chapter 4 · endometrial stromal sarcoma, low grade 8931/3 ... endometrial carcinoma definition a...

CHAPTER 4

Tumours of the Uterine Corpus

The uterine corpus represents the second most common sitefor malignancy of the female genital system. These neoplasmsare divided into epithelial, mesenchymal, mixed epithelial andmesenchymal tumours and trophoblastic tumours.

Endometrial carcinoma occurs predominantly in developedcountries and is frequently associated with obesity. Two majortypes are distinguished. Type I is estrogen-dependent anddevelops through the hyperplasia-carcinoma sequence. TypeII is not estrogen-dependent and develops independently ofendometrial hyperplasia. It occurs in older women and is moreaggressive.

Carcinosarcoma is still classified morphologically as a mixedepithelial and mesenchymal tumour, although it is consideredmonoclonal, with immunohistochemical and molecular studiesstrongly supporting its inclusion in the epithelial group. Itsprognosis is worse than that of other members of the epithelialcategory.

Gestational trophoblastic disease is approximately 10-foldmore common in the developing than in developed countries.Risk factors include a history of prior gestational trophoblasticdisease, a diet low in vitamin A and blood group A women mar-ried to group 0 men.

218 Tumours of the uterine corpus

_ _ _ _ _ _ _ _ _ _1 Morphology code of the International Classification of Diseases for Oncology (ICD-O) {921} and the Systematized Nomenclature of Medicine (http://snomed.org).Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.

Epithelial tumours and related lesionsEndometrial carcinoma

Endometrioid adenocarcinoma 8380/3 Variant with squamous differentiation 8570/3Villoglandular variant 8262/3Secretory variant 8382/3Ciliated cell variant 8383/3

Mucinous adenocarcinoma 8480/3Serous adenocarcinoma 8441/3Clear cell adenocarcinoma 8310/3Mixed cell adenocarcinoma 8323/3Squamous cell carcinoma 8070/3Transitional cell carcinoma 8120/3Small cell carcinoma 8041/3Undifferentiated carcinoma 8020/3Others

Endometrial hyperplasiaNonatypical hyperplasia

SimpleComplex (adenomatous)

Atypical hyperplasiaSimpleComplex

Endometrial polypTamoxifen-related lesions

Mesenchymal tumours Endometrial stromal and related tumours

Endometrial stromal sarcoma, low grade 8931/3Endometrial stromal nodule 8930/0Undifferentiated endometrial sarcoma 8930/3

Smooth muscle tumoursLeiomyosarcoma 8890/3

Epithelioid variant 8891/3Myxoid variant 8896/3

Smooth muscle tumour of uncertain malignant potential 8897/1Leiomyoma, not otherwise specified 8890/0

Histological variantsMitotically active variantCellular variant 8892/0Haemorrhagic cellular variantEpithelioid variant 8891/0Myxoid 8896/0Atypical variant 8893/0Lipoleiomyoma variant 8890/0

Growth pattern variantsDiffuse leiomyomatosis 8890/1

Dissectiing leiomyomaIntravenous leiomyomatosis 8890/1Metastasizing leiomyoma 8898/1

Miscellaneous mesenchymal tumoursMixed endometrial stromal and smooth muscle tumourPerivascular epithelioid cell tumourAdenomatoid tumour 9054/0Other malignant mesenchymal tumoursOther benign mesenchymal tumours

Mixed epithelial and mesenchymal tumoursCarcinosarcoma (malignant müllerian mixed tumour;

metaplastic carcinoma) 8980/3Adenosarcoma 8933/3Carcinofibroma 8934/3Adenofibroma 9013/0Adenomyoma 8932/0

Atypical polypoid variant 8932/0

Gestational trophoblastic diseaseTrophoblastic neoplasms

Choriocarcinoma 9100/3Placental site trophoblastic tumour 9104/1Epithelioid trophoblastic tumour 9105/3

Molar pregnanciesHydatidiform mole 9100/0

Complete 9100/0Partial 9103/0Invasive 9100/1Metastatic 9100/1

Non-neoplastic, non-molar trophoblastic lesionsPlacental site nodule and plaqueExaggerated placental site

Miscellaneous tumoursSex cord-like tumoursNeuroectodermal tumoursMelanotic paragangliomaTumours of germ cell typeOthers

Lymphoid and haematopoetic tumoursMalignant lymphoma (specify type)Leukaemia (specify type)

Secondary tumours

WHO histological classification of tumours of the uterine corpus

_ _ _ _ _ _ _ _ _ _1 {51,2976}.2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org.3 The classification applies to carcinomas and malignant mixed mesodermal tumours.4 The regional lymph nodes are the pelvic (hypogastric [obturator, internal iliac], common and external iliac, parametrial, and sacral) and the para-aortic nodes.

219

TNM and FIGO classification 1,2,3

T – Primary Tumour TNM FIGO Categories StagesTX Primary tumour cannot be assessedT0 No evidence of primary tumourTis 0 Carcinoma in situ (preinvasive carcinoma)T1 I* Tumour confined to corpus uteriT1a IA Tumour limited to endometriumT1b IB Tumour invades less than one half of myometriumT1c IC Tumour invades one half or more of myometriumT2 II Tumour invades cervix but does not extend

beyond uterusT2a IIA Endocervical glandular involvement onlyT2b IIB Cervical stromal invasionT3 and/or N1 III Local and/or regional spread as specified in T3a,

b, N1, and FIGO IIIA, B, C belowT3a IIIA Tumour involves serosa and/or adnexa (direct

extension or metastasis) and/or cancer cells inascites or peritoneal washings

T3b IIIB Vaginal involvement (direct extension or metastasis)N1 IIIC Metastasis to pelvic and/or para-aortic lymph nodesT4 IVA Tumour invades bladder mucosa and/or bowel

mucosaNote: The presence of bullous edema is not sufficient evidence to classify a tumouras T4.

M1 IVB Distant metastasis (excluding metastasis to vagina, pelvic serosa, or adnexa)

Note: * FIGO recommends that Stage I patients given primary radiation therapy canbe clinically classified as follows:Stage I: Tumour confined to corpus uteriStage IA: Length of uterine cavity 8cm or lessStage IB: Length of uterine cavity more than 8cm

N – Regional Lymph Nodes 4

NX Regional lymph nodes cannot be assessedN0 No regional lymph node metastasisN1 Regional lymph node metastasis

M – Distant MetastasisMX Distant metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasis

Stage Grouping

Stage 0 Tis N0 M0Stage IA T1a N0 M0Stage IB T1b N0 M0Stage IC T1c N0 M0Stage IIA T2a N0 M0Stage IIB T2b N0 M0Stage IIIA T3a N0 M0Stage IIIB T3b N0 M0Stage IIIC T1, T2, T3 N1 M0Stage IVA T4 Any N M0Stage IVB Any T Any N M1

TNM and FIGO classification of non-trophoblastic tumours of theuterine corpus


_________1 {51,2976}2 A help desk for specific questions about the TNM classification is available at http://tnm.uicc.org3 The classification applies to choriocarcinoma (9100/3), invasive hydatidiform mole (9100/1), and placental site trophoblastic tumour (9104/1).

TNM and FIGO classification of gestational trophoblastic tumours

Prognostic score

Prognostic Factor 0 1 2 4

Age <40 ≥ 40

Antecedent pregnancy Hydatidiform mole Abortion Term pregnancy

Months from index pregnancy <4 4-<7 7-12 >12

Pretreatment serum β-hCG (IU/ml) < 103 103-<104 104-<105 ≥105

Largest tumour size, including uterus <3 cm 3-<5 cm ≥5 cm

Site of metastasis Lung Spleen, kidney Gastrointestinal tract Liver, brain

Number of metastases 1-4 5-8 >8

Previous failed chemotherapy Single drug 2 or more drugs

Risk Categories: Total prognostic score 7 or less = low risk; Total score 8 or more = high risk

TNM and FIGO classification 1,2,3

T–Primary TumourTM FIGO Categories Stages*TX Primary tumour cannot be assessedT0 No evidence of primary tumourT1 I Tumour confined to uterusT2 II Tumour extends to other genital structures:

vagina, ovary, broad ligament, fallopian tube by metastasis or direct extension

M1a III Metastasis to lung(s)M1b IV Other distant metastasis Note: *Stages I to IV are subdivided into A and B according to the prognostic score

M – Distant MetastasisMX Metastasis cannot be assessedM0 No distant metastasisM1 Distant metastasisM1a Metastasis to lung(s)M1b Other distant metastasis Note: Genital metastasis (vagina, ovary, broad ligament, fallopian tube) is classified T2. Any involvement of non-genital structures, whether by direct invasion or metastasisis described using the M classification.

Stage grouping

Stage T M Risk Category

I T1 M0 UnknownIA T1 M0 LowIB T1 M0 HighII T2 M0 UnknownIIA T2 M0 LowIIB T2 M0 HighIII Any T M1a UnknownIIIA Any T M1a LowIIIB Any T M1a HighIV Any T M1b UnknownIVA Any T M1b LowIVB Any T M1b High

Epithelial tumours and related lesions S.G. Silverberg G.L. MutterR.J. Kurman R.A. Kubik-HuchF. Nogales F.A. Tavassoli

Endometrial carcinoma

DefinitionA primary malignant epithelial tumour,usually with glandular diff e re n t i a t i o n ,arising in the endometrium that has thepotential to invade into the myometriumand to spread to distant sites.

ICD-O codesEndometrioid adenocarcinoma 8380/3

Variant with squamous differentiation 8570/3

Villoglandular variant 8262/3Secretory variant 8382/3Ciliated cell variant 8383/3

Mucinous adenocarcinoma 8480/3Serous adenocarcinoma 8441/3Clear cell adenocarcinoma 8310/3Mixed adenocarcinoma 8323/3Squamous cell carcinoma 8070/3Transitional cell carcinoma 8120/3Small cell carcinoma 8041/3Undifferentiated carcinoma 8020/3

EpidemologyEndometrial carcinoma is the most com-mon malignant tumour of the female gen-ital system in developed countries, wheree s t rogen-dependent neoplasms accountfor 80-85% of cases and the non-estro g e ndependent tumours make up the re m a i n-ing 10-15% of cases. The estro g e n -dependent tumours are low grade, i.e.well or moderately diff e rentiated and pre-dominantly of endometrioid type. Patientswith this form of endometrial cancer fre-quently are obese, diabetic, nulliparo u s ,h y p e rtensive or have a late menopause.Obesity is an independent risk factor{388}, and in We s t e rn Europe, is associat-ed with up to 40% of endometrial cancer{241a}. On the other hand, patients with alarge number of births, old age at firstb i rth, a long birth period and a short pre-menopausal delivery - f ree period have areduced risk of postmenopausal endome-trial cancer, emphasizing the pro t e c t i v erole of pro g e s t e rone in the horm o n a lb a c k g round of this disease {1212}. In contrast, the non-estrogen dependenttype occurs in older postmenopausal

women; the tumours are high grade andconsist predominantly of histologicalsubtypes such as serous or clear cell aswell as other carcinomas that have highgrade nuclear features. They lack anassociation with exogenous or endoge-nous hyperoestrinism or with endometri-al hyperplasia and have an aggressivebehaviour {497,2005,2646}.

PathogenesisEndometrial cancer is made up of a bio-logically and histologically diverse groupof neoplasms that are characterized by ad i ff e rent pathogenesis. Estro g e n -dependent tumours (type I) are lowgrade and frequently associated withendometrial hyperplasias, in particularatypical hyperplasia. Unopposed estro-genic stimulation is the driving forc ebehind this group of tumours. It may bethe result of anovulatory cycles thatoccur in young women with the polycys-tic ovary syndrome or due to normallyoccurring anovulatory cycles at the timeof menopause. The iatrogenic use ofunopposed estrogens as horm o n e

replacement therapy in older womenalso is a predisposing factor for thedevelopment of endometrial cancer. Thesecond type (type II) of endometrial can-cer appears less related to sustainedestrogen stimulation.

Clinical features Signs and symptomsAlthough endometrial carcinoma andrelated lesions can be incidental findingsin specimens submitted to the pathologistfor other reasons (for example, endome-trial biopsy for infertility or hystere c t o m yfor uterine prolapse), in the great majorityof cases they present clinically witha b n o rmal uterine bleeding. Since most ofthese lesions are seen in postmenopausalwomen, the most common presentation ispostmenopausal bleeding, but earlier inlife the usual clinical finding is menometr-orrhagia {1104}. The most common typeof endometrial carcinoma, endometrioida d e n o c a rcinoma, may be manifested bysuch clinical findings as obesity, infert i l i t yand late menopause, since it is oftenrelated either to exogenous estro g e n

Fig. 4.01 Global incidence rates of cancer of the uterine corpus which occurs predominantly in countrieswith advanced economies and a Western lifestyle. Age-standardized rates (ASR) per 100,000 populationand year. From Globocan 2000 {846}.

Epithelial tumours and related lesions 221

administration or to endogenous hyper-oestrinism {2276,2648,2805}. Endometrialhyperplasia and atypical hyperplasiahave similar clinical associations.

ImagingTransvaginal ultrasound (US) is the imag-ing technique of choice for the assess-ment of the endometrium in symptomaticpatients, e.g. in cases of postmenopausalbleeding {133}. In postmenopausalwomen without hormonal replacement anendometrial thickness of 5 mm is re g a rd-ed as the upper normal limit {133,2650}.The presence of endometrial thickeningon ultrasound or cross sectional imagingis, however, a nonspecific finding. It maybe due to endometrial hyperplasia,polyps or carcinoma. The final diagnosisusually needs to be determined byendometrial sampling {133}.Whereas currently magnetic resonanceimaging (MRI) has no established role inscreening for endometrial pathology, it isregarded as the best imaging techniquefor preoperative staging of endometrialcarcinoma proven by endometrial sam-pling. MRI was shown to be superior tocomputed tomography (CT) in thisregard {1135}. It is especially useful forpatients with suspected advanced dis-ease, for those with associated uterinepathology, such as leiomyomas, and forthose with histological subtypes that sig-nify a worse prognosis {916,1136}.

MacroscopyEndometrial carcinoma usually arises inthe uterine corpus, but some cases origi-nate in the lower uterine segment, andrecent studies suggest that the latter may

have diff e rent clinical and histological fea-t u res {1323,3067}. Regardless of the his-tological type, the macroscopic appear-ance of endometrial carcinoma is general-ly that of a single dominant mass, usuallyoccurring in an enlarged uterus, althoughoccasionally the uterus is small or thetumour presents as a diffuse thickening ofmost of the endometrial surface, part i c u-larly in the serous type. Endometrial carc i-noma is seen more frequently on the pos-terior than on the anterior wall {2691}.The typical carcinoma is exophytic andhas a shaggy, frequently ulcerated sur-face beneath which a soft or firm whitetumour may extend shallowly or deeplyinto the underlying myometrium. Inadvanced cases the tumour may pene-trate the serosa or extend into the cervix.An estimate of the extent of tumour maybe requested preoperatively or operative-ly in order to determine the extent of thesurgical pro c e d u re to be perf o rmed {594}.In occasional cases no tumour may bevisible macro s c o p i c a l l y, with carc i n o m aidentified only at histological examination.

Tumour spread and stagingThe staging of uterine tumours is by theTNM/FIGO classification {51,2976}.

Endometrioid adenocarcinoma

DefinitionA primary endometrial adenocarcinomacontaining glands resembling those ofthe normal endometrium.

HistopathologyAll but a few rare endometrial carcino-mas are adenocarcinomas, and the most

common of these is the endometrioidtype {2691}. Endometrioid adenocarcino-ma represents a spectrum of histologicaldifferentiation from a very well differenti-ated carcinoma difficult to distinguishf rom atypical complex hyperplasia tominimally differentiated tumours that canbe confused not only with undifferentiat-ed carcinoma but with various sarcomasas well. A highly characteristic feature ofendometrioid adenocarcinoma is thepresence of at least some glandular orvilloglandular structures lined by simpleto pseudostratified columnar cells thathave their long axes arranged perpendi-cular to the basement membrane with atleast somewhat elongated nuclei that arealso polarized in the same direction. Asthe glandular differentiation decreasesand is replaced by solid nests andsheets of cells, the tumour is classified asless well differentiated (higher grade).Deep myometrial invasion and lymphnode metastases are both more frequentin higher grade carcinomas, and survivalrates are correspondingly lower {574,1359}. It should be noted that: (1). Only those cells which are consid-ered to be of glandular type are consid-ered in the grading schema, so that solidnests of cells showing squamous ormorular differentiation do not increasethe tumour grade.(2). Bizarre nuclear atypia should raise thegrade by one, e.g. from 1 to 2 or 2 to 3.(3). It should be emphasized that thepresence of bizarre nuclei occurring ineven a predominantly glandular tumourmay indicate serous or clear cell ratherthan endometrioid differentiation {2691}.The distinction of very well differentiated

BAFig. 4.02 Well differentiated endometrioid adenocarcinoma. A Invasion is indicated by back to back glands, complex folds and stromal disappearance. B The neo-plastic glands are lined by columnar cells with relatively uniform nuclei; note the altered stroma in the top of the field.


endometrioid adenocarcinoma fro matypical complex hyperplasia is best pro-vided by stromal disappearancebetween adjacent glands, i.e. confluent,c r i b r i f o rm or villoglandular pattern s{1433,1689,2688,2691}. Other feature sthat may be helpful include a stromaldesmoplastic response and/or tumourn e c rosis. Stromal foam cells may beassociated with adenocarcinoma or itsprecursors.

Variants of endometrioid adenocarcinomaEndometrial proliferations may exhibit avariety of differentiated epithelial typesincluding squamous/morules, mucinous,ciliated, cleared or eosinophilic cells,and architectural variations includingpapillary formations. These cell types areoften called metaplasias and may bee n c o u n t e red in benign, pre m a l i g n a n tand malignant epithelia. When prominentin a carcinoma the neoplasm is termed a"special variant" carcinoma.

Variant with squamous differentiationFrom 20-50% or more of endometrioida d e n o c a rcinomas contain vary i n gamounts of neoplastic epithelium show-ing squamous differentiation. Althoughthe distinction between endometrioidadenocarcinoma with and without squa-mous diff e rentiation is not clinicallyimportant, the recognition of squamousdifferentiation is nevertheless essentialbecause the squamous or morular ele-ments should not be considered a part ofthe solid component that increases thegrade of an endometrioid carcinoma. The criteria for squamous differentiation{2691} are as follows:(1) Keratinization demonstrated withstandard staining techniques.(2) Intercellular bridges and/or(3) Three or more of the following four cri-teria:(a) Sheet-like growth without gland for-mation or palisading.(b) Sharp cell margins.(c) Eosinophilic and thick or glassy cyto-plasm.(d) A decreased nuclear to cytoplasmicratio as compared with foci elsewhere inthe same tumour.

Villoglandular variantThis type is the next most commonlyencountered endometrioid adenocarci-noma variant and is usually seen involv-

ing part of a low grade endometrioid car-cinoma but not the entire tumour. In thispattern numerous villous fronds are seen,but their central cores are delicate, andcells with the usual cytological features(including stratification perpendicular tothe basement membrane) line the villi.These features are in contrast to themore complex papillary architecture andhigh grade nuclear features that are typ-ical of serous and clear cell adenocarci-nomas growing in a papillary pattern.

Secretory variantOccasional endometrioid adenocarcino-mas are composed of glands lined byepithelium with voluminous, usually sub-nuclear, glycogen vacuoles reminiscentof early secretory endometrium. Thesetumours have minimal nuclear atypia andare diagnosable as carcinoma only byvirtue of a confluent, cribriform or villog-landular pattern. As with the other vari-ants, this pattern may be seen as theonly one in an endometrioid adenocarci-

223Epithelial tumours and related lesions

Fig. 4.03 Endometrioid adenocarcinoma. The bizarre nuclear atypia raises the tumour grade but should alsoprompt consideration of a serous adenocarcinoma.

Fig. 4.04 Well differentiated endometrioid adenocarcinoma, ciliated cell variant. Cilia lining the neoplasticglands are prominent.

noma or may coexist with the usualendometrioid pattern within a singletumour.

Ciliated cell variantAlthough occasional ciliated cells maybe seen in many endometrioid adenocar-cinomas, the diagnosis of the ciliated cellvariant is made only when ciliated cellsline the majority of the malignant glands.Defined in this manner, this is a rare vari-ant, and the glands often have a strongresemblance to tubal epithelium.

Mucinous adenocarcinoma

DefinitionA primary adenocarcinoma of theendometrium in which most of the tumourcells contain prominent intracytoplasmicmucin.

EpidemiologyMucinous adenocarcinoma comprisesup to 9% of all cases of surgical stage Iendometrial carcinoma {2454}. However,in most published series it is a relativelyr a re type of endometrial carc i n o m a{1842}.

HistopathologyBoth endometrioid and clear cell adeno-carcinomas may have large amounts ofintraluminal mucin, but only mucinousa d e n o c a rcinoma contains the mucinwithin the cytoplasm. The mucin is usual-ly easily visible with hematoxylin andeosin staining but may also be demon-strated with a mucicarmine or othermucin stain.

VariantsSome mucinous adenocarcinomas havea microglandular pattern and may be dif-ficult to distinguish from microglandularhyperplasia of the endocervix in a biopsyspecimen {2066}. These neoplasmshave been reported as microglandularcarcinomas {3224,3241}. Rare mucinousa d e n o c a rcinomas of the endometriummay show intestinal differentiation, con-taining numerous goblet cells.

Differential diagnosisThe main differential diagnosis of theusual endometrial mucinous adenocarci-noma is with a primary mucinous adeno-carcinoma of the endocervix. The dis-tinction may be particularly difficult in abiopsy or curettage specimen but is cru-cial for therapy and may have to beresolved by clinical and imaging studies.Some studies have claimed that immuno-histochemistry is useful in determiningthe site of origin of an adenocarcinoma insuch a specimen, with endometrial carci-nomas being vimentin and estro g e nreceptor-positive and carcinoembryonicantigen-negative and the opposite find-ings for endocervical adenocarcinomas{3180}. Others have found, however, thatthis distinction is based more on differen-tiation (endometrioid vs. mucinous) thanon site of origin {1393}.

GradingMucinous adenocarcinomas are theoreti-cally graded in the same way asendometrioid adenocarcinomas, but inpractice almost all of them are grade 1.

Prognosis and predictive factorsThe prognosis appears to be similar tothat of other low grade endometrial ade-n o c a rcinomas and thus is generallyfavourable.

Serous adenocarcinoma

Definition and historical annotationA primary adenocarcinoma of theendometrium characterized by a com-plex pattern of papillae with cellular bud-ding and not infrequently containingpsammoma bodies.Although long recognized as a commontype of adenocarcinoma of the ovary,serous adenocarcinoma was first char-acterized as a common endometrialtumour in the early 1980s {1186,1590}.

Clinical featuresSerous carcinoma typifies the so-calledtype II endometrial carcinoma, which dif-

Fig. 4.06 Mucinous adenocarcinoma of theendometrium. All of the tumour cells in this fieldcontain voluminous intracytoplasmic mucin.

Fig. 4.07 Microglandular carcinoma. Atypia, mitosesand the endometrial location distinguish this tumourfrom endocervical microglandular hyperplasia.

Fig. 4.08 Mucinous metaplasia. Mucinous glandsare prominent, however, glandular crowding oratypia is not present.

Table 4.01Grading of type I (endometrioid and mucinous)endometrial adenocarcinoma.

– Grade 1: ≤ 5% non-squamous, non-morulargrowth pattern

– Grade 2: 6-50% non-squamous, non-morulargrowth pattern

– Grade 3: > 50% non-squamous, non-morulargrowth pattern

Note: Squamous/morular components areexcluded from grading. Bizarre nuclear atypiashould raise the grade by one (i.e. from 1 to 2 or2 to 3) but may also signify type II differentiation.

Fig. 4.05 Well differentiated endometrioid adeno-carcinoma, villoglandular variant. Villous frondshave delicate central cores and are lined by cellswith stratified nuclei.



fers from the prototypical type Iendometrioid adenocarcinoma by itslack of association with exogenous orendogenous hyperoestrinism, its lack ofassociation with endometrial hyperplasiaand its aggressive behaviour {497,2005,2646}.

HistopathologyS e rous adenocarcinoma is usually, butnot always, characterized by a papillarya rc h i t e c t u re with the papillae havingb road fibrovascular cores, secondaryand even tert i a ry papillary pro c e s s e sand prominent sloughing of the cells.The cells and nuclei are generally ro u n d-ed rather than columnar and lack a per-pendicular orientation to the basementmembrane. The nuclei are typicallypoorly diff e rentiated, are often apicallyrather than basally situated and usuallyhave large, brightly eosinophilicm a c ronucleoli. Mitoses, often atypicaland bizarre, and multinucleated cells arecommonly present, as are solid cellnests and foci of necrosis. Psammomabodies are found in about 30% of casesand may be numerous. When the tumourg rows in a glandular pattern, the glandsa re generally complex and "labyrinthine."S e rous carcinoma is considered a highgrade carcinoma by definition and is notgraded.

Precursor lesionsA putative precursor of serous adenocar-cinoma is serous endometrial intraepithe-lial carcinoma, which has also beencalled endometrial carcinoma in situ andsurface serous carcinoma {79,975,2764,3256}. This lesion is characterized by anoninvasive replacement of benign (mostcommonly atrophic) endometrial surfaceand glandular epithelium by highlymalignant cells that resemble those ofinvasive serous carcinoma. Sero u sendometrial intraepithelial carcinoma hasbeen proposed as the precursor or in situphase of serous carcinoma, and in mostreported studies it has co-existed withinvasive serous and, occasionally, clearcell, adenocarcinoma. Clinically, serousendometrial intraepithelial carcinoma hasa significance very similar to that of inva-sive serous adenocarcinoma since it canalso be associated with disseminateddisease outside the uterus (usually in theperitoneal cavity) even in the absence ofinvasive carcinoma in the endometrium{79,160,975,2764,3105,3256}.

Prognosis and predictive factorsThis tumour has a tendency to developdeep myometrial invasion and extensivelymphatic invasion, and patients com-monly present with extrauterine spread atthe time of diagnosis. However, even inthe absence of a large or deeply invasivetumour extrauterine spread is common,as are recurrence and a fatal outcome{160,1370,3105}.

Clear cell adenocarcinoma

DefinitionAn adenocarcinoma composed mainly ofclear or hobnail cells arranged in solid,tubulocystic or papillary patterns or acombination of these patterns.

EpidemiologyThe other major type II carcinoma of theendometrium is clear cell adenocarcino-ma. It is less common than serous carci-noma (1-5%, as opposed to 5-10% of allendometrial carcinomas) but occurs inthe same, predominantly older, patientpopulation.

Tumour spread and stagingSimilar to serous adenocarc i n o m a ,patients with clear cell adenocarcinomaare frequently diagnosed in advancedclinical stages.

HistopathologyHistologically, clear, glycogen-filled cellsand hobnail cells that project individuallyinto lumens and papillary spaces char-acterize the typical clear cell adenocarci-noma. Unlike similarly glycogen-richs e c re t o ry endometrioid adenocarc i n o-mas, clear cell adenocarcinoma containslarge, highly pleomorphic nuclei, oftenwith bizarre and multinucleated forms.The architectural growth pattern may betubular, papillary, tubulocystic or solidand most frequently consists of a mixtureof two or more of these pattern s .Although psammoma bodies are presentin approximately one-third of serous ade-nocarcinomas, they are rarely seen inclear cell adenocarcinomas. Occasion-a l l y, the tumour cells have granular

Fig. 4.10 Surface syncytial change. This benignpapillary syncytial proliferation is distinguishedfrom serous adenocarcinoma by the lack of atypia.

Fig. 4.09 Serous adenocarcinoma of the endometrium. Broad papillary stalks are covered by secondarymicropapillae with considerable exfoliation of tumour cells.

eosinophilic (oncocytic) cytoplasm ratherthan the more characteristic clear cyto-plasm {2258,2678}. This cell type maycomprise the entire tumour and make itdifficult to recognize as a clear cell ade-nocarcinoma. Endometrial clear cell ade-nocarcinomas are not graded.Serous endometrial intraepithelial carci-noma may also be seen in associationwith clear cell adenocarcinoma, and theassociated benign endometrium is gen-erally atrophic rather than hyperplastic.

Prognosis and predictive factorsPatients with clear cell adenocarcinomaare frequently diagnosed in advancedclinical stages, and, thus, have a poorp rognosis {24,400,1595,3003}. On theother hand, clear cell adenocarcinomalimited to the uterine corpus has a con-siderably better prognosis than serousadenocarcinoma of the same stage.

Mixed adenocarcinoma

DefinitionMixed adenocarcinoma is a tumour com-posed of an admixture of a type I(endometrioid carcinoma, including itsvariants, or mucinous carcinoma) and atype II carcinoma (serous or clear cell) inwhich the minor type must comprise atleast 10% of the total volume of thetumour. The percentage of the minorcomponent should be stated in the

pathology report. It is generally acceptedthat 25% or more of a type II tumourimplies a poor prognosis, although thesignificance of lesser proportions is notwell understood {2646,2691}.

Squamous cell carcinoma

DefinitionA primary carcinoma of the endometriumcomposed of squamous cells of varyingdegrees of differentiation.

EpidemiologySquamous cell carcinoma of theendometrium is uncommon; only aboutseventy cases have been re p o rt e d{2397}.

Clinical featuresSquamous cell carcinoma of theendometrium usually occurs in post-menopausal women and is often associ-ated with cervical stenosis and pyometra.

HistopathologyIts histological appearance is essentiallyidentical to that of squamous cell carci-noma of the cervix and similarly includesa rare verrucous variant {2654}.

Differential diagnosisThe much more common situation of acervical squamous cell carcinoma extend-ing into the endometrium must be exclud-

ed. Predominantly squamous diff e re n t i a-tion of an endometrioid adenocarc i n o m amust also be excluded before making thediagnosis of primary pure squamous cellc a rcinoma of the endometrium.

Prognosis and predictive factorsThe prognosis of most squamous cellcarcinomas of the endometrium is ratherpoor, although the verrucous variant maybe more favourable.

Transitional cell carcinoma

DefinitionA carcinoma in which 90% or more iscomposed of cells resembling urothelialtransitional cells. Lesser quantities oftransitional cell diff e rentiation wouldqualify the tumour as a mixed carcinomawith transitional cell differentiation.

EpidemiologyTransitional cell diff e rentiation inendometrial carcinomas is extre m e l yuncommon with fewer than 15 casesreported {1554,1669}. Among patientswith known racial origin, 50% are non-White (African, Hispanic, or Asian). Themedian age is 61.6 years (range 41-83years).

Clinical featuresThe main complaint at presentation isuterine bleeding.

MacroscopyThe tumours are often polypoid or papil-l a ry with a mean size of 3.5 cm.Infiltration of the myometrium is apparentin some cases.

HistopathologyThe transitional cell component is oftengrade 2 or 3 and assumes a papillaryconfiguration. It is always admixed withanother type of carcinoma, most oftenendometrioid, but it may be clear cell ors e rous. HPV-associated koilocytoticchanges occur rarely. Only the transition-al cell component invades themyometrum deeply {1669}. All endome-trial transitional cell carcinomas are neg-ative for cytokeratin 20 (CK20), but halfa re positive for cytokeratin 7 (CK7){1554,1669}.

Differential diagnosisThe diff e rential diagnosis includesmetastatic transitional cell carcinoma fro m


Fig. 4.11 Clear cell adenocarcinoma of the endometrium. The tumour has a predominantly solid pattern withoccasional poorly formed tubules. The cytoplasm is clear, and cell walls are distinct.

the ovary and bladder. Unlike primaryendometrial tumours, those metastatic tothe endometrium are pure transitional celltumours. The CK7 positive, CK20 nega-tive immunoprofile also supports müllerianrather than urothelial diff e re n t i a t i o n .

Somatic geneticsHuman papillomavirus (HPV) type 16 hasbeen detected in 22% of cases studied;however, the results were negative fortypes 6, 11, 18, 31 and 33 in all casesassessed {1554,1672}. These findingssuggest that HPV may play an aetiologicrole in at least some cases.

Prognostic and predictive factorsAlthough information on prognostic fac-tors is limited on these rare tumours, sev-eral women who have survived have hadlow stage (stage I) disease. At least twocases with extrauterine extension of thedisease to either the adnexa or ovarianhilus have survived over 5 years followingradiation therapy suggesting that thesetumours may have a more favourableresponse to radiation therapy than otherstage II endometrial carc i n o m a s .

Small cell carcinoma

DefinitionAn endometrial carcinoma resemblingsmall cell carcinoma of the lung.

EpidemiologySmall cell carcinoma of neuroendocrinetype is an uncommon tumour of theendometrium that comprises less than1% of all carcinomas.

HistopathologyThe histological appearance is similar tothat of small cell carcinoma in otherorgans. Small cell carcinomas are posi-tive for cytokeratin and mostly positive forneuroendocrine markers, whereas one-half are positive for vimentin.

Prognosis and predictive factorsIn contrast to small cell carcinoma else-where in the female genital tract, theprognosis is far better in stage I diseasewith a 5-year survival of about 60% {23,1271}.

Undifferentiated carcinoma

Undifferentiated carcinomas are thoselacking any evidence of differentiation.

Fig. 4.12 Squamous cell carcinoma of the endometrium. This invasive tumour forms well differentiatedsquamous pearls. Note the reactive stroma with inflammatory cells.

Fig. 4.14 Small cell carcinoma. The tumour is composed of small cells with high nuclear to cytoplasmicratios.

Fig. 4.13 Transitional cell carcinoma. The neoplasm forms papillae lined by low grade stratified transitional typeepithelium.


Rare types of endometrial carcinoma

Almost every type of carcinoma reportedelsewhere has been described in at leasta single case report as primary in theendometrium.

HistopathologyThese tumours are histologically (andusually clinically, if enough cases areavailable for analysis) identical to theirm o re common counterparts in otherorgans. They include adenoid cystic car-cinoma {985}, glassy cell carc i n o m a{1103} and mesonephric carc i n o m a{2110}. Oncocytic/oxyphilic carcinoma isthought by some to be a variant of clear

cell carcinoma, whereas others considerit to be a separate tumour.

Endometrial hyperplasia

DefinitionA spectrum of morphologic alterationsranging from benign changes, causedby an abnormal hormonal environment,to premalignant disease.

Criteria for histological typingThe endometrial hyperplasias are classi-fied by their degree of architectural com-plexity as simple or complex (adenoma-tous) and by their cytological (nuclear)f e a t u res as hyperplasia or atypicalhyperplasia.The endometrium is uniquely endowedt h roughout the female re p roductive life-span with a complex regular cycle of peri-odic proliferation, diff e rentiation, bre a k-down and regeneration. This high cellulart u rn o v e r, conditioned by ovarian hor-mones and growth factors, has manyo p p o rtunities for losing its re g u l a t o ry con-t rols. Endometrial hyperplasia encom-passes conditions that range from benigne s t rogen-dependent proliferations ofglands and stroma to monoclonal out-g rowths of genetically altered glands.

The high degree of morphological vari-ability of endometrial proliferations evenwithin the same sample is responsible forthe difficulty in defining consistent andclinically meaningful diagnostic criteria{240,3135}. A further complication isfragmentation and scantiness of manyaspiration biopsies. Nevertheless, histo-logical interpretation remains the mostaccessible, albeit somewhat subjective,method of evaluating endometrial hyper-plasias.

WHO classificationMany classifications had been proposedprior to 1994 when the World HealthOrganization (WHO) adopted its current

Table 4.02World Health Organization classification ofendometrial hyperplasia {2602}.

Fig. 4.17 Focal atypical hyperplasia. Atypicalhyperplasia is seen on the left and a cyclicendometrium on the right.


Fig. 4.16 Complex hyperplasia. A The endometrial glands show branching and budding. B There is glandularcrowding; however, cytological atypia is absent.

BAFig. 4.15 Simple hyperplasia. A The endometrialglands vary from dilated to compact and arebridged by a large squamous morule. B Note thepseudostratified columnar epithelium with elongat-ed nuclei lacking atypia.

A

B

Hyperplasias (typical)

Simple hyperplasia without atypiaComplex hyperplasia without atypia

(adenomatous without atypia)

Atypical hyperplasias

Simple atypical hyperplasiaComplex atypical hyperplasia

(adenomatous with atypia)

schema {1535,2602}. Although this clas-sification has been widely applied, itsreproducibility is somewhat disappoint-ing {240,1433}, and molecular data withdirect implications for histological diag-nosis were unavailable at the time of the1994 classification {1956}. Nevertheless,it remains the best available classifica-tion and has been adopted in this newedition.Endometrial hyperplasias are assumedto evolve as a progressive spectrum ofendometrial glandular alterations dividedinto four separate categories by architec-ture and cytology. The vast majority ofendometrial hyperplasias mimic prolifer-ative endometria, but rare examplesdemonstrate secre t o ry features. Theentire spectrum of metaplastic changesmay be observed in hyperplasticendometria.

Hyperplasias without atypiaHyperplasias without atypia re p re s e n tthe exaggerated proliferative responseto an unopposed estrogenic stimulus;the endometrium responds in a diffusemanner with a balanced increase of bothglands and stroma. In simple hyperpla-sia the glands are tubular although fre-quently cystic or angular, and some evenshow minor epithelial budding. The liningis pseudostratified with cells displayingregular, elongated nuclei lacking atypia.In complex (adenomatous) hyperplasiathe glands display extensive complicat-ed architectural changes represented byi r regular epithelial budding into bothlumina and stroma and a typical cytologywith pseudostratified but uniform, elon-

gated and polarized glandular nuclei;squamous epithelial morules can bepresent. There is most often a shift in thegland to stroma ratio in favour of theglands.

Atypical hyperplasiasThe main feature which differentiates thiscategory from the previous one is theatypical cytology of the glandular liningas represented by loss of axial polarity,unusual nuclear shapes that are oftenrounded, irregularity in the nuclear mem-branes, prominent nucleoli and clearedor dense chromatin. Atypia occurs near-ly always focally.Simple atypical hyperplasia feature satypical glandular cytology superim-posed on the arc h i t e c t u re of simplehyperplasia. This pattern is extremelyunusual. The frequently found complexatypical (adenomatous with atypia)hyperplasia is a lesion characterized byan increased glandular complexity withi r regular outgrowths and cytologicalatypia. There may be associated foci ofnon-endometrioid differentiation such assquamous morules. Due to the expan-sion and crowding of glands, the inter-glandular stroma is diminished butremains present. Characteristic featuresof adenocarcinoma are absent.The assessment of cytological atypia isthe key problem in assigning individualcases to one of the four different WHOcategories. Definitions of cytologicalatypia are difficult to apply in theendometrium because nuclear cytologi-cal changes occur frequently in hormon-al imbalance, benign regeneration and

metaplasia {1619,2033}. Paradoxically,atypical hyperplasia may exhibit moreatypical features than adenocarcinoma{2688}, and some grade 1 invasiveendometrioid carcinomas have ane x t remely bland cytology. Perhaps, itwould be more appropriate to considercytological changes in the context ofoverall glandular architecture. Indeed,architectural focality of the lesion is soclosely linked with atypia that possiblythey are inseparable. In this way, atypiais best observed by comparison withadjoining normal glands.

Caveat: sampling problemsThe focal nature of atypical endometrialhyperplasias may allow young women tomaintain fertility, but has the disadvan-tage of possible underdiagnosis due toincomplete sampling. The problem isg reatest in scanty fragmented speci-mens, something commonly encoun-tered in routine office biopsies. Clearly,this situation is responsible for the falsenegative biopsies during follow up. Hysteroscopic direction may assist in tar-geting a macroscopically apparent local-ized lesion but is not a common practicein most settings.

Contemporary approach to endometrial hyperplasiaPoor reproducibility of the 1994 WHOhyperplasia schema {240,1433} has ledto a proposal to reduce the number ofdiagnostic classes {240}. New conceptsof pathogenesis have been incorporatedinto an integrated genetic, histomorpho-metric and clinical outcome model of

BAFig. 4.18 Complex atypical hyperplasia. A There is glandular crowding with eosinophilic cytoplasm and nuclear enlargement, loss of polarity and prominent nucle-oli. On the right is a residual, non-atypical cystic gland. B The glands are tortuous with epithelial tufts (reflecting abnormal polarity) protruding into the lumens andshow cytological atypia.



premalignant disease {1956,1958} (seesection on genetics of endometrial carci-noma and precursor lesions).The clinicalrelevance of the model, however, has yetto be established.

Endometrial polyp

DefinitionA benign nodular protrusion above theendometrial surface consisting ofendometrial glands and stroma that istypically at least focally fibrous and con-tains thick-walled blood vessels.

HistopathologyHistologically, they are pedunculated orsessile lesions with a fibrous stroma inwhich characteristic thick-walled, tortu-ous, dilated blood vessels are found. Theglandular component is patchily distrib-uted and shows dilated, occasionallycrowded glands lined with an atrophicepithelium, although rarely cyclic activitymay be observed. Rare cases of atypical

stromal cells have been documented inendometrial polyps {2834}, similar tothose seen in polyps of the lower femalegenital system. Polyps can be differenti-ated from polypoid hyperplasias due tothe distinctive stromal and vascular fea-tures of the former. Atypical hyperplasiasand malignant tumours including adeno-carcinomas of endometrioid and othertypes such as serous, as well as sarco-mas and mixed tumours {2675} can befound arising in polyps.

Somatic geneticsEndometrial polyps constitute benignmonoclonal proliferations of mesenchyme{891} and frequently show kary o t y p i ca b n o rmalities of chromosomal re g i o n s6p21 and 12q15 {2854}, sites in which theH M G I C and H M G I Y genes are located.

Prognosis and predictive factorsPolyp resection or polypectomy are thet reatments of choice with few re c u r-rences reported {2928}.

Tamoxifen-related lesions

DefinitionLesions that develop in the endometriumin patients undergoing long term tamox-ifen therapy.

EpidemiologyPatients undergoing long term tamoxifentreatment often have enlarged uteri andfrequently show endometrial cysts; up to25% have endometrial polyps {531}.

MacroscopyTamoxifen-related polyps differ from non-iatrogenic endometrial polyps in that they

are larger, sessile with a wide implanta-tion base in the fundus and frequentlyshow a honeycomb appearance.

HistopathologyH i s t o l o g i c a l l y, the diff e rential feature swith normal endometrial polyps includethe bizarre stellate shape of glands andthe frequent epithelial (mucinous, ciliat-ed, eosinophilic, microglandular) ands t romal (smooth muscle) metaplasias{665,1437,2558}. There is often aperiglandular stromal condensation(cambium layer). Malignant transforma-tion occurs in up to 3% of cases, andendometrioid adenocarcinoma is themost frequent type. However, other typesof malignant neoplasm such as serousc a rcinoma and carc i n o s a rcoma maydevelop in this setting.

Somatic geneticsDespite these histological differences,the cytogenetic profile of tamoxifen-relat-ed polyps is identical to non-iatrogenicpolyps {609}.

Genetics of endometrial carcinoma and precancer

Genotype and histotypeEndometrial adenocarcinoma is charac-terized by the abrogation of PTEN orT P 5 3 tumour suppressor pathways,respectively, for the endometrioid (type I)and non-endometrioid (type II, includingserous and clear cell types) clinicopatho-logical subgroups {2647}. Deletionand/or mutation of the PTEN and TP53genes themselves are early events withw i d e s p read distribution in advancedtumours and a presence in the earliest

Fig. 4.22 TP53 mutations in endometrial carcinoma.Left: Wild type sequence in an endometrioid carci-noma: Exon 8 mutations in two serous carcinomas(arrows). Middle: GTT > TTT; Val > Phe (codon 274).R i g h t : CGT > CAT; Arg > His (codon 273).

Fig. 4.21 Uterine tamoxifen-related lesion.Thickenedmyometrium in a 69 year old patient with suben-dometrial cysts and a polyp (arrow).

Fig. 4.19 Endometrial polyp. The glands are cysticand contain mucoid material, the stroma is fibrous,and the vessels are prominent.

Fig. 4.20 Endometrial polyp with complex hyperpla-sia. Note the foci of crowded, convoluted glands inan atrophic endometrial polyp.

detectable premalignant (type I) {1959}or non-invasive malignant (type II) phas-es of tumourigenesis {2647,2863}. Ac o m p rehensive model of sequentialgenetic damage has not been formulat-ed for endometrial cancer despite agrowing number of candidate genes.PTEN checks cell division and enablesapoptosis through an Akt-dependentmechanism. Functional consequences ofPTEN mutation may be modulated in partby the hormonal environment, as PTEN isexpressed only during the estrogen-driv-en proliferative phase of the endometri-um {1957}. The use of PTEN immunohis-tochemistry as a tool for diagnosis ofclinically relevant neoplastic endometrialdisease is limited by the fact that one-third to one-half of type I cancers contin-ue to express PTEN protein, and loss ofPTEN function occurs as an early eventthat may precede cytological and archi-tectural changes {1959}. TP53 is the prototypical tumour suppres-sor gene capable of inducing a stablegrowth arrest or programmed cell death.Mutant protein accumulates in nuclei,where it can be readily demonstrated byi m m u n o h i s t o c h e m i s t ry in most sero u s(type II) adenocarcinomas {228}.Staining for TP53 is not routinely indicat-ed, but the association of positive stain-

ing with a poor clinical outcome may beinformative in suboptimal, scanty or frag-mented specimens.

Molecular delineation of premalignantdiseaseType I cancers begin as monoclonal out-growths of genetically altered premalig-nant cells, and many bear genetic stig-mata of microsatellite instability, KRASmutation and loss of PTEN function thata re conserved in subsequent cancer{1642,1956}. The earliest molecularchanges, including PTEN, are detectableat a stage before glands have under-

gone any change in morphology {1959}.The accumulation of genetic damage isthought to cause emergence of histolog-ically evident monoclonal lesions. Furtherelaboration of the histopathology ofendometrial precancers has beenaccomplished through correlative histo-morphometric analysis of geneticallyascertained premalignant lesions {1958}.Because these lesions were initiallydefined by molecular methods, theirdiagnostic criteria differ from those ofatypical endometrial hyperplasia. Theyhave been designated endometrialintraepithelial neoplasia ("EIN") {1955},

Fig. 4.23 Endometrioid adenocarcinoma (type I).Note the focal accumulation of mutant TP53 pro-tein within a TP53 wild-type carcinoma.

Fig. 4.24 Serous intraepithelial carcinoma (type II)expresses TP53 mutant protein.

Table 4.04Essential diagnostic criteria of endometrial intraepithelial neoplasia (EIN).

Table 4.03Altered gene function in sporadic endometrioid (type I) and non-endometrioid (type II) endometrial adenocarcinoma.

Gene Alteration Type I Type II References

TP53 Immunoreactivity (mutant) 5-10% 80-90% {228,2647}

PTEN No immunoreactivity 55% 11% {1957}

KRAS Activation by mutation 13-26 0-10% {228,1512,1594,1787}

Beta-catenin Immunoreactivity (mutant) 25-38% rare {1787}

MLH1 Microsatellite instability /epigenetic silencing 17% 5% {799,826,1594}

P27 Low immunoreactivity 68-81% 76% {2562}

Cyclin D1 High immunoreactivity 41-56% 19% {2562}

P16 Low immunoreactivity 20-34% 10% {2562}

Rb Low immunoreactivity 3-4% 10% {2562}

Bcl-2 Low immunoreactivity 65% 67% {1512}

Bax Low immunoreactivity 48% 43% {1512}

Receptors

ER and PR Positive immunoreactivity 70-73% 19-24% {1512}

ER = Estrogen receptor PR = Progesterone receptor

EIN Criterion Comments

1. Architecture Gland area exceeds that of stroma, usually in a localized region.

2. Cytological alterations Cytology differs between architecturally crowded focus and background.

3. Size >1 mm Maximum linear dimension should exceed 1 mm. Smaller lesions have unknown natural history.

4. Exclude benign mimics and cancer



and many examples with corre l a t i v egenotypes and morphometry can beseen online at www.endometrium.org.

Endometrial intraepithelial neoplasia (EIN)This lesion is defined as the histopatho-logical presentation of pre m a l i g n a n tendometrial disease as identified by inte-grated molecular genetic, histomorpho-metric and clinical outcome data. Tissuemorphometry (D-Score {153} predictiveof cancer outcome) and genetic studiesare cross validating in that these method-ologically independent techniques pro-vide concordant identification of EINlesions when applied to a common poolof study material {1958}. The EIN schemepartitions endometrial proliferations intodifferent therapeutic groups. Distinctivediagnostic categories include: (1) Benign architectural changes ofunopposed estrogens (endometrialhyperplasia).(2) EIN.(3) Well differentiated adenocarcinoma.

The histological changes produced byunopposed estrogens (non-atypicalhyperplasias) are quite unlike localizingEIN lesions. The latter originate focallyt h rough monoclonal outgrowth of amutant epithelial clone with altered cytol-ogy and arc h i t e c t u re. Computerizedmorphometric analysis, which quantifiesspecific architectural patterns associat-ed with increased clinical cancer risk{154}, objectively defined the morpholo-gy of monoclonal EIN lesions. Becauseof differing diagnostic criteria, only 79%of atypical endometrial hyperplasiastranslate to EIN, and approximately athird of all EIN diagnoses are garneredf rom non-atypical hyperplasia cate-gories.

Genetic susceptibilityThe overwhelming majority of endometri -al cancers are sporadic, but they mayrarely present as a manifestation of mul-

ticancer familial syndromes. Examplesinclude here d i t a ry nonpolyposis coloncancer (HNPCC), caused by mutation ofDNA mismatch repair genes that pro-duce constitutive microsatellite instability{799} and Cowden syndrome in patientswith germline PTEN inactivation {1957}.

Prognosis and predictive factorsIn addition to tumour type and, for type Iadenocarcinomas, tumour grade, otherhistological and non-histological deter-minations influence the prognosis ofendometrial carcinoma. The most impor-tant of these is the surgical stage, whichin 1988 replaced the clinical staging sys-tem that had been in use for many years{2642}. The extent of surgical stagingperformed is based in part on the med-ical condition of the patient and in part onthe preoperative or intraoperativeassessment of tumour risk factors suchas type and grade, depth of myometrialinvasion and extension to involve thecervix {2692,2714}.Myometrial invasion is thus an importantissue, both as a prognostic factor in itsown right and as a determinant of theextent of staging and of subsequent ther-apy in cases treated by hysterectomy.FIGO divides stage I tumours into IA (lim-ited to the endometrium), IB (invasion ofless than half of the myometrium), and IC(invasion of more than half of themyometrium), {51,2976}. Some oncolo-gists, however, make treatment decisionsbased on thirds (inner, mid, outer) ofmyometrial invasion or distance in mil-limetres (mm) from the serosal surface.Thus, the pathologist can best satisfy thed e s i res for all of this information byreporting the maximal depth of tumourinvasion from the endomyometrial junc-tion and the thickness of the myometriumat that point (e.g. 7 mm tumour invasioninto a 15 mm thick myometrium) {2686}.True myometrial invasion must be distin-guished from carcinomatous extension(not invasion) into pre-existing "tongues"

of endometrium penetrating themyometrium or into foci (sometimesdeep-seated) of adenomyosis {2652,2688}. It should also be noted thattumour extension to the uterine serosaraises the stage to IIIA. Vascular or lym-phatic space invasion is an unfavourableprognostic factor that should be reported{78}. Perivascular lymphocytic infiltratesmay be the first clue to vascular invasionand, thus, should prompt deeper levelswithin the suspect block and/or the sub-mission of more tissue sections for histo-logical examination.It is also important to evaluate cervicalinvolvement in the hysterectomy speci-men since extension to the cervix raisesthe stage to II. The distinction betweenstage IIA and IIB is based on whether theextension involves the endocervical sur-face and/or underlying glands only orinvades the cervical stroma. One shouldbe aware that an adenocarcinoma involv-ing glands only might be an entirely sep-arate adenocarcinoma in situ primary inthe endocervix.Non-histological factors may also play arole in determining the prognosis ofendometrial carcinoma. It is unclear atthe present time, however, what thecost/benefit ratio of performing addition-al studies might be since the prognosisand treatment are currently based on thecombination of tumour type, grade,where appropriate, and extent, as dis-cussed above. Nevertheless, patientswith carcinomas of intermediate progno-sis, such as stage I well differentiatedendometrioid adenocarcinoma with focaldeep myometrial invasion might benefitf rom additional information includingsuch factors as tumour ploidy{1349,1441}, hormone receptor status{575,1441}, tumour suppressor genes{1309,1449}, oncogenes {1205,1449},p roliferation markers {966,1449,2012}and morphometry {2751}. Which, if any,of these or other studies will prove to bemost useful is problematic at this time.

DefinitionUterine mesenchymal tumours arederived from the mesenchyme of the cor-pus consisting of endometrial stroma,smooth muscle and blood vessels ora d m i x t u res of these. Rare l y, thesetumours may show mesenchymal differ-entiation that is foreign to the uterus.

EpidemiologyThe most common malignant mesenchy-mal tumours of the uterine corpus areleiomyosarcoma and endometrial stro-mal tumours, and both are more frequentin Black than in White women {1139,1729}.

Clinical featuresSigns and symptomsThe most common presentation for mes-enchymal tumours is uterine enlarge-ment, abnormal uterine bleeding orpelvic pain.

ImagingNon-invasive imaging, usually by ultra-sound, but occasionally by magnetic res-onance imaging (MRI), can be utilized inselected cases to distinguish between asolid ovarian tumour and a pedunculatedleiomyoma or to distinguish leiomyomasfrom adenomyosis. On MRI leiomyomaspresent as well delineated lesions of lowsignal intensity on T1 and T2-weightedimages. They may, however, undergodegenerative changes resulting in vari-ous, non-specific MRI appearances{1947,2971}. On MRI the presence of a

large, heterogeneous mass with irregularcontours should raise concern for sarco-ma.

Endometrial stromal and related tumours

Definition and historical annotationEndometrial mesenchymal tumours intheir better-differentiated forms are com-posed of cells resembling those of prolif-erative phase endometrial stro m a .N u m e rous thin-walled small art e r i o l a rtype (plexiform) vessels are characteris-tically present. Endometrial stromal sarcomas (ESS)have been traditionally divided into lowand high grade types based on mitoticcount. However, since high gradeendometrial sarcomas lack specific dif-f e rentiation and bear no histologicalresemblance to endometrial stroma, ithas been proposed that they be desig-nated undiff e rentiated endometrial oruterine sarcoma {811}. In this classifica-tion the distinction between low gradeESS and undiff e rentiated endometrialsarcoma is not made on the basis ofmitotic count but on features such asnuclear pleomorphism and necrosis.

ICD-O codesEndometrial stromal sarcoma,

low grade 8931/3Endometrial stromal nodule 8930/0Undifferentiated endometrial

sarcoma 8930/3

HistopathologyEndometrial stromal tumours are com-posed of cells resembling those of prolif-erative endometrial stroma and are farless frequent than smooth muscletumours. Endometrial stromal tumoursare subdivided into benign and malig-nant groups based on the type of tumourmargin {1432,2054,2097,2883}. Those with pushing margins are benignstromal nodules, whereas those with infil-trating margins qualify as stromal sarco-mas. There is general agreement on themorphologic definition of typical cases ofboth low grade ESS and undifferentiatedendometrial sarcoma. Characteristically,low grade ESS, a clinically indolent neo-plasm, features a plexiform vasculature,minimal cytological atypia and infrequentmitotic figures. The usual undifferentiatedsarcoma, a highly aggressive neoplasm,lacks a plexiform vasculature, featuressubstantial cytological atypia and hasfrequent and often atypical mitotic fig-ures. However, there is no valid evidencethat the isolated finding of a mitotic indexof 10 or more per 10 high power fields isan adverse prognostic finding in a neo-plasm that is otherwise a typical lowgrade ESS. A small minority of casesshare features of low grade ESS andundifferentiated sarcoma, and their clas-sification is controversial.

Immunoprofile The neoplastic cells of both the stromalnodule and low grade ESS arei m m u n o reactive for vimentin, CD10

M.R. HendricksonF.A. TavassoliR.L. KempsonW.G. McCluggageU. HallerR.A. Kubik-Huch

Mesenchymal tumours and relatedlesions

BAFig. 4.25 Low grade endometrial stromal sarcoma (ESS). A Worm-like, soft, yellow masses focally replace the myometrium. B The myometrium is extensively infil -trated by basophilic islands of low grade ESS. C A tongue of low grade ESS protrudes into a vascular space.

C

233Mesenchymal tumours and related lesions


{486,1821} and at least focally for actin{914}. They are usually, but not always{914}, negative for desmin and h-caldesmon {2065,2101,2488}. Lowgrade ESS is almost always positive forboth estrogen and progesterone recep-tors. {1411,2350,2502}. Rarely, low gradeendometrial stromal tumours, particularlythose with areas displaying a sex cordpattern, may be positive for alpha-inhibin{1521}, CD99 {167} and cytokeratin {29}.The sex cord areas may also beimmunoreactive for desmin, whereas thes u r rounding endometrial stromal cellsare not {678,1661}.

Somatic genetics Fusion of two zinc finger genes (JAZF1and JJAZ1) by translocation t(7;17) ispresent in most low grade endometrials t romal tumours {1189,1252,1503}.Endometrial stromal nodules and lowgrade ESSs are typically diploid with alow S-phase fraction {292,1220}.

Prognosis and predictive factorsThe histological distinction betweenu n d i ff e rentiated endometrial sarc o m aand low grade ESS has import a n timplications re g a rding pro g n o s i s{2601} Low grade ESSs are indolenttumours with a propensity for localre c u r rence, usually many years afterh y s t e re c t o m y. Distant metastases areless common. In contrast, undiff e re n t i-ated endometrial sarcomas are highlya g g ressive tumours with the majority ofpatients presenting with extrauterinedisease at the time of diagnosis anddying within two years of diagnosis{ 2 3 2 , 8 1 1 } .

Endometrial stromal sarcoma, low grade

DefinitionThis tumour fits the definition of endome-trial stromal tumour presented above andis distinguished from the stromal noduleon the basis of myometrial infiltrationand/or vascular space invasion.

EpidemiologyLow grade ESS is a rare tumour of theuterus accounting for only 0.2% of allgenital tract malignant neoplasms {645,1509,1745}. In general low grade ESSsaffect younger women than other uterinemalignancies; studies have demonstrat-ed that the mean age ranges from 42-58years, and 10-25% of patients are pre-menopausal {437,645}.

Clinical featuresThe clinical features have been dis-cussed above.

MacroscopyLow grade ESS may present as a solitary,well delineated and predominantly intra-mural mass, but extensive permeation ofthe myometrium is more common, withextension to the serosa in approximatelyhalf of the cases. The sectioned surfaceappears yellow to tan, and the tumourhas a softer consistency than the usualleiomyoma. Cystic and myxoid degener-ation as well as necrosis and haemor-rhage are seen occasionally.

LocalizationMetastases are rarely detected prior tothe diagnosis of the primary lesion

{29,684,3222}. Extrauterine extension ispresent in up to a third of the women withlow grade ESS at the time of hysterecto-my. The extension may appear as worm-like plugs of tumour within the vessels ofthe broad ligament and adnexa.

HistopathologyLow grade ESS is usually a densely cel-lular tumour composed of uniform, ovalto spindle-shaped cells of endometrials t romal-type; by definition significantatypia and pleomorphism are absent.Although most tumours are paucimitotic,mitotic rates of 10 or more per 10 highpower fields can be encountered, and ahigh mitotic index does not in itself alterthe diagnosis. A rich network of delicatesmall arterioles resembling the spiralarterioles of the late secretory endometri-um supports the proliferating cells. Cellswith foamy cytoplasm (tumour cells,foamy histiocytes, or both) are prominentin some cases. Endometrial type glandsoccur in 11-40% of endometrial stromaltumours {516,1343,2054}. Sex cord-likes t r u c t u res may also be found {511}.Myxoid and fibrous change may occurfocally or diffusely {2054,2102}.Perivascular hyalinization and a stellatepattern of hyalinization occur in somecases. Reticulin stains usually reveal adense network of fibrils surrounding indi-vidual cells or small groups of cells.Necrosis is typically absent or inconspic-uous. Focal smooth muscle diff e re n t i a t i o n(spindle or epithelioid) or cells with differ-entiation that is ambiguous between stro-mal and smooth muscle cells may devel-op in endometrial stromal tumours; these

BAFig. 4.26 Low grade endometrial stromal sarcoma (ESS). A There is a proliferation of endometrial stromal cells lacking atypia around spiral arteriole-like blood ves-sels. B Note a sex cord-like pattern in a low grade ESS.

areas are limited to less than 30% of thetumour. When the smooth muscle com-ponent comprises 30% or more of thetumour, the lesion is designated as amixed endometrial stromal and smoothmuscle tumour. Focal rhabdoid differenti-ation has been described in one case{1813}. The differential diagnosis includes stro-mal nodule, intravenous leiomyomatosis,adenomyosis with sparse glands andadenosarcoma. In a biopsy or curettagespecimen it is often impossible to distin-guish low grade ESS from a stromal nod-ule, a non-neoplastic stromal proliferationor a highly cellular leiomyoma.

HistogenesisExtrauterine primary endometrioid stro-mal sarcomas occur and often arise fromendometriosis {280}.

Prognosis and predictive factors Low grade ESS is characterized by indo-lent growth and late recurrences; up toone-half of patients develop one or morepelvic or abdominal recurrences. Themedian interval to re c u r rence is 3-5years but may exceed 20 years.Pulmonary metastases occur in 10% ofstage I tumours {1311}. The 5-year survival rate for low gradeESS ranges from 67% {2048} to nearly100% with late metastases and a rela-

tively long-term survival despite tumourdissemination {437,811,2263}. The surgi-cal stage is the best predictor of recur-rence and survival for ESSs {300,437}. Both recurrent and metastatic ESSs mayremain localized for long periods and areamenable to successful treatment byresection, radiation therapy, pro g e s t i ntherapy or a combination there o f{300,1750,3089}. Conservative management has beenadvocated for some patients with lowgrade ESS {1677}. In some studies thathave utilized progestin therapy, 100%survival rates have been achieved evenfor patients with stage III tumours {2263}.

Endometrial stromal nodule

DefinitionA benign endometrial stromal tumourcharacterized by a well delineated,expansive margin and composed of neo-plastic cells that resemble proliferativephase endometrial stromal cells support-ed by a large number of small, thin-walled arteriolar-type vessels.

Clinical featuresWomen with a stromal nodule range inage from 23-75 years with a median of 47years {292,437,2098,2101,2102,2883}.About one-third of the women are post-menopausal. Tw o - t h i rds of the women

p resent with abnormal uterine bleedingand menorrhagia. Pelvic and abdominalpain occur less fre q u e n t l y.

MacroscopyThe tumour is characteristically a solitary,well delineated, round or oval, fleshy nod-ule with a yellow to tan sectioned surf a c e .The median tumour diameter is 4.0 cm(range 0.8-15 cm) {2883}. About two-third sa re purely intramural without any appare n tconnections to the endometrium, 18% ofthe lesions are polypoid, and others involveboth the endometrium and myometrium.

HistopathologyThe histological appearance is identical tothat described above for low grade ESSexcept for the absence of infiltrative mar-gins {292,437,2097,2098,2101,2102,2883}.R a re, focal marginal irregularity in the formof finger-like projections that do not exceed3 mm is acceptable. Smooth and skeletalmuscle along with sex cord diff e re n t i a t i o nmay be present focally {1685}. The differential diagnosis includes lowgrade ESS and highly cellular leiomy-oma. The presence of at least focal typi-cal neoplastic smooth muscle bundles,large, thick walled vessels and strongi m m u n o reactivity with desmin and h-caldesmon and the absence of reactivitywith CD10 help distinguish a highly cel-lular leiomyoma from a stromal nodule.


Fig. 4.27 Low grade endometrial stromal sarcoma(ESS). Myoinvasive low grade ESS that showsendometrial glandular differentiation. Themyometrium is seen above.

BA

DCFig. 4.28 Endometrial stromal nodule. A Note the circumscribed, bulging, yellow nodule in the myometrium. B Cytologically bland ovoid cells without discernible cytoplasm proliferate in a plexiform pattern and aresupported by small arterioles. C The circumscribed myometrial nodule is composed of closely packed cells. D The tumour cells are strongly immunoreactive for CD10.

Prognosis and predictive factors Endometrial stromal nodules are benign{437,2101,2883}. A hysterectomy may berequired if the lesion has not been com-pletely excised.

Undifferentiated endometrial sarcoma

DefinitionA high grade endometrial sarcoma thatlacks specific differentiation and bears

no histological resemblance to endome-trial stroma.

SynonymUndifferentiated uterine sarcoma.

MacroscopyMacroscopically, undifferentiated uterinesarcomas are characterized by one ormore polypoid, fleshy, grey to yellowendometrial masses and often showprominent haemorrhage and necrosis.

HistopathologyHistologically, undifferentiated endome-trial sarcomas show marked cellularatypia and abundant mitotic activity,often including atypical forms. They lackthe typical growth pattern and vasculari-ty of low grade ESS {651,811} and dis-place the myometrium in contrast to theinfiltrative pattern of low grade ESS. Theyresemble the sarcomatous component ofa carcinosarcoma, and the possibility ofcarcinosarcoma and other specific sar-comas should be excluded with ade-quate sampling. These sarcomas are most often aneu-ploid with an S-phase fraction greater

than 10% {292} and negative for estro-gen and progesterone receptors.

Prognosis and predictives factorsThese tumours are aggressive, anddeath occurs from tumour disseminationwithin three years after hysterectomy inmost cases.

Smooth muscle tumours

DefinitionBenign or malignant neoplasms com-posed of cells demonstrating smoothmuscle differentiation.

ICD-O codesLeiomyosarcoma, NOS 8890/3

Epithelioid variant 8891/3Myxoid variant 8896/3

Smooth muscle tumour of uncert a i nmalignant potential 8897/1

Leiomyoma, NOS 8890/0Leiomyoma, histological variants

Cellular leiomyoma 8892/0Epithelioid leiomyoma 8891/0Myxoid leiomyoma 8896/0Atypical leiomyoma 8893/0

Table 4.05Diagnostic criteria for leiomyosarcoma.

Standard smooth muscle differentiation Epithelioid differentiation Myxoid differentiation

Histology Fascicles of cigar-shaped spindled cells with scanty Rounded cells with central nuclei Spindle-shaped cells set within anto abundant eosinophilic cytoplasm and clear to eosinophilic cytoplasm abundant myxoid matrix

Criteria for Any coagulative tumour cell necrosis Any coagulative tumour cell necrosis Any coagulative tumour cell necrosisl e i o m y o s a r c o m a

In the absence of tumour cell necrosis the diagnosis re- In the absence of tumour cell nec- In the absence of tumour cell quires diffuse, moderate to severe cytological atypia and rosis the diagnosis requires dif- necrosis, the diagnosis requires a mitotic index of ≥ 10mf/10hpf. When the mitotic index fuse, moderate to severe cytolo- d i ffuse, moderate to severe cytolo-is less than 10mf/10hpf, the chance of recurrence is low gical atypia and a mitotic index of gical atypia and a mitotic index of(less than a 2-3%) and the tempo of recurrence is slow. ≥ 5mf/10hpf ≥ 5mf/10hpfThis group is labelled "atypical leiomyoma with low risk of recurrence".

Comments In the absence of coagulative tumour cell necrosis and Focal epithelioid differentiation The very common perinodular significant atypia a high mitotic index is compatible with may be mimicked by cross-sec- hydropic degeneration shoulda benign clinical course. When the mitotic index exceeds tioned fascicles of standard not be included in this group15 mf/10hpf the term "mitotically active leiomyoma with s m o o t h musclelimited experience" can be used

The category "leiomyoma with limited experience" is also used for smooth muscle neoplasms that have focal moderate to severe atypia

____________mf/10hpf = mitotic figure(s) per 10 high power fields. See ref. {211} for discussion of mitosis counting techniques.

Fig. 4.29 Undifferentiated endometrial sarcoma.Atypical tumour cells show no resemblance to nor-mal endometrial stromal cells. Note the presenceof an abnormal mitotic figure.


Lipoleiomyoma 8890/0Leiomyoma, growth pattern variants

Diffuse leiomyomatosis 8890/1Intravenous leiomyomatosis 8890/1Benign metastasizing leiomyoma 8898/1

Leiomyosarcoma

DefinitionA malignant neoplasm composed ofcells demonstrating smooth muscle dif-ferentiation.

EpidemiologyL e i o m y o s a rcoma re p resents the mostcommon pure uterine sarcoma and com-prises slightly over 1% of all uterinemalignancies {1139}. The incidence ofleiomyosarcoma is reported to be 0.3-0.4/100,000 women per year {1139}.Leiomyosarcoma arises nearly exclusive-

ly in adults. The median age of patientswith leiomyosarcoma was 50-55 years inlarger studies {947,1745}, and 15% ofthe patients were younger than 40 years.The risk factors for endometrial carcino-mas such as nulliparity, obesity, diabetesmellitus and hypertension are not knownto relate to leiomyosarcoma.

Clinical featuresL e i o m y o s a rcomas localized to theuterus and leiomyomas produce similarsymptoms. Although a rapid increase inthe size of the uterus after menopausemay raise the possibility of leiomyosar-coma, in fact sarcoma is not morep revalent (less than 0.5%) in womenwith "rapidly growing" leiomyomas{1622,2187}. L e i o m y o s a rcoma may spread locally,regionally or by haematogenous dis-

semination. This fact of natural historyhas implications for both diagnosis andmanagement. Local and regional exten-sion may produce an abdominal orpelvic mass and gastrointestinal or uri-n a ry tract symptoms. Haematogenousdissemination is most often to the lungs.L e i o m y o s a rcoma is only infre q u e n t l ydiagnosed on endometrial samplings{1622}.

MacroscopyLeiomyosarcomas are characteristicallysolitary intramural masses and are usual-ly not associated with leiomyomas.L e i o m y o s a rcomas average 8.0 cm indiameter and are fleshy with poorlydefined margins. Zones of haemorrhageand necrosis characteristically interrupttheir grey-yellow or pink sectioned sur-face.


DC

BA

Fig. 4.30 Leiomyosarcoma. A This tumour exhibits typical coagulative tumour cell necrosis on the right. This pattern of necrosis features an abrupt transition fromviable tumour cells to necrotic tumour cells without intervening collagen or granulation tissue. B This tumour has a low level of atypia. This degree of atypia shouldprompt careful search for more diagnostic features. C A high level of atypia and apotosis is apparent in this tumour. D Leiomyosarcoma with intravascular tumourgrowth. The differential diagnosis includes intravenous leiomyomatosis, low grade endometrial stroma sarcoma (ESS) and leiomyosarcoma with vascular invasion.High power showed a poorly differentiated neoplasm with marked cytologic atypia and a high mitotic index. These are not features of low grade ESS or intravenousleiomyomatosis.

HistopathologyThe usual leiomyosarcoma is a cellulartumour composed of fascicles of spin-dle-shaped cells that possess abundanteosinophilic cytoplasm. Ty p i c a l l y, thenuclei are fusiform, usually have roundedends and are hyperc h romatic withcoarse chromatin and prominent nucle-oli. Tumour cell necrosis is typicallyprominent but need not be present. Themitotic index usually exceeds 15 figuresper 10 high power fields. Vascular inva-sion is identified in up to 25% ofleiomyosarcomas. Giant cells resemblingosteoclasts occasionally are present inotherwise typical leiomyosarcomas, and,rarely, xanthoma cells may be prominent{1058,1776}.A diagnosis of leiomyosarcoma shouldbe made with great caution in womenless than 30 years of age and only afterexclusion of exposure to Leupro l i d e ,which sometimes induces a pattern ofnecrosis identical to coagulative tumourcell necrosis {664}.

Epithelioid variantEpithelioid leiomyosarcomas combine an"epithelioid" phenotype with the usualfeatures of malignancy, i.e. high cellulari-ty, cytological atypia, tumour cell necro-sis and a high mitotic rate {130,1538,2292}. Specifically, epithelioid differentia-tion denotes tumour cells that have arounded configuration with eosinophilicto clear cytoplasm. When the cytoplasmis totally clear the label "clear cell" isused. Most malignant epithelioid smoothmuscle tumours are of the leiomyoblas-toma type, although clear cellleiomyosarcoma has been reported.

Myxoid variantMyxoid leiomyosarcoma is a large, gelat-inous neoplasm that often appears to becircumscribed on macroscopic examina-

tion {131,1465}. The smooth muscle cellsare widely separated by myxoid material.The characteristic low cellularity largelyaccounts for the presence of only a fewmitotic figures per 10 high power fields inmost myxoid leiomyosarcomas. In almostall instances myxoid leiomyosarcomasshow cellular pleomorphism and nuclearenlargement. They commonly showmyometrial and, sometimes, vascularinvasion.

Prognosis and predictive factorsLeiomyosarcoma is a highly malignantneoplasm {1745,2096}. The variation insurvival rates re p o rted historically islargely the result of the use of differentcriteria for its diagnosis. Overall 5-yearsurvival rates range from 15-25%{185,231,377,812,1585,3005,3109}. The5-year survival rate is 40-70% in stage Iand II tumours {291,947,1381,1585,1 7 6 5 , 1 7 9 7 , 2 0 4 5 , 2 0 4 9 , 2 2 0 0 , 3 1 3 9 } .P remenopausal women have a morefavourable outcome in some series {947,1381,1585,1797,3005,3139} but not inothers {185,1148}. Most recurrences aredetected within 2 years {231,377,1148,1381}.The prognosis of leiomyosarc o m adepends chiefly upon the extent of

spread. For tumours confined to the uter-ine corpus, some investigators havefound that the size of the neoplasm is animportant prognostic factor {812,1364,2049} with the best demarcation occur-ring at 5 cm. Several recent series,including the large Gynecologic Onco-logy Group study of early stage leio-m y o s a rcoma, have found the mitoticindex to be of prognostic significance{811,947,1585,1745}, whereas othershave not {812}. The utility of gradingleiomyosarcomas is controversial, andno universally accepted grading systemexists. Pathologists should comment onthe presence or absence of extrauterineextension and/or vascular space involve-ment, the maximum tumour diameter andthe mitotic index.

Smooth muscle tumour of uncertain malignant potential

DefinitionA smooth muscle tumour that cannot bediagnosed reliably as benign or malignanton the basis of generally applied criteria.

HistopathologyThis category of smooth muscle tumourof uncertain malignant potential should


B CAFig. 4.32 Myxoid leiomyosarcoma. A A paucicellular myxoid neoplasm infiltrates the myometrium. B Relatively bland spindle-shaped tumour cells are widely spaced ina myxoid matrix containing a delicate vasculature. C Nuclear pleomorphism and mitotic figures, although few in number, can be found.

BAFig. 4.31 Epithelioid leiomyosarcoma. A Tumour cell necrosis is present in the upper half of the field adjacentto highly pleomorphic cells. B The tumour cells exhibit nuclear pleomorphism, and mitotic figures are easilyfound.

be used sparingly and is reserved forsmooth muscle neoplasms whoseappearance is ambiguous for some re a-son, and the relevant diagnostic possibil-ities differ in their clinical implications{211}. Examples include cases in whichthe subtype of smooth muscle diff e re n t i a-tion is in doubt, i.e. standard smoothmuscle, epithelioid or myxoid, and appli-cation of the competing classificationrules would lead to diff e rent clinical pre-dictions. On other occasions the assess-ment of a diagnostic feature, e.g. the typeof necrosis or the interpretation of mitoticf i g u res, is ambiguous, and the compet-ing alternative interpretations would leadto diff e rent clinical pre d i c t i o n s .

Leiomyoma

DefinitionA benign neoplasm composed of smoothmuscle cells with a variable amount offibrous stroma.

MacroscopyLeiomyomas are typically multiple,spherical and firm. The sectioned sur-face is white to tan and has a whorledtrabecular texture. Leiomyomas bulgeabove the surrounding myometrium fromwhich they are easily shelled out.Submucosal leiomyomas distort theoverlying endometrium, and, as theyenlarge, they may bulge into theendometrial cavity and produce bleed-ing. Rare examples become pedunculat-ed and prolapse through the cervix.Intramural leiomyomas are the mostcommon. Subserosal leiomyomas canbecome pedunculated, and on torsionwith necrosis of the pedicle the leiomy-oma may lose its connection with theuterus. Ve ry rare l y, some becomeattached to another pelvic structure (par-asitic leiomyoma). The appearance of aleiomyoma often is altered by degenera-tive changes. Submucosal leiomyomasfrequently are ulcerated and haemor-rhagic. Haemorrhage and necrosis areobserved in some leiomyomas, particu-larly in large ones in women who arepregnant or who are undergoing high-dose progestin therapy. Dark red areasre p resent haemorrhage and sharplydemarcated yellow areas reflect necro-sis. The damaged smooth muscle isreplaced eventually by firm white ortranslucent collagenous tissue. Cysticdegeneration also occurs, and some

leiomyomas become extensively calci-fied.

HistopathologyMost leiomyomas are composed of easi-ly recognized smooth muscle featuringwhorled, anastomosing fascicles of uni-f o rm, fusiform cells. Characteristically,the spindle-shaped cells have indistinctb o rders and abundant, often fibrillar,eosinophilic cytoplasm. Sometimes, par-ticularly in cellular leiomyomas, the cyto-plasm is sparse, and the fasciculararrangement of the cells may be muted.

Nuclei are elongated with blunt ortapered ends and have finely dispersedchromatin and small nucleoli. Mitotic fig-ures usually are infrequent.Most leiomyomas are more cellular thanthe surrounding myometrium. Leiomy-omas lacking increased cellularity areidentified by their nodular circumscrip-tion and by the disorderly arrangement ofthe smooth muscle fascicles within them,out of alignment with the surroundingmyometrium.Degenerative changes are common inleiomyomas. Hyaline fibrosis, oedemaand, on occasion, marked hydro p i cchange can be present {525}.Haemorrhage, necrosis, oedema, myx-oid change, hypercellular foci and cellu-lar hypertrophy occur in leiomyomas inwomen who are pregnant or taking prog-estins. Not infre q u e n t l y, there isincreased mitotic activity near the areasof necrosis. On the other hand, the coagulativetumour cell necrosis common inleiomyosarcoma is not associated veryoften with acute inflammation and haem-orrhage. Progestational agents are asso-ciated with a slight increase in mitoticactivity, but not to the level observed in aleiomyosarcoma. In addition, the mitoticfigures seen in conjunction with inflam-matory necrosis have a normal histologi-

Table 4.06Definition of terms used in the diagnosis of uterine smooth muscle neoplasms.

Term Definition or comment

Necrosis Death of a portion of tissue

Coagulative tumour Abrupt transition from viable tumour to necrotic tumour, ghost outlinescell necrosis of cells usual, haemorrhage and inflammation uncommon.

Hyaline necrosis Intervening zone of collagen or granulation tissue between nonviable andviable tumour, haemorrhage common, cellular outlines often not visible.

Atypia Assessed at scanning power

Diffuse vs. focal Cells diffusely present in most fields examined vs. scattered widely spaced aggregates of cells

None to mild

Moderate to severe Pleomorphic type: Nuclear pleomorphism appreciated at scanning powerUniform type: Cells lack pleomorphism but exhibit uniform but markednuclear chromatin abnormalities

Mitotic index Expressed in mitotic figures per 10 high power fields in the mitotically most active areas

Only unequivocal mitotic figures are counted {211}

Fig. 4.33 MRI showing an enlarged uterus withmultiple leiomyomas.


cal appearance. The margins of mostleiomyomas are histogically circ u m-scribed, but occasional benign tumoursdemonstrate interdigitation with the sur-rounding myometrium, which may rare l ybe extensive.

ImmunoprofileSmooth muscle neoplasms react withantibodies to muscle-specific actin,alpha-smooth muscle actin, desmin andh-caldesmon. Anomalous expression ofcytokeratin immunoreactivity is observedfrequently both in the myometrium and insmooth muscle tumours, the extent andintensity of reactivity depending on theantibodies used and the fixation of thespecimen. Epithelial membrane antigenis negative in smooth muscle tumours.CD10 reactivity may focally be present.

Histological variantsMost subtypes of leiomyoma are chieflyof interest in that they mimic malignancyin one or more aspects.

Mitotically active leiomyomaMitotically active leiomyomas occur mostoften in premenopausal women. Theyhave the typical macroscopic and histo-logical appearances of a leiomyoma withthe exception that they usually have 5 ormore mitotic figures per 10 high powerfields {211,2293}. Occasionally, thesesmooth muscle tumours contain >15mitotic figures per 10 high power fields,

in which case the term mitotically activeleiomyoma with limited experience isused. The clinical evolution is benign,even if the neoplasm is treated bymyomectomy. It is imperative that thisdiagnosis not be used for neoplasms thatexhibit moderate to severe nuclear atyp-ia, contain abnormal mitotic figures ordemonstrate zones of coagulativetumour cell necrosis.

Cellular leiomyoma Cellular leiomyoma accounts for lessthan 5% of leiomyomas, and by definitiontheir cellularity is "significantly" greaterthan that of the surrounding myometrium{211,2101}. The isolated occurrence ofhypercellularity may suggest a diagnosisof leiomyosarcoma, but cellular leiomy-omas lack tumour cell necrosis and mod-erate to severe atypia and have infre-

quent mitotic figures. A cellular leiomy-oma comprised of small cells with scantycytoplasm can be confused with anendometrial stromal tumour. This prob-lem becomes particularly difficult withwhat has been termed the highly cellularleiomyoma.

Haemorrhagic cellular leiomyoma andhormone induced changesA haemorrhagic cellular or "apoplectic"leiomyoma is a form of cellular leiomy-oma that is found mainly in women whoa re taking oral contraceptives or whoeither are pregnant or are postpart u m{1960,2050}. Macroscopic examinationreveals multiple stellate haemorrhagica reas. Coagulative tumour cell necro s i sis generally absent. Normal mitotic fig-u res are present and are usually con-fined to a narrow zone of granulation


Fig. 4.34 Leiomyomas. The sectioned surface showstypical circumscribed, rubbery, white nodules.

Fig. 4.36 Epithelioid leiomyoma. Both tumour cellson the right and normal myometrium on the left areimmunoreactive for desmin.

Fig. 4.37 Atypical leiomyoma. This cellular neo-plasm exhibits nuclear pleomorphism but no mitot-ic figures or tumour cell necrosis.

Fig. 4.35 Epithelioid leiomyoma with sex cord-like features. The presence of smooth muscle rules out anendometrial stromal or pure sex cord-like tumour.

tissue in relation to areas of haemor-r h a g e .

Epithelioid leiomyoma Epithelioid leiomyomas are composed ofepithelial-like cells {130,1538,2292}.They are yellow or grey and may containvisible areas of haemorrhage and necro-sis. They tend to be softer than the usualleiomyoma, and most are solitary.Histologically, the epithelioid cells areround or polygonal, they are arranged inclusters or cords, and their nuclei areround, relatively large and centrally posi-tioned. There are three basic subtypes ofepithelioid leiomyoma: leiomyoblastoma,clear cell leiomyoma and plexiformleiomyoma. Mixtures of the various pat-terns are common, hence the designa-tion "epithelioid" for all of them. Small tumours without cytological atypia,tumour cell necrosis or an elevated mitoticindex can be safely re g a rded as benign.P l e x i f o rm tumourlets invariably are benign.Epithelioid leiomyomas with circ u m-scribed margins, extensive hyalinizationand a predominance of clear cells gener-ally are benign. The behaviour of epithe-lioid leiomyomas with two or more of thefollowing features is not well established:(1). Large size (greater than 6 cm).(2). Moderate mitotic activity (2-4 mitoticfigures per 10 high power fields), (3) Moderate to severe cytological atypia(4) Necrosis Such tumours should be classified in theuncertain malignant potential category,and careful follow-up is warranted.Neoplasms with 5 or more mitotic figuresper 10 high power fields metastasize withsufficient frequency that all should beregarded as epithelioid leiomyosarcoma.

Myxoid leiomyoma Myxoid leiomyomas are benign smoothmuscle tumours in which myxoid materi-

al separates the tumour cells {131,1465}.They are soft and translucent.H i s t o l o g i c a l l y, abundant amorphousmyxoid material is present between thesmooth muscle cells. The margins of amyxoid leiomyoma are circumscribed,and neither cytological atypia nor mitoticfigures are present.

Atypical leiomyoma (pleomorphic, bizarreor symplastic leiomyoma)When unassociated with either coagula-tive tumour cell necrosis or a mitoticindex in excess of 10 mitotic figures per10 high power fields, cytological atypia,even when severe, is an unreliable crite-rion for identifying clinically malignantuterine smooth muscle tumours. Theseatypical cells have enlarged hyperchro-matic nuclei with prominent chromatinclumping (often smudged). Large cyto-plasmic pseudonuclear inclusions oftenare present. The atypical cells may bedistributed throughout the leiomyoma(diffuse) or they may be present focally(possibly, multifocally). When the atypiais at most multifocal and the neoplasmhas been completely sampled, suchtumours are designated "atypical leiomy-oma with minimal, if any, re c u r re n c e

potential." Such lesions have behavedbenignly except for a single reportedcase.

Lipoleiomyoma S c a t t e red adipocytes in an otherwisetypical leiomyoma are a relatively com-mon finding; a leiomyoma that contains astriking number of these cells is called alipoleiomyoma {2357,2671}.

Growth pattern variantsGrowth pattern variants may produceunusual clinical, macroscopic and/or his-tological features.

Diffuse leiomyomatosis D i ffuse leiomyomatosis is an unusualcondition in which numerous smallsmooth muscle nodules produce sym-metrical, sometimes substantial, enlarge-ment of the uterus {518}. The hyperplas-tic smooth muscle nodules range fro mhistological to 3 cm in size, but most areless than 1 cm in diameter. They are com-posed of uniform, bland, spindle-shapedsmooth muscle cells and are less circ u m-scribed than leiomyomas. The clinicalcourse may be complicated by haemor-rhage, but the condition is benign.

Dissecting leiomyoma Dissecting leiomyoma refers to a benignsmooth muscle proliferation with a bordermarked by the dissection of compressivetongues of smooth muscle into the sur-rounding myometrium and, occasionally,into the broad ligament and pelvis{2469}. This pattern of infiltration mayalso be seen in intravenous leiomy-omatosis. When oedema and congestiona re prominent, a uterine dissectingleiomyoma with extrauterine extensionmay resemble placental tissue; hencethe name cotyledonoid dissectingleiomyoma {2470}.

B CAFig. 4.38 Leiomyoma with perinodular hydropic degeneration. A Sectioned surface shows a lobulated neoplasm. B Nodules of smooth muscle are delimited by oede-matous bands of collagen in which are suspended large calibre vessels. C The tumour is composed of uniform spindle-shaped smooth muscle cells.

Fig. 4.39 Intravenous leiomyomatosis with atypical(symplastic and epithelioid) features. Note thetumour plugs in myometrial vessels at the lower leftand mid-right.


Intravenous leiomyomatosisIntravenous leiomyomatosis is a very raresmooth muscle tumour featuring nodularmasses and cords of histologicallybenign smooth muscle growing withinvenous channels outside the confines ofa leiomyoma {1928,2051}. Intravenousleiomyomatosis should be distinguishedfrom the common vascular intrusion with-in the confines of a leiomyoma.M a c ro s c o p i c a l l y, Intravenous leiomy-omatosis consists of a complex, coiled ornodular myometrial growth often withconvoluted, worm-like extensions into theuterine veins in the broad ligament or intoother pelvic veins. On occasion, thegrowth extends into the vena cava, andsometimes it extends into the right heart.H i s t o l o g i c a l l y, tumour is found withinvenous channels that are lined byendothelium. The histological appear-ance is highly variable, even within thesame tumour. The cellular composition ofsome examples of intravenous leiomy-omatosis is similar to a leiomyoma, butmost contain prominent zones of fibrosisor hyalinization. Smooth muscle cellsmay be inconspicuous and difficult toidentify. Any variant smooth muscle his-tology, i.e. cellular, atypical, epithelioid orlipoleiomyomatous, may be encounteredin intravenous leiomyomatosis.

Benign metastasizing leiomyomaBenign metastasizing leiomyoma is an ill-defined clinicopathological conditionwhich features "metastatic" histologicallybenign smooth muscle tumour depositsin the lung, lymph nodes or abdomenthat appear to be derived from a benignuterine leiomyoma {798,2923}. Reportsof this condition often are difficult to eval-uate. Almost all cases of benign metas-tasizing leiomyoma occur in women whohave a history of pelvic surgery. The pri -mary neoplasm, typically removed years

b e f o re the extrauterine deposits aredetected, often has been inadequatelystudied. Most examples of "benignmetastasizing leiomyoma," however,appear to be either a primary benignsmooth muscle lesion of the lung in awoman with a history of uterine leiomy-oma or pulmonary metastases from a his-tologically non-informative smooth mus-cle neoplasm of the uterus. The findingsof a recent cytogenetic study were mostconsistent with a monoclonal origin ofboth uterine and pulmonary tumours andthe interpretation that the pulmonarytumours were metastatic {2923}. The hor-mone dependence of this proliferation issuggested by the finding of estrogen andp ro g e s t e rone receptors in metastaticdeposits and the regression of tumourduring pregnancy, after the menopauseand after oophorectomy.

Somatic geneticsUterine leiomyomas often have chromo-somal abnormalities detectable by cyto-genetic analysis, most frequently involv-ing the H M G I C (12q15) and H M G I Y(6p21) genes {2204a}.

Miscellaneous mesenchymalt u m o u r s

DefinitionA diverse group of mesenchymaltumours of the uterus that do not showpredominantly smooth muscle or stromaldifferentiation.

Mixed endometrial stromal andsmooth muscle tumour

Definition and historical annotationThese neoplasms, previously designateds t romomyoma, are composed of anadmixture of endometrial stromal and

smooth muscle elements {1448,2098,2550,2860}. Small areas of smooth mus-cle differentiation are commonly seen inotherwise typical endometrial stro m a lneoplasms and vice versa, but a mini-mum of 30% of the minor component isrecommended for the designation ofmixed endometrial stromal-smooth mus-cle neoplasm {2098}.

MacroscopyThese neoplasms may have a predomi-nant intramural, submucosal or sub-s e rosal location. Some have beendescribed as well circumscribed, where-as others have been multinodular or havehad infiltrating margins. Some neo-plasms contain areas with a whorledappearance admixed with tan foci thata re softer than typical leiomyomas{2098}.

HistopathologyA population of small cells with round toovoid nuclei and inconspicuous cyto-plasm characterizes the endometrials t romal component. Numerous smallarterioles are a characteristic feature.The endometrial stromal component usu-ally exhibits minimal cytological atypia,and the mitotic rate is variable. Areasexhibiting sex cord-like diff e re n t i a t i o nand perivascular hyalinization may bepresent in the endometrial stromal com-ponent {2098}. A case has beendescribed with an associated glandularcomponent consisting of benignendometrial glands surrounded byendometrial stroma {1812}.The smooth muscle component is usual-ly benign in appearance and is oftenarranged in nodules with a prominentcentral area of hyalinization creating astarburst appearance. However, in somecases the smooth muscle componentmay exhibit any one or a combination of

B CAFig. 4.40 Perivascular epithelioid cell tumour. A Low power image shows a "tongue-like" growth pattern, similar to low grade endometrial stromal sarcoma. B Highpower image shows epithelioid cells with clear to pale granular cytoplasm without significant atypia or mitotic figures. C HMB-45 stain is positive.


cytological atypia, tumour cell necrosisand conspicuous mitotic activity.The smooth muscle component is posi-tive for desmin and alpha-smooth muscleactin. However, there may be positivity ofthe endometrial stromal component withthese antibodies, and they cannot beused to reliably distinguish betweenendometrial stroma and smooth muscle.Studies have shown that markers such asCD10 that stain endometrial stroma buta re focally positive in many smooth mus-cle neoplasms and h-caldesmon andcalponin that stain smooth muscle maybe of value in distinguishing the two com-ponents {44,486,1821,2065}. Sex cord -like areas may exhibit immunohistochem-ical staining with alpha-inhibin and othersex cord - s t romal markers {1521, 1808}.

Prognosis and predictive factorsThe limited literature on these rare neo-plasms suggests that they should be eval-uated and re p o rted in the same way asendometrial stromal neoplasms; i.e. malig-nant if there is vascular or myometrial inva-sion, benign otherwise {2098, 2311}.

Perivascular epithelioid celltumour

DefinitionA tumour composed predominantly orexclusively of HMB-45-positive perivas-cular epithelioid cells with eosinophilicgranular cytoplasm. It is a member of afamily of lesions thought to be com-posed, at least in part, of perivascularepithelioid cells. Other members of thisgroup include some forms of angiomy-olipoma and lymphangioleiomyomatosis,as well as clear cell ‘sugar’ tumour.

SynonymPEComa.

EpidemiologyThe age of patients ranged from 40-75years with a mean of 54 {2998}.

Clinical featuresMost patients present with abnorm a luterine bleeding.

MacroscopyA mass is present in the uterine corpus.

HistopathologyThe tumours are divided into two groups{2998}. The first demonstrates a tongue-

like growth pattern similar to that seen inlow grade ESS. These tumours are com-posed of cells that have abundant clearto eosinophilic pale granular cytoplasmand stain diffusely for HMB-45 and alsovariably express muscle markers. Thesecond group is composed of epithelioidcells with less prominent clear cell fea-tures and a smaller number of cells thata re HMB-45 positive. These tumoursexhibit more extensive muscle markere x p ression and a lesser degree oftongue-like growth than the first group.

Genetic susceptibilityOne-half of the patients in the secondgroup had pelvic lymph nodes involvedby lymphangioleiomyomatosis, and one-fourth had tuberous sclerosis.

Prognosis and predictive factorsH y s t e rectomy is the usual treatment. Someuterine cases have exhibited aggre s s i v eb e h a v i o u r. Uterine perivascular epithelioidcell tumour should be considered of uncer-tain malignant potential until long-term out-come data for a larger number of patientsbecome available {2998}.

Adenomatoid tumour

DefinitionA benign tumour of the uterine serosaand myometrium originating fro mmesothelium and forming gland-likestructures.

ICD-O code 9054/0

Clinical featuresThey are usually an incidental finding in ah y s t e rectomy specimen. Occasionally,they may be multiple or associated with asimilar lesion in the fallopian tube.

MacroscopyMacroscopically, adenomatoid tumoursmay resemble leiomyomas, being wellc i rcumscribed intramural masses.However, in many cases they are lesswell defined and of softer consistency.They may occur anywhere within themyometrium but are often locatedtowards the serosal surface.

HistopathologyOn low power examination adenomatoidtumour is usually composed of multiplesmall, often slit-like, interc o n n e c t i n gspaces within the myometrium. On high-er power these are composed of tubuleslined by a single layer of cells that maybe cuboidal or attenuated. The lesionoften has an infiltrative appearance.Sometimes the spaces are dilated result-ing in a cystic pattern that was confusedwith lymphangioma in the past, and inother cases a more solid growth patternis apparent. There is little nuclear atypiaor mitotic activity, and there is no stromaldesmoplastic response. Occasionaltumours may exhibit signet-ring cell his-tology, focally or diffusely, which may


Fig. 4.41 Uterine adenomatoid tumour. The tumour is composed of tubules lined by bland cuboidal cellswithin the myometrium.

cause obvious diagnostic pro b l e m s .Sometimes a papillary pattern may bea p p a rent. Ultrastructural examinationshows the long slender microvilli charac-teristic of mesothelial cells.

ImmunoprofileImmunohistochemical positivity with anti-cytokeratin antibodies and anti-mesothe-lial antibodies, such as HBME1 and cal-retinin, is usual. This finding may be use-ful in the distinction between adenoma-toid tumour and lymphangioma. There isno reactivity with Ber-EP4, helping toexclude a carcinoma in those cases thathave signet-ring cell morphology {211,2101,2123}.

Histogenesis The histogenesis has been debated inthe past, but immunohistochemical andultrastructural studies have shown theseneoplasms to be of mesothelial origin.When located within the uterus {654,2041,2311,2768,2924}, they are proba-bly derived from the serosal mesotheli-um.

Prognosis and predictive factorsAdenomatoid tumours are invariablybenign with no risk of recurrence ormetastasis.

Rare mesenchymal tumours

DefinitionA variety of mesenchymal tumours, bothmalignant and benign, occurring withinthe uterus that are not endometrial stro-mal, smooth muscle or mesothelial in

type. These are rare and are identicalhistologically to their counterparts arisingin more usual sites.

Malignant tumours In cases of malignancy the neoplasmshould be extensively sampled in orderto exclude sarcomatous overgrowth in aMMMT or an adenosarcoma. The mostcommon of these neoplasms to arise inthe uterus is rhabdomyosarcoma {716,1149,1814,2112}. The latter is usually ofembryonal type in young females and ofpleomorphic type in the middle aged orelderly. Occasional cases of uterine alve-olar rhabdomyosarcoma have also beendescribed {475}. Occasional re s i d u a lentrapped benign endometrial glandsmay be present, especially towards thesurface of these neoplasms. That findingshould not be taken as evidence of ana d e n o s a rcoma. Other malignant mes-enchymal neoplasms described in theuterus include malignant fibrous histiocy-toma {1404}, angiosarcoma (includingthe epithelioid variant) {2551,2853},liposarcoma {180}, osteosarcoma {784,1137,1844}, c h o n d ro s a rc o m a { 1 4 8 9 } ,alveolar soft part sarcoma {2319}, Ewingt u m o u r, malignant peripheral nervesheath tumour, malignant pigmentedn e u ro e c t o d e rmal tumour of infancy{2580} and peripheral primitive neuroec-t o d e rmal tumour {638,1894,2017}. Ingeneral, these are all bulky neoplasms,frequently high stage at presentation,and the histology is similar to their coun-terparts elsewhere. Immunohistochemi-cal studies may assist in establishing adefinitive diagnosis.

H a e m a n g i o p e r i c y t o m a has also beendescribed in the uterus, but it is likely thatmost of the reported cases representvascular endometrial stromal neoplasms{2693}. Malignant rhabdoid tumours have alsobeen described {948,1255}. Since a rhab-doid component may rarely be found in anotherwise typical endometrial stromal neo-plasm {1813}, it is possible that somerhabdoid tumours re p resent an unusualhistological variant of an endometrial stro-mal or some other neoplasm. As with othere x t r a renal rhabdoid tumours, the uterineneoplasm may re p resent a peculiar histo-logical growth pattern that may be found ina variety of neoplasms; there f o re, exten-sive sampling should be undertaken toexclude a diagnosis of rhabdoid diff e re n t i-ation in another more common neoplasm.Only when other elements are not identi-fied should a diagnosis of uterine malig-nant rhabdoid tumour be considere d .

Benign tumours Benign tumours include lipoma, haeman-gioma, lymphangioma and rhabdomy-oma {466,686}. Occasional uterine myx-omas have been described in Carneys y n d rome {2654}. Before diagnosingthese entities, a lipoleiomyoma should beexcluded in the case of lipoma, a vascu-lar leiomyoma in the case of haeman-gioma, an adenomatoid tumour in thecase of lymphangioma and a myxoidsmooth muscle neoplasm in the case ofmyxoma. A single case of postoperativespindle cell nodule of the endometriumthat occurred following a uterine curet-tage has been described {504}.


DefinitionTumours of the uterine corpus composedof an epithelial and a mesenchymal com-ponent.

ICD-O codesCarcinosarcoma 8980/3Adenosarcoma 8933/3Carcinofibroma 8934/3Adenofibroma 9013/0Adenomyoma 8932/0

Atypical polypoid variant 8932/0

Carcinosarcoma

DefinitionA neoplasm composed of an admixtureof malignant epithelial and mesenchymalcomponents.

SynonymsMalignant müllerian mixed tumour, malig-nant mesodermal mixed tumour, meta-plastic carcinoma. These tumours are still classified as"mixed" by convention, although there isincreasing evidence that they are mono-clonal and should be considered subsetsof endometrial carcinoma.

EpidemiologyCarcinosarcoma is the most commonneoplasm of this group {703}.Carcinosarcomas usually occur in elder-ly postmenopausal women, althoughoccasional cases may occur in youngerwomen and rarely even in young girls.The median age of patients presenting

with carcinosarcoma is 65 years, higherthan that of patients with leiomyosarcoma{813,1745}. Less than 5% of patients areyounger than 50 years.

AetiologyAn occasional case is secondary to priorpelvic irradiation. In recent years anassociation between long term tamoxifentherapy and the development of uterinec a rc i n o s a rcoma has been suggested{813,1811,2947}.

Clinical featuresSigns and symptomsVaginal bleeding is the most frequentpresenting symptom of patients with car-cinosarcoma, followed by an abdominalmass and pelvic pain {703}.Carcinosarcomas may be polypoid andmay prolapse through the cervix to pres-ent as an upper vaginal mass. The mostimportant diagnostic method is uterinecurettage, but in 25% of cases the diag-nosis is made following hysterectomy{2965}.

ImagingMagnetic resonance imaging (MRI) ofwomen with a typical carcinosarcomausually shows an enlarged uterus with awidened endometrial cavity and evi-dence of deep myometrial invasion.Whereas a carcinosarcoma cannot bedistinguished from endometrial carcino-ma by means of MRI, the presence of alarge tumour with extensive myometrialinvasion as well as the presence of ovar-

ian or intraperitoneal metastases shouldraise suspicion {1060,2838}.

MacroscopyAt the time of presentation uterine carci-nosarcomas are usually polypoid, bulky,necrotic and haemorrhagic neoplasmsthat fill the endometrial cavity and deeplyinvade the myometrium, often extendingbeyond the uterus. If cartilage or boneforms a significant portion of the neo-plasm, the neoplasm may have a hardc o n s i s t e n c y. Occasionally, these neo-plasms may arise within a benignendometrial polyp.

Tumour spread and stagingIntra-abdominal and re t ro p e r i t o n e a lnodal metastases are frequent {1745}.

HistopathologyThe malignant epithelial element is usual-ly glandular, although rarely it may benon-glandular, most commonly consist-ing of squamous or undifferentiated car-cinoma. The glandular component maybe either endometrioid or non-endometri-oid, such as serous or clear cell in type.The sarcomatous elements may be eitherhomologous or heterologous. In homolo-gous neoplasms the mesenchymal com-ponent usually consists of undifferentiat-ed sarcoma, leiomyosarcoma orendometrial stromal sarcoma and is usu-ally, although not always, high grade.H e t e rologous mesenchymal elementsmost commonly consist of malignant car-tilage or malignant skeletal muscle in the

W.G. McCluggageU. HallerR.J. KurmanR.A. Kubik-Huch

Mixed epithelial and mesenchymaltumours

Table 4.07Nomenclature of mixed epithelial and mesenchymal tumours defined by phenotypes of epithelial and mes-enchymal components.

Benign epithelium Malignant epithelium

Benign mesenchyme Adenofibroma Carcinofibroma

Adenomyoma (including atypical)

Malignant mesenchyme Adenosarcoma Carcinosarcoma Fig. 4.42 Carcinosarcoma. Sagittal section of the uterusshows a solid, polypoid tumour within the fundus.

245Mixed epithelial and mesenchymal tumours


form of rhabdomyoblasts, although otherelements such as osteosarcoma andliposarcoma may rarely occur.In general, both carcinomatous and sar-comatous elements are easily identifi-able, although in some cases one orother element may form a minor compo-nent that may be only identified followingextensive sampling of the neoplasm. Anyuterine neoplasm composed of highgrade sarcoma, especially when heterol-ogous elements are present, should beextensively sampled in order to rule out ac a rc i n o s a rcoma or sarcomatous over-growth in an adenosarcoma. In mostinstances the two elements are sharplydemarcated, but in some they appear tomerge with transitional forms betweenthe two elements. Eosinophilic hyalineinclusions are commonly seen, especial -ly in the sarcomatous elements {2359}. Occasionally, a carcinosarcoma may beidentified in an otherwise benignendometrial polyp. A uterine carcinosar-

coma with a component of yolk sactumour has been described in a patientwith an elevated serum alpha-fetoproteinlevel {2665}. Occasional tumours with arhabdoid phenotype {190} or a malignantneuroectodermal component {931} havealso been described. Occasional uterinecarcinosarcomas of mesonephric originhave been reported {3171}. Other unusu-al histological features includemelanocytic {77} and neuro e n d o c r i n edifferentiation {537}.

ImmunoprofileIn general, the epithelial elements arei m m u n o reactive with anti-cytokeratinantibodies and the mesenchymal ele-ments with vimentin. The mesenchymalelements often show focal staining withanti-cytokeratin antibodies supporting anepithelial origin of this component. Theusual concordance of TP53 stainsbetween the epithelial and mesenchymalcomponents supports a common mono-

clonal origin for both elements {1796,2827}. Desmin, myoD1, myoglobin andsarcomeric actin staining may highlight ar h a b d o m y o s a rcomatous mesenchymalcomponent. Cartilaginous elements usu-ally stain with S-100 protein.

HistogenesisIt should be noted that clinical, immuno-histochemical, ultrastructural and molec-ular studies have all suggested that car-cinosarcomas are really metaplastic car-cinomas in which the mesenchymal com-ponent retains at least some epithelialfeatures in the vast majority of cases{1809}. Though still classified as "mixed"by convention, these tumours are per-haps better considered subsets ofendometrial carcinoma and cert a i n l yshould not be grouped histogeneticallyor clinically with uterine sarc o m a s{1810}. On the other hand, the tumoursother than carcinosarcoma in this groupare considered to be true mixed tumours.

DC

BA

Fig. 4.43 Carcinosarcoma. A A biphasic tumour is composed of poorly differentiated malignant glands and sarcomatous elements. B A biphasic tumour is composedof a solid aggregate of malignant epithelium with central squamous differentiation and sarcomatous elements. Mitoses are frequent. C High power image shows amesenchymal component resembling rhabdomyosarcoma. D High power image shows a mesenchymal component resembling osteosarcoma.

Prognosis and predictive factorsThe clinical course of uterine carcinosar-coma is generally aggressive with a pooroverall prognosis, considerably worsethan that of a poorly diff e re n t i a t e dendometrial carcinoma. The pattern ofspread is generally similar to that of highgrade endometrial carcinoma, and deepmyometrial invasion and extrauterinespread are often observed at the time ofpresentation. The clinical staging is thesame as that for endometrial carcinoma.Some studies have found no independ-ent prognostic factors other than tumourstage, whereas others have found thatthe characteristics of the epithelial com-ponent such as high grade carcinoma,including serous or clear cell compo-nents, are associated with a worse prog-nosis {2692}. Previously, it was thoughtthat the presence of heterologous mes-enchymal components indicated a worseoutcome; however, recent larger studieshave suggested that the histological fea-tures of the mesenchymal componentbear no relationship to the overall prog-nosis {2692}. The biological behaviour of uterine carci-nosarcomas is more akin to high gradeendometrial carcinomas than to uterinesarcomas {282,2692}. Carcinosarcomasprimarily spread via lymphatics, whereaspure uterine sarcomas commonly spreadh a e m a t o g e n o u s l y. Detailed studies ofuterine carcinosarcoma have shown thatmetastatic foci and foci within lymphaticor vascular spaces are commonly carci-nomatous with pure sarcomatous ele-ments being rare {282,2692,2767}.Although the tumour stage is the most

important prognostic factor, recurrencesmay be encountered even in those rarecases lacking myometrial infiltration.However, tumours confined to an other-wise benign polyp appear to have asomewhat better outcome {188,1382}.

Adenosarcoma

DefinitionAdenosarcoma is a biphasic neoplasmcontaining a benign epithelial compo-nent and a sarcomatous mesenchymalcomponent.

EpidemiologyAdenosarcoma occurs in women of allages, ranging from 15-90 years with amedian age at diagnosis of 58.Adenosarcomas have been reported inwomen undergoing tamoxifen therapy forbreast cancer {509} and occasionallyafter prior pelvic radiation {515}. There isno association of adenosarcoma withobesity or hypertension.

Clinical featuresTypical symptoms of patients witha d e n o s a rcoma are abnormal vaginalbleeding, an enlarged uterus and tissuep rotruding from the external os. Thetumour may not be correctly diagnosedas adenosarcoma until re-excision of arecurrent polypoid lesion {515}.

MacroscopyAdenosarcomas typically grow as exo-phytic polypoid masses that extend intothe uterine cavity. Rarely, they may arisein the myometrium, presumably fro m

adenomyosis. Although the tumour isusually a single polypoid mass, it some-times may present as multiple papillarymasses. On sectioning, the surface is tanb rown with foci of haemorrhage andnecrosis. Small cysts are frequently pres-ent. Most adenosarcomas do not invadethe myometrium.

HistopathologyUnder low magnification a leaf-like patternclosely resembling phyllodes tumour ofthe breast is observed. Isolated glands,often dilated and compressed into thinslits, are dispersed throughout the mes-enchymal component. Characte- ristically,t h e re is stromal condensation surro u n d i n gthe glands and clefts. It is in these are a sw h e re the greatest degree of stro m a latypia and mitotic activity is present. Bydefinition the epithelium is benign andmay show focal metaplastic changes. Themesenchymal component of ana d e n o s a rcoma is generally a low gradehomologous stromal sarcoma containingv a rying amounts of fibrous tissue andsmooth muscle. Mesenchymal mitotic fig-u res, usually stated to be more than oneper 10 high power fields, are re q u i red inthe hypercellular cuffs. Cytological atypiais typically only mild, but is occasionallymoderate. Sex cord-like componentsresembling those in endometrial stro m a ls a rcomas are found in less than 10% ofa d e n o s a rcomas. Heterologous compo-nents consisting of striated muscle (mostcommonly), cartilage, fat and other com-ponents are present in approximately 10-15% of tumours The diagnosis of sarc o-matous overgrowth is made if the pure

BAFig. 4.44 Adenosarcoma. A The tumour is composed of tubular and convoluted, cleft-like glands of endometrioid type surrounded by a cuff of cellular mesenchyme.B A polypoid structure compresses a glandular lumen producing a leaf-like pattern similar to that of a mammary phyllodes tumour. The epithelial component is cytologi-cally bland, and the mesenchymal component is cellular and fibromatous without significant nuclear atypia but contained abundant mitoses.



sarcomatous component, usually of highgrade, occupies 25% or more of the totaltumour volume.

ImmunoprofileAs might be expected, the epithelialcomponent reacts with a broad spectrumof antibodies to cytokeratins. The mes-enchymal component usually re a c t sfocally with antibodies to CD10. Variabledegrees of staining for smooth musclemarkers, desmin and caldesmon, canalso be observed.

Differential diagnosisThe differential diagnosis includes ade-nofibroma and in children sarcoma botry-oides (embryonal rhabdomyosarcoma).

Prognosis and predictive factorsA d e n o s a rcoma is considered a lowgrade neoplasm but recurs in approxi-mately 25-40% of cases, typically in thepelvis or vagina, and distant metastasishas been reported in 5% of cases {515}.The metastases almost always are com-posed of a sarcomatous element only,but rarely epithelium has been reported.Factors in the primary tumour that arep redictive of a poor outcome areextrauterine spread, deep myometrialinvasion into the outer half of themyometrium and sarcomatous over-growth. Vascular invasion is usually notidentified but, if present, is a poor riskfactor. Rhabdomyosarcomatous differen-tiation was an adverse prognostic factorin one series {1388}. There appears to beno correlation between the pro g n o s i sand the level of mitotic activity. Long-t e rm follow-up is necessary becausere c u r rences may manifest after manyyears. Most tumour deaths occur morethan five years after the diagnosis.

Carcinofibroma

DefinitionA neoplasm composed of an admixtureof a malignant epithelial element and abenign mesenchymal component.

EpidemiologyThese are extremely uncommon neo-plasms with few cases reported in the lit-erature {1286,2228,2916}.

HistopathologyIn one case the epithelial component wasclear cell in type {2228}. The mesenchy-

mal component is usually fibro u s ,although occasional cases with a hetero l-ogous mesenchymal component havebeen described and have been designat-ed as carcinomesenchymoma {459}.

Prognosis and predictive factorsThe behaviour is not well establishedsince so few cases have been reportedbut would be expected to depend on thestage, depth of myometrial invasion andhistological subtype of the epithelialcomponent.

Adenofibroma

DefinitionA biphasic uterine neoplasm composedof benign epithelial and mesenchymalcomponents.

EpidemiologyUterine adenofibroma is an uncommonneoplasm, much less frequent thanadenosarcoma, which occurs most oftenin postmenopausal patients but also inyounger women. {3245}. Occasionalcases have been associated with tamox-ifen therapy {1258}.

MacroscopyAdenofibromas usually present as poly-poid lesions, commonly have a fibrousconsistency on sectioning, and some-times contain dilated cystic spaces.

HistopathologyAdenofibromas have a papillary or club-like growth pattern. They are composedof benign epithelial and mesenchymalcomponents, the epithelial componentforming a lining on the underlying mes-enchymal core. Cleft-like spaces areoften present. The epithelial componentmay be endometrioid or ciliated in typebut often is non-descript cuboidal orcolumnar. Rarely, there are foci of squa-mous metaplasia. The mesenchyme isusually of a non-specific fibro b l a s t i ctype, although rarely it may containendometrial stromal or smooth musclecomponents. Stromal atypia, mitoticactivity and periglandular cuffing areabsent or inconspicuous. Rare l y, adi-pose tissue or skeletal muscle compo-nents are present, and such lesions havebeen designated lipoadenofibroma oradenomyofibroma {1239,2711}.

Differential diagnosisIf there is a stromal mitotic count of >1mitosis per 10 high power fields, markedstromal hypercellularity with periglandu-lar cuffing and/or more than mild stromalatypia, a diagnosis of low gradeadenosarcoma should be made.

Prognosis and predictive factorsA d e n o f i b romas are benign lesions,although they may recur following"polypectomy" {2625}. Occasional

Fig. 4.45 Atypical polypoid adenomyoma. This polypoid lesion shows a biphasic epithelial and stromal pro-liferation. The glandular component consists of endometrioid glands with a variable degree of complexity,whereas the mesenchymal component is myofibromatous and cytologically bland.


tumours may superficially invade themyometrium, but metastases have notbeen reported. Invasion of myometrialveins has also been described {514}.Occasional cases have been focallyinvolved by adenocarcinoma, but theassociation is probably incidental {1873}.

Adenomyoma including atypicalpolypoid adenomyoma

DefinitionA lesion composed of benign epithelial(usually endometrial glands) and mes-enchymal components in which the mes-enchymal component is fibromyomatousAtypical polypoid adenomyoma is a vari-ant of adenomyoma in which the glandu-lar component exhibits arc h i t e c t u r a lcomplexity with or without cytologicalatypia.

EpidemiologyAdenomyoma may occur at any age,whereas atypical polypoid adenomyomacharacteristically occurs in pre-menopausal women {1690,1801,3228}.

MacroscopyAdenomyomas and atypical polypoidadenomyomas usually are polypoid sub-mucosal lesions but may rarely be intra-mural or subserosal {1002}. They have af i rm sectioned surface. Atypical poly-poid adenomyoma usually involves thelower uterine segment or upper endo-c e r v i x .

HistopathologyAdenomyoma is composed of an admix-t u re of benign endometrial glands (theremay be minor foci of tubal, mucinous orsquamous epithelium) with minimal cyto-logical atypia and architectural complexi-ty embedded in a benign fibro m y o m a t o u smesenchyme. Often endometrial types t roma surrounds the endometrial glandu-lar component, and the former is in turns u r rounded by smooth muscle {1002}.

Atypical polypoid adenomyomaIn atypical polypoid adenomyoma theglands characteristically show markeda rchitectural complexity; there is noendometrial type stroma around the dis-t o rted glands. There is often also cytolog-ical atypia that varies from mild to marked.Foci may be present that arc h i t e c t u r a l l yresemble well diff e rentiated adenocarc i-noma, and such tumours have been des-ignated "atypical polypoid adenomyomaof low malignant potential" {1690}.Extensive squamous or morular metapla-sia of the glandular elements, with or with-out central necrosis, is a common finding.The mesenchymal component is com-posed of swirling and interlacing fasciclesof benign smooth muscle.

Differential diagnosisIt should be noted that many simpleendometrial polyps contain a minor com-ponent of smooth muscle within the stro-ma; however, this finding alone is nots u fficient for the diagnosis of adenomy-oma. The designation adenomyoma has

also been used for a localized adeno-myosis that forms a discrete mass, butsuch usage is confusing and not re c o m-mended. D i ff e rentiation from a well diff e re n t i a t e dendometrioid adenocarcinoma invadingthe myometrium may be difficult, espe-cially on a curettage or biopsy specimen.H o w e v e r, the usual lack of pro n o u n c e dcellular atypia and the absence of a stro-mal desmoplastic response would beagainst a diagnosis of adenocarc i n o m a .Additional features against a diagnosis ofc a rcinoma are the usual youth of thepatient and the presence of norm a lendometrial fragments in the sample.

Genetic susceptibilityAtypical polypoid adenomyomas mayoccur in women with Tu rner syndro m e{ 5 1 7 } .

Prognosis and predictive factorsAdenomyoma is generally cured by sim-ple polypectomy, but if associated withmyometrial adenomyosis, symptoms maypersist. Atypical polypoid adenomyomamay re c u r, especially following incom-plete removal. In addition, superf i c i a lmyometrial infiltration is often identified inh y s t e rectomy specimens, a finding thatmay be more common in those cases withmarked glandular architectural complexi-ty {1690}. A small number of cases areassociated with an underlying endometri-oid adenocarcinoma with a transition zonebetween the two components {1882,2 8 1 3 } .


DefinitionA heterogeneous group of gestationaland neoplastic conditions arising fromtrophoblast, including molar gestationsand trophoblastic tumours.

EpidemiologyGestational trophoblastic disease (GTD)varies widely among various populationswith figures as high as 1 in 120 pregnan-cies in some areas of Asia and SouthAmerica compared to 0.6-1.1 per 1000 inthe United States {1162}. The incidenceof hydatidiform moles is greater inwomen older than 40 years {161} and isalso increased in those younger than 20years. Patients who have had prior GTDare more at risk of having a second GTDafter subsequent pregnancies. Other riskfactors include: a diet low in vitamin A,lower socioeconomic status and bloodgroup A women married to group 0 men{161,162,244,363}.

AetiologyHydatiform moles arise from abnormalconceptions. Partial moles result fromdiandric triploidy, whereas completemoles result from diandry (fertilization ofan empty ovum). Up to 50% of chorio-carcinomas and 15% of placental sitet rophoblastic tumours follow completemoles.

Clinical featuresSigns and symptomsA complete molar pregnancy usuallyp resents with first trimester bleeding, auterus larger than expected for gestation-al age and the absence of fetal parts onultrasound in association with a markedlyelevated beta-human chorionicg o n a d o t ropin (β-hCG) level {568}. Othersigns include hyperemesis, toxaemia dur-ing the first or second trimester, thecalutein cysts and hypert h y roidism. Patientswith partial molar gestations usually pre s-ent as spontaneous abortions, sometimeswith increased β-hCG levels. GTD shouldalways be considered when a patient hascontinued vaginal bleeding followingd e l i v e ry or abortion.

ImagingA characteristic pattern of multiple vesi-cles (snowstorm pattern) is commonlyseen with complete molar pregnancy.The diagnosis of partial molar pregnancyby ultrasonography is more difficult.

Tumour spread and stagingC h o r i o c a rcinoma spreads haematoge-nously and may involve the lung (57-80%), vagina (30%), pelvis (20%), brain(17%), and liver (10%) {168,243}. Sinceβ-hCG titres accurately reflect the clinicaldisease, histological verification is notrequired for diagnosis. Staging shouldbe based on history, clinical examinationand appropriate laboratory and radiolog-ical studies.Metastatic GTD is also categorized bythe WHO scoring system as low, medi-um, and high risk {51,2976}. The individ-ual scores for each prognostic factor areadded together to obtain a total score. Atotal prognostic score less than or equalto 4 is considered low risk, a total scoreof 5-7 is considered middle risk, and atotal score of 8 or greater is consideredhigh risk. (See TNM and FIGO classifica-tion of gestational trophoblastic tumoursat the beginning of the chapter).

Somatic geneticsOverexpression of TP53 protein may beassociated with more aggressive behav-iour in gestational trophoblastic disease

since it is more commonly observed incomplete moles and choriocarc i n o m a{937,1616,2307}, but TP53 mutations areuncommon {471}. Overexpression of thep21 gene has also been detected incomplete moles and choriocarc i n o m a{469}. No correlation between p21 andTP53 expression has been detected ingestational trophoblastic disease.Both complete mole and choriocarcino-ma exhibit overe x p ression of severalgrowth factors including c-Myc, epider-mal growth factors receptor (EGFR),c-erbB-2, Rb, mdm2, and bcl-2 as com-pared to normal placenta and partialmole {938,2966}. Expression of c-fmsprotein does not differ between normalplacenta and gestational trophoblasticdiseases {938}. In one study stro n gimmunostaining of c-erbB-3 and epider-mal growth factor receptor in extravilloustrophoblast of complete mole was signif-icantly correlated with the developmentof persistent gestational tro p h o b l a s t i ctumour {2966}. The molecular pathogen-esis of gestational trophoblastic diseasesmay involve these and potentially othergrowth-regulatory factors.

Prognosis and predictive factorsMajor adverse prognostic variables forGTD are:

(1) Age >39(2) Prior term pregnancy(3) Interval from antecedent

pregnancy of >12 months(4) β-hCG >105 IU/litre(5) Tumour mass >5cm(6) Disease in liver and brain (7) Failure of 2 or more prior

chemotherapiesThe above factors are included in aprognostic score (see the TNM and FIGOclassification of gestational trophoblastictumours at the beginning of the chapter).The patients are separated into low riskand high risk groups for different treat-ments {1123,3111}.The prognosis of patients with low riskdisease is very close to 100% survival,whilst patients with high risk diseasehave a survival of 85-95%, depending onthe number of patients with ultra highriskdisease in the patient population.

D.R. GenestR.S. BerkowitzR.A. FisherE.S. NewlandsM. Fehr

Gestational trophoblastic disease

Table 4.08The U.S. National Institutes of Health staging classi-fication for gestational trophoblastic disease (GTD).

I Benign GTDA. Complete hydatidiform moleB. Partial hydatidiform mole

II Malignant GTDA. Non-metastatic GTDB. Metastatic GTD

1. Good prognosis: absence of any risk factor

2. Poor prognosis: presence of any risk factor

a. Duration of GTD >4monthsb. Pre-therapy serum

β-hCG>40,000 mIU/mLc. Brain or liver metastasisd. GTD after term gestatione. Failed prior chemotherapy

for GTD

Trophoblastic tumours

DefinitionNeoplasms derived from trophoblast.

ICD-O codesChoriocarcinoma 9100/3Placental site trophoblastic tumour 9104/1Epithelioid trophoblastic tumour 9105/3

Gestational choriocarcinoma

DefinitionA malignant neoplasm composed oflarge sheets of biphasic, markedly atypi-cal trophoblast without chorionic villi.

Clinical featuresGestational choriocarcinoma may occursubsequent to a molar pregnancy (50%

of instances), an abortion (25%), a nor-mal gestation (22.5%) or an ectopicpregnancy (2.5%) {1203}. In rare cases an intraplacental choriocar-cinoma is diagnosed immediately follow-ing pregnancy from placental pathologi-cal examination {343,722,907,1923}.

HistopathologyChoriocarcinoma consists of an admix-t u re of syncytiotrophoblast, cytotro-phoblast and intermediate trophoblast assingle cells and clusters of cells withprominent haemorrhage, necrosis andvascular invasion {775a,1593,1801a,1802a,2011,2024a,2077a}. Choriocarc i -noma does not possess tumour stromaor vessels; correspondingly, the diagnos-tic viable tumour is located at the periph-ery of haemorrhagic foci.E x t r a o rd i n a r i l y, choriocarcinomas have

developed and been diagnosed asintraplacental tumours {112,343,722,907,1562,1923,2103}.

ImmunoprofileAll trophoblastic cell types are stronglyimmunoreactive for cytokeratins {640}. Inaddition, the syncytiotrophoblast isstrongly immunoreactive for β-hCG andweakly immunoreactive for human pla-cental lactogen (hPL); intermediate tro-phoblast shows the opposite immuno-profile {935}.

Differential diagnosisThe differential diagnosis of choriocarci-noma in endometrial curettings includesprevillous trophoblast from an early ges-tation, persistent molar tissue followingh y d a t i d i f o rm mole, placental site tro-phoblastic tumour, epithelioid tro-

BAFig. 4.46 A Gestational choriocarcinoma. Note the plexiform pattern with triphasic differentiation into cytotrophoblast, syncytiotrophoblast and intermediate tro-phoblast and marked cytological atypia. B Intraplacental choriocarcinoma. There is a distinct interface between malignant biphasic trophoblast in the maternalintervillous space seen on the lower right and mature chorionic villi on the left.

BAFig. 4.47 A Placental site trophoblastic tumour. Coronal section shows the neoplasm diffusely infiltrating the uterine wall. B Tumour cells show marked cytologicalatypia and numerous mitotic figures.

251Gestational trophoblastic disease


phoblastic tumour and undifferentiatedcarcinoma.

Somatic geneticsRecent studies using cDNA microarrayanalysis have demonstrated decreasedexpression of heat shock protein-27 inchoriocarcinoma, a finding which hasbeen associated with chemotherapyresponsiveness in other cancers {3014}.

Placental site trophoblastictumour

DefinitionA monophasic neoplasm composed ofi n t e rmediate trophoblast and cytotro-phoblast without a significant componentof syncytiotrophoblast.

HistopathologyThe tumour cells are medium to largesized and mononuclear or multinucleat-ed with mild to marked nuclear atypia,prominent nucleoli, eosinophilic to clearcytoplasm, scattered mitoses and occa-sional intranuclear inclusions {746,747,8 4 2 , 8 6 1 , 9 3 3 , 1 0 1 8 , 1 0 1 9 , 1 1 7 7 , 1 2 3 7 ,1 5 1 1 , 1 5 4 0 , 1 5 4 3 , 1 5 8 9 , 2 9 6 7 , 3 2 0 2 , 3 2 2 7 } .They permeate the myometrium and ves-sels in a manner reminiscent of theimplantation site trophoblast.

Differential diagnosisThe differential diagnosis of placentalsite trophoblastic tumour includes pla-cental site nodule, exaggerated implan-tation site, epithelioid leiomyosarcoma,epithelioid trophoblastic tumour andpoorly diff e rentiated carc i n o m a .Extensive sampling and immunohisto-

chemistry for keratin, β-hCG and hPL arehelpful in distinguishing among theabove lesions {2658,2659}.

Somatic geneticsA Y- c h romosomal locus and/or new(paternal) alleles not present in adjacentnormal uterine tissue was demonstratedin all cases of placental site trophoblastictumour studied confirming the placentalorigin of these neoplasms {2747}.

Prognosis and predictive factorsPlacental site trophoblastic tumours arerare, and their biological behaviour isvariable. The major prognostic variable isa long interval from the last knownantecedent pregnancy. All patient deathsfrom placental site trophoblastic tumourin the Charing Cross series occurredwhen the interval from the last knownpregnancy was greater than 4 years. Anelevated mitotic index predicts a pooroutcome {842}.

Epithelioid trophoblastic tumour

DefinitionA tumour composed of a monomorphicpopulation of intermediate trophoblasticcells closely resembling those of thechorion laeve (membranous chorion).

HistopathologyThe epithelioid trophoblastic tumour is arelatively uncommon, recently describedneoplasm that differs from the placentalsite trophoblastic tumour in that thetumour cells of the epithelioid tro-phoblastic tumour are smaller and lesspleomorphic and grow in a nodular as

opposed to a diffusely infiltrative pattern.Because they are frequently found in thecervix, they may be confused with hyalin-izing squamous cell carc i n o m a s .Epithelioid trophoblastic tumours arefocally immunoreactive for placental-likealkaline phosphatase (PLAP) and hPLbut strongly and diffusely immunoreac-tive for E-cadherin and epidermal growthfactor receptor {2658}.

Somatic geneticsA Y- c h romosomal locus and/or new( p a t e rnal) alleles not present in adjacentn o rmal uterine tissue was demonstratedin all cases of epithelioid tro p h o b l a s t i ctumour studied confirming the placentalorigin of this neoplasm {2747}.

Prognosis and predictive factorsBased on available data, the behaviour ofepithelioid trophoblastic tumour re s e m b l e sthat of placental site trophoblastic tumour.

Hydatidiform mole

DefinitionAn abnormal placenta with villoushydrops and variable degrees of tro-phoblastic proliferation.

ICD-O codesHydatidiform mole, NOS 9100/0

Complete 9100/0Partial 9103/0Invasive 9100/1

Complete hydatidiform mole

DefinitionA hydatidiform mole involving most of the

BAFig. 4.48 Epithelioid trophoblastic tumour. A Neoplastic aggregates are better defined than in placental site trophoblastic tumour and may resemble carcinoma.B Groups of tumour cells, occasionally with clear cytoplasm, are separated by a hyaline stroma.

253Gestational trophoblastic disease

chorionic villi and typically having adiploid karyotype.

HistopathologyThe villous hydrops of a complete moleis characterized by extensive cavita-tion. The trophoblastic proliferation dif-fers from normal villi by its circ u m f e re n-tial distribution, hyperplasia and cyto-logical atypia {978,1203}. Interm e d i a t et rophoblast of the molar implantationsite characteristically displays markedcytologic atypia {1901}. A gestationalsac, amnion, umbilical cord and fetaltissue are not found {481}. It has re c e n t-ly been suggested that villous stro m a lnuclear negative staining for the pater-nally imprinted gene product p57 maybe diagnostically useful for confirm i n gthe diagnosis of a complete mole {425}.The extent of trophoblastic atypia and

hyperplasia do not correlate with thebehaviour in complete mole {776,978}.In the past most complete hydatidiformmoles were diagnosed early in the sec-ond trimester at an average gestationalage of 14 weeks {1924}. Curre n t l y, withthe widespread use of routine ultra-sonography in pre g n a n c y, completemoles are diagnosed between 8 and 12weeks of gestational age {1924}. Molesdiagnosed at this "early" stage diff e rhistologically from moles diagnosed inthe second trimester {1426,1924}.Although villous cavitation may be min-imal in an "early" mole, other character-istic villous stromal features are pre s-ent, including hypercellularity and amyxoid basophilic stroma (re s e m b l i n gthat of a myxoid fibroadenoma). In addi-tion, unusual villous shapes with com-plex bulbous protrusions ("cauliflower-

like" villi) and trophoblastic atypia arep re s e n t .

Somatic geneticsComplete and partial molar pre g n a n-cies have distinctly diff e rent cytogenet-ic origins. Complete moles generallyhave a 46,XX karyotype, and the molarc h romosomes are completely of pater-nal origin {1385}. Most complete molesappear to arise from an anuclear emptyovum fertilized by a (23X) haploids p e rm that then replicates its own chro-mosomes {3172}. Whereas most com-plete moles have a 46,XX chro m o s o m a lp a t t e rn, about 10% of complete moleshave a 46,XY karyotype {2197}. The46,XY complete mole arises from fert i l-ization of an anuclear empty egg by twos p e rm. While all chromosomes in acomplete mole are entirely of patern a l

BAFig. 4.50 Invasive complete hydatidiform mole. A Sectioned surface shows dilated villi and invasion of the myometrium (arrowheads). B Note the molar villus (V)within a myometrial vein showing a fibroedematous core surrounded by hyperplastic trophoblastic proliferation (P).

BAFig. 4.49 A Classic complete hydatidiform mole. Note the dilated chorionic villi with the typical “bunch of grapes” appearance. B This molar villus is cavitated withcircumferential trophoblastic hyperplasia and atypia.


origin, the mitochondrial DNA is ofm a t e rnal origin {146}.

Partial hydatidiform mole

DefinitionA hydatidiform mole having two popula-tions of chorionic villi, one of normal sizeand the other hydropic, with focal tro-phoblastic proliferation. The lesion typi-cally has a triploid karyotype.

HistopathologyHistologically, partial moles are charac-terized by the concurrence of four fea-t u res {977,1319,1593,2170,2348,2365,2828,2829}: (1) Two populations of villi, one hydropicand one "normal"; (2) Minimal trophoblastic hyperplasiainvolving syncytiotrophoblast.(3) Enlarged cavitated villi.(4) Other villi with scalloped borders,often containing trophoblastic inclusions.S t romal blood vessels often containnucleated fetal red blood cells; other evi-dence suggesting fetal development iscommon, including portions of the chori-onic sac wall, amnion, umbilical cord andembryonic/fetal tissue. The diff e rential diagnosis of partial hyda-

t i d i f o rm mole includes:(1) Complete mole.(2) Hydropic abort u s .(3) Several rare sporadic genetic syn-d romes with focal placental hydrops anda fetus, such as the Beckwith-Weidemann syndrome {1558} and pla-cental angiomatous malformation {2522},which collectively have been termed "pla-cental mesenchymal dysplasia" {1337}.In instances in which the histologicaldiagnosis is uncertain, cytogenetic

analysis or flow cytometry may be ofassistance {549,882,933,1485,1557-1563,2170}.

Somatic geneticsIn contrast to complete moles, part i a lmoles generally have a triploid kary o t y p ethat results from fertilization of an appar-ently normal ovum by two sperm {2828}.The re p o rted incidence of triploidy in par-tial moles varies from 90-93% re s p e c t i v e l y{1560,1593}. When fetuses are identifiedwith partial moles, they usually have stig-mata of triploidy including multiple con-genital anomalies and growth re t a rd a t i o n .

Invasive hydatidiform mole

DefinitionInvasive hydatidiform mole is defined asvilli of hydatidiform mole within themyometrium or its vascular spaces.

HistopathologyMost invasive moles follow completehydatidiform mole and have the charac-teristic histological appearance of thatlesion. Rare examples of invasive partialmole have also been described {33,942,1065,2841,3131}. A hysterectomy isusually required for the histological diag-nosis.

Metastatic hydatidiform mole

DefinitionMetastatic hydatidiform mole is definedas extrauterine molar villi within bloodvessels or tissues, most commonly thevagina or the lung.

Non-neoplastic, non-molar trophoblastic lesions

Placental site nodule or plaque

The placental site nodule or plaque{1260,3203} is a well circumscribed lesionwith abundant hyalinized stroma infiltratedby scattered, degenerated-appearingi n t e rmediate trophoblastic cells; thesecells show no significant cytological atyp-ia, but rare mitoses may be present.

Exaggerated placental site

The exaggerated implantation site repre-sents a non-neoplastic exaggeration ofthe normal implantation process, usuallyfound concurrently with immature villi.

Fig. 4.52 “Early” complete mole. Some villi havetoe-like bulbous protrusions. Trophoblastic prolif-eration and cavitation are minimal. The stroma ishypercellular and myxoid.

Fig. 4.53 Partial hydatidiform mole. There are twopopulations of villi; the larger is markedly irregularwith scattered cavitation, numerous trophoblasticinclusions and minimal hyperplasia.

Fig. 4.55 Placental site nodule. Note the well cir-cumscribed eosinophilic endomyometrial nodules.

Fig. 4.54 Markedly atypical implantation site tro-phoblast in a case of early hydatidiform mole.

Fig. 4.51 MRI of hydatidiform mole adjacent to anormal fetus in a twin pregnancy.

Sex cord-like tumours

DefinitionTumours of the uterine corpus that close-ly resemble some true ovarian sex cordtumours.

EpidemiologyAmong these rare tumours the mostnumerous are the sex cord-like tumours{511}, which closely resemble some trueovarian sex cord tumours.

HistopathologyThese are diagnosed only when they arenot found within otherwise classicalendometrial stromal or smooth muscletumours. Histologically, sex cord ele-ments are represented by trabecular rib-bons and nodules or isolated cells withluteinized or foamy cytoplasm that arehistologically and immunohistochemical-ly identical to ovarian steroid-producingcells, being strongly positive for alpha-inhibin, calretinin and CD99 {167,1521,1808}. They may be capable of hor-m o n e - s e c reting activity {2034}. Theyhave a prominent epithelial componentthat can be tubular, retiform {3247} orglomeruloid. They also show frequentpositivity for cytokeratins, vimentin,smooth muscle actin and, occasionally,epithelial membrane antigen (EMA){930}.

Neuroectodermal tumours

DefinitionA variety of tumours of the uterine corpusthat show neuro e c t o d e rmal diff e re n t i a t i o n .

EpidemiologyD i ff e rent types of neuro e c t o d e rm a ltumours are found in the uterus. Whenp u re, they usually present in youngpatients {1188}; however, when mixedwith carcinoma or carc i n o s a rcoma theya re usually found in older women {638,931,2710}. Recently, peripheral primi-tive neuro e c t o d e rmal tumour/Ewingtumour has been re p o rted in both young{1597} and postmenopausal patients{ 2 7 1 0 } .

HistopathologyWell diff e rentiated variants with anappearance similar to low grade astrocy-toma {3201} should be diff e re n t i a t e dfrom non-neoplastic fetal parts implantedin the endometrium following abortion.Most often, the tumour cells differentiateinto neuroblastic, neuroepithelial, glialand neuronal elements {1188}.Peripheral primitive neuro e c t o d e rm a ltumour/Ewing tumour shows a character-istic immunophenotype positive for neu-ron-specific enolase, vimentin and CD99as well as the presence of EWS/FLI-1fusion transcripts.

Prognosis and predictive factorsAll neuroectodermal tumours except thewell diff e rentiated astrocytic form sbehave in a highly malignant fashion.

Melanotic paraganglioma

DefinitionA tumour morphologically identical toparaganglioma, but functionally produc-ing mainly melanin pigment instead ofneuroendocrine granules.

EpidemiologyOnly two examples of melanotic para-ganglioma have been described in theuterus in women 31 and 46 years of age{2866}.

MacroscopyBoth were incidental findings in uteriremoved for unrelated benign lesions.The larger lesion was 1.5 cm andappeared as a black pigmented lesionon macroscopic examination; the otherwas a histological finding.

HistopathologyBoth lesions were well circ u m s c r i b e dand composed of large nests of round orangulated polygonal cells with abundantclear or granular pale eosinophilic cyto-plasm. Both cases had psammoma bod-ies, and large amounts of coarse melanin

F. NogalesF.A. TavassoliSex cord-like, neuroectodermal and

neuroendocrine tumours, lymphomasand leukaemias

BAFig. 4.56 Sex cord-like tumour. A Trabecular pattern is prominent. B The neoplasm shows a cord-like pattern.

255Sex cord-like, neuroectodermal and neuroendocrine tumours, lymphomas and leukaemias


granules were present in many cells. Thelarge cells do not stain with S-100 pro-tein. At the ultrastructural level intracellu -lar melanosomes and premelanosomesabound, and a few neuroendocrine gran-ules are present; the cells lack microvillior dendritic processes.

Prognosis and predictive factorsBoth women were free of any recur-

rences at 2.2 and 3.2 years after the dis-covery of the tumour {2866}.

Lymphomas and leukaemias

DefinitionA malignant lymphoproliferative orhaematopoetic neoplasm that may beprimary or secondary.

Clinical findingsThe patients typically present with vagi-nal bleeding {2354}.

Tumour spread and stagingMost lymphomas and leukaemias thatinvolve the uterine corpus are a manifes-tation of disseminated disease. On rareoccasions the corpus is the first knownsite of a malignant lymphoma.

HistopathologyThe majority of cases are of the large B celltype {114}. Lymphomas of the uterine cor-pus must be distinguished from an atypicallymphoma-like inflammatory lesion of theendometrium. The latter is characterizedby a massive infiltrate of lymphoid cells,some of which are immature. The pre s e n c eof other inflammatory cells including plas-ma cells and neutrophils within the infiltrateand the typical absence of myometrialinvasion or a macroscopic mass are help-ful in the diff e rential diagnosis {851}. Casesof uterine leiomyoma massively infiltratedby lymphocytes may also mimic a lym-phoma {488}.

Rare tumours

DefinitionA variety of benign or malignant tumoursof the uterine corpus that are not other-wise categorized.

HistopathologyGerm cell tumours such as teratomasand yolk sac tumours can develop in theendometrium, either in a pure form {398,2196,2763,2836} or associated withendometrioid tumours {103,2665}.Extrarenal Wilms tumours (nephroblas-tomas) have also been reported in theuterus {1783,1934}. Their histologicalappearance is similar to that of thetumours occurring in other sites.

BAFig. 4.57 Sex cord-like tumour. A Several nodules composed of luteinized cells with ample eosinophilic to vacuolated cytoplasm are present. B The nodule of luteinized cells stains positively for alpha-inhibin.

BAFig. 4.58 Melanotic paraganglioma. A Note the nests of polyhedral cells with abundant clear cytoplasm. B Tumour cells have uniform nuclei and contain coarse melanin pigment.

DefinitionTumours of the uterine corpus that origi-nate from, but are discontinuous with, aprimary extrauterine tumour or a tumourin the cervix or elsewhere in the uterus.

Clinical features Signs and symptomsThe mean age of patients with extragen-ital tumour metastasis to the uterus is 60years. Patients have abnormal uterinebleeding since most neoplasms metasta-tic to the uterus infiltrate the endometriumdiffusely.

ImagingImaging studies are non-specific {1240,1282,1576,3184}.

MacroscopyMetastases may appear as solitary ormultiple tumours or be diffusely infiltrating.

HistopathologyThe majority of metastases to the uterusa re confined to the myometrium.However, approximately one-third involvethe endometrium and thus can bedetected in biopsy specimens {1529}.Metastatic carcinoma within theendometrium and/or myometrium char-acteristically infiltrates as single cells,cord or glands. The appearance is par-

ticularly striking in lobular carcinoma ofthe breast, which usually retains its sin-gle-file pattern, and with metastaticsignet-ring cell carcinoma of the stom-ach or colon. Metastatic colon carcinomaof the usual type may form large tumourmasses and can mimic an endometrialcarcinoma of mucinous or endometrioidtype.Metastatic carcinoma in the endometri-um should be suspected if one or moreof the following features are pre s e n t{1539}. (1) A tumour with an unusual macroscop-ic or histological pattern for primaryendometrial carcinoma.(2) Diffuse replacement by tumour ofendometrial stroma with sparing of occa-sional normal endometrial glands.(3) Lack of premalignant changes inendometrial glands.(4) Lack of tumour necrosis For specific identification of certain pri-m a ry tumours immunohistochemicalstudies are frequently required.

Origin and histogenesisIn most instances the primary tumour iswell known, or disseminated disease isclinical evident. Occasionally, a tumourdiagnosed by curettage or hysterectomyrepresents the first sign of an extrauter-ine primary tumour.

Secondary tumours of the uterine corpuscan be divided into two major groups:tumours of the genital and extragenitalorgans. Neoplasms of neighbouringorgans such as cervix, fallopian tubes,ovaries, bladder and rectum can metas-tasize to the uterine corpus via lymphat-ics or blood vessels but mostly representlocal direct extension.Haematogenous or lymphatic uterinemetastases from any extragenital pri-mary tumour may occur but are extreme-ly rare. Reported primary tumoursinclude carcinomas of the breast, stom-ach, colon, pancreas, gallbladder, lung,u r i n a ry bladder and thyroid andmelanoma {192,1452,1455,1529,1531,1620,1720}. Mammary lobular carcino-ma, gastric signet-ring cell carcinomaand colonic carcinoma are the most fre-quently re p o rted extragenital primarytumours {1529,1531}.

Prognosis and predictive factorsWhen uterine metastases are present,the patient usually has widely dissemi-nated disease. However, in one seriesthe average survival was 20 months afterthe diagnosis of uterine metastases. Thereason for this relatively favourable out-come might be the predominance ofcases of metastatic breast carcinoma{1529}.

V. AbelerU. HallerSecondary tumours of the uterine

corpus

Fig. 4.60 Metastatic melanoma to the endometrium.Tumour cells containing melanin pigment surroundan atrophic endometrial gland.

BAFig. 4.59 Metastatic colon carcinoma to the myometrium. A Note the tumour cells in lymphatic vessels in theright upper portion of the field with a plexiform pattern on the left. B The neoplastic glands are positive for cytok-eratin 20.

257Secondary tumours of the uterine corpus

chapter 4 · endometrial stromal sarcoma, low grade 8931/3 ... endometrial carcinoma definition a...

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