The Pathology Of Endometriosis

The Pathology of EndometriosisA Survey of the Many Faces of a Common Disease EmphasizingDiagnostic Pitfalls and Unusual and Newly Appreciated Aspects

Philip B. Clement, MD

Abstract: Although the histologic diagnosis of endometriosis is

usually straightforward, many diagnostic problems can arise as

a result of alterations or absence of its glandular or stromal

components. The diagnostic difficulty in such cases can be

compounded by tissue that is limited to a small biopsy specimen.

The appearance of the glandular component can be altered by

hormonal and metaplastic changes, as well as cytologic atypia

and hyperplasia. Although the last 2 findings are often referred

to collectively as ‘‘atypical endometriosis,’’ they should be

separately recognized as their premalignant potential likely

differs. In some cases, the endometriotic glands are sparse or

even absent (stromal endometriosis). The stromal component

can be obscured or effaced by infiltrates of foamy and pigmented

histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myx-

oid change, and decidual change. Occasional findings in

endometriosis that may raise concern for a neoplasm include

necrotic pseudoxanthomatous nodules, polypoid growth (poly-

poid endometriosis), bulky disease, and venous, lymphatic, or

perineural invasion. Inflammatory and reactive changes within,

adjacent to, or at a distance from foci of endometriosis can

complicate the histologic findings and include infection within

endometriotic cysts, pseudoxanthomatous salpingitis, florid

mesothelial hyperplasia, peritoneal inclusion cysts, and Liese-

gang rings. The histologic diagnosis of endometriosis can also be

challenging when it involves an unusual or unexpected site. Five

such site-specific problematic areas considered are endometriosis

on or near the ovarian surface, superficial cervical endome-

triosis, vaginal endometriosis, tubal endometriosis, and intest-

inal endometriosis, including the important distinction of an

endometrioid carcinoma arising from colonic endometriosis

from a primary colonic adenocarcinoma. Finally, endometriotic

foci can occasionally be intimately admixed with another

process, such as peritoneal leiomyomatosis or gliomatosis,

resulting in a potentially confusing histologic appearance.

Key Words: endometriosis, pathologic diagnosis, precancerous

changes, endometriosis-associated neoplasms

(Adv Anat Pathol 2007;14:241–260)

Our knowledge of the pathology and pathogenesis ofendometriosis largely stems from the work of Dr

John Albertson Sampson (1873 to 1946), the ‘‘Father ofEndometriosis.’’ In a contribution to the History Series inthe International Journal of Gynecological Pathology,1 Irecounted in some detail Sampson’s remarkable careerand seminal contributions. That article was preceded by 2others2,3 in which I reviewed the extensive post-Sampsonliterature pertaining to the macroscopic and histologicfeatures of endometriosis in pelvic and extrapelvic sites.One of those reviews appeared 17 years ago in a sourcethat is not always readily available2 and the other waswritten 7 years ago.3 Acccordingly, the current review isan update to those studies, but with a focus on diagnosticproblems and unusual morphologic features of pelvicendometriosis, some of which can lead to under-diagnosisor misdiagnosis, even as a malignant tumor (Table 1).Endometriosis-associated neoplasms, which have beenthe subject of 2 recent large series4,5 and 2 oldercomprehensive reviews,6,7 will be touched upon onlybriefly, mainly with regard to precancerous changes andrecent observations regarding origin of endometrioidcarcinomas from vaginal and intestinal endometriosis.

The pathologic diagnosis of endometriosis is notonly of obvious importance to the patient, but itsrecognition can also be of great help to the pathologistin accounting for synchronous findings that mightotherwise be problematic. For example, the intimateassociation of endometriosis with an ovarian or extra-ovarian neoplasm can suggest that the tumor is likelyprimary rather than metastatic from a known or an occultprimary tumor elsewhere. The presence of endometriosiscan also explain other potentially confusing or worrisomefindings such as florid mesothelial hyperplasia, pseudox-anthomatous salpingitis, and necrotic pseudoxanthoma-tous nodules (NPNs), lesions that will be discussed laterin more detail.

TYPICAL ENDOMETRIOSISA definitive diagnosis of endometriosis continues to

be based on histologic examination. One study8 foundthat only 50% of laparoscopic biopsy specimens fromareas suspicious for endometriosis were proven micro-scopically to be endometriosis. The histologic diagnosis ofendometriosis is usually straightforward and is based onthe typical presence of both endometriotic glands andCopyright r 2007 by Lippincott Williams & Wilkins

From the Department of Pathology, Vancouver General Hospital,Vancouver, BC, Canada.

Reprints: Philip B. Clement, MD, Department of Pathology, VancouverGeneral Hospital, 910 W. 10th Avenue, Vancouver, BC, CanadaV5Z 4E3 (e-mail: [email protected]).

REVIEW ARTICLE

Adv Anat Pathol � Volume 14, Number 4, July 2007 241

stroma, although as will be noted, the diagnosis can bemade when only one of these components is present. Theglands almost always have an overtly endometrioidappearance (Figs. 1A, B) that may range from inactiveto proliferative (or occasionally, secretory) to hyperplas-tic. The glandular cells may be ciliated, exemplifying theclose relationship of tubal-type and endometrioid epithe-lium in the female genital tract in both non-neoplastic andneoplastic states. The appearance of the glands mayreflect that of the eutopic endometrium, but often only toa limited degree.9–11 The lipofuscin and hemosiderinpigment frequently present within histiocytes in endome-triosis (as discussed below) can occasionally also be foundwithin the endometriotic epithelial cells.

The endometriotic stroma typically resembles, atleast focally, eutopic inactive or proliferative endometrialstroma, including the presence of a network of smallarterioles (Figs. 1A, B). The presence of these vessels,which may be engorged with erythrocytes, may provide ahelpful initial clue to the endometriotic nature of thelesion. In some cases, vessels are not conspicuous butfocal stromal hemorrhage can be similarly diagnosticallyhelpful. Metzger et al10 found recent hemorrhage within53% of implants with stroma but in only 15% of thosewith little or no stroma. Although hemorrhage in somespecimens might be related to the trauma of the biopsy,two-thirds of the biopsy specimens with hemorrhage inthe cited study10 also contained pigmented histiocytes, thecharacteristic inflammatory cell of endometriosis, asdiscussed below.

Like normal and neoplastic endometrial stromalcells, endometriotic stromal cells are typically immuno-reactive for CD10 (Fig. 1C).12–14 CD10-positivity canhelp confirm the endometriotic nature of stromal cells inproblematic situations such as when dealing with limitedmaterial (as in a tiny laparoscopic biopsy specimen), whenthe stromal cells on routinely stained sections are ofuncertain nature, or when the glandular component isabsent, as discussed below. The role of CD10 staining inthe diagnosis of superficial ovarian and cervical endome-triosis is discussed under the heading of ‘‘Selected Site-related Issues.’’

DIAGNOSTIC ISSUES RELATED TO THESTROMAL COMPONENT

Alterations in the typical microscopic appearance ofendometriosis that can cause diagnostic problems for thepathologist occur in both its glandular and stromalcomponents, but are more common in the latter and areaccordingly considered first. Although these changes canobscure the typical stromal component, their presenceshould increase one’s diagnostic suspicion of the endome-triotic nature of the lesion. In such cases, endometrioticstroma, if present at all, may be very subtle and confinedto a barely perceptible and often discontinuous zone thatis periglandular or that subtends the epithelial lining of anendometriotic cyst. In the latter instance, if the epithelialcells are denuded, the stromal cells may directly abut thecyst lumen. If the nature of the stromal cells is in doubt,immunostaining for CD10, as noted earlier, can behelpful.

TABLE 1. Findings in Endometriosis That can be AssociatedWith Diagnostic Problems

Alterations of the Stromal ComponentFoamy and pigmented histiocytesFibrosisElastosisSmooth muscle metaplasiaMyxoid changeDecidual change, including signet-ring–like cells

Alterations of the Glandular ComponentPostmenopausal and treatment-related changesPregnancy-related changesMetaplastic changesCytologic atypiaHyperplasiaAbsence of glands (stromal endometriosis)

Miscellaneous Tumorlike FindingsNecrotic pseudoxanthomatous nodulesPolypoid endometriosisVacular invasionPerineural invasion

Unusual Inflammatory and Reactive ChangesInfected endometriotic cystsPseudoxanthomatous salpingitisFlorid mesothelial hyperplasiaMPICsLiesegang rings

Site-Related Diagnostic ProblemsEndometriosis on or close to the ovarian surfaceSuperficial endometriosis of the uterine cervixVaginal endometriosisTubal endometriosisIntestinal endometriosis

Rare Associated LesionsPeritoneal leiomyomatosisPeritoneal gliomatosis

FIGURE 1. A, Typical endometriosis showing part of an endometriotic gland and a thin cuff of periglandular endometrioticstroma containing dilated blood vessels. B, Endometriotic gland with only focal periglandular endometriotic stroma (extreme leftof field). The remaining stroma is edematous and has a nonspecific appearance. C, Typical endometriosis. The periglandularendometriotic stroma shows immunoreactivity for CD10. D, Ovarian endometriosis. The endometriotic stroma is replaced byfoamy histiocytes (pseudoxanthoma cells), which also occupy gland lumens. Residual ovarian stroma is present at the top right.E, Endometriotic cyst. The endometriotic stroma has been replaced by pseudoxanthoma cells. F, Endometriotic cyst withnumerous pigmented histiocytes within the endometriotic stroma. G, Presumptive endometriosis. An ovarian cyst is linedby pigmented histiocytes and fibrous tissue without any diagnostic endometriotic epithelium or endometriotic stroma.H, Pseudoxanthoma cells infiltrating omental fat in a patient with pelvic endometriosis.

Clement Adv Anat Pathol � Volume 14, Number 4, July 2007

242 r 2007 Lippincott Williams & Wilkins

Adv Anat Pathol � Volume 14, Number 4, July 2007 The Pathology of Endometriosis

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Foamy and Pigmented HistiocytesHemorrhage and menstrual changes in endometrio-

sis often elicit an infiltrate of histiocytes that can obscurethe characteristic features of the stroma (Figs. 1D to G).The histiocytes typically have abundant cytoplasm thatvaries in appearance depending, at least in part, on theage of the lesion. In early lesions, which tend to benonpigmented at laparoscopy or laparotomy,15 thehistocytes are nonpigmented and have granular, eosino-philic or foamy cytoplasm, the latter due to abundantlipid or glycolipid (‘‘pseudoxanthoma cells’’), some ofwhich likely represents ceroid precursors (Figs. 1D,E).16–18 In contrast, the characteristic pigmented histio-cytes of endometriosis are common in well-developedlesions (Figs. 1F, G). Much of the pigment is ceroid orlipofuscin that appears as fine, grayish-brown cytoplas-mic granules on routinely stained sections and that stainswith the periodic acid-Schiff (PAS) method after diastasepredigestion. When collections of ceroid-rich histiocytesassociated with endometriosis (or other lesions) are wellcircumscribed, the term ‘‘ceroid granuloma’’ has some-times been applied.19 Hemosiderin is also typicallypresent but is often less conspicuous than the lipofuscinpigment and in contrast to the latter appears as coarse,irregular, golden-brown cytoplasmic granules that stainwith the Prussian blue method. Occasionally, the histio-cytic infiltrate is massive (‘‘xanthomatous endometrio-sis’’) and can extensively or completely replace theendometriotic stroma and fill the gland lumens (Figs.1D, E). The presence of endometriotic glands allows for adiagnosis of endometriosis when the endometrioticstroma has been effaced, but when both the endometrioticglands and stroma are obliterated by the histiocytes (oftenaccompanied by fibrosis, as noted below), only adiagnosis of presumptive endometriosis is possible (Fig.1G). Rarely, the lipid within endometriotic lesions can beconverted to cholesterol crystals that may evoke aforeign-body giant-cell reaction. When this finding isstriking, the term ‘‘cholesteatomatous endometriosis’’ isappropriate.

In some cases of endometriosis, pseudoxanthomacells are found at a distance from the endometriotic foci,such as within the mucosa of the fallopian tube (seePseudoxanthomatous Salpingitis), the pelvic peritoneum,pelvic lymph nodes, and omentum (Fig. 1H).18

Fibrosis and ElastosisEndometriotic lesions often elicit a fibrotic reaction

that can lead to adhesions around the focus and focal toextensive replacement of the endometriotic stroma,especially within the walls of endometriotic cysts(Figs. 2A, B). The fibroblasts within the fibrotic areasare characteristically small and stellate (Fig. 2A). Long-standing cysts may have walls composed predominantlyor entirely of hyalinized fibrous tissue (Fig. 2B); rarelyfoci of dystrophic calcification and/or heterotopic boneare present in such cases.

A less common stromal response in endometriosis iselastosis, which can sometimes be striking, resulting infocal or extensive replacement of the typical endometrio-tic stroma (Figs. 2C, D).20 In some cases, circumscribedfoci of elastosis vaguely resemble a corpus albicans.Stromal elastosis can be a helpful diagnostic clue to thediagnosis of endometriosis, especially when accompaniedby characteristic endometriotic glands. Although weinitially believed that stromal elastosis in endometriosiswas a new observation, while our report on this findingwas in press, we found that Robert Meyer had madethe same observation over 70 years earlier. In an articlepublished in 1928, Jacobsen21 refers to one of Meyer’sstudies (unfortunately the exact citation is not given) bystating ‘‘Meyer ylays much stress on his own observa-tion that elastic tissue is not found in the uterine mucosa,but is present in ectopic endometrium-like tissue.’’

Smooth Muscle MetaplasiaThe stromal component of endometriosis can be

focally or extensively replaced by smooth muscle, afinding consistent with the myofibroblastic poten-tial of endometrial and endometriotic stromal cells(Fig. 2E).22,23 Smooth muscle metaplasia is most commonwithin ovarian endometriosis, being documented in 18%of cases in one study.22 In over half the cases in thatstudy, the smooth muscle was within the wall of anendometriotic cyst. When smooth muscle is prominent,the process has been referred to as ‘‘endomyometriosis.’’Striking examples of the latter have taken the form ofuteruslike masses in the ovary,24,25 broad ligament,26 anda pelvic lymph node.27 Some uteruslike masses, however,especially if associated with congenital malformations ofthe genitourinary tract, may represent a congenital

FIGURE 2. A, Endometriotic cyst with fibrosis. Beneath the endometriotic epithelium (top right) is a thin zone of endometrioticstroma with foci of hemorrhage. The cyst wall is composed of loose fibrous tissue composed of small fibroblasts separated bycollagen. B, Endometriotic cyst (lumen at top of figure) with its wall composed of hyalinized fibrous tissue. Pseudoxanthoma cellsfocally line the cyst, which has lost its epithelial lining. C, Endometriosis with prominent stromal elastosis. The brightly eosinophilicelastotic tissue surrounds an endometriotic gland. No residual endometriotic stroma is present. D, Endometriosis with prominentstromal elastosis, elastic tissue stain. E, Endometriosis with prominent smooth muscle metaplasia. At the extreme left is part of anendometriotic gland with periglandular endometriotic stroma that merges with mature smooth muscle. F, Endometriosis withprominent myxoid change. A typical endometriotic gland with periglandular stroma (left) lies adjacent to a large pool of acellularmucin (right). This peritoneal lesion, which was found in a patient undergoing radial hysterectomy for adenocarcinoma of thecervix, was misinterpreted on frozen section examination as metastatic mucinous adenocarcinoma. G, Endometriosis inpregnancy with prominent decidual change. An atrophic endometriotic gland is lined by flattened epithelium, a finding that canbe mistaken for a vascular space. H, Endometriosis in pregnancy. Basophilic myxoid stroma separates the decidual cells. Note thecytoplasmic vacuoles within the decidual cells.



mullerian-duct anomaly rather than a variant of endo-metriosis.25,28

Smooth muscle metaplasia in endometriosis shouldbe distinguished from the much more common finding ofendometriosis involving indigenous smooth muscle, suchas the pelvic ligaments and the walls of the bowel andbladder. In such cases, the endometriosis often stimulatesthe indigenous smooth muscle to proliferate, analogous tomyometrial smooth muscle proliferation around foci ofadenomyosis. The reactive smooth muscle proliferation inthese situations often accounts for the bulk of the lesion,and if endometriosis is not identified in the initial slides,the findings may be suspicious enough for the diagnosis toprompt additional sampling.

Myxoid ChangeIn occasional cases, endometriotic stroma under-

goes striking myxoid change in which endometrioticstromal cells are separated by scanty to abundantacellular mucin; in the latter situation, pools of acellularmucin may be seen (Figs. 2F, H).29–34 The mucin in thesecases is stromal rather than epithelial mucin, and thusstains positively for toluidine blue or Alcian blue (pH 2.5)but not with PAS. Five of the 6 reported cases of myxoidchange in endometriosis have involved the skin orsuperficial soft tissues and 4 of the 6 cases occurredduring pregnancy or the puerperium, suggesting that thelocation of the lesion and the hormonal milieu may bepredisposing factors. In 2 cases, the histologic appearancesuggested the possibility of metastatic adenocarcinomaand/or pseudomyxoma peritonei,30,31 and in another case,a diagnosis of a myxoid sarcoma of soft tissue wasinitially considered.33 In the 3 patients who were pregnantat the time of the removal of the lesion, the histologicinterpretation of the specimen was further complicated bythe presence of a striking decidual transformation of theendometriotic stroma (see below) (Fig. 2H). The correctdiagnosis is facilitated by awareness of these findings andthe presence of at least occasional endometriotic glands,although these may be atrophic if the patient is pregnant,as noted below.

Decidual ChangeThe endometriotic stroma usually exhibits striking

progestational changes during pregnancy (Figs. 2G, H);similar but usually less striking changes can be seen

secondary to progestin treatment (Fig. 3A). In pregnancy,microscopic examination typically reveals a decidualreaction similar to that seen in the eutopic endometrium;the endometriotic glands are usually atrophic, as notedbelow (Fig. 2G). Necrosis of the decidual cells, stromalmyxoid change (as noted above) (Fig. 2H) or edema, andinfiltration by lymphocytes may also be seen. Addition-ally, the decidual cells in endometriosis can, like theireutopic counterparts, exhibit cytoplasmic vacuoles withdisplacement of the nucleus, resulting in a signet-ring–likeappearance (Fig. 2H).29,33 Cells of the latter type can raisea differential diagnosis with a metastatic signet-ring-celladenocarcinoma, but the merging of such cells withtypical decidual cells, the presence of acid rather thanneutral mucin in the vacuoles, and the cytokeratin-negativity of the cells facilitate the correct diagnosis.

DIAGNOSTIC ISSUES RELATED TO THEGLANDULAR COMPONENT

Postmenopausal and Treatment-relatedChanges

Diagnosing endometriosis in postmenopausal wo-men can be more difficult than in those of reproductiveage because the endometriotic tissue is often atrophic.Inactive or atrophic glandular changes in endometriosiscan also occur in premenopausal patients treated withoral contraceptives, danazol, antiprogesterone steroids(gestrinone), and progestins (Fig. 3A).35,36 In atrophicendometriosis, the endometriotic glands may be small orcystically dilated and are lined by flattened epithelial cells,with an appearance that may be similar to simple or cysticatrophy of the eutopic endometrium (Fig. 3B). Theatrophic glands may be surrounded by stroma that isoften more fibrotic (Fig. 3B) than in younger patients,although a thin cuff of typical endometriotic stroma willusually be visible around some of the glands. Immunos-taining for CD10 can be helpful in establishing thepresence of endometriotic stroma in such cases.

In some postmenopausal women, endometriosisremains clinically active. In such cases, Toki et al37 foundthat the endometriotic lesions may have a more activehistologic appearance than the eutopic endometrium, andalso more progesterone receptors and higher Ki-67activity in the endometriotic stromal cells as comparedwith the eutopic endometrial stromal cells.

FIGURE 3. A, Endometriosis in a patient treated with progestational agents. The endometriotic stromal cells are partlydecidualized and surround an atrophic gland. B, Endometriosis in a postmenopausal patient showing cystic atrophy of the glandsand fibrosis of the stroma. C, Endometriosis showing Arias-Stella reaction within the endometriotic glands in a pregnant patient.D, Endometriosis with prominent mucinous metaplasia of a large irregular endometriotic gland. E, Endometriotic cyst withatypical clear cell metaplasia of the lining epithelial cells. Most of the cyst was lined by this type of epithelium, which merged witha clear cell carcinoma (not shown). F, Endometriotic cyst with prominent cytologic atypia of the lining epithelial cells. Noteprominent neutrophilic infiltrate. G, A patient, who had been on unopposed estrogen replacement therapy for 10 years followinga hysterectomy and salpingo-oophorectomy for endometriosis, presented with a pelvic mass. The mass was composed of typicalendometriosis with foci of atypical complex endometrial hyperplasia (left) that merged with grade 1 endometrioidadenocarcinoma (right). Also see (H). H, Higher-power views of the atypical hyperplasia (left) and the grade 1 endometrioidadenocarcinoma (right) depicted in (G).



Pregnancy-related ChangesIn pregnancy, endometriotic glands usually have an

inactive appearance. They vary from small to large andcystic and are usually lined by cuboidal or flattenedepithelial cells (Fig. 2G). We have seen cases ofendometriosis in pregnant women in which the diagnosiswas missed on microscopic examination because theflattened epithelial cells were mistaken for endothelial ormesothelial cells, resulting in a diagnosis of ectopicdecidua rather than endometriosis. Occasionally, endo-metriotic glands in women with an intrauterine or ectopicpregnancy exhibit overt secretory changes that mayinclude the Arias-Stella reaction38,39 (Fig. 3C) and/oroptically clear nuclei40 similar to these pregnancy-relatedfindings in eutopic endometrial glands.

Metaplastic ChangesMetaplastic changes similar to those occurring in

eutopic endometrial glands are common in endometrioticepithelium.41,42 They were found in 68% of cases ofovarian endometriosis in one study41 but in only 12% ofcases in another study,42 and include ciliated, eosinophi-lic, hobnail, squamous, and mucinous metaplasia (Fig.3D); the last type may be composed of endocervical-typecells or, less often, goblet cells. Additionally, we have seenseveral cases of clear cell and atypical clear cell metaplasiain endometriotic cysts (Fig. 3E); in one such case, atypicalclear cells lining an endometriotic cyst merged with a clearcell carcinoma. In one of the studies of metaplasia inovarian endometriosis cited above,41 17% of the endome-triotic cysts harbored a neoplasm, all of which hadassociated epithelial metaplasia within the cyst, whereasonly 63% of the cysts without a neoplasm showedmetaplasia. Furthermore, all 4 cases of endocervical-likemucinous borderline tumors (EMBTs) encountered in thesame study were contiguous with foci of hyperplasticmucinous epithelium. The distinction between papillarymucinous metaplasia and an early EMBT in an endome-triotic cyst can be difficult and subjective, and is a notinfrequent issue in our referral material. When there isdefinite endometriotic stroma beneath the mucinousproliferation, we consider it metaplastic endometriosisunless there are well-developed papillae.

Atypical EndometriosisA number of studies have found associated en-

dometriosis in a sizable minority (20% to 30%) of all

histologic types of ovarian epithelial tumors, and in ahigh proportion of ovarian clear cell carcinomas (40% to70% of cases) and endometrioid carcinomas (30% to40% of cases).43–46 A more specific association has beenfound between ‘‘atypical endometriosis’’ and synchro-nous ovarian cancers. Of the ovarian cancers studied byOgawa et al,45 29% had associated endometriosis, and itwas atypical in 78% of them. Similarly, Fukunaga et al44

found atypical endometriosis in approximately 60% ofcases of endometriosis-associated carcinoma, whereas itwas present in only 1.7% of cases of ovarian endome-triosis not associated with an ovarian carcinoma.

The term ‘‘atypical endometriosis’’ has been used inthe literature to refer to 2 different histologic find-ings.44,45,47–52 One of them, referred to here as ‘‘cytologicatypia,’’ denotes the presence of cytologic atypia withinthe lining of endometriotic cysts, whereas the other,referred to here as ‘‘hyperplasia,’’ refers to the samespectrum of hyperplasia (simple or complex, with orwithout cytologic atypia) encountered in the endome-trium.53 Most studies have used ‘‘atypical endometriosis’’to refer collectively to both cytologic atypia andhyperplasia, but an attempt should be made to distinguishbetween them because they almost certainly differ in theirclinical significance,53 and each is considered hereseparately.

Cytologic AtypiaCytologic atypia, especially mild to moderate

atypia, within endometriotic cysts is a common find-ing.51,53–56 Its reported frequency obviously depends onone’s diagnostic threshold for this diagnosis. Czerno-bilsky and Morris55 found mild atypia in 22% of theircases of ovarian endometriosis, whereas severe atypia waspresent in only 3.6% of cases. The correspondingfrequency from another study in which the atypia wasnot graded was 12%.57

Atypia, when present, is almost always found in anendometriotic cyst, and is usually a focal or multifocalfinding in which the epithelial cells lining the cyst areenlarged and polygonal with scanty to more commonlyabundant, dense eosinophilic cytoplasm (Fig. 3F). Thereis usually no associated endometriotic glandular compo-nent. The nuclei of the atypical cells exhibit markedvariation in size and shape and are variably hyperchro-matic, often with smudged chromatin; nucleoi may beprominent (Fig. 3F). Hobnail-type cells are sometimes

FIGURE 4. A, Micronodular stromal endometriosis. Two nests of endometriotic stromal cells are present on the peritoneal surface.B, Micronodular stromal endometriosis. Two nodules of endometriotic stroma are present within submesothelial connectivetissue. Note the pigmented histiocytes. C, Micronodular stromal endometriosis. A nodule of endometriotic stromal cells is presenton the surface of the omentum. Note the dilated arterioles within the nodule. D, Stromal endometriosis of cervix. Note prominenthemorrhage. An endocervical gland is present on the extreme right. E, Necrotic pseudoxanthomatous nodule on the ovariansurface. F, NPN. The center of the nodule (lower part of field), which consists of necrotic and calcified debris, is surrounded byfoamy and pigmented histiocytes and fibrous tissue. G, Polypoid endometriosis of colon. A polypoid mass projects from themucosal surface of the colon, potentially mimicking a colonic adenocarcinoma. H, Polypoid endometriosis of colon. Mucosalpolyps, which consist mostly of endometriotic glands and stroma, are covered by colonic epithelium. Islands of endometriosis arealso present within the muscularis propria.



present. The atypical cells are usually disposed in a singlelayer but may be focally denuded or stratified, sometimesas small papillae. If there is coexistent mucinousmetaplasia, the appearance may overlap with papillarymucinous metaplasia as noted above. An associatedstromal and/or epithelial neutrophilic infiltrate is com-mon (Fig. 3F). Ballouk et al54 studied 6 endometrioticcysts with severe atypia and found that 3 of them wereaneuploid whereas endometriotic cysts with absent oronly mild atypia were diploid.

In most cases, cytologic atypia in endometrioticcysts is likely a reactive or degenerative change, and whenit is an isolated finding, the follow-up is typicallyuneventful. Seidman53 obtained follow-up (mean 8.9 y)in 20 such cases, and it was uneventful in all of themexcept for persistent endometriosis in 1 patient. Never-theless, this type of atypia can occasionally merge with anEMBT (pure58 or mixed-cell type59) or an endometrioidor clear cell carcinoma,51 suggesting that it is occasionallya premalignant change. We have recently seen a case of anendometrioid adenocarcinoma arising in an endometrio-tic cyst in which the endometriotic epithelium near thecarcinoma exhibited cellular stratification and severenuclear atypia with an appearance suggesting adenocar-cinoma in situ (AIS).

HyperplasiaA variety of hyperplastic changes, with or without

cytologic atypia, similar to these findings in the endome-trium have been described in endometriosis,43,51,53 some-times but not always related to an endogenous orexogenous estrogenic stimulus60,61 (Figs. 3G, H) ortamoxifen treatment.62,63 These changes are less commonthat the pure cytologic atypia described in the precedingsection, being encountered in only 2% of endometrioticcysts in one study55 (which is in accord with ourexperience) and 9.4% of cysts in another.42

The infrequency of hyperplasia in endometriosiscomplicates the assessment of its premalignant potential,but it is likely similar to that of endometrial hyperplasiain view of its occasional association with a synchronousor metachronous neoplasm in the same site.42,44,53 In onestudy in which 4% of endometriotic cysts harbored anendometrioid carcinoma, there was a significant associa-tion between the presence of a carcinoma and synchro-nous complex hyperplasia within the endometriosis.42

Accordingly, as in the endometrium, hyperplasia withinendometriosis should prompt a reexamination of thespecimen and additional sampling to exclude a synchro-nous neoplasm.

Molecular Evidence Supporting PrecancerousPotential

That endometriosis, particularly atypical endome-triosis, may undergo malignant transformation (anobservation that dates back to Sampson’s work64) is alsosupported by recent molecular studies. Sato et al65 foundPTEN mutations similar to those in endometrial carci-nomas in 42% of ovarian endometrioid carcinomas, 27%

of ovarian clear cell carcinomas, and 56% of endome-triotic cysts. A number of studies have found loss ofheterozygosity (LOH) within ovarian endometriosis (in-cluding atypical endometriosis) at candidate ovariantumor suppressor gene loci and LOH events or othergenetic alterations common to the endometriosis andsynchronous ovarian carcinomas.65–70 Ali-Fehmi et al47

found a significant difference in the frequency of LOHbetween endometriosis (4.3%) and ovarian carcinomas(23.5%) at D10S608, suggesting that LOH at this locusmay be an important molecular event in the progressionof endometriosis to carcinoma. Additionally, Prefumo etal71 found that endometriosis-associated ovarian carcino-mas had a higher expression of p53 and c-erb-2 than didsimilar tumors without associated endometriosis, and thatthere was a significant degree of concordance for bothoncogenes in the tumors and the adjacent endometrioticepithelium. Similarly, Sainz de la Cuesta et al48 found thatp53 was present in all examples of atypical endometriosisand 82% of endometriosis-associated ovarian carcino-mas, suggesting that the presence of p53 may be helpful inidentifying cases of endometriosis with a malignantpotential. Korner et al72 have recently found a higherfrequency of chromosomal aberrations in ovarian en-dometrioid carcinomas than in ovarian endometriosis,and a higher frequency of the same aberrations in ovarianendometriosis compared with extraovarian endometriosisand normal endometrium. These authors suggest that thehormonal milieu of the ovary may induce genetic changesin endometriosis in the same site.

Endometriosis Without Glands(Stromal Endometriosis)

In occasional cases of endometriosis, endometrioticglands are rare or absent, a phenomenon that has beenreferred to as stromal endometriosis (Figs. 4A–D).20,73

When reading the older literature, however, it isimportant to be aware that the same term was used inthe past to refer to low-grade endometrial stromalsarcoma. In some or perhaps most cases of stromalendometriosis, the apparent absence of endometrioticglands is likely because of limited sampling of the lesion.Indeed, it is quite common in small laparoscopic biopsyspecimens to find small superficial nodules or surfaceplaques that consist only of endometriotic stroma (Figs.4A–C).73 Such foci can be misinterpreted as lymphoidaggregates or a nonspecific finding, particularly if theyare not examined at high-power magnification. An indexof suspicion and also the presence of the characteristicarterioles, foci of hemorrhage, pigmented histiocytes,and CD10 immunoreactivity of the stromal cells facilitatethe diagnosis. In some cases, deeper sections will dis-close occasional endometriotic glands, although cases ofbona fide pure stromal endometriosis almost certainlyoccur.

Stromal endometriosis can also be encountered inthe ovary and uterine cervix, usually in patients withouttypical pelvic endometriosis. In the ovary, it is usuallyan incidental microscopic finding within the stroma



(‘‘benign stromatosis’’), and likely represents a metaplas-tic response of the ovarian stromal cells.74,75 Stromalendometriosis of the cervix73 can occasionally be recog-nized clinically as a small red mucosal discoloration.Microscopic examination reveals within the superficialcervical stroma well-circumscribed rounded to plaquelikefoci composed of endometrial stromal cells, smallblood vessels, and often large numbers of extravasatederythrocytes (Fig. 4D). The differential diagnosis iswith cervical involvement by low-grade endometrialstromal sarcoma. Militating against that diagnosis arethe lesion’s small size, superficial location, extravasatederythrocytes, and absence of permeative growth andvascular invasion.

MISCELLANEOUS TUMORLIKE FINDINGSA variety of findings in endometriosis can suggest

the presence of a neoplastic process. Some of these havealready been discussed, including myxoid change, signet-ring–like decidualized stromal cells, cytologic atypia andhyperplasia of the epithelial component, and stromalendometriosis. Other tumorlike findings are considered inthis section.

Necrotic Pseudoxanthomatous NodulesThese lesions (NPNs) are an uncommon manifesta-

tion of endometriosis and tend to occur in the post-menopausal and late reproductive age groups.18 Theytake the form of multiple nodules that are usuallyattached to the peritoneum or occasionally are free-floating within the peritoneal cavity. In most cases,typical endometriosis is present in the ovaries and inone case NPNs lined an endometriotic cyst.18 Theintraoperative appearance in some cases has suggested adisseminated malignant tumor. On histologic examina-tion, the nodules have a central necrotic zone that issurrounded by pseudoxanthoma cells, often in a pali-saded arrangement, hyalinized fibrous tissue, or both(Figs. 4E, F). The presence of necrosis, particularly onfrozen section examination in a patient with intraopera-tive findings suspicious for cancer, can increase concernfor the latter. Endometriotic glands and stroma areusually absent or sparse within the nodules, but may beseen elsewhere in the same specimen. Most NPNs likelyrepresent ‘‘burned-out’’ or end-stage endometriotic foci.In 1 case, however, multiple peritoneal and omentalNPNs that were not present at the time of salpingo-oophorectomy performed for a ruptured ovarian endo-metriotic cyst, were found at reexploration 7 weeks later,and were thus considered a unusual reaction to thecontents of the endometriotic cyst.76

The importance of NPNs rests on their beingdiagnostic or at least strongly suggestive of endometriosiswhen its more typical features are absent, and theirpotential to be confused with an infectious process ornecrotic tumor that might prompt unnecessary investiga-tions. NPNs should also be distinguished from necrotiz-ing peritoneal granulomas that may be seen afterdiathermy ablation treatment for endometriosis.77 The

history of previous cautery treatment, the typical presenceof black (carbon) or hematoidin pigment, and the absenceof foamy histiocytes help distinguish these granulomasfrom NPNs.

Polypoid EndometriosisThis term is used to refer to rare cases of

endometriosis that form polypoid masses that can mimica neoplasm on clinical, intraoperative, and gross patho-logic examinations.7,78–81 In the only series of suchcases,81 the patients were in the reproductive andpostmenopausal age groups (mean 52.5 y). Of the 24patients, 7 were on unopposed estrogen and 4 were oncombined estrogen-progestin therapy; 1 patient had asynchronous ovarian thecoma. Several cases of polypoidendometriosis have also been reported in patientsreceiving tamoxifen therapy78,82 and one case followedwithdrawal of GnRH-agonist treatment for severeendometriosis.83

The most common clinical presentations are relatedto a pelvic mass, a polypoid vaginal mass, or large bowelobstruction. Sites of involvement in order of frequency inthe series of Parker et al81 were colonic mucosa, ovary(involving the ovarian surface or lining an endometrioticcyst), uterine serosa, cervical or vaginal mucosa, ureter,fallopian tube, omentum, bladder, paraurethral andparavaginal soft tissue, and retroperitoneum. In 30% ofcases, multiple sites were involved. Polypoid, pink, grayor tan, masses ranged up to 14 cm in maximal dimension(Fig. 4G). On microscopic examination, the polypoidmasses were composed of an admixture of endometrioticglands and stroma (Fig. 4H). A variety of glandulararchitectural patterns were observed, sometimes incombination, most commonly cystic and non-cysticsimple hyperplasia, but also simple or complex hyperpla-sia with atypia, disordered proliferative, and cysticatrophy. Various types of epithelial metaplasia (tubal,mucinous, squamous, papillary syncytial metaplasia) werecommon. Hemorrhage, fibrosis, prominent thick-walledblood vessels, hemosiderin-laden histiocytes, and decidualchange were also present in some cases. Most of the caseswere associated with usual (nonpolypoid) endometriosis(Fig. 4H). In 1 case, polypoid endometriosis merged witha mucinous borderline tumor of endocervical-type. Of the17 patients with follow-up data, 15 were alive withoutevidence of residual disease, 1 was alive with residualendometriosis, and 1 died of other causes.

Extrauterine mullerian adenosarcoma is the mostcommon differential diagnostic consideration.84,85 Incontrast to this neoplasm, however, the reported casesof polypoid endometriosis, with 2 exceptions, lackedperiglandular stromal hypercellularity, stromal atypia,and intraglandular stromal papillae. Focal intraglandularstromal papillae were noted in 2 cases with focal mildperiglandular stromal hypercellularity in one of them, butin contrast to adenosarcoma, stromal atypia was absentin each case. Diagnosis may be particularly difficult if thepolyps of polypoid endometriosis undergo torsion withhemorrhagic infarction. In these cases, endometriotic



stromal cells may exhibit reactive atypia and mitoticactivity, complicating the differential with adenosarcoma.In rare cases in which a definite diagnosis is not possible,the patient should receive clinical follow-up.

Rare Tumorlike FindingsRarely, endometriosis may be associated with

worrisome findings that can include unusually extensiveand/or bulky disease, vascular invasion, or a poorresponse to treatment.86–93 The designation ‘‘aggressiveendometriosis’’ has sometimes been applied to such cases,but we discourage its use as a pathologic diagnosisbecause the subsequent behavior of endometriosis cannotbe reliably predicted by its morphologic features. Further,such a diagnosis could prompt unwarranted physician orpatient concern.

Vascular involvement by endometriosis (Fig. 5A) isanalogous to the more common phenomenon of endo-metrial glands and stroma (or stroma only) withinmyometrial vessels in cases of adenomyosis.94 Scolyer etal91 reported a case of an ovarian endometriotic cyst thatwas associated with florid involvement of large vascularspaces (thick-walled lymphatics and veins) within bothmesovaria. The endometriotic tissue completely occludedsome vessels or in others formed large polypoid tonguesthat partly filled their lumina. A similar case was reportedby Ooi and Valentine.90 In another report, Wuster andLeu92 documented a case of abdominal wall endome-triosis in which several veins contained endometriotictissue. Zardawi93 reported 2 cases of colonic endome-triosis that were each associated with intravascularendometriosis within the colonic wall. In one of them,there was endometriosis within a pericolic lymph nodeand in the other there was a focus of hepatic endome-triosis, findings supporting the hypothesis that some casesof endometriosis in unusual sites are a result of vascularor lymphatic embolic spread.

As has been reported in other non-neoplastic lesions(sclerosing adenosis of the breast, vasitis nodosa), perineuralinvasion has been rarely encountered in otherwise typical,benign endometriotic lesions95 (Fig. 5B) and seems to beof no clinical significance.

INFLAMMATORY AND REACTIVE CHANGES

Infected Endometriotic CystsSchmidt et al96 found pathologic evidence of

infection in 11 of 510 endometriotic cysts (2%). Thepatients had a mean age of 34.7 years and typicallypresented with fever and lower abdominal pain; abouthalf had a history of pelvic inflammatory disease.Histologic examination revealed endometriotic cysts thatcontained a fibrinopurulent exudate, microabscesses, andinflammatory cells other than neutrophils, such as plasmacells. All of the patients who had one or both fallopiantubes removed at the same operation had histologicevidence of acute and/or chronic salpingitis.

Pseudoxanthomatous SalpingitisAs noted earlier, pseudoxanthoma cells can be a

striking finding in the tubal mucosa in patients with pelvicendometriosis, a finding that has been referred to aspseudoxanthomatous salpingitis (or pseudoxanthoma-tous salpingiosis) (Figs. 5C, D).18,97,98 The process mayresult in a chocolate-brown discoloration of the tubalmucosa visible on macroscopic examination (Fig. 5C). Inour experience, pseudoxanthomatous salpingitis has al-ways been associated with pelvic endometriosis, and insuch cases likely represents an inflammatory reaction toendometriosis-derived blood or blood products that reachthe tubal lumen. One otherwise similar case, however,reported as ‘‘pigmentosis tubae,’’ was found in a patientwithout endometriosis but who had been previouslytreated with pelvic radiation.99

Mesothelial HyperplasiaEndometriosis is frequently accompanied by me-

sothelial hyperplasia of the pelvic or even extrapelvicperitoneum, which in some cases may be striking. Thehyperplasia may occur adjacent to, or at a distance from,the endometriosis. Kerner et al100 documented mesothe-lial hyperplasia (‘‘mesothelial inclusions’’) in 10% ofwomen with ovarian endometriosis, but in none of thepatients from a control group without endometriosis.Mesothelial hyperplasia in women with endometriosismost commonly involves the surface of the ovaries, thefallopian tubes, the pelvic peritoneum, and the omentum.The hyperplastic mesothelial cells typically form smalltubules, papillae, nests, cords, or even single cells, oftenentrapped within a reactive fibrous tissue, which in floridcases may create a pseudoinfiltrative pattern (Fig. 5E).Retraction artifact around the congeries of mesothelialcells is common and may incorrectly suggest lymphaticinvasion (Fig. 5E).

In our experience, the most striking cases of endo-metriosis-associated mesothelial hyperplasia are seen, notsurprisingly, on the outer aspects of endometriotic cysts.These mesothelial cells can become incorporated in thewall of the cyst (Fig. 5E), often as small tubules in lineararrangements that parallel the overlying serosa, a findingidentical to the mural mesothelial hyperplasia within thewalls of multilocular peritoneal inclusion cysts (MPICs)(see below).101 Indeed, since the report of this finding inMPICs, we have seen more cases of mural mesothelialproliferation in the walls of endometriotic cysts than inMPICs. In some such cases, the mesothelial cells mayeven approach the cyst lining, the appearance sometimesraising concern for an invasive adenocarcinoma arisingfrom the epithelial lining of the cyst. Awareness of thepitfalls associated with mesothelial hyperplasia in thissetting is crucial in avoiding a serious diagnostic error. Ifnecessary, immunohistochemical staining can be used toconfirm that the cells are mesothelial and not epithelial.

Multilocular Peritoneal Inclusion CystsA substantial proportion of women with MPICs

(also referred to as ‘‘cystic mesotheliomas’’) have or have



had endometriosis. In these cases, the cysts likelyrepresent a complication of endometriosis-related adhe-sions. Ross et al102 found that 36% of women in their

study of MPICs had coexistent endometriosis or a historyof the disease. Additionally, several reports have docu-mented an intimate admixture of the 2 lesions. Groisman

FIGURE 5. A, Endometriosis within the lumen of a thin-walled vein or lymphatic. B, Endometriosis showing perineural invasion.Figure courtesy of Dr L Roth. C, Pseudoxanthomatous salpingitis. The fallopian tube has been opened to show a thickenedmucosa that varies from yellow to brown. D, Pseudoxanthomatous salpingitis. The tubal plicae are filled with foamy andpigmented histiocytes. E, Florid mesothelia hyperplasia within the wall of an endometriotic cyst. The mesothelial cells form smallirregular aggregates within reactive fibrous tissue resulting in an infiltrative pattern. Note the retraction artifact around theaggregates of mesothelial cells, a finding that can be misinterpreted as lymphatic invasion and thus increase suspicion for amalignant tumor. F, Numerous Liesegang rings and necrotic debris occupy the lumen of an endometriotic cyst.



and Kerner103 reported an MPIC that contained foci oftypical endometriosis and NPNs within the cyst locules.Additionally, Zotalis et al104 described a 35 cm omentalmass that consisted of an admixture of endometriosis,peritoneal inclusion cysts, and nodules of smooth muscle(peritoneal leiomyomatosis, as discussed below).

Liesegang RingsLiesegang rings are a rare microscopic finding and

are typically encountered within or adjacent to necrotic,inflamed, or fibrotic tissue. They take the form ofeosinophilic, PAS-positive, acellular, variably-sized, ring-like structures (Fig. 5F). Six of the 8 reported cases ofLiesegang rings in the female genital tract were associatedwith endometriosis, usually within the walls and lumens ofendometriotic cysts (5 of the cases) or less commonlywithin endometriotic implants (1 case).105,106 These struc-tures have been histologically confused with, and should bedistinguished from, parasites and foreign material.

SELECTED SITE-RELATED ISSUES

Endometriosis on or Close to theOvarian Surface

The ovary is the most common site for endome-triosis, where its presence is usually obvious owing toappreciable foci within the ovarian parenchyma thatcontain obvious endometriotic glands or cysts andendometriotic stroma. In contrast, endometriosis con-fined to the ovarian surface or superficial cortex may beunder-diagnosed not only because of the often micro-scopic size of the foci but also because endometrioticstroma and glands are easily misinterpreted as ovarianstroma and epithelial inclusion glands (Figs. 6A–C).Surface ovarian endometriosis is often embedded withinadhesions or may form thin plaques or tiny tear-drop–shaped surface polypoid projections (Fig. 6B). Bothendometriotic glands and stroma are usually present butone component may predominate. When endometrioticfoci occupy the most superficial cortical stroma, the

glands may be numerous and cystic, increasing theirpotential resemblance to cortical epithelial inclusion cysts(Fig. 6A), and their often subtle cuffs of endometrioticstroma may not be distinguishable from ovarian stromaunless examined at high-power magnification.

Helpful diagnostic features are the tendency forendometriotic stromal cells to be less spindled thanovarian stromal cells and for the latter not to condensearound glands as in endometriosis. Ovarian stromal cellsoften have fascicular or storiform arrangements that arenot a feature of endometriotic stroma. Other findings, asnoted earlier, that should suggest the diagnosis ofendometriosis are the presence of numerous arterioles(some of which may be distended with erythrocytes),stromal hemorrhage, and foamy or pigmented histiocytes.The latter may form aggregates only loosely attached to,or even seemingly detached from, the ovarian surface.Immunoreactivity of the stromal cells for CD10 can alsobe helpful distinguishing endometriotic stromal cells fromovarian stromal cells (Fig. 6D), which are CD10-negative,12–14 although immunostaining for this markershould rarely be needed.

Superficial Endometriosis of the Uterine CervixCervical endometriosis may be superficial (mucosal)

or deep.107,108 Superficial cervical endometriosis is fre-quently localized to areas of prior biopsy or cautery,suggesting implantation of menstrual endometrium ortrauma-induced metaplasia.108 Deep cervical endometrio-sis is usually an extension of cul-de-sac involvementassociated with typical pelvic endometriosis.

Superficial endometriosis is usually an incidentalmicroscopic finding, but occasionally it can cause athickened, granular, or hemorrhagic mucosa, or beresponsible for an abnormal cervicovaginal smear. Thelesion is almost always found beneath the surfaceepithelium and/or admixed with the normal endocervicalglands (Figs. 6E, F). The endometriotic glands aretypically well spaced and round to oval but occasionallymay show irregularity in size and shape and crowding.

FIGURE 6. A, Endometriosis on the ovarian surface. The cystically dilated endometriotic glands are separated by endometrioticstroma, the appearance of which differs from that of the underlying ovarian stroma (bottom). B, Endometriosis on the ovariansurface. Polypoid projections are composed predominantly of endometriotic stroma that is congested and hemorrhagic, differingin appearance from the underlying ovarian stroma at the bottom of the field. Two cystic endometriotic glands are also presentand can be potentially confused with ovarian inclusion glands, one of which is partly represented in the extreme bottom of thefield. C, Endometriosis in superficial ovarian cortex. A single endometriotic gland is surrounded by endometriotic stroma thatmerges with ovarian stroma at the extreme left and extreme right of the figure. In a small focus such as this, the endometrioticgland and endometriotic stroma can be misinterpreted as an epithelial inclusion gland and ovarian stroma, respectively.D, Endometriosis in the superficial ovarian cortex showing immunoreactivity of the endometriotic stroma with CD10; the ovarianstroma is CD10 negative. E, Superficial endometriosis of uterine cervix. Endometriotic glands are subjacent to the normal cervicalsquamous epithelium and are separated by scanty endometriotic stroma that contains congested blood vessels. Theendometriotic stroma merges with the endocervical stroma at the lower right of the field. F, Superficial cervical endometriosis.The endometriotic glands show cellular stratification and mitotic activity, a finding that can be misinterpreted as AIS if theendometriotic nature of the focus is not recognized. The glands are separated by endometriotic stromal cells, the features ofwhich are somewhat obscured by edema and inflammatory cells. G, Intraluminal endometriosis within fallopian tube.Endometriotic glands and stroma occlude the tubal lumen. The spaces between the endometriotic tissue and the myosalpinx aredilated lymphatics. H, Endometriosis intimately admixed with peritoneal leiomyomatosis, two nodules of which are seen on theright side of the field.



They most commonly resemble the glands of a prolif-erative or weakly proliferative endometrium, includingthe presence of occasional mitotic figures (Fig. 6F).Occasionally they have a secretory appearance. Anendometriotic stromal component is obvious in mostcases, usually as periglandular collections of cells withsmall uniform, dark, naked, oval to round nuclei. In somecases, however, the stromal cells are difficult to appreciatebecause they are sparse and/or obscured by edema,hemorrhage, inflammation, or combinations thereof(Figs. 6E, F). The presence of the characteristic smallarterioles and extravasated erythrocytes can aid therecognition of the stromal component in such cases.Rarely, superficial cervical endometriosis is composedonly of endometriotic stroma (stromal endometriosis)(Fig. 4D), as considered earlier.73

The diagnosis of superficial cervical endometriosisand its distinction from the otherwise similar finding oftuboendometrioid metaplasia of the endocervicalglands108 requires the recognition of endometrioticstroma and its distinction from endocervical stroma. Thisrecognition can be facilitated by reticulin and trichromestaining, endometriotic stroma having dense reticulin butsparse collagen with the opposite findings in normalendocervical stroma.109 McCluggage et al13 found thatnormal endocervical stromal cells are immunoreactive forCD10, especially those around endocervical glands,limiting the usefulness of this marker in the diagnosis ofcervical endometriosis. In the study of Barroeta et al,110

however, endocervical stromal cells were predominantlyCD34+/CD� (‘‘CD34 dominant phenotype’’), whereasendometrial stromal cells were predominantly CD34� /CD10+ (‘‘CD10 dominant phenotype’’). Additionally,Orlandi et al111 found that cellular retinol-bindingprotein-1 is a more specific marker for endometrialstromal cells than CD10 and could be helpful in thiscontext because it does not stain endocervical stromalcells.

When superficial cervical endometriosis is over-looked on microscopic examination, reactive atypia and/or mitotic activity in the endometriotic glands and theiroccasional immunoreactivity for p16 and a high MIB1index112 can result in a misdiagnosis of endocervicalglandular dysplasia or even AIS.107 An absence of boththe marked nuclear atypia and the numerous apoptoticbodies of AIS and recognition of the endometrioticnature of at least some of the stromal cells facilitate thediagnosis. Negative or only focal p16-immunoreactivityalso favors endometriosis in this context, although moreextensive staining does not exclude the diagnosis.112

Vaginal EndometriosisThe vagina is not a common location for endome-

triosis; Stern et al5 found that only 2% of over 1000 casesof endometriosis were vaginal. As in the cervix, vaginalendometriosis can be superficial or deep.113,114 Theformer most commonly involves the vaginal vault andshares with its more common cervical counterpart anapparent relation to trauma and a lack of association

with endometriosis in other sites. Deep endometriosis ismore common, and is typically located in the posteriorfornix. The latter may represent extension of cul-de-sacdisease, and may be associated with involvement of therectovaginal septum.114

Staats et al,115 in a recent study of 18 cases ofvaginal endometrioid adenocarcinoma, found a strongassociation with vaginal endometriosis, the latter beingidentified in 14 cases. Ten tumors were located at thevaginal apex. The tumors contained an exclusive orpredominant component of endometrioid carcinoma;unusual findings in some of the tumors includedsquamous metaplasia, mucinous metaplasia, and promi-nent small nonvillous papillae.116 As noted at the verybeginning of this review, the presence of endometriosisadjacent to a mullerian-type neoplasm can be very helpfulin indicating that the tumor is likely primary in that site.This observation is particularly important in establishinga vaginal origin for endometrioid carcinomas because oftheir rarity compared to other sites in the female genitaltract and because the vagina is a common site ofrecurrence of endometrial adenocarcinoma.

Tubal EndometriosisAn unadorned diagnosis of ‘‘tubal endometriosis’’ is

ambiguous as it has been applied to 3 different lesions ofthe fallopian tube. The most common is endometriosisinvolving the tubal serosa or subserosa; it is usuallyassociated with endometriosis elsewhere in the pelvis.Sheldon et al,117 in a study of 23 such cases, found thatthe foci were confined to the serosa in 16 cases, with theremainder showing some downgrowth into the subserosaltissues; surprisingly, the myosalpinx was not involved inany of the cases. Ovarian endometriosis was present inhalf the cases.

The mucosa of the interstitial portion of one or bothtubes can be of endometrial type in as many as 25% ofwomen in the general population; the correspondingfrequency of endometrial-type lining in the isthmic and/orampullary portions of the tube is 10%.118,119 Theendometrial-type lining in these cases can be diffuse orinterspersed with tubal-type mucosa. These findings areconsidered to represent a normal morphologic variation,but it is not clear if the ectopic endometrial tissue in thesecases is developmental, metaplastic, or a result of direct orembolic spread of eutopic endometrium. The ectopicendometrial tissue may give rise to a variety of lesions,including endometrial-type polyps,118 tubal adenomyosis(analogous to salpingitis isthmica nodosa),119 and in-traluminal endometriosis with occlusion of one or bothtubal lumens (Fig. 6G).120,121 Intraluminal endometriosis,which may or may not be associated with endometriosiselsewhere, accounts for about 15% of tubal-relatedinfertility and may be associated with tubal pregnancy.120

The third type of tubal endometriosis, ‘‘postsalpin-gectomy endometriosis,’’ occurs in the tip of the proximaltubal stump, typically 1 to 4 years after tubal liga-tion.122,123 It otherwise resembles tubal adenomyosis(see above), and may be admixed with salpingitis isthmica



nodosa. Endometrial glands and stroma extend from theendosalpinx into the myosalpinx and sometimes to theserosa. Hysterosalpingography or India ink injection insome cases can demonstrate tuboperitoneal fistulae,which can lead to postligation pregnancies. Postsalpin-gectomy endometriosis has been found in 20% to 50% oftubes examined after ligation. It is more common withlong postligation intervals, the electrocautery method ofligation, and with short proximal stumps.

Intestinal EndometriosisThe typical pathologic features of intestinal endo-

metriosis have been reviewed elsewhere,2,3,124 and onlymore recent observations will be highlighted here. Thelesions can vary macroscopically from small, clinicallyinsignificant serosal or mural lesions to large tumorlikemural masses that can cause kinking of the boweland luminal obstruction. Endometriosis, including itspolypoid variant, can also involve the colonic mucosa,potentially simulating a primary colonic adenocarcinomaon gross examination. The histologic diagnosis ofintestinal endometriosis is usually straightforward, butoccasionally it may induce a variety of histologic changesthat can mimic primary bowel disease, such as colitis,mucosal prolapse, solitary rectal ulcer, and ischemic andadenomatous lesions.124–126 Thus caution is warranted inrendering a diagnosis of primary bowel disease on biopsymaterial from patients with known intestinal endome-triosis and/or when the mucosal findings are in closeproximity to foci of endometriosis in the same specimen.

Several recent studies have focused on the variety ofneoplasms that can arise from intestinal endometriosis,which are similar to those that arise from endometriosiselsewhere.127–131 About 80% of such tumors have arisenin the rectosigmoid. Approximately 60% have beenendometrioid carcinomas, 10% endometrioid stromalsarcomas, 10% mullerian adenosarcomas, 5% malignantmullerian mixed tumors (carcinosarcomas), and theremainder comprised by other carcinomas (clear celladenocarcinoma, squamous cell carcinoma), a ‘‘spindlecell’’ sarcoma, and a mixed germ cell tumor.

The studies cited above have noted the potential ofendometrioid carcinomas arising in colonic endometriosisto clinically and pathologically mimic a primary colonicadenocarcinoma. The distinction between the 2 tumors isimportant because of the much better prognosis ofendometrioid carcinomas compared with colonic carci-nomas and because of potentially different treatmentrequirements. Contiguity with or close proximity toendometriosis, a gross appearance atypical for coloniccarcinoma, no mucosal involvement, low-grade nuclearfeatures, squamous metaplasia, no dirty necrosis, and aCK7+/CK20� /CDX2� immunoprofile are featuresthat support or indicate a diagnosis of endometrioidcarcinoma rather than colonic carcinoma.

RARE ASSOCIATED LESIONSThree case of endometriosis intimately admixed

with the smooth muscle nodules of peritoneal leiomyo-

matosis have been reported (Fig. 6H)104,132,133; in 1 case,admixed peritoneal inclusion cysts were also present.104

Two of the patients had taken oral contraceptives.Although the combination of endometriosis and perito-neal leiomyomatosis might be coincidental, the intimaterelationship of the two lesions suggests a multidirectionalmetaplasia, consistent with the mullerian potential of theperitoneum (‘‘secondary mullerian system’’).134

Three cases of peritoneal gliomatosis in which theglial implants contained foci of endometriosis have beendescribed.135–137 In each case, the peritoneal lesions werefound a decade or more after removal of an ovarianteratoma that was immature in at least two of the cases.The foci of endometriosis were confined to the glialimplants in each case. Intriguingly, 2 recent studies138,139

have suggested that the glial implants of peritonealgliomatosis are genetically unrelated to the associatedteratoma and are likely of metaplastic origin. Thepresence of endometriotic tissue within the glial tissue inthese cases provides some support for this hypothesis.

ACKNOWLEDGMENTThe author thanks Dr Robert H. Young who offered

constructive criticism of the manuscript that was mosthelpful.

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The Pathology Of Endometriosis

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