er ing/inal lymph 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 B 7ee;s9 b/t as 7ith herpetic infections else7here9 latent infection of regional ner*e ganglia persists. Abo/t t7o thir1s of affecte1 7omen s/ffer rec/rrences9 7hich are less painf/l. Transmission may occ/r 1/ring acti*e or inacti*e +latent, phases9 altho/gh it is m/ch less li;ely in asymptomatic carriers. The gra*est conse6/ence of $"( infection is transmission to the neonate 1/ring birth. This T$.* 22-1 -- Anatomic #istrib/tion of Common Female Genital Infections *ocation an/ Mani&estations o& %n&ection 'r#anism $erpes*ir/s (ource "T# Vulva $erpetic /lcers -oll/sc/m lesions Genital 7arts9 intrapeithelial neoplasia9 in*asi*e carcinoma Follic/lar cer*icitis9 en1ometritis9 salpingooophoritis ";ene glan1 a1enitis (aginitis in chil1ren Ac/te Ac/te cer*icitis en1ometritis an1 salpingitis Vagina Cervix Corpus Adnexa

-oll/sc/m "T# contagios/m $P( C(lamydia trac(omatis "T# "T#

/eisseria "T# gonorr(oeae Candida

En1ogeno/s (/l*o*aginitis Cer*ico*aginitis

0ric(omonas "T#

$P(9 h/man papilloma*ir/s< "T#9 se3/ally transmitte1 1isease. ris; is highest if the infection is acti*e 1/ring 1eli*ery an1 partic/larly if it is a primary +initial, infection in the mother.
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Mycotic an1 yeast (Candida$ infections are common< abo/t ?IP of 7omen are tho/ght to be carriers of */l*o*aginal f/ngi. #iabetes mellit/s9 oral contracepti*es9 an1 pregnancy may enhance the 1e*elopment of infection9 7hich manifests as small 7hite s/rface patches similar to monilial lesions else7here. It is accompanie1 by le/;orrhea an1 pr/rit/s. The 1iagnosis is ma1e by fin1ing the organism in 7et mo/nts of the lesions. 0ric(omonas -aginalis is a large9 flagellate1 o*oi1 proto:oan that can be rea1ily i1entifie1 in 7et mo/nts of *aginal 1ischarge in infecte1 patients + Fig. 22-C ,. Infections may occ/r at any age an1 are seen in abo/t ?EP of 7omen in se3/ally transmitte1 1isease clinics. They are associate1 7ith a p/r/lent *aginal 1ischarge an1 1iscomfort< the /n1erlying *aginal an1 cer*ical m/cosa typically has a characteristic fiery re1 appearance9 calle1 stra7berry cer*i3. !n histologic e3amination9 the inflammatory reaction is /s/ally limite1 to the m/cosa an1 imme1iately s/bDacent lamina propria.
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1060

Fi#ure 22-0 Flagellate1 tropho:oites of 0ric(omonas -aginalis.

Mycoplasma species acco/nt for some cases of *aginitis an1 cer*icitis an1 ha*e been implicate1 in spontaneo/s abortion an1 chorioamnionitis. 'ardnerella is a gramnegati*e9 small bacill/s that is implicate1 in cases of *aginitis 7hen other organisms (0ric(omonas9 f/ngi, cannot be fo/n1.
%NF CT%'N( %N1'*1%NG T) *'+ , $ND 2PP , G N%T$* T,$CT Pel3ic %n&lammator" Disease 4P%D5

PI# is a common 1isor1er characteri:e1 by pel*ic pain9 a1ne3al ten1erness9 fe*er9 an1 *aginal 1ischarge< it res/lts from infection by one or more of the follo7ing gro/ps of organismsH gonococci9 chlamy1iae9 an1 enteric bacteria. The gonococc/s contin/es to be a common ca/se of PI#9 the most serio/s complication of gonorrhea in 7omen. C(lamydia infection is no7 another 7ell-recogni:e1 ca/se of PI#. 0esi1es these t7o9 infections after spontaneo/s or in1/ce1 abortions an1 normal or abnormal 1eli*eries +calle1 p/erperal infections, are important in the pro1/ction of PI#. "/ch PI# is polymicrobial an1 is ca/se1 by staphylococci9 streptococci9 coliform bacteria9 an1 Clostridium perfringens. Gonococcal inflammation /s/ally begins in the 0artholin glan1 an1 other *estib/lar glan1s or peri/rethral glan1s< cer*i3 in*ol*ement is common an1 fre6/ently asymptomatic. From any of these sites9 the organisms may sprea1 /p7ar1 to in*ol*e the t/bes an1 t/bo-o*arian region. The a1/lt *agina is remar;ably resistant to the gonococc/s9 b/t in the chil19 pres/mably beca/se of a more 1elicate lining m/cosa9 */l*o*aginitis may 1e*elop. The nongonococcal bacterial infections that follo7 in1/ce1 abortion9 1ilation an1 c/rettage of the /ter/s9 an1 other s/rgical proce1/res on the female genital tract are tho/ght to sprea1 from the /ter/s /p7ar1 thro/gh the lymphatics or

*eno/s channels rather than on the m/cosal s/rfaces. These infections therefore ten1 to pro1/ce less m/cosal in*ol*ement b/t more reaction 7ithin the 1eeper layers.
Morpholo#".

&ith the gonococc/s9 inflammatory changes appear in the affecte1 glan1s appro3imately 2 to L 1ays after inoc/lation of the organism. &here*er it occ/rs9 gonococcal 1isease is characteri:e1 by an ac/te s/pp/rati*e reaction 7ith inflammation largely confine1 to the s/perficial m/cosa an1 /n1erlying s/bm/cosa. "mears of the inflammatory e3/1ate sho/l1 1isclose the intracell/lar gram-negati*e 1iplococc/s9 b/t absol/te confirmation re6/ires c/lt/re. If sprea1 occ/rs9 the en1ometri/m is /s/ally spare19 for obsc/re reasons. !nce it is 7ithin the t/bes9 an acute suppurati3e salpin#itis ens/es. The t/bal serosa becomes hyperemic an1 layere1 7ith fibrin9 the t/bal fimbriae are similarly in*ol*e19 an1 the l/men fills 7ith p/r/lent e3/1ate that may lea; o/t of the fimbriate1 en1. In 1ays or 7ee;s9 the fimbriae may seal or become plastere1 against the o*ary to create a salpin#ooophoritis. Collections of p/s 7ithin the o*ary an1 t/be 4tu!o-o3arian a!scesses5 or t/bal l/men 4p"osalpin65 may occ/r. A1hesions of the t/bal plica may pro1/ce glan1li;e spaces +follic/lar salpingitis, + Fig. 22-E ,. In the co/rse of time9 the infecting organisms may 1isappear9 the p/s /n1ergoing proteolysis to a thin9 sero/s fl/i19 to pro1/ce a h"/rosalpin6 or hy1rosalpin3 follic/laris. PI# ca/se1 by staphylococci9 streptococci9 an1 the other p/erperal in*a1ers ten1s to ha*e less e3/1ation

Fi#ure 22-5 A9 Ac/te salpingo-oophoritis9 7ith t/bo-o*arian abscess. The fallopian t/be an1 o*aries ha*e coalesce1 into an inflammatory mass a1herent to the /ter/s. +Compare 7ith Fig/re 22-? ., B9 Chronic salpingitis 7ith f/sion of the t/bal plicae an1 inflammatory cell infiltrates.

1065

7ithin the l/mens of the t/be an1 less in*ol*ement of the m/cosa9 7ith a greater inflammatory response 7ithin the 1eeper layers. The infection ten1s to sprea1 thro/gho/t the 7all to in*ol*e the serosa an1 may often in*ol*e the broa1 ligaments9 pel*ic str/ct/res9 an1 peritone/m. 0acteremia is a more fre6/ent complication of streptococcal or staphylococcal PI# than of gonococcal infections. The complications of PI# incl/1eH Peritonitis Intestinal obstr/ction 1/e to a1hesions bet7een the small bo7el an1 the pel*ic organs

 0acteremia9 7hich may pro1/ce en1ocar1itis9 meningitis9 an1 s/pp/rati*e arthritis Infertility9 one of the most commonly feare1 conse6/ences of long-stan1ing chronic PI# In the early stages9 gonococcal infections are rea1ily controlle1 7ith antibiotics9 altho/gh penicillin-resistant strains ha*e regrettably emerge1. &hen the infection becomes 7alle1 off in s/pp/rati*e t/bes or t/bo-o*arian abscesses9 it is 1iffic/lt to achie*e a s/fficient le*el of antibiotic 7ithin the centers of s/ch s/pp/ration to control these infections effecti*ely. Postabortion an1 postpart/m PI#s are also amenable to antibiotics b/t are far more 1iffic/lt to control than the gonococcal infections. It sometimes becomes necessary to remo*e the organs s/rgically.

Vulva
#iseases of the */l*a in the aggregate constit/te only a small fraction of gynecologic practice. -any inflammatory 1ermatologic 1iseases that affect hair-bearing s;in else7here on the bo1y may also occ/r on the */l*a9 so */l*itis may be enco/ntere1 in psoriasis9 ec:ema9 an1 allergic 1ermatitis. The */l*a is prone to s;in infections beca/se it is constantly e3pose1 to secretions an1 moist/re. Nonspecific */l*itis is partic/larly li;ely to occ/r in bloo1 1yscrasias9 /remia9 1iabetes mellit/s9 maln/trition9 an1 a*itaminoses. -ost s;in cysts +epi1ermal incl/sion cysts, an1 t/mors can also occ/r in the */l*a. $ere 7e 1isc/ss 1isor1ers pec/liar to the */l*a9 incl/1ing 0artholin cyst9 *estib/lar a1enitis9 */l*ar 1ystrophies9 an1 t/mors of the */l*a.
.artholin C"st

Ac/te infection of the 0artholin glan1 pro1/ces an ac/te inflammation of the glan1 +a1enitis, an1 may res/lt in a 0artholin abscess. 0artholin cysts are relati*ely common9 occ/r at all ages9 an1 res/lt from obstr/ction of the 0artholin 1/ct9 /s/ally by a prece1ing infection. These cysts may become large9 /p to B to E cm in 1iameter. The cyst is line1 by either the transitional epitheli/m of the normal 1/ct or s6/amo/s metaplasia. The cysts pro1/ce pain an1 local 1iscomfort< the cysts are either e3cise1 or opene1 permanently +mars/piali:ation,.
1ul3ar 1esti!ulitis

The */l*ar *estib/le is locate1 in the posterior introit/s at the entrance to the *agina an1 contains small glan1s in the s/bm/cosa +*estib/lar glan1s,. A *ariety of 1isor1ers ca/se chronic pain in this area9 ;no7n as -ul-odynia. Chief among them are inflammation of the s/rface m/cosa an1 *estib/lar glan1s associate1 7ith a chronic9 rec/rrent9 an1 e36/isitely painf/l con1ition ;no7n as */l*ar *estib/litis. The inflammatory con1ition9 7hich in*ol*es the glan1s an1 m/cosa9 pro1/ces small /lcerations9 7hich acco/nt for e3treme point ten1erness in the *estib/le. The ca/se of the con1ition is /n;no7n9 an1 the

con1ition is relie*e19 in some b/t not in all cases9 by s/rgical remo*al of the inflame1 m/cosa.
>?K@

Non-Neoplastic pithelial Disor/ers

A spectr/m of inflammatory lesions of the */l*a is characteri:e1 by opa6/e9 7hite9 scaly9 pla6/eli;e m/cosal thic;enings that pro1/ce */l*ar 1iscomfort an1 itching +pr/rit/s,. 0eca/se of their 7hite appearance9 these 1isor1ers ha*e tra1itionally been terme1 le/;opla;ia by clinicians. This is a clinical 1escripti*e term beca/se 1(ite pla2ues may indicate a -ariety of benign, premalignant, or malignant lesions. In fact9 a biopsy of Gle/;opla;iaG may re*eal one of se*eral con1itionsH +?, *itiligo +loss of pigment,< +2, inflammatory 1ermatoses +e.g.9 psoriasis9 chronic 1ermatitis > Chapter 2E @,< +B, */l*ar intraepithelial neoplasia9 Paget 1isease9 or e*en in*asi*e carcinoma< an1 +C, a *ariety of alterations of /n;no7n etiology that el/1e proper classification. To eliminate the conf/sion generate1 by /sing m/ltiple terms to characteri:e 7hite */l*ar lesions +e.g.9 ;ra/rosis */l*ae9 le/;opla;ia9 atrophic */l*itis,9 clinical 1escripti*e terminology has been separate1 from histologic 1iagnosis. E3cl/1ing neoplasms an1 specific 1isease entities9 nonspecific inflammatory alterations of the */l*a are no7 classifie1 /sing accepte1 1ermatologic 1iagnoses or are place1 7ithin t7o a11itional categoriesH +?, lic(en sclerosus9 a characteristic 1isor1er manifeste1 by s/bepithelial
>?L@

1066

fibrosis9 an1 +2, lic(en simple% c(ronicus9 manifeste1 by epithelial thic;ening +acanthosis, an1 hyper;eratosis + Fig. 22-K ,. The t7o forms may coe3ist in 1ifferent areas of the same */l*a9 an1 the lesions are often m/ltiple9 ma;ing their clinical management partic/larly 1iffic/lt.
>?J@

*%C) N (C* ,'(2(

%ichen scleros/s9 also calle1 chronic atrophic */l*itis9 lea1s to atrophy9 fibrosis9 an1 scarring. The s;in becomes pale gray an1 parchment-li;e9 the labia are atrophie19 an1 the introit/s is narro7e1 + Fig. 22-L ,. The fo/r car1inal histologic feat/res are ?, atrophy +thinning, of the epi1ermis9 7ith 1isappearance of the rete pegs9 2, hy1ropic 1egeneration of the basal cells9 B, replacement of the /n1erlying 1ermis by 1ense collageno/s fibro/s tiss/e9 an1 C, a monoclonal ban1li;e lymphocytic infiltrate + Fig. 22-K ,. %ichen scleros/s occ/rs in all age gro/ps b/t is most common after menopa/se. The pathogenesis is /nclear9 b/t it has many feat/res of an a/toimm/ne 1isor1er. At all ages9 the 1isor1er ten1s to be slo7 in
>?J@ >?O@

Fi#ure 22-6 Inflammatory */l*ar 1isor1ers. %ichen scleros/s +upper panel,. %ichen simple3 chronic/s +lo1er panel,. The main feat/res of the lesions are in1icate1 in the fig/res.

Fi#ure 22-7 %ichen scleros/s9 e3hibiting the 7hite parchment-li;e patches of the s;in of the */l*a an1 labial atrophy.

1e*eloping9 insi1io/s9 an1 progressi*e. %ichen scleros/s is not recogni:e1 as a precancero/s con1ition9 b/t it has been associate1 7ith genetic alterations an1 confers a greater than e3pecte1 ris; of s/bse6/ent carcinoma9 7hich may occ/r in ?P to CP of cases.
>?O@ >2I@

*%C) N (%MP* 8 C),'N%C2(

Pre*io/sly calle1 hyperplastic 1ystrophy9 lichen simple3 chronic/s is a non-specific con1ition res/lting from r/bbing or scratching the s;in to relie*e pr/rit/s. The latter may res/lt from ;no7n or /n;no7n irritants. %ichen simple3 chronic/s is characteri:e1 by acanthosis of the */l*ar s6/amo/s epitheli/m9 fre6/ently 7ith hyper;eratosis. The epitheli/m is thic;ene1 an1 may sho7 increase1 mitotic acti*ity in both the basal an1 pric;le cell layers + Fig. 22-K , 7ith *ariable le/;ocytic infiltration of the 1ermis. "imilar to lichen scleros/s9 lichen simple3 chronic/s is sometimes associate1 7ith carcinoma. It is not9 ho7e*er9 consi1ere1 a significant cancer prec/rsor /nless there is coe3isting epithelial atypia9 in 7hich case it is classifie1 as a precancero/s lesion +*/l*ar intraepithelial neoplasia,.
>2?@

Because lic(en simple% c(ronicus is secondary to pruritus, it is, by definition, non3 specific. Its ca/ses incl/1e specific infections +tinea9 can1i1a9 etc.,9 m/cosal irritations secon1ary to chemical e3pos/res9 an1 /n;no7n ca/ses of pr/rit/s. 0eca/se the lesions may present as 7hite */l*ar pla6/es9 they may be in1isting/ishable clinically from more serio/s 1isor1ers. Th/s9 biopsy is in1icate1 in all lesions9 e*en those that are remotely s/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*e been recor1e19 both benign an1 malignant9 incl/1ing neoplasms of the a1ne3al glan1s9 epitheli/m9 an1 /n1erlying soft tiss/e. -any of these t/mors are /ncommon an1 are histologically similar to t/mors occ/rring else7here in the bo1y. Attention 7ill be foc/se1 on the more common t/mors /ni6/e to the */l*a.
. N%GN T2M',(

1067 Papillar" )i/ra/enoma

%i;e the breast9 the */l*a contains mo1ifie1 apocrine s7eat glan1s. In fact9 the */l*a may contain tiss/e closely resembling breast +Gectopic breastG, an1 1e*elop t7o t/mors 7ith co/nterparts in the breast. !ne of these9 papillary hi1ra1enoma9 is i1entical in appearance

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 labia maDora or interlabial fol1s9 an1 may be conf/se1 clinically 7ith carcinoma beca/se of its ten1ency to /lcerate. !n histologic e3amination9 hi1ra1enomas consist of t/b/lar 1/cts line1 by a single or 1o/ble layer of nonciliate1 col/mnar cells9 7ith a layer of flattene1 Gmyoepithelial cellsG /n1erlying the epitheli/m. These myoepithelial elements are characteristic 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 *enereal 7art9 is9 by far9 the most common< +2, m/cosal polyps9 7hich are benign stromal proliferations co*ere1 7ith s6/amo/s epitheli/m< an1 +B, syphilitic con1yloma lat/m9 1escribe1 in Chapter J . Con1ylomata ac/minata are se3/ally transmitte19 benign t/mors that ha*e a 1istinctly *err/co/s gross appearance + Fig. 22-JA ,. Altho/gh they may be solitary9 they are more fre6/ently m/ltiple an1 often coalesce< they in*ol*e perineal9 */l*ar9 an1 perianal regions as 7ell as the *agina an19 less commonly9 the cer*i3. The lesions are i1entical to those fo/n1 on the penis an1 aro/n1 the an/s in males + Chapter 2? ,. !n histologic e3amination9 they consist of a branching9 treeli;e proliferation of stratifie1 s6/amo/s epitheli/m s/pporte1 by a fibro/s stroma + Fig. 22-JB ,. Acanthosis9 para;eratosis9 hyper;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(9 principally types K an1 ??9 7hich are associate1 7ith benign genital lesions an1 replicate in the s6/amo/s epitheli/m. The *ir/s life cycle is complete1 in the mat/re s/perficial cells of the epitheli/m. This 1epen1ence of *iral gro7th on s6/amo/s
>22@ >2B@

Fi#ure 22-9 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 sho7ing acanthosis9 hyper;eratosis9 an1 cytoplasmic *ac/olation +;oilocytosis9 center,.

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 GcytopathicG effect. E3cept in imm/nos/ppresse1 in1i*i1/als9 con1ylomata ac/minata fre6/ently regress spontaneo/sly9 an1 are not consi1ere1 to be precancero/s lesions. 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/ 1ul3ar %ntraepithelial Neoplasia

Carcinoma of the */l*a is an /ncommon malignant neoplasm +appro3imately one eighth as fre6/ent as cer*ical cancer, representing abo/t BP of all genital cancers in the female< appro3imately t7o thir1s occ/r in 7omen ol1er than KI years. Eig(ty3fi-e per cent of t(ese malignant tumors are s2uamous cell carcinomas9 the remain1er being basal cell carcinomas9 melanomas9 or a1enocarcinomas. In terms of etiology9 pathogenesis9 an1 clinical presentation9 */l*ar s6/amo/s cell carcinomas may be 1i*i1e1 into t7o general gro/ps.
>2C@

0(e first group is associated 1it( cancer3related ((ig(3ris $ )459 an1 fre6/ently coe3ists 7ith or is prece1e1 by a classic an1 easily recogni:e1 precancero/s change calle1 */l*ar intraepithelial neoplasia +(IN,. This form of (IN incl/1es lesions classifie1 as carcinoma in sit/ or 0o7en 1isease. (IN is characteri:e1 by n/clear atypia in the epithelial cells9 increase1 mitoses9 an1 lac; of s/rface 1ifferentiation + Fig. 22-OA ,. It is analogo/s to high-gra1e s6/amo/s intraepithelial lesions of the cer*i3 +see /n1er cer*i3,. These lesions /s/ally present as 7hite or pigmente1 pla6/es on the */l*a. (IN is appearing 7ith increasing fre6/ency in 7omen yo/nger than CI years of age. &ith or 7itho/t associate1 in*asi*e carcinoma9 56/ is fre2uently multicentric9 an1 ?IP to BIP are associate1 7ith another primary s6/amo/s neoplasm in the *agina or cer*i3. This association in1icates a common etiologic agent. In1ee19 OIP of cases of (IN an1 associate1 cancers contain $P( #NA9 specifically types ?K9 ?J9 an1 other cancerassociate1 +high-ris;, types. "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 CE years of age, or imm/nos/ppresse1 7omen.
>2E@ >2I@ >2E@

1069

Fi#ure 22-9 A9 $istopathology of classic +$P( positi*e, */l*ar intraepithelial neoplasia 7ith 1iff/se cell/lar atypia9 n/clear cro71ing9 an1 increase1 mitotic in1e3. B9 1ifferentiate1 +$P( negati*e, (IN9 sho7ing mat/ration9 hyper;eratosis an1 basal cell atypia +arro1,.

0(e second group of s2uamous cell carcinomas is associated 1it( s2uamous cell (yperplasia and lic(en sclerosus. The etiology of this gro/p of carcinomas is /nclear9 an1 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 step in 7hich atypia 1e*elops 7ithin hyperplasia or lichen scleros/s9 lea1ing to an /n/s/al form of (IN terme1 1ifferentiate1 +simple3, (IN + Fig. 22-OB ,. These t/mors ha*e also been associate1 7ith increase1 acc/m/lation of pEB protein. +-/tations of the p78 gene increase its half-life an1 hence it is possible to 1etect the m/tant pEB protein rea1ily by imm/nohistochemistry., A *ariety of chromosome abnormalities are lin;e1 to in*asi*e */l*ar cancer9 some of 7hich may be specific for $P(-positi*e t/mors.
>2K@ >2L@ >2L@ >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 be hyper;eratotic. Coe3isting carcinomas may be e3ophytic or in1/rate19 fre6/ently 7ith /lceration. Carcinomas associate1 7ith lichen scleros/s9 lichen simple3 chronic/s9 an1 1ifferentiate1 (IN may 1e*elop 6/ic;ly as no1/les in a bac;gro/n1 of */l*ar inflammation. The often s/btle emergence of the latter may be misinterprete1 as 1ermatitis9 ec:ema9 or le/;opla;ia for long perio1s. The clinical manifestations are chiefly non-specific9 incl/1ing local 1iscomfort9 itching9 an1 e3/1ation beca/se of

s/perficial secon1ary infection9 an1 /n1erscore the importance of repeate1 e3amination in 7omen 7ith */l*ar inflammatory 1isor1ers. !n histologic e3amination9 t/mors associate1 7ith $P( or (IN fre6/ently e3hibit in*asi*e gro7th patterns that mimic intraepithelial neoplasia. These Gintraepithelial-li;eG patterns may be 7ell 1ifferentiate1 +7arty, or poorly 1ifferentiate1 +basaloi1, + Fig. 22-?IA ,. $P(-negati*e t/mors9 7hich at times arise from lichen scleros/s or s6/amo/s hyperplasia9 typically e3hibit an in*asi*e pattern 7ith prominent ;eratini:ation + Fig. 22?IB ,.
>2E@ >2O@

'is; of cancer 1e*elopment in (IN is principally a f/nction of age9 e3tent of t/mor9 an1 imm/ne stat/s. !nce in*asi*e cancer 1e*elops9 metastatic sprea1 is lin;e1 to the si:e of t/mor9 1epth of in*asion9 an1 in*ol*ement of lymphatic *essels. The ing/inal9 pel*ic9 iliac9 an1 periaortic lymph no1es are most commonly in*ol*e1. )ltimately9 lymphohematogeno/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 KIP to JIP E-year s/r*i*al rate after treatment 7ith one-stage */l*ectomy an1 lympha1enectomy< larger lesions 7ith lymph no1e in*ol*ement yiel1 a less than ?IP E-year s/r*i*al rate.
>BI@ >B?@

'are *ariants of s6/amo/s cell carcinoma incl/1e -errucous carcinomas9 7hich are f/ngating t/mors resembling con1yloma ac/minat/m9 an1 basal cell carcinomas9 7hich are i1entical to their co/nterparts on the s;in + Fig. 22-?? ,. Neither t/mor is associate1 7ith papilloma*ir/ses. 0oth t/mors rarely metastasi:e an1 can /s/ally be c/re1 by 7i1e e3cision.
>B2@ >BB@

6tramammar" 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 + Chapter 2B ,. As a */l*ar neoplasm9 it manifests as a pr/ritic9 re19 cr/ste19 sharply 1emarcate19 mapli;e area9 occ/rring /s/ally on the labia maDora. It may be accompanie1 by a palpable s/bm/cosal thic;ening or t/mor.
>2C@

1069

Fi#ure 22-10 A9 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 22-11 A9 (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 lying singly or in small cl/sters 7ithin the epi1ermis an1 its appen1ages. These cells are 1isting/ishe1 by a clear separation +GhaloG, from the s/rro/n1ing epithelial cells + Fig. 22-?2 , an1 a finely gran/lar cytoplasm containing m/copolysacchari1e that stains 7ith perio1ic aci1-"chiff9 Alcian bl/e or m/cicarmine. )ltrastr/ct/rally9 Paget cells 1isplay apocrine9 eccrine9 an1 ;eratinocyte 1ifferentiation an1 pres/mably arise from primiti*e epithelial progenitor cells. In contrast to Paget 1isease of the nipple9 in 7hich ?IIP of patients sho7 an /n1erlying 1/ctal breast carcinoma9 */l*ar lesions are most fre6/ently confine1 to the epi1ermis of the s;in an1 a1Dacent hair follicles an1 s7eat glan1s. The prognosis of Paget 1isease is poor in the /ncommon cases 7ith associate1 carcinoma9 b/t intraepi1ermal Paget 1isease may 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 *isible lesion9 often into s;in appen1ages9 they are prone to rec/rrence.

Fi#ure 22-12 Paget 1isease of the */l*a 7ith a cl/ster of large clear t/mor cells 7ithin the s6/amo/s epitheli/m.

1070

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

Mali#nant Melanoma

-elanomas of the */l*a are rare9 representing less than EP of all */l*ar cancers an1 2P of all melanomas in 7omen. Their pea; inci1ence is in the si3th or se*enth 1eca1e< they ten1 to ha*e the same biologic an1 histologic characteristics as melanomas occ/rring else7here an1 are capable of 7i1esprea1 metastatic 1issemination + Fig. 22-?B ,. The Eyear s/r*i*al rate is less than B2P9 pres/mably o7ing to 1elays in 1etection an1 the fact that the maDority of these t/mors rapi1ly enter a *ertical gro7th phase follo7ing inception + Chapter 2E ,. Prognosis is lin;e1 principally to 1epth of in*asion9 7ith greater than KIP mortality for lesions in*a1ing 1eeper than ? mm. 0eca/se it is initially confine1 to the epitheli/m9 melanoma may resemble Paget 1isease9 both grossly an1 histologically. It can /s/ally be 1ifferentiate1 by its /niform reacti*ity 7ith antibo1ies to "?II protein9 absence of reacti*ity 7ith antibo1ies to carcinoembryonic antigen9 an1 lac; of m/copolysacchari1es9 both of 7hich are present in Paget 1isease.
>BC@

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 an1 sprea1 to the cer*i3 7itho/t significant in*ol*ement of the *agina. The maDor serio/s primary lesion of this str/ct/re is the /ncommon primary carcinoma. The remaining entities can therefore be cite1 briefly.
Con#enital $nomalies

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

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 that occ/r s/bm/cosally. !ther cysts incl/1e m/co/s cysts9 7hich occ/r in the pro3imal *agina9 are 1eri*e1 from mAllerian epitheli/m9 an1 often contain s6/amo/s metaplasia. Another mAllerian-1eri*e1
1071

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

Premali#nant an/ Mali#nant Neoplasms

-ost benign t/mors of the *agina occ/r in repro1/cti*e-age 7omen an1 are s;eletal m/scle t/mors +rhab1omyomas, or stromal t/mors +stromal polyps,. The latter may e3hibit cell/lar atypia b/t are benign9 locali:e19 an1 self-limite1. !thers incl/1e benign leiomyomas9 hemangiomas9 an1 rare mi3e1 t/mors. Clinically important malignant t/mors in terms of fre6/ency an1 biologic beha*ior are carcinoma an1 embryonal rhab1omyosarcoma +sarcoma botryoi1es,.
>BK@

1$G%N$* %NT,$ P%T) *%$* N 'P*$(%$ $ND (:2$M'2( C ** C$,C%N'M$

Primary carcinoma of the *agina is an e3tremely /ncommon cancer +abo/t I.K per ?II9III 7omen yearly, acco/nting for abo/t ?P of malignant neoplasms in the female genital tract9 an1 of these9 OEP 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< ?P to 2P of patients 7ith an in*asi*e cer*ical carcinoma e*ent/ally 1e*elop a *aginal s6/amo/s carcinoma.
Morpholo#".

-ost often9 the t/mor affects the /pper posterior *agina9 partic/larly along the posterior 7all at the D/nction 7ith the ectocer*i3. It begins as a foc/s of epithelial thic;ening9 often in association 7ith 1ysplastic changes9 progressing to a pla6/eli;e mass that e3ten1s centrif/gally an1 in*a1es9 by 1irect contin/ity9 the cer*i3 an1 peri*aginal str/ct/res. The lesions in the lo7er t7o-thir1s metastasi:e to the ing/inal no1es9 7hereas /pper lesions ten1 to in*ol*e the regional iliac no1es. These t/mors first come to the patientQs attention by the appearance of irreg/lar spotting or the 1e*elopment of a fran; *aginal 1ischarge +le/;orrhea,. At other times9 they remain totally silent an1 become clinically manifest only 7ith the onset of /rinary or rectal fist/las.
$D N'C$,C%N'M$

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

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 I.2 to ?I cm in greatest 1iameter. They are /s/ally 1isco*ere1 bet7een the

Fi#ure 22-10 Clear cell a1enocarcinoma of the *agina sho7ing *ac/olate1 t/mor cells in cl/sters an1 glan1li;e str/ct/res.

ages of ?E an1 2I years an1 are often compose1 of *ac/olate19 glycogen-containing cells9 hence the term clear cell carcinoma + Fig. 22-?C ,. These cancers can also arise in the cer*i3. A probable prec/rsor of the t/mor is 3a#inal a/enosis9 a con1ition in 7hich glan1/lar col/mnar epitheli/m of mAllerian type either appears beneath the s6/amo/s epitheli/m or replaces it. A1enosis presents clinically as re19 gran/lar foci contrasting 7ith the normal pale pin;9 opa6/e *aginal m/cosa. !n microscopic e3amination9 the glan1/lar epitheli/m may be either m/c/s secreting9 resembling en1ocer*ical m/cosa9 or socalle1 t/boen1ometrial9 often containing cilia. A1enosis has been reporte1 in BEP to OIP of the offspring of estrogen-treate1 mothers9 b/t as mentione1 earlier9 malignant transformation is e3tremely rare.
>BJ@

0eca/se of its insi1io/s9 in*asi*e gro7th9 *aginal cancer +s6/amo/s an1 a1enocarcinomato/s, is 1iffic/lt to c/re. Th/s9 early 1etection by caref/l follo7-/p is man1atory in #E"-e3pose1 7omen. "/rgery an1 irra1iation ha*e s/ccessf/lly era1icate1 #E"-relate1 t/mors in /p to JIP 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 pree3isting cer*ical lesion m/st be r/le1 o/t.
M.,;'N$* ,)$.D'M;'($,C'M$

Also calle1 sarcoma botryoides9 this is an interesting b/t /ncommon *aginal t/mor most fre6/ently fo/n1 in infants an1 in chil1ren yo/nger than E years of age. The t/mor consists pre1ominantly of malignant embryonal rhab1omyoblasts an1 is th/s a type of rhab1omyosarcoma.
>BO@

1072 Morpholo#"

These t/mors ten1 to gro7 as polypoi19 ro/n1e19 b/l;y masses that sometimes fill an1 proDect 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-?E ,. !n histologic e3amination9 the t/mor cells are small an1 ha*e o*al n/clei9 7ith small protr/sions of cytoplasm 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 a so-calle1 cambi/m layer< b/t in the 1eep regions9 they lie 7ithin a loose fibromy3omato/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 an1 ca/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 in cases 1iagnose1 s/fficiently early.
>CI@

Fi#ure 22-15 "arcoma botryoi1es +embryonal rhab1omyosarcoma, of the *agina appearing as a polypoi1 mass protr/1ing from the *agina. (Courtesy of *r. Mic(ael *ono-an, C(ildren9s )ospital, Boston, MA.$

Cervix
The cer*i3 is both a sentinel for potentially serio/s /pper genital tract infections an1 a target for *iral an1 other carcinogens9 7hich may lea1 to in*asi*e carcinoma. Infection constit/tes one of the most common clinical complaints in gynecologic practice an1 fre6/ently *e3es both patient an1 clinician. The potential threat of cancer9 ho7e*er9 is central to Papanicolao/ smear screening programs an1 histologic interpretation of biopsy specimens by the pathologist. &orl17i1e9 cer*ical carcinoma alone is responsible for abo/t EP of all cancer 1eaths in 7omen.
%n&lammations

$C2T $ND C),'N%C C ,1%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 the glycogen pro*i1es a s/bstrate for en1ogeno/s *aginal aerobes an1 anaerobes9 streptococci9 enterococci9 Esc(eric(ia coli9 an1 staphylococci. The bacterial gro7th pro1/ces a 1rop in *aginal p$. The e3pose1 en1ocer*i3 is sensiti*e to these changes in chemical en*ironment an1 bacterial flora an1 respon1s by /n1ergoing a *ariety of changes incl/1ing proliferation of reser*e cells lea1ing to s6/amo/s metaplasia. This process of transformation from a col/mnar to a s6/amo/s lining is also hastene1 by tra/ma an1 other infections occ/rring in the repro1/cti*e years. As the s6/amo/s epitheli/m o*ergro7s an1 obliterates the s/rface col/mnar papillae9 it co*ers an1 obstr/cts crypt openings9 7ith the acc/m/lation of m/c/s in 1eeper crypts +glan1s, to form m/co/s +nabothian, cysts. This process is in*ariably associate1 7ith an inflammatory infiltrate compose1 of a mi3t/re of polymorphon/clear le/;ocytes an1 monon/clear cells9 an1 if the inflammation is se*ere9 it may be associate1 7ith loss of the epithelial lining +erosion or /lceration, an1 epithelial repair +reparati*e atypia or anaplasia of repair,. All of these components characteri:e 7hat is ;no7n as c(ronic cer-icitis + Fig. 22-?K ,. "ome 1egree of cer*ical inflammation may be fo/n1 in *irt/ally all m/ltiparo/s an1 in many n/lliparo/s a1/lt 7omen9 an1 it is /s/ally of little clinical conse6/ence. Principal concerns 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 be i1entifie1 for their rele*ance to /pper genital tract 1isease9 pregnancy complications9 or se3/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 stromal changes. Ac/te cer*icitis is characteri:e1 by ac/te inflammatory cells9
107-

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

erosion9 an1 reacti*e or reparati*e epithelial change. Chronic cer*icitis incl/1es inflammation9 /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 is not specific9 some patterns are associate1 7ith certain organisms. $"( is most strongly associate1 7ith epithelial /lcers +often 7ith intran/clear incl/sions in epithelial cells, an1 a lymphocytic infiltrate9 an1 C. trac(omatis 7ith lymphoi1 germinal centers an1 a prominent plasmacytic infiltrate. Epithelial spongiosis is associate1 7ith 0. -aginalis infection.
>C?@ >C2@

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. These changes9 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/s cells that mimic precancero/s lesions9 beca/se cells /n1ergoing repair are 1eplete1 of their normal content of glycogen an1 may ha*e n/clear atypia.
ND'C ,1%C$* P'*;P(

En1ocer*ical polyps are relati*ely innoc/o/s9 inflammatory t/mors that occ/r in 2P to EP of a1/lt 7omen. Perhaps the maDor significance of polyps lies in their pro1/ction of irreg/lar *aginal GspottingG or blee1ing that aro/ses s/spicion of some more omino/s lesion. -ost polyps arise 7ithin the en1ocer*ical canal an1 *ary from small an1 sessile to large9 E-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/ssecreting en1ocer*ical glan1s9 often accompanie1 by inflammation an1 s6/amo/s metaplasia + Fig. 22-?L ,. In almost all instances9 simple c/rettage or s/rgical e3cision effects a c/re.
%ntraepithelial an/ %n3asi3e (<uamous Neoplasia

No form of cancer better 1oc/ments the remar;able effects of pre*ention9 early 1iagnosis9 an1 c/rati*e therapy on the mortality rate than 1oes cancer of the cer*i3. Fifty years ago9 carcinoma of the cer*i3 7as the lea1ing ca/se of cancer 1eaths in 7omen in the )nite1 "tates9 b/t the 1eath rate has 1ecline1 by t7o-thir1s to its present ran; as the eighth lea1ing ca/se of cancer mortality. Cancer of the cer*i3 ca/ses abo/t CEII 1eaths ann/ally +behin1 cancers of the l/ng9 breast9 colon9

Fi#ure 22-17 En1ocer*ical polyp compose1 of a 1ense fibro/s stroma co*ere1 7ith en1ocer*ical col/mnar epitheli/m.

1070

pancreas9 o*ary9 lymph no1es9 an1 bloo1,. In sharp contrast to this re1/ce1 mortality9 the 1etection fre6/ency of early cancers an1 precancero/s con1itions is high. -/ch cre1it for these 1ramatic gains belongs to the effecti*eness of the Papanicolao/ cytologic test in 1etecting cer*ical precancers an1 to the accessibility of the cer*i3 to colposcopy an1 biopsy. There are an estimate1 ?B9III ne7 cases of in*asi*e cancer ann/ally an1 nearly ? million precancero/s con1itions +s6/amo/s intraepithelial lesions, of *arying gra1e. Th/s9 it is e*i1ent that Papanicolao/ smear screening has increase1 the 1etection of
>CB@

potentially c/rable cancers an1 the 1etection an1 era1ication of prein*asi*e lesions9 some of 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 factors in*ol*e1 in its 1e*elopment9 7hich ha*e been i1entifie1 from a series of clinical9 epi1emiologic9 pathologic9 an1 molec/lar st/1ies. Epi1emiologic 1ata ha*e long implicate1 a se3/ally transmitte1 agent9 7hich is no7 establishe1 to be the h/man papilloma*ir/s. $P( is c/rrently consi1ere1 to be the most important agent in cer*ical oncogenesis. 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/s cell carcinomas< it is also s/specte1 of being an oncogenic agent in a *ariety of other s6/amo/s t/mors or proliferati*e lesions of s;in an1 m/co/s membranes9 as 1etaile1 in Chapter L .
>CB@

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.

>CB@ >CC@

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,

Fi#ure 22-19 A9 Post/late1 steps in the pathogenesis of cer*ical neoplasia. Con1itions infl/encing progression 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 +rig(t,. The interme1iate steps incl/1e ris;s of infection 7ith high-ris; $P( types9 1e*elopment of a1*ance1 cer*ical intraepithelial neoplasia +CIN,9 an1 progression to in*asi*e carcinoma.

There is mo/nting molec/lar e*i1ence lin;ing $P( to cancer in general an1 cer*ical cancer in partic/lar. ?. $P( #NA is 1etecte1 by hybri1i:ation techni6/es in o*er OEP of cer*ical cancers. 2. "pecific $P( types are associate1 7ith cer*ical cancer +high ris;, *ers/s con1ylomata +lo7 ris;,< lo7 +incl/1e types K9 ??9 C29 CC9 EB9 EC9 K29 an1 KK, an1 high-ris; types +incl/1e types ?K9 ?J9 B?9 BB9 BE9 BO9 CE9 E?9 E29 EK9 EJ9 EO9 an1 KJ, + Fig. 22-?JA ,. B. E3perimental 1ata in1icate that *iral +E: an1 E;, genes of high ris; $P(s can 1isr/pt the cell cycle *ia bin1ing to '0 7ith /p-reg/lation of Cyclin E +EL, an1 p?KINRC< interr/pt cell 1eath path7ays by bin1ing to pEB +EK,< in1/ce centrosome 1/plication an1 genomic instability +EK9 EL,< an1 pre*ent replicati*e senescence by /p-reg/lation of telomerase +EK, + Chapter L ,. $P( EK in1/ces rapi1 1egra1ation of pEB *ia /bi6/itin-1epen1ent proteolysis9 re1/cing pEB 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 to the E2F transcription factor9 the t7o *iral oncogenes cooperate to promote #NA synthesis 7hile interr/pting pEB-me1iate1 gro7th arrest an1 apoptosis of genetically altere1 cells. Th/s9 the *iral oncogenes are critical
>2B@ >2B@ >CE@ >CK@ >CL@ >CJ@

1075

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

C. The physical state of the *ir/s 1iffers in 1ifferent lesions9 being integrate1 into the host #NA in cancers9 an1 present as free +episomal, *iral #NA in con1ylomata an1 most precancero/s lesions. E. Certain chromosome abnormalities9 incl/1ing 1eletions at Bp an1 amplifications of B69 ha*e been associate1 7ith cancers containing specific +$P(-?K, papilloma*ir/ses. K. -ost compelling9 recent 1ata in1icate that *accines 1irecte1 against papilloma*ir/ses can pre*ent infection an1 the 1e*elopment of precancero/s 1isor1ers.
>CC@ >CJ@ >CO@ >EI@ >E?@

)o1e-er, t(e e-idence does not implicate )45 as t(e only factor. A high percentage of yo/ng 7omen are infecte1 7ith one or more $P( types 1/ring their repro1/cti*e years9

an1 only a fe7 1e*elop cancer. !ther cocarcinogens9 the imm/ne stat/s of the in1i*i1/al9 n/trition9 an1 many other factors infl/ence 7hether the $P( infection remains s/bclinical +latent,9 t/rns into a precancer9 or e*ent/ally progresses to cancer. Fig/re 22?J presents an attempt to e3plain the role of $P( in cer*ical carcinogenesis an1 its impact on the pop/lation in the )nite1 "tates.
C ,1%C$* %NT,$ P%T) *%$* N 'P*$(%$

The reason that Papanicolao/ smear screening is so effecti*e in pre*enting cer*ical cancer is that the maDority of cancers are prece1e1 by a precancero/s lesion. This lesion may e3ist in the nonin*asi*e stage for as long as 2I years an1 she1 abnormal cells that can be 1etecte1 on cytologic e3amination. These precancero/s changes sho/l1 be *ie7e1 7ith the follo7ing in min1H +?, they represent a contin//m of morphologic change 7ith in1istinct bo/n1aries< +2, they 1o not in*ariably progress to cancer an1 may spontaneo/sly regress9 7ith the ris; of persistence or progression to cancer increasing 7ith the se*erity of the precancero/s change< +B, they are associate1 7ith papilloma*ir/ses9 an1 high-ris; $P( types are fo/n1 in increasing fre6/ency in the higher-gra1e prec/rsors.
>E2@ >EB@

Fi#ure 22-19 "pectr/m of cer*ical intraepithelial neoplasiaH normal s6/amo/s epitheli/m for comparison< CIN I 7ith ;oilocytotic atypia< CIN II 7ith progressi*e atypia in all layers of the epitheli/m< CIN III +carcinoma in sit/, 7ith 1iff/se atypia an1 loss of mat/ration.

Cer*ical precancers ha*e been classifie1 in a *ariety of 7ays. The ol1est is the dysplasia<carcinoma in situ system 7ith mil1 1ysplasia on one en1 an1 se*ere 1ysplasiaNcarcinoma in sit/ on the other. Another is the cer-ical intraepit(elial neoplasia +CIN, classification9 7ith mil1 1ysplasias terme1 CIN gra1e I an1 carcinoma in sit/ lesions terme1 CIN III. "till another re1/ces these entities to t7o9 terming them lo13 grade and (ig(3grade intraepit(elial lesions. 0eca/se these systems 1escribe nonin*asi*e lesions of in1eterminate biology that are /s/ally easily treate19 none of these classifications is in1ispensable to clinical management or imm/ne to re*ision. In this chapter9 7e refer to lesions by the CIN terminology.
>EB@ >EC@

Morpholo#".

Fig/re 22-?O an1 Fig/re 22-2I ill/strate a spectr/m of morphologic alterations that range from normal to the highest-gra1e precancer9 an1 the host cell genes in*ol*e1 in this process. !n the e3treme lo7 en1 of the spectr/m are lesions that are often in1isting/ishable histologically from con1ylomata ac/minata an1 may be either raise1 +ac/minat/m, or mac/lar +flat con1yloma, in appearance + Fig. 22-?O an1 Fig. 22-2IA ,. These lesions typically e3hibit n/clear enlargement an1 hyperchromasia in the s/perficial epithelial cells9 signifying the effects of acti*e *iral replication in the mat/ring cells +*iral cytopathic effect,. The n/clear changes may be accompanie1 by cytoplasmic halos +;oilocytotic atypia, 7ith fe7 alterations in the lo7er epithelial cells. "/ch changes fall 7ithin the range of CIN I. CIN I often contains ab/n1ant papilloma*ir/s n/cleic aci1s + Fig. 22-2IB ,. 'aise1 lesions +ac/minat/m, often contain lo7-ris; $P(s. Flat CIN /s/ally contain high-ris; $P(s. $o7e*er9 they ha*e a lo7 rate of progression to cancer9 /n1erscoring the fact that the se6/ence of molec/lar e*ents re6/ire1 for lesion progression often 1oes not transpire or is interr/pte1 by the host imm/ne system. The ne3t change in the spectr/m consists of the appearance of atypical cells in the lo7er layers of the
1076

Fi#ure 22-20 A9 $istology of CIN I +flat con1yloma,9 ill/strating the prominent ;oilocytotic atypia in the /pper epithelial cells9 as e*i1ence1 by the prominent perin/clear halos. B9 N/cleic aci1 in sit/ hybri1i:ation of the same lesion for $P( n/cleic aci1s. The bl/e staining 1enotes $P( #NA9 7hich is typically most ab/n1ant in the ;oilocytes. C9 #iff/se imm/nostaining of CIN II for Ri-KL9 ill/strating 7i1esprea1 1ereg/lation of cell cycle controls. *9 )p-reg/lation of p?K?NRC +seen as intense imm/nostaining, characteri:es high-ris; $P( infections.

s6/amo/s epitheli/m b/t nonetheless 7ith persistent +b/t abnormal, 1ifferentiation to7ar1 the pric;le an1 ;eratini:ing cell layers. The atypical cells sho7 changes in n/cleocytoplasmic ratio< *ariation in n/clear si:e< loss of polarity< increase1 mitotic fig/res9 incl/1ing abnormal mitoses< an1 hyperchromasia=in other 7or1s9 they ta;e on some of the characteristics of malignant cells. These lesions fall 7ithin the range of CIN II +see Fig. 22-?O ,. These feat/res ha*e been associate1 7ith ane/ploi1 cell pop/lations an1 correlate strongly 7ith high-ris; $P( types. Pres/mably they reflect early changes in the replicating +basalNparabasal, cell pop/lation associate1 7ith the effects of the EKNEL oncogenes on cell cycle an1 genomic stability. These incl/1e cell cycle 1isreg/lation an1 /p-reg/lation of p!:!/=> + Fig. 22-2IC an1 * ,. Increase1 e3pression of p!:9 a cyclin1epen1ent ;inase inhibitor9 is possibly a compensatory response to cell 1ist/rbances bro/ght on by the *iral oncogenes. As the lesion e*ol*es9 there is progressi*e loss of 1ifferentiation accompanie1 by greater atypia in more layers of the epitheli/m9 /ntil it is totally replace1 by immat/re atypical cells9 e3hibiting no s/rface 1ifferentiation +CIN III, + Fig. 22-?O ,. The cell/lar changes on Papanicolao/ smear that correspon1 to this histologic spectr/m are ill/strate1 in Fig/re 22-2? .
>EE@ >EC@

Altho/gh often ill/strate1 as a simple progression from CIN I to cancer9 the spectr/m of prec/rsor lesions is 6/ite comple3 o7ing to its origins in a site +transformation :one, that s/pports a 7i1e range of epithelial 1ifferentiation9 incl/1ing s6/amo/s9 col/mnar an1 mi3t/res of the t7o. The lo7est-gra1e CIN lesions9 incl/1ing con1ylomata9 most li;ely 1o not progress9 7hereas lesions containing greater 1egrees of cell/lar atypia are at greater ris;. /ot all lesions begin as condylomata or as C6/ 6, and t(ey may enter at any point in t(e se2uence9 1epen1ing on the associate1 $P( type an1 other host factors9 incl/1ing the type of cell +mat/re s6/amo/s9 immat/re metaplastic9 col/mnar9 etc., infecte1 by the *ir/s. The rates of progression are by no means /niform9 an1 altho/gh $P( type is a potential pre1ictor of lesion beha*ior9 it is 1iffic/lt to pre1ict the o/tcome in an in1i*i1/al patient. These fin1ings /n1erscore that ris of cancer is conferred only in part by )45 type an1 may 1epen1 on both host-*ir/s interactions an1 en*ironmental factors to bring abo/t the e*ol/tion of a precancer. Pre1ictably9 lesions that ha*e completely e*ol*e1 +CIN III, constit/te the greatest cancer ris;. CIN III is most fre6/ently associate1 7ith in*asi*e cancer 7hen the latter is i1entifie1. Progression to in*asi*e carcinoma9 7hen it occ/rs9 may 1e*elop in a fe7 months to more than 2I years.
>B@ >EK@

(:2$M'2( C ** C$,C%N'M$

"6/amo/s cell carcinoma may occ/r at any age from the secon1 1eca1e of life to senility. The pea; inci1ence is occ/rring at an increasingly yo/nger ageH CI to CE years for in*asi*e cancer an1 abo/t BI years for high-gra1e precancers. This represents the combination of earlier onset of se3/al acti*ity +i.e.9 earlier ac6/isition of $P( infection, an1 acti*e Papanicolao/ smear screening programs in the )nite1 "tates9 7hich 1etect either cancers or precancero/s lesions at an earlier point in life.
Morpholo#".

%n3asi3e cer3ical carcinoma manifests in three some7hat 1istincti*e patternsH &un#atin# 4or e6oph"tic5= ulceratin#= an/ in&iltrati3e cancers. &ith the a1*ent of

7i1esprea1 screening9 many s6/amo/s cell carcinomas are 1etecte1 at a s/bclinical stage9 often 1/ring e*al/ation of an abnormal Papanicolao/
1077

Fi#ure 22-21 The cytology of cer*ical intraepithelial neoplasia as seen on the Papanicolao/ smear. Cytoplasmic staining in s/perficial cells +A?B , may be either re1 or bl/e. A9 Normal e3foliate1 s/perficial s6/amo/s epithelial cells. B9 CIN I. C9 CIN II. *9 CIN III. Note the re1/ction in cytoplasm an1 the increase in the n/cle/s to cytoplasm ratio9 7hich occ/rs as the gra1e of the lesion increases. This reflects the progressi*e loss of cell/lar 1ifferentiation on the s/rface of the lesions from 7hich these cells are e3foliate1 +see Fig/re 22-?O ,. (Courtesy of *r. Edmund @. Cibas, Brig(am and Women9s )ospital, Boston, MA.$

smear. &hen ob*io/s to the na;e1 eye9 the most common *ariant is the f/ngating t/mor9 7hich pro1/ces an ob*io/sly neoplastic mass that proDects abo*e the s/rro/n1ing m/cosa + Fig. 22-22A ,. A1*ance1 cer*ical carcinoma e3ten1s by 1irect sprea1 to in*ol*e e*ery contig/o/s str/ct/re9 incl/1ing the peritone/m9 /rinary bla11er9 /reters9 rect/m9 an1 *agina. %ocal an1 1istant lymph no1es are also in*ol*e1. #istant metastasis occ/rs to the li*er9 l/ngs9 bone marro79 an1 other str/ct/res. !n histologic e3amination9 abo/t OEP of s6/amo/s carcinomas are compose1 of relati*ely large cells9 either ;eratini:ing +7ell-1ifferentiate1, or non;eratini:ing +mo1erately 1ifferentiate1, patterns. A small s/bset of t/mors +less than EP, are poorly 1ifferentiate1 small cell s6/amo/s or9 more rarely9 small cell /n1ifferentiate1 carcinomas

+ne/roen1ocrine or oat cell carcinomas, + Fig. 22-2B ,. The latter closely resemble oat cell carcinomas of the l/ng an1 ha*e an /n/s/ally poor prognosis o7ing to early sprea1 by lymphatics an1 systemic sprea1. These t/mors are also fre6/ently associate1 7ith a specific high-ris; $P(9 type ?J.
>EL@

Cer*ical cancer is stage1 as follo7sH (ta#e 0. Carcinoma in sit/ +CIN III, (ta#e %. Carcinoma confine1 to the cer*i3 %a. Preclinical carcinoma9 that is9 1iagnose1 only by microscopy %a1. "tromal in*asion no greater than B mm an1 no 7i1er than L mm +so-calle1 microin3asi3e carcinoma, + Fig. 22-22B ,. %a2. -a3im/m 1epth of in*asion of stroma greater than B mm an1 no greater than E mm ta;en from base of epitheli/m9 either s/rface or glan1/lar9 from 7hich it originates< hori:ontal in*asion not more than L mm %!. $istologically in*asi*e carcinoma confine1 to the cer*i3 an1 greater than stage Ia2 (ta#e %%. Carcinoma e3ten1s beyon1 the cer*i3 b/t not onto the pel*ic 7all. Carcinoma in*ol*es the *agina b/t not the lo7er thir1. (ta#e %%%. Carcinoma has e3ten1e1 onto pel*ic 7all. !n rectal e3amination9 there is no cancer-free space bet7een the t/mor an1 the pel*ic 7all. The t/mor in*ol*es the lo7er thir1 of the *agina. (ta#e %1. Carcinoma has e3ten1e1 beyon1 the tr/e pel*is or has in*ol*e1 the m/cosa of the bla11er or rect/m. This stage ob*io/sly incl/1es those 7ith metastatic 1issemination. Ten per cent to 2EP of cer*ical carcinomas are a/enocarcinomas= a/enos<uamous carcinomas=
1079

Fi#ure 22-22 The spectr/m of in*asi*e cer*ical cancer. A9 Carcinoma of the cer*i39 7ell a1*ance1. B9 Early stromal in*asion occ/rring in a cer*ical intraepithelial neoplasm.

un/i&&erentiate/ carcinomas9 or other rare histologic types. The a1enocarcinomas pres/mably arise in the en1ocer*ical glan1s an1 are often prece1e1 by an intraepithelial glan1/lar neoplasm +precancer, terme1 a1enocarcinoma in sit/ that is appro3imately one fifth as common as its s6/amo/s co/nterpart. !nce

Fi#ure 22-2- -orphology of cer*ical cancers. A9 "6/amo/s carcinoma. B9 A1enocarcinoma in sit/ +lo1er,9 associate1 7ith CIN B +upper,. C9 A1enocarcinoma. *9 Ne/roen1ocrine carcinoma.

in*asion 1e*elops9 a1enocarcinomas appear grossly an1 beha*e li;e the s6/amo/s cell lesions9 7ith the e3ception of association 7ith $P( type ?J. The a/enos<uamous carcinomas ha*e mi3e1 glan1/lar an1 s6/amo/s patterns an1 are tho/ght to arise from the m/ltipotent reser*e cells in the basal layers of the en1ocer*ical epitheli/m. They ten1 to ha*e a less fa*orable prognosis than 1oes s6/amo/s cell carcinoma of similar stage. Clear cell a1enocarcinomas of the cer*i3 in #E"-e3pose1 7omen are similar to those occ/rring in the *agina9 1escribe1 earlier. Their relationship to papilloma*ir/ses is /ncertain.
>EJ@

Clinical Course an/ Mana#ement.

Cer*ical cancer pre*ention an1 control can be 1i*i1e1 into se*eral components. !ne incl/1es cytologic screening an1 management of Papanicolao/ smear abnormalities9 both of 7hich may entail the /se of $P( testing. Another is the histologic 1iagnosis an1 remo*al of precancers. "till another component is s/rgical remo*al of in*asi*e cancers9 7ith a1D/ncti*e ra1iation an1 chemotherapy. A final aspect that is c/rrently /n1er

in*estigation is the /se of *accines9 either for pre*enting $P( infection or treating e3isting 1isease. It is apparent from the prece1ing 1isc/ssion that cancer of the cer*i3 e*ol*es slo7ly o*er many years. #/ring this inter*al9 the only sign of 1isease may be the she11ing of abnormal cells from the cer*i3. Therefore9 perio1ic Papanicolao/ smears sho/l1 be performe1 on all 7omen after they become se3/ally acti*e. 'e1/ction in cer*ical cancer 1eaths 7o/l1 theoretically be greatest if all 7omen 7ere screene1 an1 if the acc/racy of 1etecting Papanicolao/ smear abnormalities 7as ma3imi:e1. !nce a cytologic abnormality is 1etecte19 management is pre1icate1 on 7hether the abnormality is clearc/t +CIN, or of /ncertain significance +atypical cells,. The former re6/ires f/rther e3amination by colposcopy. In the latter instance9 $P( testing has been sho7n to ai1 in i1entifying 7hich patients are amenable to yearly follo7-/p +$P( negati*es9 7ith a less than ?P ris; of high-gra1e CIN, or merit colposcopy +$P( positi*es9 7ith a ?EP to 2IP ris; of high-gra1e CIN I,. At some point in the f/t/re9 $P( testing may be /se1 for primary screening of 7omen o*er the age of BI.
>EO@ >KI@

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 or cancero/s con1ition9 treatment re6/ires first that the abnormalities be *is/ali:e1 by colposcopic e3amination of the cer*i3. CIN lesions are characteri:e1 on colposcopic e3am by 7hite patches on the cer*i3 after the application of acetic aci1. In a11ition9 1istinct *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 is facilitate1 by both the application of morphologic criteria an1 also9 recently9 the imm/nohistochemical i1entification of increase1 e3pression of host cell biomar;ers +s/ch as p!:6/=>9 cyclin E9 an1 Ri-KL,. These mar;ers are e3presse1 in a greater proportion of cells in precancero/s lesions +1/e to cell cycle 1ist/rbances, an1 7ill fre6/ently 1isting/ish these from non-neoplastic epithelial changes.
>K2@ >KB@

!nce CIN is confirme1 histologically9 mo1es of treatment 1epen1 on the stage of the neoplasm< treatment of prec/rsor lesions incl/1es Papanicolao/ smear follo7-/p for CIN I9 an1 cryotherapy9 laser9 loop electrical e3cision proce1/res +%EEP,9 an1 cone biopsy for CIN II or CIN III. 'arely +appro3imately ? in EII, a patient 7ith a treate1 CIN III e*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 cone biopsy alone9 most in*asi*e cancers are manage1 by hysterectomy 7ith lymph no1e 1issection an19 for a1*ance1 lesions9 ra1iation. The prognosis an1 s/r*i*al for in*asi*e carcinomas 1epen1 largely on the stage at 7hich cancer is first 1isco*ere1 an1 to some 1egree 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.

&ith c/rrent metho1s of treatment9 there is a E-year s/r*i*al rate of at least OEP for stage IA +incl/1ing microin*asi*e, carcinomas9 abo/t JIP to OIP 7ith stage I09 LEP 7ith stage II9 an1 less than EIP for stage III an1 higher. -ost patients 7ith stage I( cancer 1ie as a conse6/ence of local e3tension of the t/mor +e.g.9 into an1 abo/t the /rinary bla11er an1 /reters9 lea1ing to /reteral obstr/ction9

Fi#ure 22-20 Electron micrograph of *ir/s-li;e papilloma*ir/s particles +(%Ps, pro1/ce1 in e/;aryotic cells 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*e9 early 1etection has re1/ce1 the n/mber of patients 7ith stage I( cancer by o*er t7othir1s in the past EI years. 0eginning in ?OO? a series of p/blications 1escribe1 the pro1/ction in *itro of papilloma*ir/s-li;e particles +(%Ps, by transfecting e/;aryotic cells 7ith *ector-1ri*en $P( #NA + Fig. 22-2C ,. This 1isco*ery pro*i1e1 the /ni6/e opport/nity to manip/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 host response in h/mans. 'ecent p/blications ha*e sho7n that $P( *accines may pre*ent cer*ical $P( infection an19 by inference9 cer*ical cancer. Ass/ming *accination trials against cer*ical papilloma*ir/ses bear fr/it9 it is concei*able that the ne3t 2I years 7ill 7itness 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.
>EI@ >E?@

Body of Uterus and Endometrium

The /ter/s is compose1 principally of smooth m/scle +myometri/m,9 7hich encases the en1ometrial ca*ity. The latter is compose1 of a m/cosa ma1e /p of en1ometrial glan1s an1 s/rro/n1ing stroma. The /ter/s is stim/late1 contin/ally by hormones9 1en/1e1 monthly of its en1ometrial m/cosa9 an1 transiently inhabite1 by fet/ses. It is s/bDect to a

*ariety of 1isor1ers9 the most common of 7hich res/lt from en1ocrine imbalances9 complications of pregnancy9 an1 neoplastic proliferation. Together 7ith the lesions that affect the cer*i3 +ca/sing abnormal pap smears,9 the lesions of the corp/s of the /ter/s an1 the en1ometri/m +ca/sing abnormal *aginal blee1ing, acco/nt for most patient *isits to gynecologic practices.
1090

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

G#atingG the en1ometri/m by its histologic appearance is helpf/l clinically to assess hormonal stat/s9 1oc/ment o*/lation9 an1 1etermine ca/ses of en1ometrial blee1ing an1 infertility. &e can begin 7ith the she11ing of the /pper half to t7o-thir1s of the en1ometri/m 1/ring the menstr/al perio1 + Fig. 22-2E ,. The basal thir1 1oes not respon1 to o*arian steroi1s an1 is retaine1 at the concl/sion of the menstr/al flo7. From the basal thir1 of this preo*/latory proliferati*e

Fi#ure 22-25 Appro3imate 6/antitati*e changes in se*en morphologic criteria fo/n1 to be most /sef/l in 1ating h/man en1ometri/m. (Modified from /oyes AW: /ormal p(ases of t(e endometrium. 6n /orris )J, et al (eds$: 0(e ,terus. Baltimore, Williams ? Wil ins, !";8.$

phase of the cycle9 there is e3tremely rapi1 gro7th of both glan1s an1 stroma +proliferati-e p(ase,. The glan1s are straight9 t/b/lar str/ct/res line1 by reg/lar9 tall9 pse/1ostratifie1 col/mnar cells. -itotic fig/res are n/mero/s9 an1 there is no e*i1ence of m/c/s secretion or *ac/olation + Fig. 22-2KA ,. The en1ometrial stroma is compose1 of thic;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 apparent mitotic acti*ity 7ithin 1ays after o*/lation. The posto*/latory en1ometri/m is initially mar;e1 by basal secretory *ac/oles beneath the n/clei in the

1091

Fi#ure 22-26 $istology of the menstr/al cycle9 incl/1ing the proliferati*e phase 7ith mitoses + A,9 the early secretory 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 ,. This secretory acti-ity is most prominent 1/ring the thir1 7ee; of the menstr/al cycle9 7hen the basal *ac/oles progressi*ely p/sh past the n/clei. 0y the fo/rth 7ee;9 the secretions are 1ischarge1 into the glan1 l/mens. &hen secretion is ma3imal9 bet7een ?J an1 2C 1ays9 the glan1s are 1ilate1. 0y the fo/rth 7ee;9 the glan1s are tort/o/s9 pro1/cing a serrate1 appearance 7hen they are c/t in their long a3is. This serrate1 or Gsa7-toothe1G appearance is accent/ate1 by secretory e3ha/stion an1 shrin;ing of the glan1s. The stromal changes in late secretory phase are important for 1ating the en1ometri/m an1 consist of the 1e*elopment of prominent spiral arterioles by 1ays 2? to 22. A consi1erable increase in gro/n1 s/bstance an1 e1ema bet7een the stromal cells occ/rs + Fig. 22-2KC , an1 is follo7e1 in 1ays 2B to 2C by stromal cell hypertrophy 7ith acc/m/lation of cytoplasmic eosinophilia +pre1eci1/al change, an1 res/rgence of stromal mitoses + Fig. 22-2K* ,. Pre1eci1/al changes sprea1 thro/gho/t the f/nctionalis +the hormonally responsi*e /pper :one, 1/ring 1ays 2C to 2J an1 are accompanie1 by scattere1 ne/trophils an1 occasional lymphocytes + Fig. 22-2KE ,9 7hich here 1o not imply inflammation. This is follo7e1 by 1isintegration of the f/nctionalis an1 escape of bloo1 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*/lation is confirme1 by prominent basal *ac/olation of glan1/lar epithelial cells9 secretory e3ha/stion9 or pre1eci1/al changes. !b*io/sly9 o*/lation cannot be confirme1 1/ring the proliferati*e phase or in the late stages of en1ometrial she11ing 7hen only the basalis is present.
>KC@

Functional n/ometrial Disor/ers 4D"s&unctional 2terine .lee/in#5

#/ring acti*e repro1/cti*e life9 the en1ometri/m is constantly engage1 in the 1ynamics of she11ing an1 regro7th. It is controlle1 by the rise an1 fall of pit/itary an1 o*arian hormones9 an1 this control is e3ec/te1 by proper timing of hormonal release in both absol/te an1 relati*e amo/nts. Alterations in this fine-t/ning mechanism may res/lt in a

spectr/m of 1ist/rbances9 incl/1ing atrophy9 abnormal proliferati*e or secretory patterns9 an1 hyperplasia.
>KC@

0y far the most common problem is the occ/rrence of e3cessi*e blee1ing 1/ring or bet7een 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 instances9 blee1ing is the res/lt of a 7ell-1efine1 organic abnormality9 s/ch as chronic en1ometritis9 s/bm/cosal leiomyomas9 en1ometrial polyp9 or en1ometrial neoplasms. $o7e*er9 the largest single gro/p encompasses f/nctional 1ist/rbances +so-calle1 1ysf/nctional /terine blee1ing, 1/e to abnormalities in the menstr/al cycle or systemic 1iseases.
>KC@

$N'12*$T',; C;C*

In most instances9 1ysf/nctional blee1ing is 1/e to the occ/rrence of an ano*/latory cycle9 7hich res/lts in e3cessi*e an1 prolonge1 estrogenic stim/lation 7itho/t the 1e*elopment of the progestational phase that reg/larly follo7s o*/lation. %ess commonly9 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 Prep/berty A1olescence 'epro1/cti*e age Causes Precocio/s p/berty +hypothalamic9 pit/itary9 or o*arian origin, Ano*/latory cycle9 coag/lation 1isor1ers Complications of pregnancy +abortion9 trophoblastic 1isease9 ectopic pregnancy, !rganic lesions +leiomyoma9 a1enomyosis9 polyps9 en1ometrial hyperplasia9 carcinoma, Ano*/latory cycle !*/latory 1ysf/nctional blee1ing +e.g.9 ina1e6/ate l/teal phase, Perimenopa/sal Ano*/latory cycle Irreg/lar she11ing !rganic lesions +carcinoma9 hyperplasia9 polyps, Postmenopa/sal !rganic lesions +carcinoma9 hyperplasia9 polyps, En1ometrial atrophy

1092

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, a generali:e1 metabolic 1ist/rbance9 s/ch as mar;e1 obesity9 se*ere maln/trition9 or any chronic 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 changes9 incl/1ing cystic 1ilation +persistent proliferati*e en1ometri/m,. )nsche1/le1 brea;1o7n of the stroma may also occ/r +Gano*/latory menstr/ationG,9 7ith no e*i1ence of en1ometrial secretory acti*ity + Fig. 22-2LA ,. -ore se*ere conse6/ences of ano*/lation are 1isc/sse1 /n1er en1ometrial hyperplasia.
%N$D :2$T *2T $* P)$(

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 manifests clinically as infertility9 7ith either increase1 blee1ing or amenorrhea. En1ometrial

Fi#ure 22-27 Common ca/ses of abnormal /terine blee1ing. A9 The most common is 1ysf/nctional /terine blee1ing9 seen here as ano*/latory en1ometri/m 7ith stromal brea;1o7n. Note brea;1o7n associate1 7ith proliferati*e glan1s. B9 Chronic en1ometritis. C9 En1ometrial polyp. *9 "/bm/cosal leiomyoma +lo1er,

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

biopsy performe1 at an estimate1 posto*/latory 1ate sho7s secretory en1ometri/m9 7hich9 ho7e*er9 lags in its secretory characteristics 7ith respect to the e3pecte1 1ate.
ND'M T,%$* C)$NG ( %ND2C D .; ',$* C'NT,$C PT%1 (

As might be s/specte19 oral contracepti*es containing synthetic or 1eri*ati*e o*arian steroi1s in1/ce a 7i1e *ariety of en1ometrial changes9 1epen1ing on the steroi1 /se1 an1 the 1ose. A common response pattern is a 1iscor1ant appearance bet7een glan1s an1 stroma9 /s/ally 7ith inacti*e glan1s ami1 a stroma sho7ing large cells 7ith ab/n1ant cytoplasm reminiscent of the 1eci1/a of pregnancy. &hen s/ch therapy is 1iscontin/e19 the en1ometri/m re*erts to normal. All these changes ha*e been minimi:e1 7ith the ne7er lo7-1ose contracepti*es.
M N'P$2($* $ND P'(TM N'P$2($* C)$NG (

0eca/se the menopa/se is characteri:e1 by ano*/latory cycles9 architect/ral alterations in the en1ometrial glan1s may be present transiently9 follo7e1 by o*arian fail/re an1 atrophy of the en1ometri/m. As 1isc/sse1 ne3t9 a component of
109-

ano*/latory cycles an1 /ninterr/pte1 estrogen pro1/ction incl/1es mil1 hyperplasias 7ith cystic 1ilation of glan1s. If this is follo7e1 by complete o*arian atrophy an1 loss of stim/l/s9 the cystic 1ilation may remain9 7hile the o*arian stroma an1 glan1 epitheli/m /n1ergo atrophy. In this case9 so-calle1 cystic atrophy res/lts. "/ch cystic changes sho/l1 not be conf/se1 7ith more acti*e cystic hyperplasia9 7hich e3hibits e*i1ence of glan1/lar an1 stromal proliferation.
%n&lammation

The en1ometri/m an1 myometri/m are relati*ely resistant to infections9 primarily beca/se the en1ocer*i3 normally forms a barrier to ascen1ing infection. Th/s9 altho/gh chronic inflammation in the cer*i3 is an e3pecte1 an1 fre6/ently insignificant fin1ing9 it is a concern in the en1ometri/m9 e3cl/1ing the menstr/al phase. Ac/te en1ometritis is /ncommon an1 limite1 to bacterial infections that arise after 1eli*ery or miscarriage. 'etaine1 pro1/cts of conception are the /s/al pre1isposing infl/ence9 ca/sati*e agents incl/1ing gro/p A hemolytic streptococci9 staphylococci9 an1 other bacteria. The inflammatory response is chiefly limite1 to the interstiti/m an1 is entirely non-specific. 'emo*al of the retaine1 gestational fragments by c/rettage is promptly follo7e1 by remission of the infection.
C),'N%C ND'M T,%T%(

Chronic inflammation of the en1ometri/m occ/rs in the follo7ing settingsH +?, in patients s/ffering from chronic PI#< +2, in patients 7ith postpartal or postabortal en1ometrial ca*ities9 /s/ally 1/e to retaine1 gestational tiss/e< +B, in patients 7ith intra/terine contracepti*e 1e*ices< an1 +C, in patients 7ith t/berc/losis9 either from miliary sprea1 or9 more commonly9 from 1rainage of t/berc/lo/s salpingitis. The last is 1istinctly rare in &estern co/ntries. The chronic en1ometritis in all these cases represents a secon1ary 1isease9 an1 /n1er these circ/mstances there is a pla/sible ca/se. In abo/t ?EP of cases9 no s/ch primary ca/se is ob*io/s9 yet plasma cells +7hich are not present in normal en1ometri/m, are seen together 7ith macrophages an1 lymphocytes + Fig. 22-2LB ,. "ome 7omen 7ith this so-calle1 non-specific chronic en1ometritis ha*e gynecologic complaints s/ch as abnormal blee1ing9 pain9 1ischarge9 an1 infertility. C(lamydia may be in*ol*e1 an1 is commonly associate1 7ith both ac/te +e.g.9 polymorphon/clear le/;ocytes, an1 chronic +e.g.9 lymphocytes9 plasma cells, inflammatory cell infiltrates. The organisms may or may not be s/ccessf/lly c/lt/re1. Importantly9 antibiotic therapy is in1icate1 beca/se it may pre*ent other se6/elae +e.g.9 salpingitis,.
>KE@

n/ometriosis an/ $/enom"osis

Endometriosis is the term /se1 to 1escribe the presence of endometrial glands or stroma in abnormal locations outside t(e uterus. It occ/rs in the follo7ing sites9 in 1escen1ing or1er of fre6/encyH +?, o*aries< +2, /terine ligaments< +B, recto*aginal sept/m< +C, pel*ic peritone/m< +E, laparotomy scars< an1 +K, rarely in the /mbilic/s9 *agina9 */l*a9 or appen1i3. A closely relate1 1isor1er9 adenomyosis9 is 1efine1 as the presence of endometrial tissue in t(e uterine 1all +myometri/m,. A1enomyosis remains in contin/ity 7ith the en1ometri/m9 pres/mably signifying 1o7ngro7th of en1ometrial tiss/e into an1 bet7een the smooth m/scle fascicles of the myometri/m. A1enomyosis occ/rs in /p to 2IP of /teri. !n microscopic e3amination9 irreg/lar nests of en1ometrial stroma9 7ith or 7itho/t glan1s9 are arrange1 7ithin the myometri/m9 separate1 from the basalis by at least 2 to B mm. In some patients9 the most important conse6/ence of a1enomyosis is she11ing of the en1ometri/m 1/ring the menstr/al cycle + Fig. 22-2J ,. $emorrhage 7ithin these small a1enomyotic nests res/lts in menorrhagia9 colic;y 1ysmenorrhea9 1yspare/nia9 an1 pel*ic pain9 partic/larly 1/ring the premenstr/al perio1. En1ometriosis is an important clinical con1ition< it often ca/ses infertility, dysmenorr(ea, pel-ic pain9 an1 other problems. The 1isor1er is principally a 1isease of 7omen in acti*e repro1/cti*e life9 most often in the thir1 an1 fo/rth 1eca1es9 an1 afflicts appro3imately ?IP of 7omen. Three potential e3planations e3ist regar1ing the origin of these 1isperse1 lesions< they are not m/t/ally e3cl/si*e + Fig. 22-2O ,. ?. 0(e regurgitation<implantation t(eory. 'etrogra1e menstr/ation thro/gh the fallopian t/bes occ/rs reg/larly e*en in normal 7omen an1 co/l1 me1iate sprea1

of en1ometrial tiss/e to the peritoneal ca*ity. En1ometriosis is common in the cer*ical m/cosa9 partic/larly follo7ing s/rgical proce1/res9 s/pporting implantation from abo*e. 2. 0(e metaplastic t(eory. En1ometri/m co/l1 arise 1irectly from coelomic epitheli/m9 from 7hich the mAllerian 1/cts an1 /ltimately the en1ometri/m itself originate 1/ring embryonic 1e*elopment. B. 0(e -ascular or lymp(atic dissemination t(eory. #issemination thro/gh pel*ic *eins an1 lymphatics 7o/l1 e3plain the presence of en1ometriotic lesions in the l/ngs or lymph no1es9 a phenomenon not rea1ily e3plainable by the first t7o theories.

Fi#ure 22-29 A1enomyosis. This 1isor1er is characteri:e1 by f/nctional en1ometrial nests 7ithin the myometri/m9 pro1/cing foci of hemorrhagic cysts 7ithin the /terine 7all.

1090

Fi#ure 22-29 The potential origins of en1ometriosis.

The reg/rgitation implantation theory is the most reasonable e3planation for en1ometriosis seen in the cer*i3 or pel*ic sites9 7hereas the metaplastic theory is an attracti*e e3planation for other sites s/ch as the o*ary. Genetic9 hormonal9 an1 imm/ne factors ha*e also been post/late1 to increase s/sceptibility of some 7omen to en1ometriosis. 0ase1 on the
>KK@

Fi#ure 22--0 En1ometriosis. A9 This o*ary has been sectione1 to re*eal a large en1ometriotic cyst containing necrotic bro7n material consisting of 1egenerate1 bloo1 +chocolate cyst,. B9 %ining of an en1ometriotic cyst from a pregnant patient. !n the right is an en1ometrial glan1< on the left is en1ometrial stroma 7ith pl/mp stromal cells characteristic of 1eci1/al changes. In the center are n/mero/s macrophages containing hemosi1erin.

fin1ing of aromatase cytochrome PCEI in en1ometriotic tiss/e b/t not in normal en1ometri/m9 it has been s/ggeste1 that the en1ometriotic tiss/e possesses the capacity to pro1/ce its o7n estrogens *ia this en:yme. !ther reports in1icate that en1ometriosis is clonal in origin9 s/ggesting important biochemical 1ifferences bet7een en1ometriotic tiss/e an1 normal /terine en1ometri/m.
>KL@

Morpholo#".

The foci of en1ometri/m respon1 to both e3trinsic cyclic +o*arian, an1 intrinsic hormonal stim/lation 7ith perio1ic blee1ing. This pro1/ces no1/les 7ith a re1-bl/e to yello7-bro7n appearance on or D/st beneath the serosal s/rfaces in the site of in*ol*ement. &hen the 1isease is e3tensi*e9 organi:ing hemorrhage ca/ses e3tensi*e fibro/s a1hesions bet7een t/bes9 o*aries9 an1 other str/ct/res an1 obliteration of the po/ch of #o/glas. The o*aries may become mar;e1ly 1istorte1 by large cystic masses +B to E cm in 1iameter, fille1 7ith bro7n bloo1 1ebris +chocolate cysts, + Fig. 22-BIA ,. The histologic 1iagnosis of en1ometriosis is /s/ally straightfor7ar1 b/t may be 1iffic/lt in long-stan1ing cases in 7hich the en1ometrial tiss/e is obsc/re1 by the fibroobliterati*e response. A histologic 1iagnosis of en1ometriosis is satisfie1 if en1ometrial stroma is present9 or in its absence9 mAllerian epitheli/m 7ith s/bDacent hemosi1erin pigment + Fig. 22-BIB ,.
Clinical Course.

Clinical signs an1 symptoms /s/ally consist of se*ere 1ysmenorrhea9 1yspare/nia9 an1 pel*ic pain 1/e to the intrapel*ic blee1ing an1 peri/terine a1hesions. Pain on 1efecation in1icates rectal 7all in*ol*ement9 an1 1ys/ria reflects in*ol*ement of the serosa of the bla11er. Intestinal 1ist/rbances may appear 7hen the small intestine is affecte1. -enstr/al irreg/larities are common9 an1 infertility is the presenting complaint in BIP to

CIP of 7omen. -alignancies may 1e*elop in en1ometriotic lesions at any site9 prompting theories that en1ometriosis is an Gat-ris;G epitheli/m.
>KJ@

1095

n/ometrial Pol"ps

En1ometrial polyps are sessile masses of *ariable si:e that proDect into the en1ometrial ca*ity. They may be single or m/ltiple an1 are /s/ally I.E to B cm in 1iameter b/t occasionally large an1 pe1/nc/late1. Polyps may be asymptomatic or may ca/se abnormal blee1ing if they /lcerate or /n1ergo necrosis. They are generally of t7o histologic types9 ma1e /p of +?, f/nctional en1ometri/m9 paralleling the a1Dacent cycling en1ometri/m9 or +2, more commonly9 hyperplastic en1ometri/m9 mostly of the cystic *ariety. "/ch polyps may 1e*elop in association 7ith generali:e1 en1ometrial hyperplasia an1 are responsi*e to the gro7th effect of estrogen b/t e3hibit no progesterone response + Fig. 22-2LC ,. 'arely9 a1enocarcinomas may arise 7ithin en1ometrial polyps. En1ometrial polyps ha*e been obser*e1 in association 7ith the a1ministration of tamo3ifen9 an antiestrogen fre6/ently /se1 in the therapy of breast cancer. Cytogenetic st/1ies in1icate that the stromal cells in en1ometrial polyps are clonal9 7ith chromosome +Kp2?, rearrangements9 in1icating that genetic alterations may play a role in their 1e*elopment.
>KO@ >LI@

n/ometrial )"perplasia 4 n/ometrial %ntraepithelial Neoplasia5

En1ometrial hyperplasia=recently terme1 endometrial intraepit(elial neoplasia=is another ca/se of abnormal blee1ing that 1iffers from typical ano*/lation by an increase1 glan1 to stroma ratio an1 abnormalities in epithleial gro7th relati*e to normal en1ometri/m. En1ometrial hyperplasia 1eser*es special attention beca/se of its relationship 7ith en1ometrial carcinoma. N/mero/s st/1ies ha*e largely confirme1 the malignant potential of certain en1ometrial hyperplasias an1 the concept of a contin//m of glan1/lar atypia c/lminating9 in some cases9 in carcinoma.
>L?@

En1ometrial hyperplasia is lin;e1 to prolonge1 estrogen stim/lation of the en1ometri/m by ano*/lation or increase1 estrogen pro1/ction. Con1itions promoting hyperplasia incl/1e menopa/se9 polycystic o*arian 1isease +incl/1ing "tein-%e*enthal syn1rome,9 f/nctioning gran/losa cell t/mors of the o*ary9 e3cessi*e cortical f/nction +cortical stroma hyperplasia,9 an1 prolonge1 a1ministration of estrogenic s/bstances +estrogen replacement therapy,. These are the same infl/ences post/late1 to be of pathogenetic significance in some en1ometrial carcinomas9 1isc/sse1 later. A ;ey factor in the 1e*elopment of en1ometrial hyperplasia an1 relate1 cancers is inacti*ation of the 40E/ t/mor s/ppressor gene thro/gh 1eletion an1Nor inacti*ation. It enco1es a phosphatase 7ith 1/al lipi1 an1 protein specificity + Chapter L ,. Its most important f/nction is as a lipi1 phosphatase bloc;ing A;t phosphorylation in the P?BR

path7ay. )noppose1 estrogens normally increase nati*e en1ometrial glan1 PTEN protein pro1/ction9 7hich is constantly e3presse1 1/ring the proliferati*e phase b/t is absent 1/ring the secretory phase. In the absence of PTEN en1ometrial cells become more sensiti*e to stim/lation by estrogens9 an1 this may be integral to the 1e*elopment of hyperplasias an1 s/bse6/ent cancer. 40E/ inacti*ation is seen in KBP of premalignant en1ometrial hyperplasias an1 EIP to JIP of en1ometrial carcinomas. It sho/l1 also be note1 that PTEN loss has been 1oc/mente1 in some normal-appearing en1ometrial glan1s of CBP of premenopa/sal 7omen. The latter obser*ation s/ggests that loss of PTEN e3pression may be an early step in en1ometrial carcinogenesis.
>L2@ >LB@

Morpholo#".

En1ometrial hyperplasia has tra1itionally been s/b1i*i1e1 into lo7er gra1e +simple, an1 higher gra1e +atypical, s/bgro/ps. C/rrently the lo7er-gra1e hyperplasias incl/1e both ano*/latory epitheli/m an19 less commonly9 s/btle en1ometrial intraepithelial neoplasms +EIN,. In contrast9 higher-gra1e hyperplasias9 also terme1 atypical hyperplasias9 typically ha*e the morphologic feat/res +glan1 cro71ing an1 cytologic atypia, an1 genetic characteristics +40E/ m/tations, of intraepithelial neoplasia.
>L?@ >L2@

(imple non-at"pical h"perplasias9 also ;no7n as cystic or mil1 hyperplasias9 are characteri:e1 by architect/ral changes in glan1s of *ario/s si:es9 pro1/cing irreg/larity in glan1 shape9 7ith cystic alterations. The epithelial gro7th pattern an1 cytology are similar to those of proliferati*e en1ometri/m9 altho/gh mitoses are not as prominent + Fig. 22-B?A ,. These lesions /ncommonly progress to a1enocarcinoma an1 largely reflect a response to persistent estrogen stim/lation. These simple cystic GhyperplasiasG fre6/ently e*ol*e into cystic atrophy in 7hich both the epitheli/m an1 stroma become atrophic. Comple6 at"pical h"perplasias 4en/ometrial intraepithelial neoplasias5 e3hibit an increase in the n/mber an1 si:e of en1ometrial glan1s9 7ith glan1 cro71ing9 enlargement9 an1 irreg/lar shape. The latter is principally a manifestation of increase1 cell stratification an1 n/clear enlargement an1 may 1emonstrate comple3ity of the lining epitheli/m 7ith scallope1 or t/fte1 s/rface. The glan1s remain 1istinct an1 nonconfl/ent9 characteristic of an intraepithelial neoplasm + Fig. 22-B?B ,. -itotic fig/res are common. Pre1ictably9 in the most se*ere forms9 cytologic an1 architect/ral atypia may bor1er on a1enocarcinoma9 an1 an acc/rate 1istinction bet7een atypical hyperplasia an1 cancer may not be ma1e 7itho/t hysterectomy. The shift in glan1 morphology from benign to precancero/s is often highlighte1 by a loss of 40E/ gene e3pression + Fig. 22-B?C ,9 altho/gh this is not in*ariable9 an1 the 1iagnosis of hyperplasia is ma1e on histologic gro/n1s. In one st/1y9 2BP of patients 7ith atypical hyperplasias e*ent/ally 1e*elope1 a1enocarcinoma. In another st/1y9 in 7hich atypical hyperplasias 7ere treate1 7ith progestin therapy alone9 EIP persiste1 1espite therapy9 2EP rec/rre19 an1 2EP progresse1 to carcinoma. C/rrently en1ometrial intraepithelial neoplasias are manage1 by hysterectomy or9 in yo/ng 7omen9 a trial of progestin therapy an1 close follo7-/p. Ne*ertheless9 the lo7 rate of regression /s/ally re6/ires e*ent/al remo*al of the /ter/s.
>L?@ >LC@

A proportion of en1ometrial hyperplasias are less easily classifie19 incl/1ing comple3 lesions 7itho/t cell/lar atypia
1096

Fi#ure 22--1 A9 %o7er-gra1e hyperplasias of the en1ometri/m sho7 principally architect/ral glan1/lar changes 7ith cystic glan1/lar 1ilatation an1 are synonymo/s 7ith ano*/latory changes. B9 Atypical hyperplasias +en1ometrial intraepithelial neoplasia, e3hibit increase1 glan1Nstroma ratio +glan1 cro71ing, an1 epithelial stratification +arro1s,. C9 %oss of 40E/ gene e3pression in intraepithelial neoplasia9 seen here as absence of staining. Compare to normal glan1s +arro1s,9 7hich e3press the gene (Courtesy of *r. 'eorge L. Mutter, Brig(am and Women9s )ospital, Boston, MA.$ *9 En1ometrial hyperplasia 7ith s6/amo/s metaplasia.

+/ncommon, an1 those 7ith altere1 cell/lar 1ifferentiation +metaplasia,9 incl/1ing the presence of s6/amo/s9 ciliate1 cell9 an1 m/cino/s metaplasia + Fig. 22-B?* ,. The latter may res/lt from alterations in epithelial-stromal relationships in1/cing the basal en1ometrial cells to follo7 1ifferent 1ifferentiation path7ays. 0eca/se of these n/ances of cell gro7th an1 1ifferentiation9 interpretation of en1ometrial hyperplasia may be highly s/bDecti*e9 an1 th/s precise classification of e*ery change is not possible. Any assessment of a s/specte1 hyperplasia sho/l1 incl/1e the 1egree of atypia in a manner clearly /n1erstan1able by the clinician. The selection of 1iagnostic terminology may
>LE@

mean the 1ifference bet7een cyclic progestin therapy on one han1 an1 contin/o/s high1ose progestin therapy or hysterectomy +or both, on the other.
Mali#nant Tumors o& the n/ometrium
C$,C%N'M$ 'F T) ND'M T,%2M

En1ometrial carcinoma is the most common in*asi*e cancer of the female genital tract an1 acco/nts for LP of all in*asi*e cancer in 7omen9 e3cl/1ing s;in cancer. At one time9 it 7as far less common than cancer of the cer*i39 b/t earlier 1etection an1 era1ication of CIN an1 an increase in en1ometrial carcinomas in yo/nger age gro/ps ha*e re*erse1 this ratio. There are no7 BC9III ne7 en1ometrial cancers per year9 compare1 7ith ?B9III ne7 in*asi*e cer*ical cancers. #espite their high fre6/ency9 en1ometrial cancers arise mainly in postmenopa/sal 7omen9 ca/sing abnormal +postmenopa/sal, blee1ing. This permits early 1etection an1 c/re at an early stage.
%nci/ence an/ Patho#enesis.

Carcinoma of the en1ometri/m is /ncommon in 7omen yo/nger than CI years of age. The pea; inci1ence is in the EE- to KE-year-ol1 7oman. A higher fre6/ency of this form of neoplasia is seen 7ith +?, obesity9 +2, 1iabetes +abnormal gl/cose tolerance is fo/n1 in more than KIP,9 +B, hypertension9 an1 +C, infertility +7omen 7ho 1e*elop cancer of the en1ometri/m ten1 to be single an1 n/lliparo/s an1 to ha*e a history of f/nctional menstr/al irreg/larities consistent 7ith ano*/latory cycles,. Infre6/ently9 both en1ometrial an1 breast carcinomas arise in the same patient.
>LK@

In terms of potential pathogenesis9 t7o general gro/ps of en1ometrial cancer can be i1entifie1. The first 1e*elops on a bac;gro/n1 of prolonge1 estrogen stim/lation an1 endometrial (yperplasia. The close relationship bet7een hyperplasia an1 cancer of the en1ometri/m in this setting is s/pporte1 by the follo7ingH
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0oth hyperplasia an1 cancer are also lin;e1 7ith obesity an1 ano*/latory cycles. &omen 7ith o*arian estrogen-secreting t/mors ha*e a higher ris; of en1ometrial cancer.
1097

En1ometrial cancer is e3tremely rare in 7omen 7ith o*arian agenesis an1 in those castrate1 early in life. Estrogen replacement therapy is associate1 7ith increase1 ris;. Prolonge1 a1ministration of #E" to laboratory animals may pro1/ce en1ometrial polyps9 hyperplasia9 an1 carcinoma. In postmenopa/sal 7omen9 there is greater synthesis of estrogens in bo1y fat from a1renal an1 o*arian an1rogen prec/rsors9 a fin1ing that may partly e3plain 7hy there is increase1 ris; of en1ometrial cancer 7ith age an1 obesity. As 1isc/sse1 pre*io/sly9 inacti*ation of the 40E/ gene is common to en1ometrial hyperplasia an1 cancer9 as is microsatellite instability.
>L2@ >LB@ >LJ@ >LO@

En1ometrial carcinomas that are associate1 7ith hyperplasia an1 the aforementione1 ris; factors ten1 either to be 7ell 1ifferentiate19 mimic;ing normal en1ometrial glan1s +endometrioid, in histologic appearance9 or to 1isplay altere1 1ifferentiation +m/cino/s9 t/bal9 s6/amo/s 1ifferentiation,. This latter gro/p of t/mors is associate1 7ith a more fa*orable prognosis than t/mors 7itho/t hyperplasia. Altho/gh en1ometrial carcinomas may be associate1 7ith separate primary neoplasms arising in o*arian en1ometriosis9 they ten1 to not sprea1 to the peritoneal s/rfaces.
>LL@

A secon1 s/bset of patients 7ith en1ometrial cancer less commonly e3hibits the stigmata of hyperestrinism or pre-e3isting hyperplasia9 an1 ac6/ires the 1isease at a some7hat ol1er a*erage age. In this gro/p9 t/mors are generally more poorly 1ifferentiate19 incl/1ing t/mors that resemble s/btypes of o*arian carcinomas +serous carcinomas,. !*erall9 these t/mors ha*e a poorer prognosis than estrogen-relate1 cancers 1o. In contrast to en1ometrioi1 t/mors9 sero/s s/btypes infre6/ently 1isplay microsatellite instability an1
>LO@

Fi#ure 22--2 A9 En1ometrial a1enocarcinoma presenting as a f/ngating mass in the f/n1/s of the /ter/s. B9 &ell-1ifferentiate1 en1ometrial a1enocarcinoma. Glan1/lar architect/re is preser*e1 b/t the tiss/e is confl/ent 7itho/t inter*ening stroma9 7hich 1isting/ishes carcinoma from hyperplasia. C9 Papillary sero/s carcinoma of the en1ometri/m9 7ith acc/m/lation of n/clear pEB protein as seen by imm/nohistochemistry +inset upper left,.

are lin;e1 to m/tation of p78. They pres/mably begin as s/rface epithelial neoplasms that e3ten1 into a1Dacent glan1 str/ct/res an1 later in*a1e en1ometrial stroma. Their generally poorer prognosis is a conse6/ence of their propensity to e3foliate9 /n1ergo transt/bal sprea19 an1 implant on peritoneal s/rfaces li;e their o*arian co/nterparts.
>LJ@ >LO@

Morpholo#".

In gross appearance9 en1ometrial carcinoma presents either as a locali:e1 polypoi1 t/mor or as a 1iff/se t/mor in*ol*ing the entire en1ometrial s/rface + Fig. 22-B2A ,. "prea1 generally occ/rs by 1irect myometrial in*asion 7ith e*ent/al e3tension to the peri/terine str/ct/res by 1irect contin/ity. "prea1 into the broa1 ligaments may create a clinically palpable mass. #issemination to the regional lymph no1es e*ent/ally occ/rs9 an1 in the late stages9 the t/mor may metastasi:e to the l/ngs9 li*er9 bones9 an1 other organs. In certain types9 specifically papillary sero/s carcinoma9 relati*ely s/perficial en1ometrial in*ol*ement may be associate1 7ith e3tensi*e peritoneal 1isease9 s/ggesting sprea1 by ro/tes +i.e.9 t/bal or lymphatic transmission, other than 1irect in*asion. !n histologic e3amination9 most en1ometrial carcinomas +abo/t JEP, are a/enocarcinomas characteri:e1 by more or less 7ell-1efine1 glan1 patterns closely resembling normal en1ometrial epitheli/m + Fig. 22-B2B ,. A three-step gra1ing system is applie1 to en1ometrioi1 t/mors an1 incl/1es 7ell 1ifferentiate1 +gra1e ?,9 7ith easily recogni:able glan1/lar patterns< mo1erately 1ifferentiate1 +gra1e 2,9 sho7ing 7ellforme1 glan1s mi3e1 7ith soli1 sheets of malignant cells< or poorly 1ifferentiate1 +gra1e B,9 characteri:e1 by soli1 sheets of cells 7ith barely recogni:able glan1s an1 a greater 1egree of n/clear atypia an1 mitotic acti*ity +see belo7,.
1099

)p to 2IP of en1ometrioi1 carcinomas contain foci of s6/amo/s 1ifferentiation. "6/amo/s elements may be histologically benign-appearing 7hen they are associate1 7ith 7ell-1ifferentiate1 a1enocarcinomas. %ess commonly9 mo1erately or poorly 1ifferentiate1 en1ometrioi1 carcinomas contain s6/amo/s elements that appear fran;ly malignant. Terms s/ch as a1enoacanthoma an1 a1enos6/amo/s carcinoma 7ere pre*io/sly assigne1 to these t/mors. C/rrent classification systems gra1e the carcinomas base1 on glan1/lar 1ifferentiation alone an1 /se the term s6/amo/s 1ifferentiation for t/mors falling into these categories.
>LL@ >JI@

As mentione1 earlier9 a s/bset of en1ometrial cancers resemble sero/s carcinomas of the o*ary. They comprise appro3imately 2IP of en1ometrial carcinomas. Gra1ing of these non-en1ometrioi1 carcinomas is /nnecessary 1/e to the poor prognosis conferre1 by these t/mor types. Papillar" serous carcinomas an/ clear cell carcinomas are manage1 as gra1e B carcinomas irrespecti*e of histologic pattern + Fig. 22-B2C ,. "ero/s t/mors in partic/lar are a highly aggressi*e form of /terine cancer9 JIP of 7hich harbor p78 m/tations an1 acc/m/late pEB protein + Fig. 22-B2C inset,.
>LO@ >J?@

"taging of en1ometrial a1enocarcinoma is as follo7sH

>JI@

(ta#e %. Carcinoma is confine1 to the corp/s /teri itself. (ta#e %%. Carcinoma has in*ol*e1 the corp/s an1 the cer*i3. (ta#e %%%. Carcinoma has e3ten1e1 o/tsi1e the /ter/s b/t not o/tsi1e the tr/e pel*is.

(ta#e %1. Carcinoma has e3ten1e1 o/tsi1e the tr/e pel*is or has ob*io/sly in*ol*e1 the m/cosa of the bla11er or the rect/m. Cases in *ario/s stages can also be s/bgro/pe1 7ith reference to the three gra1es 1escribe1 abo*eH G1. &ell-1ifferentiate1 a1enocarcinoma G2. #ifferentiate1 a1enocarcinoma 7ith partly soli1 +less than EIP, areas G-. Pre1ominantly soli1 or entirely /n1ifferentiate1 carcinoma. "ero/s an1 clear cell carcinomas are a/tomatically classifie1 as gra1e B.
Clinical Course.

Carcinoma of the en1ometri/m may be asymptomatic for perio1s of time b/t /s/ally pro1/ces irreg/lar *aginal blee1ing 7ith e3cessi*e le/;orrhea. )terine enlargement in the early stages may be 1ecepti*ely absent. Cytologic 1etection on Papanicolao/ smears is *ariable an1 most li;ely associate1 7ith sero/s carcinomas9 7hich pro1/ce easily 1etache1 cl/sters of cells that are sample1 in pap smears. E3cl/sion of a cer*ical a1enocarcinoma can /s/ally be base1 on cer*i3 e3am an1 the fact that ol1er age gro/ps are m/ch more s/sceptible to primary en1ometrial +*ers/s cer*ical, cancer. $o7e*er9 /pper genital tract carcinomas +fallopian t/be an1 o*ary, may be associate1 7ith abnormal cytology. The 1iagnosis of en1ometrial cancer m/st /ltimately be establishe1 by c/rettage an1 histologic e3amination of the tiss/e. As 7o/l1 be anticipate19 the prognosis 1epen1s hea*ily on the clinical stage of the 1isease 7hen it is 1isco*ere19 an1 its histologic gra1e an1 type. In the )nite1 "tates9 most 7omen +abo/t JIP, ha*e stage I 1isease clinically an1 ha*e 7ell-1ifferentiate1 or mo1erately 7ell-1ifferentiate1 en1ometrioi1 carcinomas. "/rgery9 alone or in combination 7ith irra1iation9 gi*es abo/t OIP E-year s/r*i*al in stage I +gra1e ? or 2, 1isease. This rate 1rops to appro3imately LEP for gra1e BNstage I an1 to EIP or less for stage II an1 III en1ometrial carcinomas. As mentione19 /terine papillary sero/s an1 clear cell carcinomas ha*e a propensity for e3tra/terine +lymphatic or transt/bal, sprea19 e*en 7hen confine1 to the en1ometri/m or its s/rface epitheli/m. !*erall9 fe7er than EIP of patients 7ith these t/mors are ali*e B years after 1iagnosis an1 BEP after E years. If peritoneal cytology an1 a1ne3al histologic e3am are negati*e9 the fi*e year s/r*i*al of stage I 1isease is appro3imately JIP to JEP. The a11itional a1*antage of prophylactic ra1iation or chemotherapy in early-stage 1isease is /nclear.
>J2@ >JB@ >JC@

Tumors o& the n/ometrium >ith (tromal Di&&erentiation

A proportion of en1ometrial a1enocarcinomas /n1ergo stromal 1ifferentiation an1 are terme1 carcinosarcomas. A secon1 gro/p is compose1 of stromal neoplasias in

association 7ith benign glan1s +a1enosarcomas,. A thir1 gro/p consists of p/re stromal neoplasms9 ranging from benign +stromal no1/le, to malignant +stromal sarcoma,. Together9 these t/mors comprise less than EP of en1ometrial cancers.
C$,C%N'($,C'M$(

Carcinosarcomas +formerly terme1 malignant mi3e1 mAllerian t/mors, consist of en1ometrial a1enocarcinomas in 7hich malignant stromal 1ifferentiation ta;es place. The stroma ten1s to 1ifferentiate into a *ariety of malignant meso1ermal components9 incl/1ing m/scle9 cartilage9 an1 e*en osteoi1. The epithelial an1 stromal components are pres/mably 1eri*e1 from the same cell9 a concept s/pporte1 by the obser*ation that the stromal cells often stain positi*e for epithelial cell mar;ers. Carcinosarcomas occ/r in postmenopa/sal 7omen an1 manifest9 similarly to a1enocarcinoma9 7ith postmenopa/sal blee1ing. -any affecte1 patients gi*e a history of pre*io/s ra1iation therapy.
>JE@

Morpholo#".

In gross appearance9 s/ch t/mors are some7hat more fleshy than a1enocarcinomas9 may be b/l;y an1 polypoi19 an1 sometimes protr/1e thro/gh the cer*ical os. !n histology9 the t/mors consist of a1enocarcinoma mi3e1 7ith the stromal +sarcoma, elements + Fig. 22BBA ,< alternati*ely9 the t/mor may contain t7o 1istinct an1 separate epithelial an1 mesenchymal components. "arcomato/s components may mimic e3tra/terine tiss/es +i.e.9 striate1 m/scle cells9 cartilage9 a1ipose tiss/e9 an1 bone,. !/tcome is 1etermine1 primarily by 1epth of in*asion an1 stage. As 7ith en1ometrial carcinomas9 the prognosis may be infl/ence1 by the gra1e an1 type of the a1enocarcinoma9 being poorest 7ith sero/s 1ifferentiation. It is note7orthy that carcinosarcomas /s/ally metastasi:e as a1enocarcinomas. The t/mors are highly malignant9 an1 patients ha*e a E-year s/r*i*al rate of 2EP to BIP.
>JE@

1099

Fi#ure 22--- A9 Carcinosarcoma9 sho7ing both epithelial +upper rig(t, an1 stromal +arro1, 1ifferentiation. B9 En1ometrial stromal sarcoma infiltrating myometri/m. C9 Fl/orescent in sit/ hybri1i:ation /sing t7o fl/orescently labele1 probes +green and red, that flan; the brea;point of the gene in*ol*e1 in the chromosomal translocation t+L<?L, in en1ometrial stromal sarcoma. The yello7 signal is in1icati*e of the normal copy of chromosome L. A separate green an1 re1 signal in1icates that the gene on chromosome L has been re1istrib/te1. (Courtesy of *r. Marisa A. /ucci, Brig(am and Women9s )ospital, Boston, MA.$

$D N'($,C'M$(

A1enosarcomas present most commonly as large broa1-base1 en1ometrial polypoi1 gro7ths9 an1 may prolapse thro/gh the cer*ical os. The 1iagnosis is base1 on malignant appearing stroma9 7hich coe3ists 7ith benign b/t abnormally shape1 en1ometrial glan1s. These t/mors pre1ominate in 7omen bet7een the fo/rth an1 fifth 1eca1es an1 are generally consi1ere1 to be of lo7 gra1e malignancy< rec/rrences 1e*elop in one-fo/rth an1 are nearly al7ays confine1 to the pel*is. The principal 1iagnostic 1ilemma is 1isting/ishing these t/mors from large benign polyps. The 1istinction is important beca/se oophorectomy is typically performe1 in cases of a1enosarcoma since they are estrogen sensiti*e.
>JK@

(T,'M$* T2M',(

The en1ometrial stroma occasionally gi*es rise to neoplasms that may resemble normal stromal cells. "imilar to most neoplasms9 they may be 7ell or poorly 1ifferentiate1. "tromal neoplasms are 1i*i1e1 into t7o categoriesH +?, benign stromal no1/les an1 +2, en1ometrial stromal sarcomas.
Morpholo#".

(tromal no/ule is a 7ell-circ/mscribe1 aggregate of en1ometrial stromal cells in the myometri/m that 1oes not penetrate the myometri/m an1 is of little conse6/ence. (tromal sarcoma consists of neoplastic en1ometrial stroma lying bet7een m/scle b/n1les of the myometri/m an1 is 1isting/ishe1 from stromal no1/les by either 1iff/se infiltration of myometrial tiss/e or the penetration of lymphatic channels +pre*io/sly terme1 en/ol"mphatic stromal m"osis, + Fig. 22-BBB ,. Abo/t half of these t/mors rec/r9 7ith relapse rates of BKP to o*er JIP for "tage I an1 "tage IIINI( t/mor9 respecti*ely< relapse cannot be pre1icte1 by either mitotic in1e3 or 1egree of cytologic atypia. #istant metastases9 7hich sometimes may occ/r 1eca1es after initial 1iagnosis9 an1 1eath from metastatic t/mor occ/r in abo/t ?EP of cases. Fi*e-year s/r*i*al rates a*erage EIP. 'ecent st/1ies in1icate that a rec/rrent chromosomal translocation9 t+L<?L,+p?E<62?,9 occ/rs in en1ometrial stromal sarcoma. As a conse6/ence of this translocation9 the f/sion of t7o pre*io/sly /n;no7n genes9 JAB+! an1 JJAB! occ/rs9 7ith pro1/ction of a f/sion transcript an1 protein + Fig. 22-BBC ,.
>JL@ >JJ@

Tumors o& the M"ometrium

* %'M;'M$(

)terine leiomyomas +commonly calle1 fibroids, are perhaps the most common t/mor in h/mans. These benign t/mors may be present in abo/t LEP of females of repro1/cti*e age9 an1 each /ter/s harbors an a*erage of K.E t/mors. Each /terine leiomyoma is a /ni6/e clonal neoplasm. -ost leiomyomas ha*e normal ;aryotypes9 b/t appro3imately CIP ha*e a simple chromosomal abnormality. "i3 cytogenetic s/bgro/ps ha*e been recogni:e1H a balance1 translocation bet7een chromosomes ?2 an1 ?C +i.e.9 t+?2<?C,+6?C?C<62B-2C,,9 partial 1eletions of the long arm of chromosome L +i.e.9 1el+L,+6226B2,,9 trisomy ?29 an1 rearrangements of Kp9 B6 an1 ?I6. The n/mber an1 *ariety of cytogenetic abnormalities s/ggest that more than one genetic mechanism can lea1 to leiomyoma gro7th.
>JO@ >OI@

1090

Fi#ure 22--0 A9 %eiomyomas of the myometri/m. The /ter/s is opene1 to re*eal the t/mors b/lging into the en1ometrial ca*ity an1 1isplaying a firm 7hite appearance on sectioning. B9 %eiomyoma sho7ing 7ell1ifferentiate19 reg/lar9 spin1le-shape1 smooth m/scle cells.

Morpholo#".

%eiomyomas are sharply circ/mscribe19 1iscrete9 ro/n19 firm9 gray-7hite t/mors *arying in si:e from small9 barely *isible no1/les to massi*e t/mors that fill the pel*is. E3cept in rare instances9 they are fo/n1 7ithin the myometri/m of the corp/s. !nly infre6/ently 1o they in*ol*e the /terine ligaments9 lo7er /terine segment9 or cer*i3. They can occ/r 7ithin the myometri/m +intram/ral,9 D/st beneath the en1ometri/m +s/bm/cosal, + Fig. 22-BCA an1 Fig. 22-2L* ,9 or beneath the serosa +s/bserosal,. &hate*er their si:e9 the characteristic 7horle1 pattern of smooth m/scle b/n1les on c/t section /s/ally ma;es these lesions rea1ily i1entifiable on gross inspection. %arge t/mors may 1e*elop areas of yello7-bro7n to re1 softening +re1 1egeneration,. !n histologic e3amination9 the leiomyoma is compose1 of 7horle1 b/n1les of smooth m/scle cells that resemble the /nin*ol*e1 myometri/m + Fig. 22-BCB ,. )s/ally9 the

in1i*i1/al m/scle cells are /niform in si:e an1 shape an1 ha*e the characteristic o*al n/cle/s an1 long9 slen1er bipolar cytoplasmic processes. -itotic fig/res are scarce. 0enign *ariants of leiomyoma incl/1e atypical or bi:arre +symplastic, t/mors 7ith n/clear atypia an1 giant cells an1 cell/lar leiomyomas. Importantly9 both ha*e a lo7 mitotic in1e3. An e3tremely rare *ariant9 !eni#n metastasi?in# leiom"oma9 consists of a /terine t/mor that e3ten1s into *essels an1 migrates to other sites9 most commonly the l/ng. Another *ariant9 /isseminate/ peritoneal leiom"omatosis9 presents as m/ltiple small no1/les on the peritone/m. 0oth are consi1ere1 benign 1espite their /n/s/al beha*ior. %eiomyomas of the /ter/s9 e*en 7hen they are e3tensi*e9 may be asymptomatic. The most important symptoms are pro1/ce1 by s/bm/cosal leiomyomas +abnormal blee1ing,9 compression of the bla11er +/rinary fre6/ency,9 s/11en pain if 1isr/ption of bloo1 s/pply occ/rs9 an1 impaire1 fertility. -yomas in pregnant 7omen increase the fre6/ency of spontaneo/s abortion9 fetal malpresentation9 /terine inertia9 an1 postpart/m hemorrhage. -alignant transformation +leiomyosarcoma, 7ithin a leiomyoma is e3tremely rare.
* %'M;'($,C'M$(

These /ncommon malignant neoplasms arise 1e no*o 1irectly from the myometri/m or en1ometrial stroma /n1ergoing smooth m/scle 1ifferentiation. In contrast to leiomyomas9 leiomyosarcomas ha*e ;aryotypes that are comple3 an1 more ran1om relati*e to those 1escribe1 abo*e for leiomyomas. These incl/1e 1eletions i1entifie1 on a n/mber of chromosomes that are not seen in the benign t/mors.
>O?@

Morpholo#".

%eiomyosarcomas gro7 7ithin the /ter/s in t7o some7hat 1istincti*e patternsH b/l;y9 fleshy masses that in*a1e the /terine 7all9 or polypoi1 masses that proDect into the /terine l/men + Fig. 22-BEA ,. !n histologic e3amination9 they contain a 7i1e range of atypia9 from those that are e3tremely 7ell 1ifferentiate1 to anaplastic lesions that ha*e the cytologic abnormalities of 7il1ly gro7ing sarcomas + Fig. 22-BEB ,. The 1istinction of leiomyosarcomas from leiomyomas is base1 on the combination of 1egree of n/clear atypia9 mitotic in1e39 an1 :onal necrosis. &ith fe7 e3ceptions9 the presence of ten or more mitoses per ten high-po7er +2CII, fiel1s in1icates malignancy9 7ith or 7itho/t cell/lar atypism. If the t/mor contains n/clear atypia or large +epithelioi1, cells9 fi*e mitoses per ten high-po7er fiel1s are s/fficient to D/stify a 1iagnosis of malignancy. 'are e3ceptions incl/1e mitotically acti*e leiomyomas in yo/ng or pregnant 7omen9 an1 ca/tion sho/l1 be e3ercise1 in interpreting s/ch neoplasms as malignant. A proportion of smooth m/scle neoplasms may be impossible to classify an1 are terme1 smooth m/scle t/mors of G/ncertain malignant potential.G
>O2@ >O2@

%eiomyosarcomas are e6/ally common before an1 after menopa/se9 7ith a pea; inci1ence at CI to KI years of age. These t/mors ha*e a stri;ing ten1ency to rec/r after remo*al9 an1 more than half the cases e*ent/ally metastasi:e thro/gh the bloo1stream to 1istant organs9 s/ch as l/ngs9 bone9 an1 brain. #issemination thro/gho/t the ab1ominal ca*ity is also enco/ntere1. The E-year s/r*i*al rate a*erages abo/t CIP. The 7ell-

1ifferentiate1 lesions ha*e a better prognosis than the anaplastic lesions9 7hich ha*e a lo7 E-year s/r*i*al rate of abo/t ?IP to ?EP.
>O2@

1091

Fi#ure 22--5 %eiomyosarcoma. A, A large hemorrhagic t/mor mass 1isten1s the lo7er corp/s an1 is flan;e1 by t7o leiomyomas. B, The t/mor cells are irreg/lar in si:e an1 ha*e hyperchromatic n/clei.

Fallopian Tubes
The most common 1isor1ers in these str/ct/res are inflammations9 follo7e1 in fre6/ency by ectopic +t/bal, pregnancy +see 1isc/ssion later in this chapter, an1 en1ometriosis.
%n&lammations

@uppurati-e salpingitis may be ca/se1 by any of the pyogenic organisms9 an1 often more than one is in*ol*e1. The gonococc/s still acco/nts for more than KIP of cases of s/pp/rati*e salpingitis9 7ith chlamy1iae less often a factor. These t/bal infections are a part of PI# 1escribe1 earlier in this chapter 0uberculous salpingitis is e3tremely /ncommon in the )nite1 "tates an1 acco/nts for probably not more than ?P to 2P of all forms of salpingitis. It is more common9 ho7e*er9 in parts of the 7orl1 7here t/berc/losis is pre*alent an1 is an important ca/se of infertility in these areas.

Tumors an/ C"sts

The most common primary lesions of the fallopian t/be +e3cl/1ing en1ometriosis, are min/te9 I.?- to 2-cm transl/cent cysts fille1 7ith clear sero/s fl/i19 calle1 paratubal cysts. %arger *arieties are fo/n1 near the fimbriate1 en1 of the t/be or in the broa1 ligaments an1 are referre1 to as (ydatids of Morgagni. These cysts are pres/me1 to arise in remnants of the mAllerian 1/ct an1 are of little significance. T/mors of the fallopian t/be are /ncommon. 0enign t/mors incl/1e adenomatoid tumors +mesotheliomas,9 7hich occ/r s/bserosally on the t/be or sometimes in the mesosalpin3. These small no1/les are the e3act co/nterparts of those alrea1y 1escribe1 in relation to the testes or epi1i1ym/s + Chapter 2? , an1 are benign. Primary adenocarcinoma of the fallopian t/bes is rare an1 is 1efine1 as an a1enocarcinoma 7ith a 1ominant t/bal mass an1 l/minal an1 m/cosal in*ol*ement. These t/mors are 1etecte1 by pel*ic e3am9 abnormal 1ischarge or blee1ing9 an1 occasionally9 cer*ical cytology. Appro3imately one half are stage I at 1iagnosis9 b/t nearly CIP of these patients 7ill not s/r*i*e E years. $igher stage t/mors ha*e a poor prognosis. Patients are typically manage1 7ith o*arian cancer chemotherapy protocols. 'ecently9 occ/lt carcinoma of the fallopian t/be has been associate1 7ith BACA m/tations9 re6/iring attention to this site as a potential so/rce of t/mors in patients 7ith BACA germ-line m/tations.
>OB@ >OC@

1092

Ovaries
The most common types of lesions enco/ntere1 in the o*ary incl/1e f/nctional or benign cysts an1 t/mors. Intrinsic inflammations of the o*ary +oophoritis, are /ncommon9 /s/ally accompanying t/bal inflammation. 'arely9 a primary inflammatory 1isor1er in*ol*ing o*arian follicles +a/toimm/ne oophoritis, occ/rs an1 is associate1 7ith infertility.
Non-Neoplastic an/ Functional C"sts
F'**%C2*$, $ND *2T $* C;(T(

Cystic follicles in the o*ary are so common as to be *irt/ally physiologic. They originate in /nr/pt/re1 graafian follicles or in follicles that ha*e r/pt/re1 an1 imme1iately seale1.
Morpholo#".

These cysts are /s/ally m/ltiple. They range in si:e /p to 2 cm in 1iameter9 are fille1 7ith a clear sero/s fl/i19 an1 are line1 by a gray9 glistening membrane. !n occasion9 larger cysts e3cee1ing 2 cm +follic/lar cysts, may be 1iagnose1 by palpation or /ltrasonography an1 ca/se pel*ic pain. Gran/losa lining cells can be i1entifie1 histologically if the intral/minal press/re has not been too great. The o/ter theca cells may be conspic/o/s 7ith increase1 cytoplasm an1 a pale appearance +l/teini:e1,. As 1isc/sse1 s/bse6/ently9 7hen this alteration is prono/nce1 +hyperthecosis,9 it may /ltimately res/lt in increase1 estrogen pro1/ction an1 en1ometrial abnormalities.

Gran/losa luteal c"sts +corpora l/tea, are normally present in the o*ary. These cysts are line1 by a rim of bright yello7 l/teal tiss/e containing l/teini:e1 gran/losa cells. They occasionally r/pt/re an1 ca/se a peritoneal reaction. &hen a1*ance19 the combination of ol1 hemorrhage an1 fibrosis may ma;e their 1istinction from en1ometriotic cysts 1iffic/lt.
P'*;C;(T%C '1$,% ( $ND (T,'M$* );P ,T) C'(%(

4olycystic o-arian disease +PC!#9 formerly terme1 @tein3Le-ent(al syndrome, affects BP to KP of repro1/cti*e-age 7omen. The central pathologic abnormality is n/mero/s cystic follicles or follicle cysts9 often associate1 7ith oligomenorrhea. Patients 7ith PC!# ha*e persistent ano*/lation9 obesity +CIP,9 hirs/tism +EIP,9 an19 rarely9 *irilism.
>OE@ >OK@

Morpholo#".

The o*aries are /s/ally t7ice normal si:e9 gray-7hite 7ith a smooth o/ter corte39 an1 are st/11e1 7ith s/bcortical cysts I.E to ?.E cm in 1iameter. !n histologic e3amination9 there is a thic;ene1 s/perficial corte3 beneath 7hich are inn/merable follicle cysts 7ith hyperplasia of the theca interna +follic/lar hyperthecosis, + Fig. 22-BKAC* ,. Corpora l/tea are fre6/ently b/t not in*ariably absent. The initiating e*ent in polycystic o*arian 1isease is not clear. Increase1 secretion of l/teini:ing hormone may stim/late the theca-l/tein cells of the follicles9 7ith e3cessi*e pro1/ction of an1rogen +an1rostene1ione,9 7hich is con*erte1 to estrone. For years9 these en1ocrine abnormalities 7ere attrib/te1 to primary o*arian 1ysf/nction beca/se large 7e1ge resections of the o*aries sometimes restore1 fertility. It is no7 belie*e1 that a *ariety of en:ymes in*ol*e1 in an1rogen biosynthesis are poorly reg/late1 in polycystic o*arian 1isease. 'ecent st/1ies lin; polycystic o*arian 1isease9 li;e type II 1iabetes9 to ins/lin resistance. A1ministration of ins/lin me1iators has been associate1 7ith res/mption of o*/lation.
>OL@

@tromal (ypert(ecosis9 also calle1 cortical stromal hyperplasia9 is a 1isor1er of o*arian stroma most commonly seen in postmenopa/sal 7omen9 b/t it may blen1 7ith polycystic o*arian 1isease in yo/nger 7omen. The 1isor1er is characteri:e1 by /niform enlargement of the o*ary +/p to L cm, 7ith a 7hite to tan appearance on sectioning. The in*ol*ement is /s/ally bilateral an1 microscopically consists of hypercell/lar stroma 7ith l/teini:ation of the stromal cells9 7hich are *isible as 1iscrete nests 7ith *ac/olate1 cytoplasm. The clinical presentation an1 effects on the en1ometri/m are similar to those of polycystic o*arian 1isease9 altho/gh *irili:ation may be stri;ing.
>OE@

A physiologic con1ition mimic;ing the abo*e syn1romes is t(eca lutein (yperplasia of pregnancy. In response to pregnancy

Fi#ure 22--6 Polycystic o*arian 1isease an1 cortical stromal hyperplasia. A, The o*arian corte3 re*eals n/mero/s clear cysts. B, "ectioning of the corte3 re*eals se*eral s/bcortical cystic follicles. C, Cystic follicles seen in a lo7-po7er microphotograph. *, Cortical stromal hyperplasia manifests as 1iff/se stromal proliferation 7ith symmetrical enlargement of the o*ary.

109-

hormones +gona1otropins,9 proliferation of theca cells 7ith e3pansion of the perifollic/lar :one occ/rs. As the follicles regress9 the concentric theca-l/tein hyperplasia may appear no1/lar. This change is not to be conf/se1 7ith tr/e l/teomas of pregnancy +see belo7,.
'3arian Tumors

T/mors of the o*ary are common forms of neoplasia in 7omen. Among cancers of the female genital tract9 the inci1ence of o*arian cancer ran;s belo7 only carcinoma of the cer*i3 an1 the en1ometri/m. !*arian cancer acco/nts for KP of all cancers in the female an1 is the fifth most common form of cancer in 7omen in the )nite1 "tates +e3cl/1ing s;in cancer,. In a11ition9 beca/se many of these o*arian neoplasms cannot be 1etecte1 early in their 1e*elopment9 they acco/nt for a 1isproportionate n/mber of fatal cancers9 being responsible for almost half of the 1eaths from cancer of the female genital tract. There are n/mero/s types of o*arian t/mors9 both benign an1 malignant. Abo/t JIP are benign9 an1 these occ/r mostly in yo/ng 7omen bet7een the ages of 2I an1 CE years. The malignant t/mors are more common in ol1er 7omen bet7een the ages of CI an1 KE years.
>OJ@

Patho#enesis.

'is; factors for o*arian cancer are m/ch less clear than for other genital t/mors9 b/t n/lliparity9 family history9 an1 heritable m/tations play a role in t/mor 1e*elopment. There is a higher fre6/ency of carcinoma in /nmarrie1 7omen an1 in marrie1 7omen 7ith lo7 parity. Gona1al 1ysgenesis in chil1ren is associate1 7ith a higher ris; of o*arian cancer. &omen CI to EO years of age 7ho ha*e ta;en oral contracepti*es or

>OC@ >OO@

/n1ergone t/bal ligation ha*e a re1/ce1 ris; of 1e*eloping o*arian cancer. The most intrig/ing ris; factors are genetic. As 1isc/sse1 in Chapter L an1 Chapter 2B 9 m/tations in both BACA! an1 BACAD increase s/sceptibility to o*arian cancer. BACA! m/tations occ/r in abo/t EP of patients yo/nger than LI years of age 7ith o*arian cancer. The estimate1 ris; of o*arian cancer in 7omen bearing BACA! or BACAD m/tations is 2IP to KIP by the age of LI years. -ost of these cancers are sero/s cysta1enocarcinomas. Appro3imately BIP of o*arian a1enocarcinomas e3press high le*els of )EAD<neu +E'0-02, oncogene9 7hich correlates 7ith a poor prognosis. -/tations in the t/mor-s/ppressor gene p78 are fo/n1 in EIP of o*arian carcinomas.
>?II@ >?I?@ >?I2@ >OC@ >OO@ >OO@ >OO@

Classi&ication.

The classification of o*arian t/mors gi*en in Table 22-B an1 Fig/re 22-BL is a simplifie1 *ersion of the &orl1 $ealth !rgani:ation $istological Classification9 7hich separates o*arian neoplasms accor1ing to the most probable tiss/e of origin. It is no7 belie*e1 that t/mors of the o*ary arise /ltimately from one of three o*arian componentsH +?, s/rface epitheli/m 1eri*e1 from either the coelomic epitheli/m or ectopic en1ometrial epitheli/m +see en1ometriosis9 later,. The former gi*es rise to the mAllerian epitheli/m 1/ring embryonic 1e*elopment. From it are 1eri*e1 the fallopian t/bes +ciliate1 col/mnar sero/s cells,9 the en1ometrial lining +nonciliate19 col/mnar cells,9 or the en1ocer*ical glan1s +m/cino/s nonciliate1 cells,< +2, the germ cells9 7hich migrate to the o*ary from the yol; sac an1 are totipotential< an1 +B, the stroma of the o*ary9 7hich incl/1es the se3 cor1s9 forer/nners of the en1ocrine apparat/s of the postnatal o*ary. There is9 as /s/al9 a gro/p of t/mors that 1efy classification9 an1 finally there are secon1ary or metastatic t/mors9 the o*ary T$.* 22-- -- !*arian Neoplasms +?OOB &$! Classification, Surface Epithelial-Stromal Tumors "ero/s t/mors 0enign +cysta1enoma, Cysta1enoma of bor1erline malignancy -alignant +sero/s cysta1enocarcinoma, -/cino/s t/mors9 en1ocer*ical-li;e an1 intestinal type 0enign !f bor1erline malignancy -alignant En1ometrioi1 t/mors 0enign

!f bor1erline malignancy -alignant Epithelial-stromal A1enosarcoma -eso1ermal +mAllerian, mi3e1 t/mor Clear cell t/mors 0enign !f bor1erline malignancy -alignant Transitional cell t/mors 0renner t/mor 0renner t/mor of bor1erline malignancy -alignant 0renner t/mor Transitional cell carcinoma +non-0renner type, Sex Cord-Stromal Tumors Gran/losa-stromal cell t/mors Gran/losa cell t/mors T/mors of the thecoma-fibroma gro/p "ertoli-stromal cell t/mors< an1roblastomas "e3 cor1 t/mor 7ith ann/lar t/b/les Gynan1roblastoma "teroi1 +lipi1, cell t/mors Germ Cell Tumors Teratoma Immat/re -at/re +a1/lt,

"oli1 Cystic +1ermoi1 cyst, -ono1ermal +e.g.9 str/ma o*arii9 carcinoi1, #ysgerminoma 5ol; sac t/mor +en1o1ermal sin/s t/mor, -i3e1 germ cell t/mors Malignant, Not ther!ise Specified Metastatic Nonovarian Cancer "from Nonovarian #rimar$% *ata from t(e W)E Classification. (Courtesy *r. Aobert @cully, Massac(usetts 'eneral )ospital, Boston, MA.$

being a common site of metastases from a *ariety of other cancers. Altho/gh some of the specific t/mors ha*e 1istincti*e feat/res an1 are hormonally acti*e9 most are nonf/nctional an1 ten1 to pro1/ce relati*ely mil1 symptoms /ntil they ha*e reache1 a large si:e. -alignant t/mors ha*e /s/ally sprea1 o/tsi1e the o*ary by the time a 1efiniti*e 1iagnosis is ma1e. "ome of these t/mors9 principally epithelial t/mors9 ten1 to be bilateral. Table 22-C lists these t/mors an1 their s/btypes an1 sho7s the fre6/ency of bilateral occ/rrence. Ab1ominal pain an1 1istention9 /rinary an1 gastrointestinal tract symptoms 1/e to compression by t/mor or cancer in*asion9 an1 ab1ominal an1 *aginal blee1ing are the most common symptoms. The benign forms may be entirely asymptomatic an1 occasionally are /ne3pecte1 fin1ings on ab1ominal or pel*ic e3amination or 1/ring s/rgery.
1090

Fi#ure 22--7 #eri*ation of *ario/s o*arian neoplasms an1 some 1ata on their fre6/ency an1 age 1istrib/tion.

T$.* 22-0 -- Fre6/ency of -aDor !*arian T/mors T"pe "ero/s 0enign +KIP, 0or1erline +?EP, -alignant +2EP, -/cino/s 0enign +JIP, 0or1erline +?IP, -alignant +?IP, ?I E ?I SE Percenta#e o& Mali#nant '3arian Tumors CI 2E BI KE Percenta#e That $re .ilateral

T$.* 22-0 -- Fre6/ency of -aDor !*arian T/mors T"pe En1ometrioi1 carcinoma )n1ifferentiate1 carcinoma Clear cell carcinoma Gran/losa cell t/mor Teratoma 0enign +OKP, -alignant +CP, -etastatic !thers ? E B 'are TEI = Percenta#e o& Mali#nant '3arian Tumors 2I ?I K E Percenta#e That $re .ilateral CI = CI E ?E

T2M',( 'F M@** ,%$N P%T) *%2M

Most primary neoplasms in t(e o-ary fall 1it(in t(is category. There are three maDor types of s/ch t/morsH sero/s9 en1ometrioi1 an1 m/cino/s t/mors. These neoplasms range in si:e an1 composition. T/mors may be small an1 grossly imperceptible or massi*e9 filling the pel*is an1 e*en the ab1ominal ca*ity. Components of the t/mors may incl/1e cystic areas +cysta1enomas,9 cystic an1 fibro/s areas +cysta1enofibromas,9 an1 pre1ominantly fibro/s areas +a1enofibromas,. !n gross e3amination9 t(e ris of malignancy increases as a function of t(e amount of discernible solid epit(elial gro1t(9 incl/1ing papillary proDections of soft t/mor9 thic;ene1 t/mor lining the cyst spaces9 or soli1 necrotic friable tiss/e 1epicting necrosis.
>OJ@

The most 7i1ely accepte1 theory for the 1eri*ation of mAllerian epithelial t/mors is thro/gh the transformation of coelomic mesotheli/m. This *ie7 is base1 on the embryologic path7ay by 7hich the mAllerian ducts are formed and e-ol-e into serous (tubal$, endometrioid (endometrium$, and mucinous (cer-i%$ epithelia present in the normal female genital tract +see the section on anatomy,. "/ch t/mors occ/r pre1ominantly in the o*ary beca/se coelomic epitheli/m is incorporate1 into the o*arian corte3 to form mesothelial incl/sion cysts. This incorporation occ/rs by the formation of s/rface a1hesions9 atrophy 7ith epithelial infol1ing9 an1
1095

repair of o*/lation sites. The close association of o*arian carcinomas 7ith either the o*arian s/rface mesotheli/m or incl/sion cysts may e3plain the 1e*elopment of

e3trao*arian carcinomas of similar histology from similar coelomic epithelial rests +socalle1 en1osalpingiosis, in the mesentery. $o7e*er9 this is clearly an o*ersimplification of the pathogenesis of o*arian cancer. For e3ample9 en1ometrioi1 carcinomas may be 1eri*e1 from transplante1 en1ometriosis9 an1 some o*arian sero/s an1 m/cino/s +mAllerian m/cino/s, t/mors arise in association 7ith en1ometriosis. The origin of most m/cino/s t/mors is /nclear. "ome arise 7ithin en1ometriosis< other propose1 origins incl/1e teratomato/s epitheli/m.
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An intrig/ing 6/estion is the origin of the cortical mAllerian incl/sion cyst +CIC, an1 its relationship to sero/s carcinomas + Fig. 22-BJ ,. The contin/ity of pel*ic mesotheli/m 7ith these mAllerian cysts s/ggests that the former gi*es rise to the latter. $o7e*er9 similarities bet7een some of these cysts an1 en1ometrial or t/bal epitheli/m raise the possibility of a /terine or t/bal origin for the epitheli/m. #irect lin;s bet7een CICs an1 sero/s carcinoma are not common an1 st/1ies of o*aries from 7omen 7ith BACA m/tations ha*e not 1isclose1 premalignant changes in these cysts. 'egar1less of their specific origin+s,9 o*arian epithelial t/mors compose1 of sero/s9 m/cino/s9 an1 en1ometrioi1 cell types are emblematic of the plasticity of mAllerian epitheli/m an1 range from clearly benign9 to t/mors of bor1erline malignancy9 to malignant t/mors.
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(erous Tumors

These common cystic neoplasms are line1 by tall9 col/mnar9 ciliate1 epithelial cells an1 are fille1 7ith clear sero/s fl/i1. Altho/gh the term sero/s appropriately 1escribes the cyst fl/i19 it has become synonymo/s 7ith the t/bal-li;e epitheli/m in these t/mors. Together the benign9 bor1erline9 an1 malignant types acco/nt for abo/t BIP of all o*arian t/mors. Abo/t LEP are benign or of bor1erline malignancy9 an1 2EP are malignant. "ero/s cysta1enocarcinomas acco/nt for appro3imately CIP of all cancers of the o*ary an1 are the most common malignant o*arian t/mors. 0enign an1 bor1erline t/mors are most common bet7een the ages of 2I an1 EI years. Cysta1enocarcinomas occ/r later in life on a*erage9 altho/gh some7hat earlier in familial cases.

Fi#ure 22--9 Cortical incl/sion cysts of the o*ary. These cysts appear to arise from the o*erlying mesotheli/m an1 are pres/me1 to be the site of origin for many o*arian epithelial neoplasms. Another

so/rce of o*arian epitheli/m neoplasia is en1ometriosis +see Fig/re 22-2O ,.

Morpholo#".

The characteristic sero/s t/mor may present on gross e3amination as either a cystic lesion in 7hich the papillary epitheli/m is containe1 7ithin a fe7 fibro/s 7alle1 cysts +intracystic, + Fig. 22-BOA ,9 or proDecting from the o*arian s/rface. 0enign t/mors typically present 7ith a smooth glistening cyst 7all 7ith no epithelial thic;ening or 7ith small papillary proDections +i.e.9 papillary cysta1enoma,. 0or1erline t/mors contain an increase1 n/mber of papillary proDections + Fig. 22-BOA an1 B ,. %arger amo/nts of soli1 or papillary t/mor mass9 irreg/larity in the t/mor mass9 an1 fi3ation or no1/larity of the caps/le are all important in1icators of probable malignancy + Fig. 22-BOB ,. 0ilaterality is common9 occ/rring in 2IP of benign cysta1enomas9 BIP of bor1erline t/mors9 an1 appro3imately KKP of cysta1enocarcinomas. A significant proportion of both bor1erline an1 malignant sero/s t/mors in*ol*e +or originate from, the s/rface of the o*ary + Fig. 22-BOC ,. !n histologic e3amination9 the lining epitheli/m is compose1 of col/mnar epitheli/m 7ith ab/n1ant cilia in benign t/mors + Fig. 22-CI ,. -icroscopic papillae may be fo/n1. T/mors of bor1erline malignancy contain increase1 comple3ity of

Fi#ure 22--9 A9 0or1erline sero/s cysta1enoma opene1 to 1isplay a cyst ca*ity line1 by 1elicate papillary t/mor gro7ths. B9 Cysta1enocarcinoma. The cyst is opene1 to re*eal a large9 b/l;y t/mor mass. C9 Another bor1erline t/mor gro7ing on the o*arian s/rface +lo1er,.

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Fi#ure 22-00 Papillary sero/s cysta1enoma re*ealing stromal papillae 7ith a col/mnar epitheli/m.

the stromal papillae 7ith stratification of the epitheli/m an1 n/clear atypia9 b/t 1estr/cti*e infiltrati*e gro7th into the stroma is not seen + Fig. 22-C? ,. Cysta1enocarcinomas e3hibit e*en more comple3 gro7th 7ith infiltration or fran; effacement of the /n1erlying stroma by soli1 t/mor + Fig. 22-C2 ,. The in1i*i1/al t/mor cells in the carcinomato/s lesions 1isplay the /s/al feat/res of all malignant neoplasia9 an1 7ith the more e3treme 1egrees of atypia9 the cells may become /n1ifferentiate1. Concentric calcifications +psammoma bo1ies, characteri:e sero/s t/mors9 altho/gh they are not specific for neoplasia 7hen they are fo/n1 alone.
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A small n/mber of t/mors ha*e been 1escribe1 that share feat/res of both bor1erline an1 malignant sero/s neoplasms9 e3hibiting epithelial comple3ity an1 a greater ris; of in*asi*e peritoneal implants + Fig. 22-CB ,. These so-calle1 micropapillary sero/s carcinomas may acco/nt in part for the occasional aggressi*e beha*ior of Gbor1erlineG sero/s cysta1enomas.
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Is there a relationship bet7een bor1erline an1 malignant sero/s neoplasiaU "t/1ies of 7omen 7ith BACA m/tations

Fi#ure 22-01 0or1erline sero/s cysta1enoma e3hibiting increase1 architect/ral comple3ity an1 epithelial cell stratification.

Fi#ure 22-02 Papillary sero/s cysta1enocarcinoma of the o*ary 7ith in*asion of /n1erlying stroma.

ha*e not sho7n an increase in ris; of bor1erline neoplasms9 /n1erscoring 1ifferences in pathogenesis for these t7o histologically similar b/t biologically 1istinct t/mors.
>?IC@

The biologic beha*ior of sero/s t/mors 1epen1s on 1egree of 1ifferentiation9 1istrib/tion9 an1 characteristics of the peritoneal implants9 if present. Importantly9 sero/s t/mors may occ/r on the s/rface of the o*aries an19 rarely9 as primary t/mors of the peritoneal s/rface + Fig. 22-BOB ,. Pre1ictably9 /nencaps/late1 sero/s t/mors of the o*arian s/rface are more li;ely to e3ten1 to the peritoneal s/rfaces9 an1 prognosis is closely relate1 to the histologic appearance of the t/mor an1 its gro7th pattern on the peritone/m. Peritoneal sprea1 may manifest as nonin*asi*e or in*asi*e implants9 the latter signifying malignancy. 0or1erline t/mors may arise from or e3ten1 to the peritoneal s/rfaces as nonin*asi*e implants9 remaining locali:e1 an1 ca/sing no symptoms9 or slo7ly sprea19 pro1/cing intestinal obstr/ction or other complications after many years. Implants of carcinomas in*a1e the a1Dacent stroma in1/cing 1esmoplasia +in*asi*e implants, an1 may form large intra-ab1ominal masses 7ith rapi1 clinical 1eterioration. Conse6/ently9 caref/l pathologic classification of the t/mor9 e*en if it has e3ten1e1 to the peritone/m9 is rele*ant
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Fi#ure 22-0- Comple3 micropapillary gro7th 1efines a lo7 gra1e GmicropapillaryG sero/s carcinoma.

1097

to both prognosis an1 selection of therapy. The E-year s/r*i*al rate for bor1erline an1 malignant t/mors confine1 7ithin the o*arian mass is9 respecti*ely9 ?IIP an1 LIP9 7hereas the E-year s/r*i*al rate for the same t/mors in*ol*ing the peritone/m is abo/t OIP an1 2EP9 respecti*ely. 0eca/se of their protracte1 co/rse9 bor1erline t/mors may rec/r after many years9 an1 E-year s/r*i*al is not synonymo/s 7ith c/re.
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Mucinous Tumors

These t/mors closely resemble their sero/s co/nterparts. They are some7hat less common9 acco/nting for abo/t 2EP of all o*arian neoplasms. They occ/r principally in mi11le a1/lt life an1 are rare before p/berty an1 after menopa/se. Eighty per cent are benign or bor1erline9 an1 abo/t ?EP are malignant. -/cino/s cysta1enocarcinomas are relati*ely /ncommon an1 acco/nt for only ?IP of all o*arian cancers.
Morpholo#".

In gross appearance9 the m/cino/s t/mors 1iffer from the sero/s *ariety in se*eral 7ays. They are characteri:e1 by more cysts of *ariable si:e an1 a rarity of s/rface in*ol*ement. They are less fre6/ently bilateral. Appro3imately EP of primary m/cino/s cysta1enomas an1 m/cino/s cysta1enocarcinomas are bilateral. -/cino/s t/mors ten1 to pro1/ce larger cystic masses9 an1 some ha*e been recor1e1 7ith 7eights of more than 2E ;g. They appear grossly as m/ltiloc/late1 t/mors fille1 7ith stic;y9 gelatino/s fl/i1 rich in glycoproteins + Fig. 22-CCA ,. !n histologic e3amination9 benign m/cino/s t/mors are characteri:e1 by a lining of tall col/mnar epithelial cells 7ith apical m/cin an1 the absence of cilia9 a;in to benign cer*ical or intestinal epithelia + Fig. 22-CCB ,. !ne gro/p of typically benign or bor1erline m/cino/s t/mors arises in en1ometriosis an1 is terme1 GmAllerian m/cino/sG

cysta1enoma9 resembling en1ometrial or cer*ical epitheli/m. These t/mors are /ncommonly malignant. The secon19
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Fi#ure 22-00 A9 A m/cino/s cysta1enoma 7ith its m/lticystic appearance an1 1elicate septa. Note the presence of glistening m/cin 7ithin the cysts. B9 Col/mnar cell lining of m/cino/s cysta1enoma.

more common gro/p incl/1es t/mors e3hibiting ab/n1ant glan1-li;e or papillary gro7th 7ith n/clear atypia an1 stratification an1 is stri;ingly similar to t/b/lar a1enomas or *illo/s a1enomas of the intestine. These t/mors are pres/me1 prec/rsors to most cysta1enocarcinomas. Cysta1enocarcinomas contain more soli1 gro7th 7ith conspic/o/s epithelial cell atypia an1 stratification9 loss of glan1 architect/re9 an1 necrosis9 an1 are similar to colonic cancer in appearance. 0eca/se both bor1erline an1 malignant m/cino/s cysta1enomas form comple3 glan1s in the stroma9 the 1oc/mentation of clear-c/t stromal in*asion9 7hich is easily ascertaine1 in sero/s t/mors9 is more 1iffic/lt. "ome a/thors 1escribe a category of Gnonin*asi*eG m/cino/s carcinomas +intraepithelial carcinomas, for those t/mors 7ith mar;e1 epithelial atypia 7itho/t ob*io/s stromal alterations. Appro3imate ?I-year s/r*i*al rates for stage I bor1erline9 nonin*asi*e malignant9 an1 fran;ly in*asi*e malignant t/mors are greater than OEP9 OIP9 an1 KKP9 respecti*ely.
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A con1ition associate1 7ith m/cino/s o*arian neoplasms is pseudomy%oma peritonei. This 1isor1er consists of an o*arian t/mor 7ith e3tensi*e m/cino/s ascites9 cystic epithelial implants on the peritoneal s/rfaces9 an1 a1hesions + Fig. 22-CEA an1 B ,. Pse/1omy3oma peritonei9 if e3tensi*e9 may res/lt in intestinal obstr/ction an1 1eath. 'ecent e*i1ence points to the presence of9 in most cases9 e3trao*arian +/s/ally appen1iceal, primary m/cino/s t/mor 7ith secon1ary o*arian an1 peritoneal sprea1 + Chapter ?L ,. 0ilateral presentation of m/cino/s t/mors al7ays re6/ires e3cl/sion of a non-o*arian origin.
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n/ometrioi/ Tumors

These neoplasms acco/nt for appro3imately 2IP of all o*arian cancers9 e3cl/1ing en1ometriosis9 7hich is consi1ere1 non-neoplastic. -ost en1ometrioi1 t/mors are carcinomas. %ess commonly9 benign forms=/s/ally cysta1enofibromas=are
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Fi#ure 22-05 A9 Pse/1omy3oma peritonei *ie7e1 at laparotomy re*ealing massi*e o*ergro7th of a gelatino/s metastatic t/mor originating from the appen1i3. (Courtesy of *r. 4aul ). @ugarba er, Was(ington )ospital Cancer Center, Was(ington, *C.$. B9 $istology of peritoneal implants from an appen1iceal t/mor9 sho7ing m/cin-pro1/cing epitheli/m an1 free m/cin +arro1s,.

enco/ntere1. They are 1isting/ishe1 from sero/s an1 m/cino/s t/mors by the presence of t/b/lar glan1s bearing a close resemblance to benign or malignant en1ometri/m. Fifteen per cent to BIP of en1ometrioi1 carcinomas are accompanie1 by a carcinoma of the en1ometri/m9 an1 the relati*ely goo1 prognosis in s/ch cases s/ggests that the t7o may arise in1epen1ently rather than by metastatic sprea1 from one another. Abo/t ?EP of cases 7ith en1ometrioi1 carcinoma coe3ist 7ith en1ometriosis9 altho/gh an origin 1irectly from o*arian coelomic epitheli/m is also possible.
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Morpholo#".

In gross appearance9 en1ometrioi1 carcinomas present as a combination of soli1 an1 cystic areas9 similar to other cysta1enocarcinomas. Forty per cent in*ol*e both o*aries9 an1 s/ch bilaterality /s/ally9 altho/gh not al7ays9 implies e3tension of the neoplasm beyon1 the genital tract. !n histologic e3amination9 glan1/lar patterns bearing a strong resemblance to those of en1ometrial origin are seen. The E-year s/r*i*al rate for patients 7ith stage I t/mors is appro3imately LEP.
Clear Cell $/enocarcinoma

This /ncommon pattern of s/rface epithelial t/mor of the o*ary is characteri:e1 by large epithelial cells 7ith ab/n1ant clear cytoplasm. 0eca/se these t/mors sometimes occ/r in association 7ith en1ometriosis or en1ometrioi1 carcinoma of the o*ary an1 resemble

clear cell carcinoma of the en1ometri/m9 they are no7 tho/ght to be of mAllerian 1/ct origin an1 *ariants of en1ometrioi1 a1enocarcinoma. The clear cell t/mors of the o*ary can be pre1ominantly soli1 or cystic. In the soli1 neoplasm9 the clear cells are arrange1 in sheets or t/b/les. In the cystic *ariety9 the neoplastic cells line the spaces. The E-year s/r*i*al rate is appro3imately KEP 7hen the t/mors are confine1 to the o*aries< ho7e*er9 these t/mors ten1 to be aggressi*e9 an1 7ith sprea1 beyon1 the o*ary9 a s/r*i*al of E years is e3ceptional.
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C"sta/eno&i!roma

Cysta1enofibromas are *ariants in 7hich there is more prono/nce1 proliferation of the fibro/s stroma that /n1erlies the col/mnar lining epitheli/m. These benign t/mors are /s/ally small an1 m/ltiloc/lar an1 ha*e simple papillary processes that 1o not become so complicate1 an1 branching as those fo/n1 in the or1inary cysta1enoma. They may be compose1 of m/cino/s9 sero/s9 en1ometrioi19 an1 transitional +0renner t/mors, epitheli/m. 0or1erline lesions 7ith cell/lar atypia an19 rarely9 t/mors 7ith focal carcinoma occ/r9 b/t metastatic sprea1 of either is e3tremely /ncommon.
.renner Tumor

0renner t/mors are /ncommon a1enofibromas in 7hich the epithelial component consists of nests of transitional cells resembling those lining the /rinary bla11er. %ess fre6/ently9 the nests contain microcysts or glan1/lar spaces line1 by col/mnar9 m/cin-secreting cells. For /n;no7n reasons9 0renner t/mors are occasionally enco/ntere1 in m/cino/s cysta1enomas.
Morpholo#".

These neoplasms may be soli1 or cystic9 are /s/ally /nilateral +appro3imately OIP,9 an1 *ary in si:e from small lesions less than ? cm in 1iameter to massi*e t/mors /p to 2I an1 BI cm + Fig. 22-CKA ,. The fibro/s stroma9 resembling that of the normal o*ary9 is mar;e1 by sharply 1emarcate1 nests of epithelial cells resembling the epitheli/m of the /rinary tract9 often 7ith m/cino/s glan1s in their center + Fig. 22-CKB ,. Infre6/ently9 the stroma is compose1 of some7hat pl/mp fibroblasts resembling theca cells9 an1 s/ch neoplasms may ha*e hormonal acti*ity. -ost 0renner t/mors are benign9 b/t bor1erline +proliferati*e 0renner t/mor, an1 malignant co/nterparts ha*e been reporte1. "e*eral reports ha*e emphasi:e1 the occ/rrence of o*arian t/mors that are compose1 in part or all of neoplastic epitheli/m similar to transitional carcinoma of the bla11er b/t 7itho/t a coe3isting 0renner component. Altho/gh often referre1 to as transitional cell carcinoma9 these t/mors are fre6/ently seen in association 7ith con*entional sero/s or en1ometrioi1 carcinomas an1 li;ely represent altere1 1ifferentiation patterns of the t/mor cells.
Clinical Course= Detection= an/ Pre3ention o& (ur&ace pithelial Tumors

All o*arian epithelial carcinomas pro1/ce similar clinical manifestations9 most commonly lo7er ab1ominal pain an1 ab1ominal enlargement. Gastrointestinal

complaints9 /rinary fre6/ency9 1ys/ria9 pel*ic press/re9 an1 many other symptoms may appear. 0enign lesions are easily resecte19 7ith c/re. The malignant forms9 ho7e*er9 ten1 to ca/se the progressi*e 7ea;ness9 7eight loss9 an1 cache3ia characteristic of all malignant neoplasms. If the carcinomas e3ten1 thro/gh the caps/le of the t/mor to see1 the peritoneal ca*ity9 massi*e ascites is common. Characteristically9 the ascitic fl/i1 is fille1 7ith 1iagnostic e3foliate1 t/mor cells. The peritoneal see1ing that these
1099

Fi#ure 22-06 A9 0renner t/mor +rig(t, associate1 7ith a benign cystic teratoma +left,. B9 $istologic 1etail of characteristic epithelial nests 7ithin the o*arian stroma. (Courtesy of *r. M. /ucci, Brig(am and Women9s )ospital, Boston, MA.$

malignant neoplasms pro1/ce is 1istincti*eH they ten1 to see1 all serosal s/rfaces 1iff/sely 7ith I.? to I.E cm no1/les of t/mor. These s/rface implants rarely in*a1e 1eeply into the /n1erlying parenchyma of the organ. The regional no1es are often in*ol*e19 an1 metastases may be fo/n1 in the li*er9 l/ngs9 gastrointestinal tract9 an1 else7here. -etastasis across the mi1line to the opposite o*ary is 1isco*ere1 in abo/t half the cases by the time of laparotomy an1 heral1s a progressi*e 1o7nhill co/rse to 1eath 7ithin a fe7 months or years. 0eca/se o*arian carcinomas often remain /n1iagnose1 /ntil they are large9 or originate on the o*arian s/rface from 7here they rea1ily sprea1 to the pel*is9 many patients are first seen 7ith lesions that are no longer confine1 to the o*ary. This is perhaps the primary reason for the relati*ely poor E- an1 ?I-year s/r*i*al rates for these patients9 compare1 7ith rates in cer*ical an1 en1ometrial carcinoma. For these reasons9 both early 1iagnosis an1 pre*ention are top priorities. "pecific biochemical mar;ers for t/mor antigens or t/mor pro1/cts in the plasma of these patients are being so/ght *igoro/sly. !ne s/ch mar;er is a high-molec/lar-7eight glycoprotein present in more than JIP of sero/s an1 en1ometrioi1 carcinomas9 ;no7n as CA-?2E. &hether its /se 7ill infl/ence o/tcome is /npro*en. Ne7ly i1entifie1 biomar;ers s/ch as osteopontin9 7hich is e3presse1 at significantly higher le*els in o*arian cancer patients9 may impro*e early 1etection. Assays base1 on proteomics attempt to 1isting/ish cancer patients from non>??I@ >???@

affecte1 in1i*i1/als thro/gh patterns of circ/lating proteins generate1 by mass spectroscopic analysis of patient sera. These an1 other approaches may9 in the f/t/re9 create a more cost-effecti*e9 nonin*asi*e approach to o*arian cancer screening9 b/t still nee1 to be *ali1ate1.
>??2@

Pre*ention of o*arian cancer remains an el/si*e goal9 b/t both fallopian t/bal ligation an1 oral contracepti*e therapy are associate1 7ith significant re1/ctions in relati*e ris;. %ong-term contracepti*e /se has re1/ce1 ris; by half in patients 7ith a family history of o*arian cancer. T/bal ligation re1/ces ris; by more than half an1 may be effecti*e in s/bsets of 7omen 7ith BACA m/tations an1 family history of o*arian cancer. "creening strategies base1 on i1entifying 7omen at ris; +positi*e for BACA m/tations, an1 employing prophylactic oophorectomy are c/rrently stan1ar19 b/t the long-term impact of these approaches on o*arian cancer 1eath rates remains to be 1etermine1.
>?II@ >OO@ >?I?@ >??B@

G ,M C ** T2M',(

Germ cell t/mors constit/te ?EP to 2IP of all o*arian t/mors. -ost are benign cystic teratomas9 b/t the remain1er9 7hich are fo/n1 principally in chil1ren an1 yo/ng a1/lts9 ha*e a higher inci1ence of malignant beha*ior an1 pose problems in histologic 1iagnosis an1 in therapy. They bear a remar;able homology to germ cell t/mors in the male testis9 + Chapter 2? , an1 arise from germ cell 1ifferentiation in a similar manner + Fig. 22-CL ,.
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Teratomas

Teratomas are 1i*i1e1 into three categoriesH +?, mat/re +benign,9 +2, immat/re +malignant,9 an1 +B, mono1ermal or highly speciali:e1.
Mature 4.eni#n5 Teratomas.

-ost benign teratomas are cystic an1 are better ;no7n in clinical parlance as dermoid cysts. These neoplasms are pres/mably 1eri*e1 from the ecto1ermal 1ifferentiation of totipotential cells. Cystic teratomas are /s/ally fo/n1 in yo/ng 7omen 1/ring the acti*e repro1/cti*e years.
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Morpholo#".

0enign teratomas are bilateral in ?IP to ?EP of cases. Characteristically9 they are /niloc/lar cysts containing hair an1 cheesy sebaceo/s material + Fig. 22-CJ ,. !n section9 they re*eal a thin 7all line1 by an opa6/e9 gray-7hite9 7rin;le19 apparent epi1ermis. From

Fi#ure 22-07 $istogenesis an1 interrelationships of t/mors of germ cell origin.

1100

Fi#ure 22-09 !pene1 mat/re cystic teratoma +1ermoi1 cyst, of the o*ary. $air +bottom, an1 a mi3t/re of tiss/es are e*i1ent.

this epi1ermis9 hair shafts fre6/ently protr/1e. &ithin the 7all9 it is common to fin1 tooth str/ct/res an1 areas of calcification. !n histologic e3amination9 the cyst 7all is compose1 of stratifie1 s6/amo/s epitheli/m 7ith /n1erlying sebaceo/s glan1s9 hair shafts9 an1 other s;in a1ne3al str/ct/res + Fig. 22CO ,. In most cases9 str/ct/res from other germ layers can be i1entifie19 s/ch as cartilage9 bone9 thyroi1 tiss/e9 an1 other organoi1 formations. #ermoi1 cysts are sometimes incorporate1 7ithin the 7all of a m/cino/s cysta1enoma. $!out 1A o& the /ermoi/s

un/er#o mali#nant trans&ormation o& an" one o& the component elements 4e.#.= th"roi/ carcinoma= melanoma= !ut most commonl"= s<uamous cell carcinoma5. In rare instances9 a teratoma is soli1 b/t is compose1 entirely of benign-loo;ing heterogeneo/s collections of tiss/es an1 organi:e1 str/ct/res 1eri*e1

Fi#ure 22-09 0enign cystic teratoma. %o7-po7er *ie7 of s;in +top,9 beneath 7hich there is brain tiss/e +bottom,.

from all three germ layers. These t/mors pres/mably ha*e the same histogenetic origin as 1ermoi1 cysts b/t lac; prepon1erant 1ifferentiation into ecto1ermal 1eri*ati*es. These neoplasms may be initially 1iffic/lt to 1ifferentiate from the malignant9 immat/re teratomas9 7hich almost al7ays are largely soli1. The origin of teratomas has been a matter of fascination for cent/ries. "ome common beliefs blame1 7itches9 nightmares9 or a1/ltery 7ith the 1e*il. The c/rrent parthenogenetic theory s/ggests origin from a meiotic germ cell. The ;aryotype of all benign o*arian teratomas is CK922. From the res/lts of chromosome ban1ing techni6/es an1 the 1istrib/tion of electrophoretic *ariants of en:ymes in the normal an1 teratoma cells9 %in1er an1 co7or;ers s/ggeste1 that t/mors arise from an o*/m after the first meiotic 1i*ision. !ther 1eri*ations ha*e been propose1.
>??C@ >??E@

Mono/ermal or (peciali?e/ Teratomas.

The speciali:e1 teratomas are a remar;able9 rare gro/p of t/mors9 the most common of 7hich are str/ma o*arii an1 carcinoi1. They are al7ays /nilateral9 altho/gh a contralateral teratoma may be present. "tr/ma o*arii is compose1 entirely of mat/re thyroi1 tiss/e. Interestingly9 these thyroi1al neoplasms may hyperf/nction9 ca/sing

hyperthyroi1ism. The o*arian carcinoi19 7hich pres/mably arises from intestinal epitheli/m in a teratoma9 might in fact be f/nctioning9 partic/larly in large +greater than L cm, t/mors9 pro1/cing E-hy1ro3ytryptamine an1 the carcinoi1 syn1rome. Primary o*arian carcinoi1 can be 1isting/ishe1 from metastatic intestinal carcinoi19 the latter *irt/ally al7ays bilateral. E*en more rare is the str/mal carcinoi19 a combination of str/ma o*arii an1 carcinoi1 in the same o*ary. Primary carcinoi1s are /ncommonly +less than 2P, malignant.
%mmature Mali#nant Teratomas.

These are rare t/mors that 1iffer from benign teratomas in that the component tiss/e resembles that obser*e1 in the fet/s or embryo rather than in the a1/lt. The t/mor is fo/n1 chiefly in prep/bertal a1olescents an1 yo/ng 7omen9 the mean age being ?J years.
>??K@

Morpholo#".

The t/mors are b/l;y an1 ha*e a smooth e3ternal s/rface. !n section9 they ha*e a soli1 +or pre1ominantly soli1, str/ct/re. There are areas of necrosis an1 hemorrhage. $air9 gr/mo/s material9 cartilage9 bone9 an1 calcification may be present. !n microscopic e3amination9 there are *arying amo/nts of immat/re tiss/e 1ifferentiating to7ar1 cartilage9 glan1s9 bone9 m/scle9 ner*e9 an1 others. An important ris; for s/bse6/ent e3trao*arian sprea1 is the histologic gra1e of t/mor +I thro/gh III,9 7hich is base1 on the proportion of tiss/e +in histologic sections, containing immat/re ne/roepitheli/m + Fig. 22-EI ,. Immat/re teratomas gro7 rapi1ly an1 fre6/ently penetrate the caps/le 7ith local sprea1 or metastases. "tage I t/mors9 ho7e*er9 partic/larly those 7ith lo7-gra1e +gra1e ?, histology9 ha*e an e3cellent prognosis. $igher-gra1e t/mors confine1 to the o*ary are generally treate1 7ith prophylactic chemotherapy. -ost rec/rrences 1e*elop in the first 2 years9 an1 absence of 1isease beyon1 this perio1 carries an e3cellent chance of c/re.
1101

Fi#ure 22-50 Immat/re teratoma of the o*ary ill/strating primiti*e ne/roepitheli/m.

D"s#erminoma

The 1ysgerminoma is best consi1ere1 as the o*arian co/nterpart of the seminoma of the testis. "imilar to the seminoma9 it is compose1 of large *esic/lar cells ha*ing a clear cytoplasm9 7ell-1efine1 cell bo/n1aries9 an1 centrally place1 reg/lar n/clei. 'elati*ely /ncommon t/mors9 the 1ysgerminomas acco/nt for abo/t 2P of all o*arian cancers yet form abo/t half of malignant germ cell t/mors. They may occ/r in chil1hoo19 b/t LEP occ/r in the secon1 an1 thir1 1eca1es. "ome occ/r in patients 7ith gona1al 1ysgenesis9 incl/1ing pse/1ohermaphro1itism. -ost of these t/mors ha*e no en1ocrine f/nction. A fe7 pro1/ce ele*ate1 le*els of chorionic gona1otropin an1 may ha*e syncytiotrophoblastic giant cells on histologic e3amination.
>??L@

Morpholo#".

)s/ally /nilateral +JIP to OIP,9 they most fre6/ently are soli1 t/mors ranging in si:e from barely *isible no1/les to masses that *irt/ally fill the entire ab1omen. !n c/t s/rface9 they ha*e a yello7-7hite to gray-pin; appearance an1 are often soft an1 fleshy. !n histologic e3amination9 the 1ysgerminoma cells are 1isperse1 in sheets or cor1s separate1 by scant fibro/s stroma + Fig. 22-E? ,. As in the seminoma9 the fibro/s stroma is infiltrate1 7ith mat/re lymphocytes an1 occasional gran/lomas. !n occasion9 small no1/les of 1ysgerminoma are enco/ntere1 in the 7all of an other7ise benign cystic teratoma< con*ersely9 a pre1ominantly 1ysgerminomato/s t/mor may contain a small cystic teratoma. All 1ysgerminomas are malignant9 b/t the 1egree of histologic atypia is *ariable9 an1 only abo/t one thir1 are aggressi*e. Th/s9 a /nilateral t/mor that has not bro;en thro/gh the caps/le an1 has not sprea1 has an e3cellent prognosis +/p to OKP c/re rate, after simple salpingo-oophorectomy. These neoplasms are e3tremely ra1iosensiti*e9 an1 e*en those that ha*e e3ten1e1 beyon1 the o*ary can generally be controlle1 by ra1iotherapy. !*erall s/r*i*al e3cee1s JIP.
n/o/ermal (inus 4;olB (ac5 Tumor

This t/mor is rare b/t is the secon1 most common malignant t/mor of germ cell origin. It is tho/ght to be 1eri*e1

Fi#ure 22-51 #ysgerminoma sho7ing polyhe1ral t/mor cells 7ith ro/n1 n/clei an1 a1Dacent inflammation.

from 1ifferentiation of malignant germ cells to7ar1 e3traembryonic yol; sac str/ct/re + Fig. 22-CL ,. "imilar to the yol; sac9 the t/mor is rich in V-fetoprotein an1 V? -antitrypsin. Its characteristic histologic feat/re is a glomer/l/s-li;e str/ct/re compose1 of a central bloo1 *essel en*elope1 by germ cells 7ithin a space line1 by germ cells +"chiller-#/*al bo1y, + Fig. 22-E2 ,. "imilar str/ct/res are obser*e1 in the yol; sac of the rat placenta. Conspic/o/s intracell/lar an1 e3tracell/lar hyaline 1roplets are present in all t/mors9 an1 some of these can be staine1 for V-fetoprotein by imm/nopero3i1ase techni6/es. -ost patients are chil1ren or yo/ng 7omen presenting 7ith ab1ominal pain an1 a rapi1ly 1e*eloping pel*ic mass. The t/mors /s/ally appear to in*ol*e a single o*ary b/t gro7 rapi1ly an1 aggressi*ely. These t/mors 7ere once almost /niformly fatal 7ithin 2 years of 1iagnosis9 b/t combination chemotherapy has meas/rably impro*e1 the o/tcome.
Choriocarcinoma

-ore commonly of placental origin9 the choriocarcinoma9 similar to the en1o1ermal sin/s t/mor9 is an e3ample of e3traembryonic 1ifferentiation of malignant germ cells. It is

Fi#ure 22-52 A "chiller-#/*al bo1y in yol; sac carcinoma.

1102

generally hel1 that a germ cell origin can be confirme1 only in the prep/bertal girl beca/se after this age9 an origin from an o*arian ectopic pregnancy cannot be e3cl/1e1. -ost o*arian choriocarcinomas e3ist in combination 7ith other germ cell t/mors9 an1 p/re choriocarcinomas are e3tremely rare. They are histologically i1entical 7ith the more common placental lesions9 1escribe1 later. The o*arian primaries are aggressi*e t/mors that generally ha*e metastasi:e1 7i1ely thro/gh the bloo1stream to the l/ngs9 li*er9 bone9 an1 other *iscera by the time of 1iagnosis. %i;e all choriocarcinomas9 they elaborate high le*els of chorionic gona1otropins that are sometimes helpf/l in establishing the 1iagnosis or 1etecting rec/rrences. In contrast to choriocarcinomas arising in placental tiss/e9 those arising in the o*ary are generally /nresponsi*e to chemotherapy an1 are often fatal.
'ther Germ Cell Tumors

These incl/1e +?, embryonal carcinoma9 another highly malignant t/mor of primiti*e embryonal elements9 histologically similar to t/mors arising in the tests + Chapter 2? ,< +2, polyembryoma9 a malignant t/mor containing so-calle1 embryoi1 bo1ies< an1 +B, mi3e1 germ cell t/mors containing *ario/s combinations of 1ysgerminoma9 teratoma9 en1o1ermal sin/s t/mor9 an1 choriocarcinoma.
( 8 C',D-(T,'M$* T2M',(

>OJ@

These o*arian neoplasms are 1eri*e1 from the o*arian stroma9 7hich in t/rn is 1eri*e1 from the se3 cor1s of the embryonic gona1. 0eca/se the /n1ifferentiate1 gona1al mesenchyme e*ent/ally pro1/ces str/ct/res of specific cell type in both male +"ertoli an1 %ey1ig, an1 female +gran/losa an1 theca, gona1s9 t/mors resembling all of these cell types can be i1entifie1 in the o*ary. -oreo*er9 beca/se some of these cells normally secrete estrogens +theca cells, or an1rogens +%ey1ig cells,9 their correspon1ing t/mors
>??J@

may be either femini:ing +gran/losa-theca cell t/mors, or masc/lini:ing +%ey1ig cell t/mors,.
Granulosa-Theca Cell Tumors

This 1esignation embraces o*arian neoplasms compose1 of *arying proportions of gran/losa an1 theca cell 1ifferentiation. These

Fi#ure 22-5- Gran/losa cell t/mor. A9 The t/mor cells are arrange1 in sheets p/nct/ate1 by small follicleli;e str/ct/res +Call-E3ner bo1ies,. B9 "trong imm/nohistochemical positi*ity 7ith an antibo1y to inhibin characteri:es these t/mors.

t/mors are compose1 almost entirely of gran/losa cells or a mi3t/re of gran/losa an1 theca cells. Collecti*ely9 these neoplasms acco/nt for abo/t EP of all o*arian t/mors. Altho/gh they may be 1isco*ere1 at any age9 appro3imately t7o thir1s occ/r in postmenopa/sal 7omen.
Morpholo#".

Gran/losa cell t/mors are /s/ally /nilateral an1 *ary from microscopic foci to large9 soli19 an1 cystic encaps/late1 masses. T/mors that are hormonally acti*e ha*e a yello7 coloration to their c/t s/rfaces9 pro1/ce1 by containe1 lipi1s. The p/re thecomas are soli19 firm t/mors. The gran/losa cell component of these t/mors ta;es one of many histologic patterns. The small9 c/boi1al to polygonal cells may gro7 in anastomosing cor1s9 sheets9 or stran1s + Fig. 22-EB ,. In occasional cases9 small9 1istincti*e9 glan1li;e str/ct/res fille1 7ith an aci1ophilic material recall immat/re follicles +Call-E3ner bo1ies,. &hen these str/ct/res are e*i1ent9 the 1iagnosis is consi1erably more simple. The thecoma component consists of cl/sters or sheets of c/boi1al to polygonal cells. In some t/mors9 the gran/losa or theca cells may appear more pl/mp 7ith ample cytoplasm characteristic of l/teini:ation +i.e.9 l/teini:e1 gran/losa-theca cell t/mors,.

Gran/losa-theca cell t/mors ha*e clinical importance for t7o reasonsH +?, their potential elaboration of large amo/nts of estrogen an1 +2, the small b/t 1istinct ha:ar1 of malignancy in the gran/losa cell forms. F/nctionally acti*e t/mors in yo/ng girls +D/*enile gran/losa cell t/mors, may pro1/ce precocio/s se3/al 1e*elopment in prep/bertal girls. In a1/lt 7omen9 they may be associate1 7ith en1ometrial hyperplasia9 cystic 1isease of the breast9 an1 en1ometrial carcinoma. Abo/t ?IP to ?EP of patients 7ith steroi1-pro1/cing t/mors e*ent/ally 1e*elop an en1ometrial carcinoma. !ccasional gran/losa cell t/mors pro1/ce an1rogens9 masc/lini:ing the patient. The a11itional clinical significance of these t/mors lies in the fact that all are potentially malignant. It is 1iffic/lt9 from the histologic e*al/ation of gran/losa cell t/mors9 to pre1ict their biologic beha*ior. The estimates of clinical malignancy +rec/rrence9 e3tension, range from EP to 2EP. In general9
>??J@

110-

malignant t/mors p/rs/e an in1olent co/rse in 7hich local rec/rrences may be amenable to s/rgical therapy. 'ec/rrences 7ithin the pel*is an1 ab1omen may appear many years +?I to 2I, after remo*al of the original t/mor. The ?I-year s/r*i*al rate is appro3imately JEP. T/mors compose1 pre1ominantly of theca cells are almost ne*er malignant. 'ecently9 ele*ate1 tiss/e an1 ser/m le*els of in(ibin9 an o*arian pro1/ct9 ha*e been associate1 7ith gran/losa cell t/mors. This biomar;er may be /sef/l for i1entifying gran/losa an1 other se3 cor1 stromal t/mors9 an1 for monitoring patients /n1er therapy for these neoplasms + Fig. 22-EBB ,.
>??O@

Fi!roma-Thecomas

T/mors arising in the o*arian stroma that are compose1 of either fibroblasts +fibromas, or more pl/mp spin1le cells 7ith lipi1 1roplets +thecomas, are relati*ely common an1 acco/nt for abo/t CP of all o*arian t/mors + Fig. 22-ECA ,. 0eca/se many t/mors contain a mi3t/re of these cells9 they are terme1 fibroma3t(ecomas. P/re thecomas are rare9 b/t t/mors in 7hich these cells pre1ominate may be hormonally acti*e. -ost are compose1 principally of fibroblasts an1 are hormonally inacti*e. Fibroma-thecomas of the o*ary are /nilateral in abo/t OIP of cases an1 are /s/ally soli19 spherical or slightly lob/late19 encaps/late19 har19 gray-7hite masses co*ere1 by glistening9 intact o*arian serosa + Fig. 22-ECB ,. !n histologic e3amination9 they are compose1 of 7ell-1ifferentiate1 fibroblasts 7ith a more or less scant collageno/s connecti*e tiss/e intersperse1 bet7een the cells. Areas of thecal 1ifferentiation may be i1entifie1 an1 can be confirme1 by fat stains. This step9 ho7e*er9 is consi1ere1 /nnecessary on clinical gro/n1s. In a11ition to the relati*ely non-specific fin1ings of pain an1 pel*ic mass9 the t/mors may be accompanie1 by t7o c/rio/s associations. The first is ascites9 fo/n1 in abo/t CIP of cases9 in 7hich the t/mors meas/re more than K cm in 1iameter. )ncommonly9 there is

also hy1rothora39 /s/ally only of the right si1e. This combination of fin1ings +i.e.9 o*arian t/mor9 hy1rothora39 an1 ascites, is 1esignate1 -eigs syn1rome. Its genesis is /n;no7n. The secon1 association is 7ith the basal cell ne*/s syn1rome9 1escribe1 in Chapter 2E . 'arely9 cell/lar t/mors 7ith mitotic acti*ity an1 increase1 n/clearH cytoplasmic ratio are i1entifie1< beca/se they may p/rs/e a malignant co/rse9 they are terme1 fibrosarcomas.
>?2I@

Fi#ure 22-50 A9 Thecoma-fibroma compose1 of pl/mp9 1ifferentiate1 stromal cells 7ith thecal appearance. B9 %arge bisecte1 fibroma of the o*ary apparent as a 7hite9 firm mass +rig(t,. The fallopian t/be is attache1.

(ertoli-*e"/i# Cell Tumors 4$n/ro!lastomas5

These t/mors recapit/late9 to a certain e3tent9 the cells of the testis at *ario/s stages of 1e*elopment. They commonly pro1/ce masc/lini:ation or at least 1efemini:ation9 b/t a fe7 ha*e estrogenic effects. They occ/r in 7omen of all ages9 altho/gh the pea; inci1ence is in the secon1 an1 thir1 1eca1es. The embryogenesis of s/ch male-1irecte1 stromal cells remains a p/::le. These t/mors are /nilateral an1 resemble gran/losa-theca cell neoplasms.
>?2?@

Morpholo#".

The c/t s/rface is /s/ally soli1 an1 *aries from gray to gol1en bro7n in appearance + Fig. 22-EEA ,. !n histologic e3amination9 the 7ell-1ifferentiate1 t/mors e3hibit t/b/les compose1 of "ertoli cells or %ey1ig cells intersperse1 7ith stroma + Fig. 22-EEB ,. The interme1iate forms sho7 only o/tlines of immat/re t/b/les an1 large eosinophilic %ey1ig cells. The poorly 1ifferentiate1 t/mors ha*e a sarcomato/s pattern 7ith a 1isor1erly 1isposition of epithelial cell cor1s. %ey1ig cells may be absent. $eterologo/s elements9 s/ch as m/cino/s glan1s9 bone9 an1 cartilage9 may be present in some t/mors. The inci1ence of rec/rrence or metastasis by "ertoli-%ey1ig cell t/mors is less than EP. These neoplasms may bloc; normal female se3/al 1e*elopment in chil1ren an1 may ca/se 1efemini:ation of 7omen9 manifeste1 by atrophy of the breasts9 amenorrhea9 sterility9 an1 loss of hair. The syn1rome may progress to stri;ing *irili:ation9 that is9 hirs/tism9 male 1istrib/tion of hair9 hypertrophy of the clitoris9 an1 *oice changes.

'ther (e6 Cor/-(tromal Tumors

The o*arian hil/m normally contains cl/sters of polygonal cells arrange1 aro/n1 *essels +hilar cells,. )ilus cell tumors (pure Leydig cell tumor$ are 1eri*e1 from these cells an1 are rare9 /nilateral9 an1 characteri:e1 histologically by large lipi1-la1en cells 7ith 1istinct bor1ers. A typical cytoplasmic str/ct/re characteristic of %ey1ig cells +'ein;e crystalloi1s, is /s/ally present. Typically9 patients 7ith hil/s cell t/mors present 7ith e*i1ence of masc/lini:ation9 hirs/tism9 *oice changes9 an1 clitoral enlargement. The t/mors are /nilateral. The most consistent laboratory fin1ing is an ele*ate1 ?L-;etosteroi1 e3cretion le*el /nresponsi*e to cortisone s/ppression.
1100

Fi#ure 22-55 "ertoli cell t/mor. A9 Gross photograph ill/strating characteristic gol1en yello7 appearance of the t/mor. B9 Photomicrograph sho7ing 7ell-1ifferentiate1 "ertoli cell t/b/les. (Courtesy of *r. William Welc(, Brig(am and Women9s )ospital, Boston, MA.$

Treatment is s/rgical e3cision. Tr/e hil/s cell t/mors are almost al7ays benign. !n occasion9 histologically i1entical t/mors occ/r in the cortical stroma +non(ilar Leydig cell tumors,. In a11ition to %ey1ig cell t/mors9 the stroma may rarely gi*e rise to t/mors compose1 of p/re l/teini:e1 cells9 pro1/cing small benign t/mors generally less than B cm in 1iameter. The t/mor may pro1/ce the clinical effects of an1rogen9 estrogen9 or progestogen stim/lation. As mentione1 pre*io/sly9 the o*ary in pregnancy may e3hibit microscopic no1/lar proliferation of theca cells in response to gona1otropins. 'arely9 a fran; t/mor may 1e*elop +terme1 pregnancy luteoma, that closely resembles a corp/s l/te/m of pregnancy. These t/mors ha*e been associate1 7ith *irili:ation in pregnant patients an1 in their respecti*e female infants.

'onadoblastoma is an /ncommon t/mor tho/ght to be compose1 of germ cells an1 se3 cor1-stroma 1eri*ati*es. It occ/rs in in1i*i1/als 7ith abnormal se3/al 1e*elopment an1 in gona1s of in1eterminate nat/re. Eighty per cent of patients are phenotypic females9 an1 2IP are phenotypic males 7ith /n1escen1e1 testicles an1 female internal secon1ary organs. !n microscopic e3amination9 the t/mor consists of nests of a mi3t/re of germ cells an1 se3 cor1 1eri*ati*es resembling immat/re "ertoli an1 gran/losa cells. A coe3istent 1ysgerminoma occ/rs in EIP of the cases. The prognosis is e3cellent if the t/mor is completely e3cise1.
>?22@

Another t/mor of possible stromal origin is small cell carcinoma of the o*ary. These malignant t/mors occ/r pre1ominantly in yo/ng 7omen an1 may be associate1 7ith hypercalcemia.
>?2B@

Metastatic Tumors

The most common GmetastaticG t/mors of the o*ary are probably 1eri*e1 from t/mors of mAllerian originH the /ter/s9 fallopian t/be9 contralateral o*ary9 or pel*ic peritone/m. The most common e3tramAllerian primaries are the breast an1 gastrointestinal tract9 incl/1ing colon9 stomach9 biliary tract9 an1 pancreas. Also incl/1e1 in this gro/p are the rare cases of pse/1omy3oma peritonei9 1eri*e1 from appen1iceal t/mors. A classic e3ample of metastatic gastrointestinal neoplasia to the o*aries is terme1 Rr/;enberg t/mor9 characteri:e1 by bilateral metastases compose1 of m/cin-pro1/cing9 signet-ring cancer cells9 most often of gastric origin.
>?2C@

Gestational and Placental

isorders

#iseases of pregnancy an1 pathologic con1itions of the placenta are important ca/ses of intra/terine or perinatal 1eath9 congenital malformations9 intra/terine gro7th retar1ation9 maternal 1eath9 an1 a great 1eal of morbi1ity for both mother an1 chil1. $ere 7e 1isc/ss only a limite1 n/mber of 1isor1ers in 7hich ;no7le1ge of the morphologic lesions contrib/tes to an /n1erstan1ing of the clinical problem. This 1isc/ssion is 1i*i1e1 into selecte1 1isor1ers of early pregnancy9 complications of late pregnancy9 an1 trophoblastic neoplasia.
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1105

Disor/ers o& arl" Pre#nanc"

(P'NT$N '2( $.',T%'N

Ten per cent to ?EP of recogni:e1 pregnancies terminate in spontaneo/s abortion. $o7e*er9 st/1ies /sing highly sensiti*e imm/noassay of chorionic gona1otropin to 1etect pregnancy i1entifie1 an a11itional 22P loss of pres/mably fertili:e1 an1 implante1 o*a in other7ise healthy 7omen. The mechanisms lea1ing to early loss of pregnancy are still mysterio/s.
>?2E@

The ca/ses of recogni:e1 spontaneo/s abortion are both fetal an1 maternal. #efecti*e implantation ina1e6/ate to s/pport fetal 1e*elopment an1 1eath of the o*/m or fet/s in /tero beca/se of some genetic or ac6/ire1 abnormality constit/te the maDor origins of spontaneo/s abortion. N/mero/s st/1ies ha*e in1icate1 chromosome abnormalities in more than half of spontaneo/s abort/ses.
>?2K@

-aternal infl/ences9 7hich are less 7ell /n1erstoo19 incl/1e inflammatory 1iseases9 both locali:e1 to the placenta an1 systemic< /terine abnormalities< an1 possibly tra/ma. The role of tra/ma is generally o*eremphasi:e1 an1 m/st be consi1ere1 a rare to e3ceptional trigger of spontaneo/s abortion. 0o%oplasma9 Mycoplasma9 Listeria9 an1 *iral infections ha*e also been implicate1 as ca/ses of abortion.
>?I@

The morphologic changes /s/ally seen in en1ometrial c/rettage specimens 1epen19 of co/rse9 on the inter*al bet7een fetal 1eath an1 passage of the pro1/cts of conception. In general9 there are focal areas of 1eci1/al necrosis 7ith intense ne/trophilic infiltration9 thrombi 7ithin 1eci1/al bloo1 *essels9 an1 consi1erable amo/nts of hemorrhage9 both recent an1 ol19 7ithin the necrotic 1eci1/a. Placental *illi may be mar;e1ly e1emato/s an1 1e*oi1 of bloo1 *essels. The changes enco/ntere1 in the o*/m or fet/s are highly *ariable. In many spontaneo/s abortions9 no fetal pro1/cts can be i1entifie19 b/t 7hen they are present9 they sho/l1 be caref/lly e3amine1 for anomalies that 7o/l1 s/ggest specific genetic or ;aryotypic 1efects. Chromosomal st/1ies are recommen1e1 +?, in habit/al or rec/rrent abortion an1 +2, 7hen there is a malforme1 fet/s.
>?2L@

CT'P%C P, GN$NC;

Ectopic pregnancy is the term applie1 to implantation of the fet/s in any site other than a normal /terine location. The most common site is 7ithin the t/bes +appro3imately OIP,. The other sites are the o*ary9 the ab1ominal ca*ity9 an1 the intra/terine portion of the fallopian t/be +corn/al pregnancy,. Ectopic pregnancies occ/r abo/t once in e*ery ?EI pregnancies. The most important pre1isposing con1ition in BEP to EIP of patients is PI# 7ith chronic salpingitis. !ther factors are perit/bal a1hesions 1/e to appen1icitis or en1ometriosis9 leiomyomas9 an1 pre*io/s s/rgery. Fifty per cent9 ho7e*er9 occ/r in t/bes that are apparently normal. Intra/terine 1e*ices may also increase ris;.
>?2J@

!*arian pregnancy is pres/me1 to res/lt from the rare fertili:ation an1 trapping of the o*/m 7ithin the follicle D/st at the time of its r/pt/re. Ab1ominal pregnancies may 1e*elop 7hen the fertili:e1 o*/m 1rops o/t of the fimbriate1 en1 of the t/be. In all these abnormal locations9 the fertili:e1 o*/m /n1ergoes its /s/al 1e*elopment 7ith the formation of placental tiss/e9 amniotic sac9 an1 fet/s9 an1 the host implantation site 1e*elops 1eci1/al changes.
Morpholo#".

In t/bal pregnancy9 the placenta is poorly attache1 to the 7all of the t/be. Intrat/bal hemorrhage may th/s occ/r from partial placental separation 7itho/t t/bal r/pt/re + Fig. 22-EK ,. T/bal pregnancy is the most common ca/se of hematosalpin3 an1 sho/l1 al7ays be s/specte1 7hen a t/bal hematoma is present. -ore often9 the placental tiss/e in*a1es

the t/bal 7all an1 ca/ses t/bal r/pt/re an1 intraperitoneal hemorrhage. %ess commonly9 the t/bal pregnancy may /n1ergo spontaneo/s regression an1 resorption of the entire gestation. "till less commonly9 the t/bal pregnancy is e3tr/1e1 thro/gh the fimbriate1 en1 into the ab1ominal ca*ity +t/bal abortion,. The clinical co/rse of ectopic pregnancy is p/nct/ate1 by the onset of se*ere ab1ominal pain abo/t K 7ee;s after a pre*io/s normal menstr/al perio19 7hen r/pt/re of the t/be lea1s to pel*ic hemorrhage. In s/ch cases9 the patient may rapi1ly 1e*elop a shoc;li;e state 7ith signs of an ac/te ab1omen9 an1 early 1iagnosis becomes critical. Chorionic gona1otropin assays9 /ltraso/n1 st/1ies9 an1 laparoscopy may be helpf/l. En1ometrial biopsy specimens may or may not 1isclose 1eci1/al changes b/t9 e3cl/1ing the e3tremely rare 1/al pregnancy9 1o not e3hibit chorionic *illi. '/pt/re of a t/bal pregnancy constit/tes a me1ical emergency.
Disor/ers o& *ate Pre#nanc"

The m/ltit/1e of 1isor1ers that may occ/r in the thir1 trimester reflect the comple3 anatomy of the mat/ring placenta + Fig. 22-EL ,. Any interr/ption of bloo1 flo7 thro/gh the /mbilical cor1 +s/ch as constricting ;nots or compression, 7ill be lethal to the fet/s. Ascen1ing infections in*ol*ing the chorioamnionic membranes may lea1 to premat/re r/pt/re an1 1eli*ery. 'etroplacental hemorrhage at the interface of placenta an1 myometri/m +abr/ptio placentae, 7ill threaten both mother an1 fet/s. '/pt/re of the fetal *essels in terminal *illi +inter*illo/s hemorrhage, may pro1/ce a s/11en 1rop in fetal bloo1 *ol/me9 7ith fetal stress or 1eath. )teroplacental ins/fficiency can be precipitate1 by abnormal placentation9 altere1 placental 1e*elopment9 or maternal *asc/lar thrombosis9 an1 the effects may range from mil1 intra/terine gro7th retar1ation to se*ere /teroplacental ischemia an1 maternal to3emia. The more common of these con1itions are 1isc/sse1.
P*$C NT$* $.N',M$*%T% ( $ND T+%N P*$C NT$(

Abnormalities in placental shape9 str/ct/re9 an1 implantation are not /ncommon. Accessory placental lobes9 bipartite placenta +placenta ma1e /p of t7o e6/al segments,9 an1 circ/m*allate placenta +ha*ing an e3trachorial part, are e3amples of abnormalities that ha*e limite1 clinical significance. 4lacenta accreta is ca/se1 by partial or complete absence of the 1eci1/a 7ith a1herence of the placenta 1irectly to the myometri/m. It is important for t7o reasonsH +?, postpart/m blee1ing9 often life-threatening9 occ/rs beca/se of fail/re of placental separation< +2, in /p to KIP of cases9 it is associate1
1106

Fi#ure 22-56 Potential sites for ectopic pregnancy9 incl/1ing the fallopian t/be9 o*ary9 corn/9 an1 +rarely, ab1ominal *iscera.

7ith placenta pre*ia9 a con1ition in 7hich the placenta implants in the lo7er /terine segment or cer*i39 often 7ith serio/s antepart/m blee1ing an1 premat/re labor. -any cases of placenta pre*ia-associate1 accreta occ/r in patients 7ith cesarean section scars. T7in pregnancies arise from fertili:ation of t7o o*a +1i:ygotic, or from 1i*ision of one fertili:e1 o*/m +mono:ygotic,. There are three basic types of t7in placentas + Fig. 22EJ ,H 1ichorionic 1iamnionic +7hich may be f/se1,9 monochorionic 1iamnionic9 an1 monochorionic monoamnionic. -onochorionic placentas imply mono:ygotic +i1entical, t7ins9 an1 the time at 7hich splitting occ/rs 1etermines 7hether one or t7o amnions are present. #ichorionic gestation may occ/r 7ith either mono:ygotic or 1i:ygotic t7ins an1 is not specific.
>?2O@

!ne complication of t7in pregnancy is t7in-t7in transf/sion9 in 7hich placental *asc/lar anastomoses +connections, create an abnormal sharing of fetal circ/lations thro/gh sh/nting. If an imbalance in bloo1 flo7 occ/rs9 a mar;e1 1isparity in fetal bloo1 *ol/mes may res/lt in the 1eath of one or both fet/ses + Fig. 22-EO ,.
P*$C NT$* %NF*$MM$T%'N( $ND %NF CT%'N(

Infections may occ/r in the placenta +placentitis9 *illitis,9 in the fetal membranes +chorioamnionitis,9 an1 in the /mbilical cor1 +f/nisitis,. They reach the placenta by t7o path7aysH +?, ascen1ing infection thro/gh the birth canal an1 +2, hematogeno/s
>?BI@

+transplacental, infection. Ascen1ing infections are by far the most common an1 are most often bacterial< in many s/ch instances9 locali:e1 infection of the membranes by an organism pro1/ces premat/re r/pt/re of membranes an1 entry of the organisms. "e3/al interco/rse has been implicate1 in enhancing ascen1ing infections. The amniotic fl/i1 may be clo/1y 7ith p/r/lent e3/1ate9 an1 the chorion-amnion histologically contains a le/;ocytic polymorphon/clear infiltration 7ith accompanying e1ema an1 congestion of the *essels + Fig. 22-KIA an1 B ,. The infection fre6/ently elicits a fetal response 7ith /mbilical cor1 *asc/litis. )ncommonly9 bacterial infections of the placenta an1 fetal membranes may arise by the hematogeno/s sprea1 of bacteria 1irectly to the placenta. The *illi are most often affecte1 histologically +*illitis, + Fig. 22-KIC ,. Classically9 T!'C$ +to3oplasmosis an1 others >syphilis9 t/berc/losis9 listeriosis@9 r/bella9 cytomegalo*ir/s9 herpes simple3, sho/l1 be consi1ere19 altho/gh the ca/se is /s/ally obsc/re an1 may in*ol*e imm/nologic phenomena. +"ee also Chapter ?I .,
>?I@

T'8 M%$ 'F P, GN$NC; 4P,

C*$MP(%$ $ND C*$MP(%$5

To3emia of pregnancy refers to a symptom comple3 characteri:e1 by hypertension9 protein/ria9 an1 e1ema +preeclampsia,. It occ/rs in abo/t KP of pregnant 7omen9 /s/ally in the last trimester an1 more commonly in primiparas than in m/ltiparas. Certain of these patients become more serio/sly ill9 1e*eloping con*/lsions< this more se*ere form of to3emia is terme1 eclampsia. Patients 7ith eclampsia 1e*elop 1isseminate1 intra*asc/lar coag/lation +#IC, 7ith lesions in the li*er9 ;i1neys9 heart9 placenta9 an1 sometimes the brain. There is no absol/te correlation bet7een the se*erity of eclampsia an1 the magnit/1e of the anatomic changes.
1107

Fi#ure 22-57 A9 #iagram of placental anatomy. &ithin the o/ter bo/n1ary of myometri/m is a layer of 1eci1/a9 from 7hich the maternal *essels originate an1 1eli*er bloo1 to an1 from the inter*illo/s spaces. )mbilical *essels branch an1 terminate in placental *illi9 7here n/trient e3change ta;es place. B9 Normal term placenta +fetal s/rface, 7ith /mbilical cor1.

Patho#enesis.

The many theories on the nat/re of to3emia of pregnancy are beyon1 o/r scope9 b/t three e*ents that seem to be of prime importance in this 1isor1er are a11resse1H placental ischemia9 hypertension9 an1 #IC + Fig. 22-K? ,.
>?B?@ >?B2@ >?BB@ >?BC@ >?BE@ >?BK@

The ca/ses of the initial e*ents of to3emia are /n;no7n9 b/t e*i1ence points to an abnormality of placentation9 lea1ing to placental isc(emia. This may in*ol*e 1efects in

both trophoblast in*asion an1 the 1e*elopment of the physiologic alterations in the placental *essels re6/ire1 to perf/se the placental be1 a1e6/ately. Imm/nologic9 genetic9 an1 other factors ha*e been post/late1 as ca/ses of these abnormalities. The net effect is a s(allo1 implantation 7ith incomplete con*ersion of 1eci1/al *essels to *essels a1e6/ate for the pregnancy state. In*estigators ha*e hypothesi:e1 that an intrinsic defect in t(e in-ading trop(oblast may contrib/te to altere1 *asc/lar flo7. This abnormality is manifest by the inability of the in*a1ing cytotrophoblast to ass/me the phenotype of normal en1othelial cells9 7hich normally incl/1es the e3pression of a1hesion receptors. These 1efects in trophoblastic con*ersion may f/rther infl/ence remo1eling of /terine *asc/lat/re9 re1/cing bloo1 flo7 an1 lea1ing to placental isc(emia, t(e basis for t(e to%emic placenta. It is tho/ght that this 1ecrease1 /teroplacental perf/sion in1/ces stim/lation of *asoconstrictor s/bstances +thrombo3ane9 angiotensin9 en1othelin, an1 the inhibition of *aso1ilator infl/ences +prostaglan1in I2 9 prostaglan1in E2 9 nitric o3i1e, from the ischemic placenta. #IC9 hypertension9 an1 organ 1amage then 1e*elop + Fig. 22-K? ,.
>?B2@ >?BB@ >?BC@

As to the pathogenesis of #IC in to3emia9 en1othelial 1amage9 abnormalities in the le*el an1 acti*ities of coag/lation
1109

Fi#ure 22-59 #iagrammatic representation of the *ario/s types of t7in placentation an1 their membrane relationships. (Adapted from 'ersell *, et al: *iseases of t(e placenta. 6n =urman, A (ed$: Blaustein9s 4at(ology of t(e +emale 'enital 0ract. /e1 For , @pringer35erlag, !"">.$

factors9 an1 primary platelet alteration may play a role. For e3ample9 1/ring to3emia9 the placental ischemia lea1s to a higher o/tp/t of thromboplastic s/bstances9 an1 antithrombin III le*els are re1/ce1. The characteristic lesions in eclampsia are in large part 1/e to thrombosis of arterioles an1 capillaries thro/gho/t the bo1y9 partic/larly in the li*er9 ;i1neys9 brain9 pit/itary9 an1 placenta.
>?BE@

"e*eral mechanisms ha*e been propose1 to e3plain to3emic hypertension. !ne mechanism in*ol*es renin-angiotensin an1 prostaglan1ins. Normal pregnant 7omen 1e*elop a resistance to the *asoconstricti*e an1 hypertensi*e effects of angiotensin9 b/t 7omen 7ith to3emia lose s/ch resistance9 1e*eloping a ten1ency to hypertension. Prostaglan1ins of the E series9 pro1/ce1 in the /teroplacental *asc/lar be1 1/ring
>?BK@

Fi#ure 22-59 T7in-t7in transf/sion syn1rome res/lting in the 1eath of both fet/ses beca/se of e3cessi*e +left, or 1eficient +rig(t, bloo1 *ol/me.

pregnancy9 are tho/ght to me1iate the normal resistance of pregnant 7omen to angiotensin9 an1 prostaglan1in pro1/ction is in1ee1 1ecrease1 in the placenta of to3emic 7omen. Th/s9 the increase in angiotensin hypersensiti*ity9 characteristic of to3emia9 may be 1/e to 1ecrease1 synthesis of prostaglan1in by the to3emic placenta. There is also e*i1ence that renin pro1/ction by the to3emic placenta is increase19 another potentially *asoconstricti*e e*ent. Fig/re 22-K? presents a hypothetical schema for the pathogenesis of eclampsia. An a11itional mechanism recently propose1 in*ol*es circ/lating sol/ble fms-li;e tyrosine ;inase +sFlt?,9 7hich

Fi#ure 22-60 Placental infections 1eri*e1 from ascen1ing an1 bloo1-borne ro/tes. Ac/te chorioamnionitis. A9 !n gross e3amination9 the placenta contains greenish opa6/e membranes. Compare 7ith Fig/re 22-EEB . B9 A photomicrograph ill/strates a 1ense ban1-li;e inflammatory e3/1ate on the amniotic s/rface +top,. C9 Ac/te necroti:ing inter*illositis9 from a fetal-maternal infection by listeria.

1109

Fi#ure 22-61 Propose1 se6/ence of e*ents in the pathogenesis of to3emia of pregnancy. The main feat/res are +?, 1ecrease1 /teroplacental perf/sion< +2, increase1 *asoconstrictors an1 1ecrease1 *aso1ilators9 res/lting in local an1 systemic *asoconstriction< an1 +B, 1isseminate1 intra*asc/lar coag/lation +#IC,. (Adapted from +riedman @A: 4re3eclampsia: a re-ie1 of t(e role of prostaglandins. Ebstet 'ynecol ;!:!DD, !"##. Aeprinted by permission of t(e American College of Ebstetricians and 'ynecologistsG and =(ong 0F, et al: 6nade2uate maternal -ascular response to placentation in pregnancies complicated by pre3eclampsia and by small for gestational age infants. Br J Ebstet 'ynecol "8:!H>", !"#:.$

bin1s both placental gro7th factor +PIGF, an1 *asc/lar en1othelial gro7th factor +(EGF,. Normally9 ser/m sFlt? increases9 an1 PIGF an1 (EGF 1ecrease near term9 reflecting a re1/ction in angiogenic acti*ity. In preeclampsia9 1ecrease1 angiogenesis occ/rs m/ch earlier than in normal pregnancy. The premat/re application of an antiangiogenic Gbra;eG may9 th/s9 be a ;ey factor in the initiation of preeclampsia. A1ministration of sFlt? to pregnant rats pro1/ces the characteristic systemic an1 renal abnormalities seen in h/man preeclampsia.
>?BKA@ >?BK0@

Morpholo#".

The placenta is the site of *ariable changes9 most of 7hich reflect ischemia an1 *essel inD/ry. +?, Placental infarcts9 7hich occ/r in normal f/ll-term placentas9 are larger an1

more n/mero/s. +2, There is increase1 fre6/ency of retroplacental hematomas. +B, There is e*i1ence of increase1 *illo/s ischemia< formation of prominent syncytial ;nots9 thic;ening of trophoblastic basement membrane9 an1 *illo/s hypo*asc/larity. +C, A characteristic fin1ing in the 7alls of /terine *essels is stri;ing fibrinoi1 necrosis an1 intram/ral lipi1 1eposition +ac/te atherosis, + Fig. 22-K2 ,. The li3er lesions9 7hen present9 ta;e the form of irreg/lar9 focal9 s/bcaps/lar9 an1 intraparenchymal hemorrhages. !n histologic e3amination9 there are fibrin thrombi in the portal capillaries 7ith foci of characteristic peripheral hemorrhagic necrosis. The Bi/ne" lesions are *ariable. Glomer/lar lesions are 1iff/se9 7hen assesse1 by electron microscopy. They consist of stri;ing s7elling of en1othelial cells9 the 1eposition of fibrinogen-1eri*e1 amorpho/s 1ense 1eposits on the en1othelial si1e of the basement membrane9 an1 mesangial cell hyperplasia. Imm/nofl/orescent st/1ies confirm the ab/n1ance of
1110

Fi#ure 22-62 Ac/te atherosis of /terine *essels in eclampsia. Note fibrinoi1 necrosis of the *essel 7alls9 s/ben1othelial macrophages an1 peri*asc/lar lymphocytic infiltrate. (Courtesy of *r. *rucilla J. Aoberts, Massac(usetts 'eneral )ospital, Boston, MA.$

fibrin in glomer/li. In the more 7ell-1efine1 cases9 fibrin thrombi are present in the glomer/li an1 capillaries of the corte3. &hen the lesion is far a1*ance19 it may pro1/ce complete 1estr/ction of the corte3 in the pattern referre1 to as bilateral renal cortical necrosis + Chapter 2I ,. The !rain may ha*e gross or microscopic foci of hemorrhage along 7ith small-*essel thromboses. "imilar changes are often fo/n1 in the heart an1 the anterior pituitar".
Clinical Course.

Preeclampsia /s/ally starts after the B2n1 7ee; of pregnancy b/t begins earlier in patients 7ith hy1ati1iform mole +1isc/sse1 belo7, or pre-e3isting ;i1ney 1isease or hypertension. The onset is typically insi1io/s9 characteri:e1 by hypertension an1 e1ema9 7ith protein/ria follo7ing 7ithin se*eral 1ays. $ea1aches an1 *is/al 1ist/rbances are common. Eclampsia is heral1e1 by central ner*o/s system in*ol*ement9 incl/1ing con*/lsions an1 e*ent/al coma. -il1 an1 mo1erate forms of to3emia can be controlle1 by be1 rest9 a balance1 1iet9 an1 antihypertensi*e agents9 b/t in1/ction of 1eli*ery is the only 1efiniti*e treatment of establishe1 preeclampsia an1 eclampsia. Protein/ria an1 hypertension /s/ally 1isappear 7ithin ? or 2 7ee;s after 1eli*ery e3cept in patients in 7hom these fin1ings pre1ate the pregnancy.
%NT,$2T ,%N G,'+T) , (T,%CT%'N

Intra/terine gro7th restriction is an important ca/se of infant mortality an1 morbi1ity an1 is 1efine1 as a birth 7eight belo7 the ?Ith percentile + Chapter ?I ,. -aDor ca/ses incl/1e ob*io/s fetal 1isor1ers s/ch as chromosomal abnormalities an1 malformations +2IP,9 an1 maternal *asc/lar 1isease9 incl/1ing to3emia +BIP,. !ther ca/ses incl/1e thrombolytic 1isor1ers9 maternal an1 fetal infections9 a/toimm/ne 1isor1ers +chronic *illitis,9 fetal *asc/lar 1isor1ers +fetal thrombosis,9 an1 other metabolic 1isor1ers. In o*er one-thir1 the placenta is small for 1ate9 implying poor perf/sion. -anagement of these 1isor1ers9 partic/larly 7hen the fet/s is other7ise normal9 re6/ires caref/l monitoring of fetal an1 placental 1e*elopment an1 rapi1 1eli*ery if placental bloo1 flo7 appears compromise1.
>?BL@

Gestational Tropho!lastic Disease

Gestational trophoblastic 1isease constit/tes a spectr/m of t/mors an1 t/mor-li;e con1itions characteri:e1 by proliferation of pregnancy-associate1 trophoblastic tiss/e of progressi*e malignant potential. The lesions incl/1e the hy1ati1iform mole +complete an1 partial,9 the in*asi*e mole9 an1 the fran;ly malignant choriocarcinoma. Gestational trophoblastic 1isease is important for the follo7ing reasonsH
>?BJ@

The hy1ati1iform mole is a common complication of gestation9 occ/rring abo/t once in e*ery ?III to 2III pregnancies in the )nite1 "tates an19 c/rio/sly9 far more commonly in the Far East. It has become possible9 by monitoring the circ/lating le*els of h/man chorionic gona1otropin9 to 1etermine the early 1e*elopment of persistent trophoblastic 1isease. Choriocarcinoma9 once a 1rea1e1 an1 /niformly fatal complication9 is no7 highly responsi*e to chemotherapy.
>?BO@

);D$T%D%F',M M'* 4C'MP* T $ND P$,T%$*5

$y1ati1iform mole is characteri:e1 by cystic s7elling of the chorionic *illi9 accompanie1 by *ariable trophoblastic proliferation. The most important reason for the correct recognition of tr/e moles is that they may prece1e choriocarcinoma. -ost patients present in the fo/rth or fifth month of pregnancy 7ith *aginal blee1ing an1 7ith a /ter/s
>?BJ@

that is /s/ally9 b/t not al7ays9 larger than e3pecte1 for the 1/ration of pregnancy. These moles can occ/r at any age 1/ring acti*e repro1/cti*e life9 b/t the ris; is higher in pregnant 7omen in their teens or bet7een the ages of CI an1 EI years. For poorly e3plaine1 reasons9 the inci1ence *aries consi1erably in 1ifferent regions of the 7orl1H ? in ?III pregnancies in the )nite1 "tates b/t ?I in ?III in In1onesia.
>?CI@

T"pes an/ Patho#enesis.

T7o types of benign9 nonin*asi*e moles=complete an1 partial=can be i1entifie1 by histologic9 cytogenetic9 an1 flo7 cytometric st/1ies + Table 22-E ,. In complete +or classic, mole9 all or most of the *illi are e1emato/s9 an1 there is 1iff/se trophoblast hyperplasia. Cytogenetic
>?C?@

T$.* 22-5 -- Feat/res of Complete (ers/s Partial $y1ati1iform -ole Feature Raryotype (illo/s e1ema Trophoblast proliferation Atypia "er/m hCG $CG in tiss/e 0eha*ior All *illi #iff/se< circ/mferential !ften present Ele*ate1 WWWW 2P choriocarcinoma Complete Mole CK922 +CK925, Triploi1 "ome *illi Focal< slight Absent %ess ele*ate1 W 'are choriocarcinoma Partial Mole

$CG9 h/man chorionic gona1otropin.

1111

Fi#ure 22-6- Patterns of fertili:ation to acco/nt for chromosomal origin of complete +CK922, an1 triploi1 partial moles +225,. In a complete mole9 one or t7o sperm fertili:e an egg that has lost its chromosomes. Partial moles are 1/e to fertili:ation of an egg by one 1iploi19 or t7o haploi1 sperm9 1epicte1 in this e3ample as one 2B92 an1 one 2B95.

st/1ies of these moles sho7 that more than OIP ha*e a CK922 1iploi1 pattern9 all 1eri*e1 from the sperm +a phenomenon calle1 an1rogenesis,. They are pres/me1 to res/lt from fertili:ation by a single sperm of an egg that has lost its chromosomes + Fig. 22-KB ,. The remaining ?IP are from the fertili:ation of s/ch an empty egg by t7o sperm +CK922 an1 CK925,. In both circ/mstances9 embryonic 1e*elopment 1oes not occ/r9 an1 th/s complete moles sho7 no fetal parts. In partial moles9 some of the *illi are e1emato/s9 an1 other *illi sho7 only minor changes< the trophoblastic proliferation is focal. In these moles9 the ;aryotype is triploi1 +e.g.9 KO9225, or e*en occasionally tetraploi1 +O292225,. The moles res/lt from fertili:ation of an egg 7ith one or t7o sperm + Fig. 22-KB ,. The embryo is *iable for 7ee;s9 an1 th/s fetal parts may be present 7hen the res/ltant mole is aborte1. In contrast to complete moles9 partial moles are rarely follo7e1 by choriocarcinoma. !nly a portion of triploi1 gestations res/lt in partial moles. A recent st/1y sho7e1 that partial moles 7ere significantly more li;ely 7hen the gestation 7as diandric9 that is9 t7o of the three haploi1 chromosomal sets 7ere 1eri*e1 from the male +*ia 1ispermy,. This is

in contrast to digynic triploi1 gestations9 in 7hich t7o haploi1 sets 1e*elop 1/e to errors in meiosis.
>?C2@

Morpholo#".

In most instances9 moles 1e*elop 7ithin the /ter/s9 b/t they may occ/r in any site9 incl/1ing ectopic pregnancies. Timing of 1isco*ery is relate1 to type of mole +partial *ers/s complete9 an1 le*el of pregnancy s/r*eillance,. Partial moles may be 1iagnose1 in early spontaneo/s abortions or later9 follo7ing fetal 1e*elopment. Caref/l 1issection may 1isclose a small9 /s/ally collapse1 amniotic sac. Fetal parts are fre6/ently seen in partial moles b/t are ne*er fo/n1 in complete moles +/nless there is a t7in pregnancy,. C/rrently9 complete moles are being 1iagnose1 an1 remo*e1 at an earlier mean gestational age +J.E *ers/s ?L.I 7ee;s, 1/e to ro/tine /ltraso/n1 an1 close monitoring of early pregnancy9 combine1 7ith more efficient histologic recognition of early complete hy1ati1iform mole. The classic presentation is a /terine ca*ity fille1 7ith a 1elicate9 friable mass of thin-7alle19 transl/cent9 cystic9 grapeli;e str/ct/res consisting of s7ollen e1emato/s +hy1ropic, *illi + Fig. 22-KC ,.
>?CB@ >?CC@

!n histologic e3amination9 partial moles + Fig. 22-KEA , 1emonstrate *illo/s hy1rops an1 architect/ral 1ist/rbances in only a proportion of *illi. The trophoblastic proliferation is minimal an1 limite1 to the syncitiotrophoblast. In contrast9 complete moles sho7 hy1ropic s7elling of most chorionic *illi an1
1112

Fi#ure 22-60 Complete hy1ati1iform mole s/spen1e1 in saline sho7ing n/mero/s s7ollen +hy1ropic, *illi.

*irt/al absence or ina1e6/ate 1e*elopment of *asc/lari:ation of *illi. Early complete moles e3hibit s/btle conformational changes in the *illi accompanie1 by stromal cell ;arryorrhe3is an1 mo1est syncytial an1 cytotrophoblastic hyperplasia. -ore a1*ance1 complete moles e3hibit the classic spectr/m of 1iff/se *illo/s s7elling9 central ca*itation

+cisterns, an1 e3tensi*e concentric *illo/s an1 e3tra*illo/s trophoblastic proliferation + Fig. 22-KEB ,. The implantation

Fi#ure 22-65 A9 Photomicrograph of partial hy1ati1iform mole re*ealing s7ollen *illi an1 slight hyperplasia of the s/rface trophoblast. B9 Complete hy1ati1iform mole 7ith e3tensi*e cytotrophoblastic hyperplasia +lo1er field, (Courtesy of *r. *a-id A. 'enest, Brig(am and Women9s )ospital, Boston, MA.$. C9 Complete moles lac; e3pression of p7; in the cytotrophoblast +arro1(eads, an1 *illo/s stroma +arro1,. *9 Normal placenta imm/nostaine1 for p7; e3hibits staining in both stromal +arro1s, an1 cytotrophoblast +arro1(eads, n/clei. (Courtesy of *r. *iego C. Castrillon, Brig(am and Women9s )ospital, Boston, MA.$

site often 1isplays increase1 atypia. $istologic gra1ing 1oes not pre1ict the o/tcome< therefore9 all moles sho/l1 be caref/lly obser*e1 by monitoring of the h/man chorionic gona1otropin le*els.
Clinical Course.

>?CE@

-ost patients 7ith partial an1 early complete moles present 7ith spontaneo/s pregnancy loss or /n1ergo c/rettage 1/e to abnormalities in /ltraso/n1. &atery fl/i1 an1 bits of tiss/e seen as small9 grapeli;e masses may be seen in the /terine contents. )ltraso/n1 e3amination 7ill confirm the 1iff/se *illo/s enlargement. In complete moles9 6/antitati*e analysis of h/man chorionic gona1otropin sho7s le*els of hormone greatly e3cee1ing those pro1/ce1 by a normal pregnancy of similar age. "erial hormone 1etermination in1icates a rapi1ly mo/nting le*el that climbs faster than for the /s/al normal single or e*en m/ltiple pregnancy. The *ast maDority of moles are remo*e1 by thoro/gh c/rettage. (irt/ally no partial an1 only 2.EP of complete moles e*ol*e into a malignant trophoblastic neoplasm

+choriocarcinoma,. Ten per cent of complete moles 1e*elop into in*asi*e moles. 0eca/se /natten1e1 complete moles may persist an1 rec/r9 1istinction of these moles from non-molar hy1ropic an1 partial molar gestations is important. A strongly paternally imprinte1 gene9 the cell cycle inhibitor9 pEL9 may be /se1 to i1entify complete moles by absence of e3pression in the syncytial trophoblast an1 stromal cells of molar *illi + Fig. 22-KEC an1 * ,. 0eca/se p7; is paternally imprinte19 an1 both the 2 chromosomes in complete moles are 1eri*e1 from the father9 there is no e3pression of pEL protein.
>?CK@ >?CL@

111%N1$(%1 M'*

This is 1efine1 as a mole that penetrates an1 may e*en perforate the /terine 7all. There is in*asion of the myometri/m by hy1ropic chorionic *illi9 accompanie1 by proliferation of both cytotrophoblast an1 syncytiotrophoblast + Fig. 22-KK ,. The t/mor is locally 1estr/cti*e an1 may in*a1e parametrial tiss/e an1 bloo1 *essels. $y1ropic *illi may emboli:e to 1istant sites9 s/ch as l/ngs an1 brain9 b/t 1o not gro7 in these organs as tr/e metastases9 an1 e*en before the a1*ent of chemotherapy9 they e*ent/ally regresse1 /nless fatal hemorrhage occ/rre1. The t/mor is manifeste1 clinically by *aginal blee1ing an1 irreg/lar /terine enlargement. It is al7ays associate1 7ith a persistent ele*ate1 h/man chorionic gona1otropin le*el an1 *arying 1egrees of l/teini:ation of the o*aries. The t/mor respon1s 7ell to chemotherapy b/t may res/lt in /terine r/pt/re an1 necessitate hysterectomy.
C)',%'C$,C%N'M$

Gestational choriocarcinoma is an epithelial malignant neoplasm of trophoblastic cells 1eri*e1 from any form of pre*io/sly normal or abnormal pregnancy. Altho/gh most cases arise in the /ter/s9 ectopic pregnancies pro*i1e e3tra/terine sites of origin. Choriocarcinoma is a rapi1ly in*asi*e9 7i1ely metastasi:ing malignant neoplasm9 b/t once it is i1entifie19 it respon1s 7ell to chemotherapy.
>?IE@

%nci/ence.

This is an /ncommon con1ition that arises in ? in 2I9III to BI9III pregnancies in the )nite1 "tates. It is m/ch more common in some African co/ntries< for e3ample9 it occ/rs in ? in 2EII pregnancies in Iba1an9 Nigeria. It is prece1e1 by se*eral con1itionsH EIP arise in hy1ati1iform moles9 2EP in pre*io/s abortions9 appro3imately 22P in normal pregnancies +intraplacental choriocarcinoma,. The remain1er occ/r in ectopic pregnancies an1 genital an1 e3tragenital teratomas. Abo/t ? in CI hy1ati1iform moles may be e3pecte1 to gi*e rise to a choriocarcinoma9 in contrast to ? in appro3imately ?EI9III normal pregnancies.

Fi#ure 22-66 A9 In*asi*e mole presenting as a hemorrhagic mass a1herent to the /terine 7all. B9 !n crosssection9 the t/mor in*a1es into the myometri/m. (Courtesy of *r. *a-id A. 'enest, Brig(am and Women9s )ospital, Boston, MA.$

Morpholo#".

The choriocarcinoma is classically a soft9 fleshy9 yello7-7hite t/mor 7ith a mar;e1 ten1ency to form large pale areas of ischemic necrosis9 foci of cystic softening9 an1 e3tensi*e hemorrhage + Fig. 22-KLA ,. !n histologic e3amination9 it is a p/rely epithelial t/mor that 1oes not pro1/ce chorionic *illi an1 that gro7s by the abnormal proliferation of both cytotrophoblast an1 syncytiotrophoblast + Fig. 22-KLB ,. It is sometimes possible to i1entify anaplasia 7ithin s/ch abnormal proliferation9 replete 7ith abnormal mitoses. The t/mor in*a1es the /n1erlying myometri/m9 fre6/ently penetrates bloo1 *essels an1 lymphatics9 an1 in some cases e3ten1s o/t onto the /terine serosa an1 a1Dacent str/ct/res. In its rapi1 gro7th9 it is s/bDect to hemorrhage9 ischemic necrosis9 an1 secon1ary inflammation. In fatal cases9 metastases are fo/n1 in the l/ngs9 brain9 bone marro79 li*er9 an1 other organs. !n occasion9 metastatic choriocarcinoma is 1isco*ere1 7itho/t a 1etectable primary in the /ter/s +or o*ary,9 pres/mably beca/se the primary has /n1ergone total necrosis.
Clinical Course.

The /terine choriocarcinoma 1oes not classically pro1/ce a large9 b/l;y mass. It becomes manifest only by irreg/lar spotting of a bloo1y9 bro7n9 sometimes fo/l-smelling fl/i1. This 1ischarge may appear in the co/rse of an apparently normal pregnancy9 after a miscarriage9 or after a c/rettage. "ometimes the t/mor 1oes not appear /ntil months after these e*ents. )s/ally9 by the time the t/mor is 1isco*ere1 locally9 ra1iographs of the chest an1 bones alrea1y 1isclose the presence of metastatic lesions. The titers of h/man chorionic gona1otropin are ele*ate1 to le*els abo*e those enco/ntere1 in hy1ati1iform moles. !ccasional t/mors9 ho7e*er9 pro1/ce little hormone9 an1 some t/mors ha*e become so necrotic as to become f/nctionally inacti*e.

&i1esprea1 metastases are characteristic of these t/mors. Fa*ore1 sites of in*ol*ement are the l/ngs +EIP, an1 *agina +BIP to CIP,9 follo7e1 in 1escen1ing or1er of fre6/ency by the brain9 li*er9 an1 ;i1ney.
1110

Fi#ure 22-67 A9 Choriocarcinoma presenting as a b/l;y hemorrhagic mass in*a1ing the /terine 7all. B9 Photomicrograph of choriocarcinoma ill/strating both neoplastic cytotrophoblast an1 syncytiotrophoblast. (Courtesy of *r. *a-id A. 'enest, Brig(am and Women9s )ospital, Boston, MA.$

The treatment of trophoblastic neoplasms 1epen1s on the type an1 stage of t/mor an1 incl/1es e*ac/ation of the contents of the /ter/s9 s/rgery9 an1 chemotherapy. Chemotherapy consists of the a1ministration of one or more of a gro/p of 1r/gs incl/1ing methotre3ate9 actomycin #9 an1 etoposi1e. The res/lts of chemotherapy for gestational choriocarcinoma are spectac/lar an1 ha*e res/lte1 in /p to ?IIP c/re or remission in all patients e3cept some 7ho ha1 high-ris; metastatic trophoblastic 1isease. -any of the c/re1 patients ha*e ha1 normal s/bse6/ent pregnancies an1 1eli*eries. 0y contrast9 nongestational choriocarcinomas are m/ch more resistant to therapy.
>?BJ@ >?BO@ >?CI@

P*$C NT$* (%T T,'P)'.*$(T%C T2M',

In contrast to syncytial cytotrophoblast9 7hich is present on the chorionic *illi9 interme1iate trophoblast is fo/n1 in the implantation site an1 placental membranes. Interme1iate trophoblast is compose1 of monon/clear cells 7ith ab/n1ant cytoplasm that 1isting/ish them from the syncytial cytotrophoblast. In

Fi#ure 22-69 A9 Placental site trophoblastic t/mor9 presenting as a 1iscrete mass in the myometri/m. B9 $istology of P"TT. (Courtesy of *r. Bradley J. .uade, Brig(am and Women9s )ospital, Boston, MA.$

contrast to syncytiotrophoblasts +7hich pro1/ce h/man chorionic gona1otropin,9 interme1iate trophoblast cells are 7ea;ly imm/noreacti*e for h/man placental lactogen. Interme1iate trophoblasts compose the placental site trophoblast an1 resi1/al placental site +implantation site no1/le, follo7ing pregnancy9 an1 may gi*e rise to placental site trop(oblastic tumors +P"TTs, + Fig. 22-KJ ,. P"TTs comprise less than 2P of gestational trophoblastic neoplasms an1 present as neoplastic polygonal cells infiltrating the en1omyometri/m. P"TTs may be prece1e1 by a normal pregnancy +one-half,9 spontaneo/s abortion +one-si3th,9 or hy1ati1iform mole +one-fifth,. 0eta h/man chorionic gona1otropin le*els may be high. Patients 7ith locali:e1 +"tage I or II, 1isease or a less than 2-year inter*al from the prior pregnancy to 1iagnosis ha*e an e3cellent prognosis. T/mors 1iagnose1 C or more years follo7ing pregnancy9 7ith l/ng in*ol*ement or 7ith a1*ance1 stage ha*e a poor prognosis. !*erall9 abo/t ?IP res/lt in 1isseminate1 metastases an1 1eath. #istinction of P"TTs from normal e3aggerate1 placental implantation site trophoblast may be 1iffic/lt an1 can be achie*e1 by /sing biomar;ers +-el-Cam an1 Ri-KL, that 1etect increase1 proliferation in the trophoblastic cells.
>?CO@ >?EI@ >?E?@ >?E2@

1115

,e&erences
?. 'obboy

"M9 et alH Embryology of the female genital tract. In R/rman ' +e1,H 0la/steinQs Pathology of the Female Genital Tract9 Cth e1. Ne7 5or;9 "pringer-(erlag9 ?OOC9 pp BB?.
2. R/rita

T9 Coo;e P"9 C/nha G'. Epithelial-stromal tiss/e interaction in paramesonephric +-Allerian, epithelial 1ifferentiation. #e* 0iol 2CIH?OC9 2II?.

B. 4/a1e

0M9 5ang A9 &ang 59 "/n #9 Par; M9 "heets EE9 C*i;o A9 Fe1erschnei1er M-9 Peters '9 -cReon F#9 Cr/m CPH E3pression of the pEB homolog/e pKB in early cer*ical neoplasia. Gynecol !ncol JIH2C9 2II?.
C. -alasanos E. Ince

T$H "e3/al 1e*elopment of the fet/s an1 p/bertal chil1. Clin !bstet Gynecol CIH?EB9 ?OOL.

T9 C*i;o A9 4/a1e 0M9 5ang A9 -cReon F9 -/tter G%9 Cr/m CPH PKB coor1inates anogenital mo1eling an1 epithelial 1ifferentiation in the 1e*eloping female /rogenital tract. Am M Pathol ?K?H????9 2II2.
K. 'ichart

'-H Cer*ical intraepithelial neoplasia. Pathol Ann/ JHBI?9 ?OLB. -EH -ean *ers/s in1i*i1/al hormonal profiles in the menstr/al cycle. Fertil "teril LJHOI9 2II2. ' +e1,H 0la/steinQs Pathology of the Female Genital Tract9 Cth e1. Ne7 5or;9 "pringer-(erlag9

L. Allien1e J. R/rman

?OOC.
O. Fo3

$ +e1,H $aines an1 TaylorQs !bstetrical an1 Gynaecologic Pathology9 Cth e1. E1inb/rgh9 Ch/rchill %i*ingstone9 ?OJL.
?I. 0enirsch;e

R9 Ra/fmann PH Pathology of the $/man Placenta9 Br1 e1. Ne7 5or;9 "pringer-(erlag9

?OOE.
??. 'obboy

"M9 An1erson -C9 '/ssell PH Pathology of the female repro1/cti*e tract. %on1on9 Ch/rchill %i*ingstone9 2II2.
?2. $olmes ?B. 0r/gha ?C. Prober ?E. $eine

RR9 et al +e1s,H "e3/ally Transmitte1 #iseases9 2n1 e1. Ne7 5or;9 -cGra7-$ill9 ?OOI. '9 et alH Genital herpes infectionH a re*ie7. Int M Epi1emiol 2KHKOJ9 ?OOL.

CGH $erpetic *aginitis in ?OOB. Clin !bstet Gynecol BKH?LL9 ?OOB.

P9 -cGregor MAH Trichomonas *aginalisH a reemerging pathogen. Clin !bstet Gynecol BKH?BL9

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?K. 'osenman ?L. &il;inson

"#H (/l*ar *estib/litisH a reappraisal. Conn -e1. KKHEJO9 2II2.

EMH Normal histology9 an1 nomenclat/re of the */l*a an1 malignant neoplasms9 incl/1ing (IN. #ermatol Clin ?IH2JB9 ?OO2.
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EM9 "tone RIH Atlas of (/l*ar #isease. 0altimore9 &illiams X &il;ins9 ?OOE.

"9 'eich !9 0eham-"chmi1 CH -onoclonal gamma-T-cell receptor rearrangement in */l*ar lichen scleros/s an1 s6/amo/s cell carcinomas. Am M Pathol ?KIH?IBE9 2II2.
2I. Pinto

AP9 %in -C9 "heets EE9 -/to -G9 "/n #9 Cr/m CPH Allelic imbalance in lichen scleros/s9 hyperplasia9 an1 intraepithelial neoplasia of the */l*a. Gynecol !ncol LLH?L?9 2III.
2?. Cr/m

CPH (/l*ar intraepithelial neoplasiaH histology an1 associate1 *iral changes. Contemp Iss/es "/rg Pathol OH??O9?OJL.
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N%H Con1yloma Ac/minat/mH Int M #ermatol BCH2OL9 ?OOE.

2B. :/r

$a/sen $H Papilloma*ir/s infectionsH a maDor ca/se of h/man cancers. 0iochim 0iophys Acta ?2JJHFEE9 ?OOK.
2C. R/rman

'M9 et alH T/mors of the cer*i39 *agina9 an1 */l*a. Atlas of T/mor Pathology9 Br1 series9 fascicle C. &ashington9 #C9 Arme1 Forces Instit/te of Pathology9 ?OO29 p ?O?.
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CPH Carcinoma of the */l*aH epi1emiology an1 pathogenesis. !bstet Gynecol LOHB9 ?OO2.

2K. %eibo7itch

-9 et alH The epithelial changes associate1 7ith s6/amo/s cell carcinoma of the */l*aH a re*ie7 of the clinical9 histological an1 *iral fin1ings in LJ 7omen. 0r M !bstet Gynaecol OLH??BE9 ?OOI.
2L. $art

&'H (/l*ar intraepithelial neoplasiaH historical aspects an1 c/rrent stat/s. Int M Gynecol Pathol 2IH?K9 2II?.
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-M9 et alH Consistent chromosome abnormalities in s6/amo/s cell carcinoma of the */l*a. Genes Chromosomes Cancer BHC2I9 ?OO?.
2O. R/rman

'M9 et alH 0asaloi1 an1 7arty carcinomas of the */l*a. #istincti*e types of s6/amo/s cell carcinoma fre6/ently associate1 7ith h/man papilloma*ir/ses. Am M "/rg Pathol ?LH?BB9 ?OOB. >P/blishe1 errat/m appears in Am M "/rg Pathol ?LHEBK9 ?OOB@.
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'&H The nat/ral history of */l*ar intraepithelial neoplasia. 0r M !bstet Gynaecol ?I2HLKC9 ?OOE.

'&9 'o7an #-H "pontaneo/s regression of */l*ar intraepithelial neoplasia 2B. !bstet Gynecol OKHCLI9 2III.
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#I9 -a/ng '9 #/ggan -AH (err/co/s carcinoma of the genital tractH is it a 1istinct entityU Can M "/rg BKH?CL9 ?OOB.
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GE9 Ahme1 IH Perianal an1 genital basal cell carcinomaH A clinicopathologic re*ie7 of E? cases. M Am Aca1 #ermatol CEHKJ9 2II?.
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0R9 Ranter-%e7ensohn %'9 %agerlof 09 Nilsson 0'9 'ingborg )RH -alignant melanoma of the */l*a in a nation7i1e9 2E-year st/1y of 2?O "7e1ish femalesH clinical obser*ations an1 histopathologic feat/res. Cancer JKH?2LB9 ?OOO.
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0o;ho*en $9 -cReon FH -/tations in the pEB homolog pKBH allele-specific 1e*elopmental syn1romes in h/mans. Tren1s -ol -e1 JH?BB9 2II2.
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-'9 Fletcher C#H (/l*o*aginal soft tiss/e t/mo/rsH /p1ate an1 re*ie7. $istopathology BKHOL9

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BL. -itten1of BJ. "c/lly

'9 $erbst A%H #E" e3pos/reH an /p1ate. Contemp Pe1iatr ??HEO9 ?OOC.

'E9 &elch &'H Pathology of the female genital tract after prenatal e3pos/re to 1iethylstilbestrol. In $erbst A%9 0ern $A +e1s,H #e*elopmental Effects of #iethylstilbestrol in Pregnancy. Ne7 5or;9 Thieme-"tratton9 ?OJ?9 pp 2KCE.
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%M9 et alH "arcoma botryoi1es of the female genital tract. !bstet Gynecol KKH2K29 ?OJE. 'M9 et alH Conser*ati*e s/rgical management of *aginal an1 */l*ar pe1iatric

rhab1omyosarcomaH a report from the Intergro/p 'hab1omyosarcoma "t/1y III. M Pe1iatr "/rg BIH?IBC9 ?OOE.
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C2. Ri*iat

N09 et alH $istopathology of en1ocer*ical infection by C(lamydia trac(omatis9 herpes simple3 *ir/s9 0ric(omonas -aginalis, an1 /eisseria gonorr(oeae. $/m Pathol 2?HJB?9 ?OOI.
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%H Epi1emiology of genital h/man papilloma*ir/s infection. Am M -e1 ?I2HB9 ?OOL.

CPH $/man papilloma*ir/sesH applications9 ca*eats an1 pre*ention. M 'epro -e1 CLHE?O9 2II2.

CE. -/nger

R9 $o7ley P-H $/man papilloma*ir/s immortali:ation an1 transformation f/nctions. (ir/s 'es JOH2?B9 2II2.
CK. Rlingelh/t:

AM9 Foster "A9 -c#o/gall MRH Telomerase acti*ation by the EK gene pro1/ct of h/man papilloma*ir/s type ?K. Nat/re BJIHLO9 ?OOK.
CL. #/ensing

"9 %ee %59 #/ensing A9 0asile M9 Piboonniyom "9 Gon:ale: "9 Cr/m CP9 -/nger RH The h/man papilloma*ir/s type ?K EK an1 EL oncoproteins cooperate to in1/ce mitotic 1efects an1 genomic instability by /nco/pling centrosome 1/plication from the cell 1i*ision cycle. Proc Natl Aca1 "ci ) " A OLH?III29 2III.
CJ. $eselmeyer

R9 et alH Gain in chromosome B6 1efines the transition from se*ere 1ysplasia to in*asi*e carcinoma of the /terine cer*i3. Proc Natl Aca1 "ci ) " A OBHCLO9 ?OOK.
CO. 'a1er

M"9 Gerhar1 #"9 !Q"/lli*an -M9 %i 59 %i %9 %iapis $9 $/ettner PCH Cer*ical intraepithelial neoplasia III sho7s fre6/ent allelic loss in Bp an1 Kp. Genes Chromosomes Cancer 22HEL9 ?OOJ.
EI. Yho/

M9 "/n 259 "ten:el #M9 Fra:er I$H E3pression of *accinia recombinant $P( ?K %? an1 %2 !'F proteins in epithelial cells is s/fficient for assembly of $P( *irion-li;e particles. (irology ?JEH2E?9 ?OO?.
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%A9 A/lt RA9 &heeler C-9 0ro7n #'9 0arr E9 Al*are: F09 Chiacchierini %-9 Mansen R)H A controlle1 trial of a h/man papilloma*ir/s type ?K *accine. N Engl M -e1. BCLH?KCE9 2II2.
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EO. "olomon

#9 "chiffman -9 Tarone 'H Comparison of three management strategies for patients 7ith atypical s6/amo/s cells of /n1etermine1 significanceH baseline res/lts from a ran1omi:e1 trial. M Natl Cancer Inst OBH2OB9 2II?.
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