1. REVIEW ARTICLE
The Pathology of Endometriosis
A Survey of the Many Faces of a Common Disease Emphasizing
Diagnostic Pitfalls and Unusual and Newly Appreciated Aspects
Philip B. Clement, MD
O ur knowledge of the pathology and pathogenesis of
Abstract: Although the histologic diagnosis of endometriosis is endometriosis largely stems from the work of Dr
usually straightforward, many diagnostic problems can arise as John Albertson Sampson (1873 to 1946), the ‘‘Father of
a result of alterations or absence of its glandular or stromal Endometriosis.’’ In a contribution to the History Series in
components. The diagnostic difficulty in such cases can be the International Journal of Gynecological Pathology,1 I
compounded by tissue that is limited to a small biopsy specimen. recounted in some detail Sampson’s remarkable career
The appearance of the glandular component can be altered by and seminal contributions. That article was preceded by 2
hormonal and metaplastic changes, as well as cytologic atypia others2,3 in which I reviewed the extensive post-Sampson
and hyperplasia. Although the last 2 findings are often referred literature pertaining to the macroscopic and histologic
to collectively as ‘‘atypical endometriosis,’’ they should be features of endometriosis in pelvic and extrapelvic sites.
separately recognized as their premalignant potential likely One of those reviews appeared 17 years ago in a source
differs. In some cases, the endometriotic glands are sparse or that is not always readily available2 and the other was
even absent (stromal endometriosis). The stromal component written 7 years ago.3 Acccordingly, the current review is
can be obscured or effaced by infiltrates of foamy and pigmented an update to those studies, but with a focus on diagnostic
histiocytes, fibrosis, elastosis, smooth muscle metaplasia, myx- problems and unusual morphologic features of pelvic
oid change, and decidual change. Occasional findings in endometriosis, some of which can lead to under-diagnosis
endometriosis that may raise concern for a neoplasm include or misdiagnosis, even as a malignant tumor (Table 1).
necrotic pseudoxanthomatous nodules, polypoid growth (poly- Endometriosis-associated neoplasms, which have been
poid endometriosis), bulky disease, and venous, lymphatic, or the subject of 2 recent large series4,5 and 2 older
perineural invasion. Inflammatory and reactive changes within, comprehensive reviews,6,7 will be touched upon only
adjacent to, or at a distance from foci of endometriosis can briefly, mainly with regard to precancerous changes and
complicate the histologic findings and include infection within recent observations regarding origin of endometrioid
endometriotic cysts, pseudoxanthomatous salpingitis, florid carcinomas from vaginal and intestinal endometriosis.
mesothelial hyperplasia, peritoneal inclusion cysts, and Liese- The pathologic diagnosis of endometriosis is not
gang rings. The histologic diagnosis of endometriosis can also be only of obvious importance to the patient, but its
challenging when it involves an unusual or unexpected site. Five recognition can also be of great help to the pathologist
such site-specific problematic areas considered are endometriosis in accounting for synchronous findings that might
on or near the ovarian surface, superficial cervical endome- otherwise be problematic. For example, the intimate
triosis, vaginal endometriosis, tubal endometriosis, and intest- association of endometriosis with an ovarian or extra-
inal endometriosis, including the important distinction of an ovarian neoplasm can suggest that the tumor is likely
endometrioid carcinoma arising from colonic endometriosis primary rather than metastatic from a known or an occult
from a primary colonic adenocarcinoma. Finally, endometriotic primary tumor elsewhere. The presence of endometriosis
foci can occasionally be intimately admixed with another can also explain other potentially confusing or worrisome
process, such as peritoneal leiomyomatosis or gliomatosis, findings such as florid mesothelial hyperplasia, pseudox-
resulting in a potentially confusing histologic appearance. anthomatous salpingitis, and necrotic pseudoxanthoma-
tous nodules (NPNs), lesions that will be discussed later
Key Words: endometriosis, pathologic diagnosis, precancerous
in more detail.
changes, endometriosis-associated neoplasms
(Adv Anat Pathol 2007;14:241–260)
TYPICAL ENDOMETRIOSIS
A definitive diagnosis of endometriosis continues to
be based on histologic examination. One study8 found
that only 50% of laparoscopic biopsy specimens from
From the Department of Pathology, Vancouver General Hospital,
Vancouver, BC, Canada. areas suspicious for endometriosis were proven micro-
Reprints: Philip B. Clement, MD, Department of Pathology, Vancouver
scopically to be endometriosis. The histologic diagnosis of
General Hospital, 910 W. 10th Avenue, Vancouver, BC, Canada
endometriosis is usually straightforward and is based on
V5Z 4E3 (e-mail: Phil.clement@vch.ca).
the typical presence of both endometriotic glands and
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2. Clement Adv Anat Pathol Volume 14, Number 4, July 2007
The endometriotic stroma typically resembles, at
TABLE 1. Findings in Endometriosis That can be Associated
least focally, eutopic inactive or proliferative endometrial
With Diagnostic Problems
stroma, including the presence of a network of small
Alterations of the Stromal Component
arterioles (Figs. 1A, B). The presence of these vessels,
Foamy and pigmented histiocytes
which may be engorged with erythrocytes, may provide a
Fibrosis
helpful initial clue to the endometriotic nature of the
Elastosis
lesion. In some cases, vessels are not conspicuous but
Smooth muscle metaplasia
Myxoid change focal stromal hemorrhage can be similarly diagnostically
Decidual change, including signet-ring–like cells
helpful. Metzger et al10 found recent hemorrhage within
Alterations of the Glandular Component
53% of implants with stroma but in only 15% of those
Postmenopausal and treatment-related changes
with little or no stroma. Although hemorrhage in some
Pregnancy-related changes
Metaplastic changes specimens might be related to the trauma of the biopsy,
Cytologic atypia
two-thirds of the biopsy specimens with hemorrhage in
Hyperplasia
the cited study10 also contained pigmented histiocytes, the
Absence of glands (stromal endometriosis)
characteristic inflammatory cell of endometriosis, as
Miscellaneous Tumorlike Findings
discussed below.
Necrotic pseudoxanthomatous nodules
Polypoid endometriosis Like normal and neoplastic endometrial stromal
Vacular invasion
cells, endometriotic stromal cells are typically immuno-
Perineural invasion
reactive for CD10 (Fig. 1C).12–14 CD10-positivity can
Unusual Inflammatory and Reactive Changes
help confirm the endometriotic nature of stromal cells in
Infected endometriotic cysts
Pseudoxanthomatous salpingitis problematic situations such as when dealing with limited
Florid mesothelial hyperplasia
material (as in a tiny laparoscopic biopsy specimen), when
MPICs
the stromal cells on routinely stained sections are of
Liesegang rings
uncertain nature, or when the glandular component is
Site-Related Diagnostic Problems
absent, as discussed below. The role of CD10 staining in
Endometriosis on or close to the ovarian surface
Superficial endometriosis of the uterine cervix the diagnosis of superficial ovarian and cervical endome-
Vaginal endometriosis
triosis is discussed under the heading of ‘‘Selected Site-
Tubal endometriosis
related Issues.’’
Intestinal endometriosis
Rare Associated Lesions
Peritoneal leiomyomatosis
DIAGNOSTIC ISSUES RELATED TO THE
Peritoneal gliomatosis
STROMAL COMPONENT
Alterations in the typical microscopic appearance of
endometriosis that can cause diagnostic problems for the
stroma, although as will be noted, the diagnosis can be pathologist occur in both its glandular and stromal
made when only one of these components is present. The components, but are more common in the latter and are
glands almost always have an overtly endometrioid accordingly considered first. Although these changes can
appearance (Figs. 1A, B) that may range from inactive obscure the typical stromal component, their presence
to proliferative (or occasionally, secretory) to hyperplas- should increase one’s diagnostic suspicion of the endome-
tic. The glandular cells may be ciliated, exemplifying the triotic nature of the lesion. In such cases, endometriotic
close relationship of tubal-type and endometrioid epithe- stroma, if present at all, may be very subtle and confined
lium in the female genital tract in both non-neoplastic and to a barely perceptible and often discontinuous zone that
neoplastic states. The appearance of the glands may is periglandular or that subtends the epithelial lining of an
reflect that of the eutopic endometrium, but often only to endometriotic cyst. In the latter instance, if the epithelial
a limited degree.9–11 The lipofuscin and hemosiderin cells are denuded, the stromal cells may directly abut the
pigment frequently present within histiocytes in endome- cyst lumen. If the nature of the stromal cells is in doubt,
triosis (as discussed below) can occasionally also be found immunostaining for CD10, as noted earlier, can be
within the endometriotic epithelial cells. helpful.
FIGURE 1. A, Typical endometriosis showing part of an endometriotic gland and a thin cuff of periglandular endometriotic
stroma containing dilated blood vessels. B, Endometriotic gland with only focal periglandular endometriotic stroma (extreme left
of field). The remaining stroma is edematous and has a nonspecific appearance. C, Typical endometriosis. The periglandular
endometriotic stroma shows immunoreactivity for CD10. D, Ovarian endometriosis. The endometriotic stroma is replaced by
foamy 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 with
numerous pigmented histiocytes within the endometriotic stroma. G, Presumptive endometriosis. An ovarian cyst is lined
by 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.
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Foamy and Pigmented Histiocytes Fibrosis and Elastosis
Hemorrhage and menstrual changes in endometrio- Endometriotic lesions often elicit a fibrotic reaction
sis often elicit an infiltrate of histiocytes that can obscure that can lead to adhesions around the focus and focal to
the characteristic features of the stroma (Figs. 1D to G). extensive replacement of the endometriotic stroma,
The histiocytes typically have abundant cytoplasm that especially within the walls of endometriotic cysts
varies in appearance depending, at least in part, on the (Figs. 2A, B). The fibroblasts within the fibrotic areas
age of the lesion. In early lesions, which tend to be are characteristically small and stellate (Fig. 2A). Long-
nonpigmented at laparoscopy or laparotomy,15 the standing cysts may have walls composed predominantly
histocytes are nonpigmented and have granular, eosino- or entirely of hyalinized fibrous tissue (Fig. 2B); rarely
philic or foamy cytoplasm, the latter due to abundant foci of dystrophic calcification and/or heterotopic bone
lipid or glycolipid (‘‘pseudoxanthoma cells’’), some of are present in such cases.
which likely represents ceroid precursors (Figs. 1D, A less common stromal response in endometriosis is
E).16–18 In contrast, the characteristic pigmented histio- elastosis, which can sometimes be striking, resulting in
cytes of endometriosis are common in well-developed focal or extensive replacement of the typical endometrio-
tic stroma (Figs. 2C, D).20 In some cases, circumscribed
lesions (Figs. 1F, G). Much of the pigment is ceroid or
lipofuscin that appears as fine, grayish-brown cytoplas- foci of elastosis vaguely resemble a corpus albicans.
mic granules on routinely stained sections and that stains Stromal elastosis can be a helpful diagnostic clue to the
with the periodic acid-Schiff (PAS) method after diastase diagnosis of endometriosis, especially when accompanied
predigestion. When collections of ceroid-rich histiocytes by characteristic endometriotic glands. Although we
associated with endometriosis (or other lesions) are well initially believed that stromal elastosis in endometriosis
circumscribed, the term ‘‘ceroid granuloma’’ has some- was a new observation, while our report on this finding
times been applied.19 Hemosiderin is also typically was in press, we found that Robert Meyer had made
present but is often less conspicuous than the lipofuscin the same observation over 70 years earlier. In an article
published in 1928, Jacobsen21 refers to one of Meyer’s
pigment and in contrast to the latter appears as coarse,
irregular, golden-brown cytoplasmic granules that stain studies (unfortunately the exact citation is not given) by
with the Prussian blue method. Occasionally, the histio- stating ‘‘Meyer ylays much stress on his own observa-
cytic infiltrate is massive (‘‘xanthomatous endometrio- tion that elastic tissue is not found in the uterine mucosa,
sis’’) and can extensively or completely replace the but is present in ectopic endometrium-like tissue.’’
endometriotic stroma and fill the gland lumens (Figs.
Smooth Muscle Metaplasia
1D, E). The presence of endometriotic glands allows for a
diagnosis of endometriosis when the endometriotic The stromal component of endometriosis can be
stroma has been effaced, but when both the endometriotic focally or extensively replaced by smooth muscle, a
glands and stroma are obliterated by the histiocytes (often finding consistent with the myofibroblastic poten-
accompanied by fibrosis, as noted below), only a tial of endometrial and endometriotic stromal cells
(Fig. 2E).22,23 Smooth muscle metaplasia is most common
diagnosis of presumptive endometriosis is possible (Fig.
1G). Rarely, the lipid within endometriotic lesions can be within ovarian endometriosis, being documented in 18%
of cases in one study.22 In over half the cases in that
converted to cholesterol crystals that may evoke a
foreign-body giant-cell reaction. When this finding is study, the smooth muscle was within the wall of an
striking, the term ‘‘cholesteatomatous endometriosis’’ is endometriotic cyst. When smooth muscle is prominent,
appropriate. the process has been referred to as ‘‘endomyometriosis.’’
In some cases of endometriosis, pseudoxanthoma Striking examples of the latter have taken the form of
uteruslike masses in the ovary,24,25 broad ligament,26 and
cells are found at a distance from the endometriotic foci,
a pelvic lymph node.27 Some uteruslike masses, however,
such as within the mucosa of the fallopian tube (see
Pseudoxanthomatous Salpingitis), the pelvic peritoneum, especially if associated with congenital malformations of
pelvic lymph nodes, and omentum (Fig. 1H).18 the genitourinary tract, may represent a congenital
FIGURE 2. A, Endometriotic cyst with fibrosis. Beneath the endometriotic epithelium (top right) is a thin zone of endometriotic
stroma with foci of hemorrhage. The cyst wall is composed of loose fibrous tissue composed of small fibroblasts separated by
collagen. B, Endometriotic cyst (lumen at top of figure) with its wall composed of hyalinized fibrous tissue. Pseudoxanthoma cells
focally line the cyst, which has lost its epithelial lining. C, Endometriosis with prominent stromal elastosis. The brightly eosinophilic
elastotic tissue surrounds an endometriotic gland. No residual endometriotic stroma is present. D, Endometriosis with prominent
stromal elastosis, elastic tissue stain. E, Endometriosis with prominent smooth muscle metaplasia. At the extreme left is part of an
endometriotic gland with periglandular endometriotic stroma that merges with mature smooth muscle. F, Endometriosis with
prominent myxoid change. A typical endometriotic gland with periglandular stroma (left) lies adjacent to a large pool of acellular
mucin (right). This peritoneal lesion, which was found in a patient undergoing radial hysterectomy for adenocarcinoma of the
cervix, was misinterpreted on frozen section examination as metastatic mucinous adenocarcinoma. G, Endometriosis in
pregnancy with prominent decidual change. An atrophic endometriotic gland is lined by flattened epithelium, a finding that can
be mistaken for a vascular space. H, Endometriosis in pregnancy. Basophilic myxoid stroma separates the decidual cells. Note the
cytoplasmic vacuoles within the decidual cells.
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mullerian-duct anomaly rather than a variant of endo- secondary to progestin treatment (Fig. 3A). In pregnancy,
metriosis.25,28 microscopic examination typically reveals a decidual
Smooth muscle metaplasia in endometriosis should reaction similar to that seen in the eutopic endometrium;
be distinguished from the much more common finding of the endometriotic glands are usually atrophic, as noted
endometriosis involving indigenous smooth muscle, such below (Fig. 2G). Necrosis of the decidual cells, stromal
as the pelvic ligaments and the walls of the bowel and myxoid change (as noted above) (Fig. 2H) or edema, and
bladder. In such cases, the endometriosis often stimulates infiltration by lymphocytes may also be seen. Addition-
the indigenous smooth muscle to proliferate, analogous to ally, the decidual cells in endometriosis can, like their
myometrial smooth muscle proliferation around foci of eutopic counterparts, exhibit cytoplasmic vacuoles with
adenomyosis. The reactive smooth muscle proliferation in displacement of the nucleus, resulting in a signet-ring–like
appearance (Fig. 2H).29,33 Cells of the latter type can raise
these situations often accounts for the bulk of the lesion,
and if endometriosis is not identified in the initial slides, a differential diagnosis with a metastatic signet-ring-cell
the findings may be suspicious enough for the diagnosis to adenocarcinoma, but the merging of such cells with
prompt additional sampling. typical decidual cells, the presence of acid rather than
neutral mucin in the vacuoles, and the cytokeratin-
Myxoid Change negativity of the cells facilitate the correct diagnosis.
In occasional cases, endometriotic stroma under-
goes striking myxoid change in which endometriotic DIAGNOSTIC ISSUES RELATED TO THE
stromal cells are separated by scanty to abundant GLANDULAR COMPONENT
acellular mucin; in the latter situation, pools of acellular
Postmenopausal and Treatment-related
mucin may be seen (Figs. 2F, H).29–34 The mucin in these
Changes
cases is stromal rather than epithelial mucin, and thus
stains positively for toluidine blue or Alcian blue (pH 2.5) Diagnosing endometriosis in postmenopausal wo-
but not with PAS. Five of the 6 reported cases of myxoid men can be more difficult than in those of reproductive
change in endometriosis have involved the skin or age because the endometriotic tissue is often atrophic.
superficial soft tissues and 4 of the 6 cases occurred Inactive or atrophic glandular changes in endometriosis
during pregnancy or the puerperium, suggesting that the can also occur in premenopausal patients treated with
location of the lesion and the hormonal milieu may be oral contraceptives, danazol, antiprogesterone steroids
predisposing factors. In 2 cases, the histologic appearance (gestrinone), and progestins (Fig. 3A).35,36 In atrophic
suggested the possibility of metastatic adenocarcinoma endometriosis, the endometriotic glands may be small or
and/or pseudomyxoma peritonei,30,31 and in another case, cystically dilated and are lined by flattened epithelial cells,
a diagnosis of a myxoid sarcoma of soft tissue was with an appearance that may be similar to simple or cystic
initially considered.33 In the 3 patients who were pregnant atrophy of the eutopic endometrium (Fig. 3B). The
at the time of the removal of the lesion, the histologic atrophic glands may be surrounded by stroma that is
interpretation of the specimen was further complicated by often more fibrotic (Fig. 3B) than in younger patients,
the presence of a striking decidual transformation of the although a thin cuff of typical endometriotic stroma will
endometriotic stroma (see below) (Fig. 2H). The correct usually be visible around some of the glands. Immunos-
diagnosis is facilitated by awareness of these findings and taining for CD10 can be helpful in establishing the
the presence of at least occasional endometriotic glands, presence of endometriotic stroma in such cases.
although these may be atrophic if the patient is pregnant, In some postmenopausal women, endometriosis
as noted below. remains clinically active. In such cases, Toki et al37 found
that the endometriotic lesions may have a more active
Decidual Change histologic appearance than the eutopic endometrium, and
The endometriotic stroma usually exhibits striking also more progesterone receptors and higher Ki-67
progestational changes during pregnancy (Figs. 2G, H); activity in the endometriotic stromal cells as compared
similar but usually less striking changes can be seen with the eutopic endometrial stromal cells.
FIGURE 3. A, Endometriosis in a patient treated with progestational agents. The endometriotic stromal cells are partly
decidualized and surround an atrophic gland. B, Endometriosis in a postmenopausal patient showing cystic atrophy of the glands
and 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 with
atypical clear cell metaplasia of the lining epithelial cells. Most of the cyst was lined by this type of epithelium, which merged with
a clear cell carcinoma (not shown). F, Endometriotic cyst with prominent cytologic atypia of the lining epithelial cells. Note
prominent neutrophilic infiltrate. G, A patient, who had been on unopposed estrogen replacement therapy for 10 years following
a hysterectomy and salpingo-oophorectomy for endometriosis, presented with a pelvic mass. The mass was composed of typical
endometriosis with foci of atypical complex endometrial hyperplasia (left) that merged with grade 1 endometrioid
adenocarcinoma (right). Also see (H). H, Higher-power views of the atypical hyperplasia (left) and the grade 1 endometrioid
adenocarcinoma (right) depicted in (G).
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Pregnancy-related Changes histologic types of ovarian epithelial tumors, and in a
high proportion of ovarian clear cell carcinomas (40% to
In pregnancy, endometriotic glands usually have an
70% of cases) and endometrioid carcinomas (30% to
inactive appearance. They vary from small to large and
40% of cases).43–46 A more specific association has been
cystic and are usually lined by cuboidal or flattened
found between ‘‘atypical endometriosis’’ and synchro-
epithelial cells (Fig. 2G). We have seen cases of
nous ovarian cancers. Of the ovarian cancers studied by
endometriosis in pregnant women in which the diagnosis
Ogawa et al,45 29% had associated endometriosis, and it
was missed on microscopic examination because the
was atypical in 78% of them. Similarly, Fukunaga et al44
flattened epithelial cells were mistaken for endothelial or
found atypical endometriosis in approximately 60% of
mesothelial cells, resulting in a diagnosis of ectopic
cases of endometriosis-associated carcinoma, whereas it
decidua rather than endometriosis. Occasionally, endo-
was present in only 1.7% of cases of ovarian endome-
metriotic glands in women with an intrauterine or ectopic
triosis not associated with an ovarian carcinoma.
pregnancy exhibit overt secretory changes that may
include the Arias-Stella reaction38,39 (Fig. 3C) and/or The term ‘‘atypical endometriosis’’ has been used in
optically clear nuclei40 similar to these pregnancy-related the literature to refer to 2 different histologic find-
ings.44,45,47–52 One of them, referred to here as ‘‘cytologic
findings in eutopic endometrial glands.
atypia,’’ denotes the presence of cytologic atypia within
Metaplastic Changes the lining of endometriotic cysts, whereas the other,
referred to here as ‘‘hyperplasia,’’ refers to the same
Metaplastic changes similar to those occurring in
spectrum of hyperplasia (simple or complex, with or
eutopic endometrial glands are common in endometriotic
without cytologic atypia) encountered in the endome-
epithelium.41,42 They were found in 68% of cases of
trium.53 Most studies have used ‘‘atypical endometriosis’’
ovarian endometriosis in one study41 but in only 12% of
to refer collectively to both cytologic atypia and
cases in another study,42 and include ciliated, eosinophi-
hyperplasia, but an attempt should be made to distinguish
lic, hobnail, squamous, and mucinous metaplasia (Fig.
between them because they almost certainly differ in their
3D); the last type may be composed of endocervical-type
clinical significance,53 and each is considered here
cells or, less often, goblet cells. Additionally, we have seen
separately.
several cases of clear cell and atypical clear cell metaplasia
in endometriotic cysts (Fig. 3E); in one such case, atypical
Cytologic Atypia
clear cells lining an endometriotic cyst merged with a clear
cell carcinoma. In one of the studies of metaplasia in Cytologic atypia, especially mild to moderate
ovarian endometriosis cited above,41 17% of the endome- atypia, within endometriotic cysts is a common find-
ing.51,53–56 Its reported frequency obviously depends on
triotic cysts harbored a neoplasm, all of which had
associated epithelial metaplasia within the cyst, whereas one’s diagnostic threshold for this diagnosis. Czerno-
bilsky and Morris55 found mild atypia in 22% of their
only 63% of the cysts without a neoplasm showed
metaplasia. Furthermore, all 4 cases of endocervical-like cases of ovarian endometriosis, whereas severe atypia was
mucinous borderline tumors (EMBTs) encountered in the present in only 3.6% of cases. The corresponding
same study were contiguous with foci of hyperplastic frequency from another study in which the atypia was
not graded was 12%.57
mucinous epithelium. The distinction between papillary
mucinous metaplasia and an early EMBT in an endome- Atypia, when present, is almost always found in an
triotic cyst can be difficult and subjective, and is a not endometriotic cyst, and is usually a focal or multifocal
infrequent issue in our referral material. When there is finding in which the epithelial cells lining the cyst are
definite endometriotic stroma beneath the mucinous enlarged and polygonal with scanty to more commonly
proliferation, we consider it metaplastic endometriosis abundant, dense eosinophilic cytoplasm (Fig. 3F). There
unless there are well-developed papillae. is usually no associated endometriotic glandular compo-
nent. The nuclei of the atypical cells exhibit marked
Atypical Endometriosis variation in size and shape and are variably hyperchro-
A number of studies have found associated en- matic, often with smudged chromatin; nucleoi may be
dometriosis in a sizable minority (20% to 30%) of all prominent (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 connective
tissue. Note the pigmented histiocytes. C, Micronodular stromal endometriosis. A nodule of endometriotic stromal cells is present
on the surface of the omentum. Note the dilated arterioles within the nodule. D, Stromal endometriosis of cervix. Note prominent
hemorrhage. An endocervical gland is present on the extreme right. E, Necrotic pseudoxanthomatous nodule on the ovarian
surface. F, NPN. The center of the nodule (lower part of field), which consists of necrotic and calcified debris, is surrounded by
foamy and pigmented histiocytes and fibrous tissue. G, Polypoid endometriosis of colon. A polypoid mass projects from the
mucosal surface of the colon, potentially mimicking a colonic adenocarcinoma. H, Polypoid endometriosis of colon. Mucosal
polyps, which consist mostly of endometriotic glands and stroma, are covered by colonic epithelium. Islands of endometriosis are
also present within the muscularis propria.
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present. The atypical cells are usually disposed in a single of ovarian clear cell carcinomas, and 56% of endome-
layer but may be focally denuded or stratified, sometimes triotic cysts. A number of studies have found loss of
as small papillae. If there is coexistent mucinous heterozygosity (LOH) within ovarian endometriosis (in-
metaplasia, the appearance may overlap with papillary cluding atypical endometriosis) at candidate ovarian
mucinous metaplasia as noted above. An associated tumor suppressor gene loci and LOH events or other
stromal and/or epithelial neutrophilic infiltrate is com- genetic alterations common to the endometriosis and
mon (Fig. 3F). Ballouk et al54 studied 6 endometriotic synchronous ovarian carcinomas.65–70 Ali-Fehmi et al47
cysts with severe atypia and found that 3 of them were found a significant difference in the frequency of LOH
aneuploid whereas endometriotic cysts with absent or between endometriosis (4.3%) and ovarian carcinomas
only mild atypia were diploid. (23.5%) at D10S608, suggesting that LOH at this locus
In most cases, cytologic atypia in endometriotic may be an important molecular event in the progression
cysts is likely a reactive or degenerative change, and when of endometriosis to carcinoma. Additionally, Prefumo et
al71 found that endometriosis-associated ovarian carcino-
it is an isolated finding, the follow-up is typically
uneventful. Seidman53 obtained follow-up (mean 8.9 y) mas had a higher expression of p53 and c-erb-2 than did
in 20 such cases, and it was uneventful in all of them similar tumors without associated endometriosis, and that
except for persistent endometriosis in 1 patient. Never- there was a significant degree of concordance for both
theless, this type of atypia can occasionally merge with an oncogenes in the tumors and the adjacent endometriotic
EMBT (pure58 or mixed-cell type59) or an endometrioid epithelium. Similarly, Sainz de la Cuesta et al48 found that
or clear cell carcinoma,51 suggesting that it is occasionally p53 was present in all examples of atypical endometriosis
a premalignant change. We have recently seen a case of an and 82% of endometriosis-associated ovarian carcino-
endometrioid adenocarcinoma arising in an endometrio- mas, suggesting that the presence of p53 may be helpful in
tic cyst in which the endometriotic epithelium near the identifying cases of endometriosis with a malignant
potential. Korner et al72 have recently found a higher
carcinoma exhibited cellular stratification and severe ¨
nuclear atypia with an appearance suggesting adenocar- frequency of chromosomal aberrations in ovarian en-
cinoma in situ (AIS). dometrioid carcinomas than in ovarian endometriosis,
and a higher frequency of the same aberrations in ovarian
Hyperplasia endometriosis compared with extraovarian endometriosis
A variety of hyperplastic changes, with or without and normal endometrium. These authors suggest that the
cytologic atypia, similar to these findings in the endome- hormonal milieu of the ovary may induce genetic changes
trium have been described in endometriosis,43,51,53 some- in endometriosis in the same site.
times but not always related to an endogenous or
Endometriosis Without Glands
exogenous estrogenic stimulus60,61 (Figs. 3G, H) or
(Stromal Endometriosis)
tamoxifen treatment.62,63 These changes are less common
that the pure cytologic atypia described in the preceding In occasional cases of endometriosis, endometriotic
section, being encountered in only 2% of endometriotic glands are rare or absent, a phenomenon that has been
cysts in one study55 (which is in accord with our referred to as stromal endometriosis (Figs. 4A–D).20,73
experience) and 9.4% of cysts in another.42 When reading the older literature, however, it is
The infrequency of hyperplasia in endometriosis important to be aware that the same term was used in
complicates the assessment of its premalignant potential, the past to refer to low-grade endometrial stromal
but it is likely similar to that of endometrial hyperplasia sarcoma. In some or perhaps most cases of stromal
in view of its occasional association with a synchronous endometriosis, the apparent absence of endometriotic
or metachronous neoplasm in the same site.42,44,53 In one glands is likely because of limited sampling of the lesion.
study in which 4% of endometriotic cysts harbored an Indeed, it is quite common in small laparoscopic biopsy
endometrioid carcinoma, there was a significant associa- specimens to find small superficial nodules or surface
tion between the presence of a carcinoma and synchro- plaques that consist only of endometriotic stroma (Figs.
nous complex hyperplasia within the endometriosis.42 4A–C).73 Such foci can be misinterpreted as lymphoid
Accordingly, as in the endometrium, hyperplasia within aggregates or a nonspecific finding, particularly if they
endometriosis should prompt a reexamination of the are not examined at high-power magnification. An index
specimen and additional sampling to exclude a synchro- of suspicion and also the presence of the characteristic
nous neoplasm. arterioles, foci of hemorrhage, pigmented histiocytes,
and CD10 immunoreactivity of the stromal cells facilitate
Molecular Evidence Supporting Precancerous the diagnosis. In some cases, deeper sections will dis-
Potential close occasional endometriotic glands, although cases of
That endometriosis, particularly atypical endome- bona fide pure stromal endometriosis almost certainly
triosis, may undergo malignant transformation (an occur.
observation that dates back to Sampson’s work64) is also Stromal endometriosis can also be encountered in
supported by recent molecular studies. Sato et al65 found the ovary and uterine cervix, usually in patients without
PTEN mutations similar to those in endometrial carci- typical pelvic endometriosis. In the ovary, it is usually
nomas in 42% of ovarian endometrioid carcinomas, 27% an incidental microscopic finding within the stroma
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11. Adv Anat Pathol Volume 14, Number 4, July 2007 The Pathology of Endometriosis
(‘‘benign stromatosis’’), and likely represents a metaplas- history of previous cautery treatment, the typical presence
tic response of the ovarian stromal cells.74,75 Stromal of black (carbon) or hematoidin pigment, and the absence
endometriosis of the cervix73 can occasionally be recog- of foamy histiocytes help distinguish these granulomas
nized clinically as a small red mucosal discoloration. from NPNs.
Microscopic examination reveals within the superficial
Polypoid Endometriosis
cervical stroma well-circumscribed rounded to plaquelike
foci composed of endometrial stromal cells, small This term is used to refer to rare cases of
blood vessels, and often large numbers of extravasated endometriosis that form polypoid masses that can mimic
erythrocytes (Fig. 4D). The differential diagnosis is a neoplasm on clinical, intraoperative, and gross patho-
logic examinations.7,78–81 In the only series of such
with cervical involvement by low-grade endometrial
cases,81 the patients were in the reproductive and
stromal sarcoma. Militating against that diagnosis are
the lesion’s small size, superficial location, extravasated postmenopausal age groups (mean 52.5 y). Of the 24
erythrocytes, and absence of permeative growth and patients, 7 were on unopposed estrogen and 4 were on
vascular invasion. combined estrogen-progestin therapy; 1 patient had a
synchronous ovarian thecoma. Several cases of polypoid
endometriosis have also been reported in patients
MISCELLANEOUS TUMORLIKE FINDINGS
receiving tamoxifen therapy78,82 and one case followed
A variety of findings in endometriosis can suggest
withdrawal of GnRH-agonist treatment for severe
the presence of a neoplastic process. Some of these have
endometriosis.83
already been discussed, including myxoid change, signet-
The most common clinical presentations are related
ring–like decidualized stromal cells, cytologic atypia and
to a pelvic mass, a polypoid vaginal mass, or large bowel
hyperplasia of the epithelial component, and stromal
obstruction. Sites of involvement in order of frequency in
endometriosis. Other tumorlike findings are considered in
the series of Parker et al81 were colonic mucosa, ovary
this section.
(involving the ovarian surface or lining an endometriotic
Necrotic Pseudoxanthomatous Nodules cyst), uterine serosa, cervical or vaginal mucosa, ureter,
These lesions (NPNs) are an uncommon manifesta- fallopian tube, omentum, bladder, paraurethral and
tion of endometriosis and tend to occur in the post- paravaginal soft tissue, and retroperitoneum. In 30% of
menopausal and late reproductive age groups.18 They cases, multiple sites were involved. Polypoid, pink, gray
take the form of multiple nodules that are usually or tan, masses ranged up to 14 cm in maximal dimension
attached to the peritoneum or occasionally are free- (Fig. 4G). On microscopic examination, the polypoid
floating within the peritoneal cavity. In most cases, masses were composed of an admixture of endometriotic
typical endometriosis is present in the ovaries and in glands and stroma (Fig. 4H). A variety of glandular
one case NPNs lined an endometriotic cyst.18 The architectural patterns were observed, sometimes in
intraoperative appearance in some cases has suggested a combination, most commonly cystic and non-cystic
disseminated malignant tumor. On histologic examina- simple hyperplasia, but also simple or complex hyperpla-
tion, the nodules have a central necrotic zone that is sia with atypia, disordered proliferative, and cystic
surrounded by pseudoxanthoma cells, often in a pali- atrophy. Various types of epithelial metaplasia (tubal,
saded arrangement, hyalinized fibrous tissue, or both mucinous, squamous, papillary syncytial metaplasia) were
(Figs. 4E, F). The presence of necrosis, particularly on common. Hemorrhage, fibrosis, prominent thick-walled
frozen section examination in a patient with intraopera- blood vessels, hemosiderin-laden histiocytes, and decidual
tive findings suspicious for cancer, can increase concern change were also present in some cases. Most of the cases
for the latter. Endometriotic glands and stroma are were associated with usual (nonpolypoid) endometriosis
usually absent or sparse within the nodules, but may be (Fig. 4H). In 1 case, polypoid endometriosis merged with
seen elsewhere in the same specimen. Most NPNs likely a mucinous borderline tumor of endocervical-type. Of the
represent ‘‘burned-out’’ or end-stage endometriotic foci. 17 patients with follow-up data, 15 were alive without
In 1 case, however, multiple peritoneal and omental evidence of residual disease, 1 was alive with residual
NPNs that were not present at the time of salpingo- endometriosis, and 1 died of other causes.
oophorectomy performed for a ruptured ovarian endo- Extrauterine mullerian adenosarcoma is the most
common differential diagnostic consideration.84,85 In
metriotic cyst, were found at reexploration 7 weeks later,
and were thus considered a unusual reaction to the contrast to this neoplasm, however, the reported cases
contents of the endometriotic cyst.76 of polypoid endometriosis, with 2 exceptions, lacked
The importance of NPNs rests on their being periglandular stromal hypercellularity, stromal atypia,
diagnostic or at least strongly suggestive of endometriosis and intraglandular stromal papillae. Focal intraglandular
when its more typical features are absent, and their stromal papillae were noted in 2 cases with focal mild
potential to be confused with an infectious process or periglandular stromal hypercellularity in one of them, but
necrotic tumor that might prompt unnecessary investiga- in contrast to adenosarcoma, stromal atypia was absent
tions. NPNs should also be distinguished from necrotiz- in each case. Diagnosis may be particularly difficult if the
ing peritoneal granulomas that may be seen after polyps of polypoid endometriosis undergo torsion with
diathermy ablation treatment for endometriosis.77 The hemorrhagic infarction. In these cases, endometriotic
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12. Clement Adv Anat Pathol Volume 14, Number 4, July 2007
Pseudoxanthomatous Salpingitis
stromal cells may exhibit reactive atypia and mitotic
activity, complicating the differential with adenosarcoma. As noted earlier, pseudoxanthoma cells can be a
In rare cases in which a definite diagnosis is not possible, striking finding in the tubal mucosa in patients with pelvic
the patient should receive clinical follow-up. endometriosis, a finding that has been referred to as
pseudoxanthomatous salpingitis (or pseudoxanthoma-
tous salpingiosis) (Figs. 5C, D).18,97,98 The process may
Rare Tumorlike Findings result in a chocolate-brown discoloration of the tubal
Rarely, endometriosis may be associated with mucosa visible on macroscopic examination (Fig. 5C). In
worrisome findings that can include unusually extensive our experience, pseudoxanthomatous salpingitis has al-
and/or bulky disease, vascular invasion, or a poor ways been associated with pelvic endometriosis, and in
response to treatment.86–93 The designation ‘‘aggressive such cases likely represents an inflammatory reaction to
endometriosis’’ has sometimes been applied to such cases, endometriosis-derived blood or blood products that reach
but we discourage its use as a pathologic diagnosis the tubal lumen. One otherwise similar case, however,
because the subsequent behavior of endometriosis cannot reported as ‘‘pigmentosis tubae,’’ was found in a patient
be reliably predicted by its morphologic features. Further, without endometriosis but who had been previously
such a diagnosis could prompt unwarranted physician or treated with pelvic radiation.99
patient concern.
Mesothelial Hyperplasia
Vascular involvement by endometriosis (Fig. 5A) is
analogous to the more common phenomenon of endo- Endometriosis is frequently accompanied by me-
metrial glands and stroma (or stroma only) within sothelial hyperplasia of the pelvic or even extrapelvic
myometrial vessels in cases of adenomyosis.94 Scolyer et peritoneum, which in some cases may be striking. The
al91 reported a case of an ovarian endometriotic cyst that hyperplasia may occur adjacent to, or at a distance from,
the endometriosis. Kerner et al100 documented mesothe-
was associated with florid involvement of large vascular
spaces (thick-walled lymphatics and veins) within both lial hyperplasia (‘‘mesothelial inclusions’’) in 10% of
mesovaria. The endometriotic tissue completely occluded women with ovarian endometriosis, but in none of the
some vessels or in others formed large polypoid tongues patients from a control group without endometriosis.
that partly filled their lumina. A similar case was reported Mesothelial hyperplasia in women with endometriosis
by Ooi and Valentine.90 In another report, Wuster and most commonly involves the surface of the ovaries, the
Leu92 documented a case of abdominal wall endome- fallopian tubes, the pelvic peritoneum, and the omentum.
triosis in which several veins contained endometriotic The hyperplastic mesothelial cells typically form small
tissue. Zardawi93 reported 2 cases of colonic endome- tubules, papillae, nests, cords, or even single cells, often
triosis that were each associated with intravascular entrapped within a reactive fibrous tissue, which in florid
endometriosis within the colonic wall. In one of them, cases may create a pseudoinfiltrative pattern (Fig. 5E).
there was endometriosis within a pericolic lymph node Retraction artifact around the congeries of mesothelial
and in the other there was a focus of hepatic endome- cells is common and may incorrectly suggest lymphatic
triosis, findings supporting the hypothesis that some cases invasion (Fig. 5E).
of endometriosis in unusual sites are a result of vascular In our experience, the most striking cases of endo-
or lymphatic embolic spread. metriosis-associated mesothelial hyperplasia are seen, not
As has been reported in other non-neoplastic lesions surprisingly, on the outer aspects of endometriotic cysts.
(sclerosing adenosis of the breast, vasitis nodosa), perineural These mesothelial cells can become incorporated in the
invasion has been rarely encountered in otherwise typical, wall of the cyst (Fig. 5E), often as small tubules in linear
benign endometriotic lesions95 (Fig. 5B) and seems to be arrangements that parallel the overlying serosa, a finding
of no clinical significance. identical to the mural mesothelial hyperplasia within the
walls of multilocular peritoneal inclusion cysts (MPICs)
(see below).101 Indeed, since the report of this finding in
MPICs, we have seen more cases of mural mesothelial
INFLAMMATORY AND REACTIVE CHANGES
proliferation in the walls of endometriotic cysts than in
Infected Endometriotic Cysts MPICs. In some such cases, the mesothelial cells may
Schmidt et al96 found pathologic evidence of even approach the cyst lining, the appearance sometimes
infection in 11 of 510 endometriotic cysts (2%). The raising concern for an invasive adenocarcinoma arising
patients had a mean age of 34.7 years and typically from the epithelial lining of the cyst. Awareness of the
presented with fever and lower abdominal pain; about pitfalls associated with mesothelial hyperplasia in this
half had a history of pelvic inflammatory disease. setting is crucial in avoiding a serious diagnostic error. If
Histologic examination revealed endometriotic cysts that necessary, immunohistochemical staining can be used to
contained a fibrinopurulent exudate, microabscesses, and confirm that the cells are mesothelial and not epithelial.
inflammatory cells other than neutrophils, such as plasma
Multilocular Peritoneal Inclusion Cysts
cells. All of the patients who had one or both fallopian
tubes removed at the same operation had histologic A substantial proportion of women with MPICs
evidence of acute and/or chronic salpingitis. (also referred to as ‘‘cystic mesotheliomas’’) have or have
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13. Adv Anat Pathol Volume 14, Number 4, July 2007 The Pathology of Endometriosis
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 thickened
mucosa that varies from yellow to brown. D, Pseudoxanthomatous salpingitis. The tubal plicae are filled with foamy and
pigmented histiocytes. E, Florid mesothelia hyperplasia within the wall of an endometriotic cyst. The mesothelial cells form small
irregular aggregates within reactive fibrous tissue resulting in an infiltrative pattern. Note the retraction artifact around the
aggregates of mesothelial cells, a finding that can be misinterpreted as lymphatic invasion and thus increase suspicion for a
malignant tumor. F, Numerous Liesegang rings and necrotic debris occupy the lumen of an endometriotic cyst.
had endometriosis. In these cases, the cysts likely study of MPICs had coexistent endometriosis or a history
represent a complication of endometriosis-related adhe- of the disease. Additionally, several reports have docu-
sions. Ross et al102 found that 36% of women in their mented an intimate admixture of the 2 lesions. Groisman
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15. Adv Anat Pathol Volume 14, Number 4, July 2007 The Pathology of Endometriosis
and Kerner103 reported an MPIC that contained foci of glands may be numerous and cystic, increasing their
typical endometriosis and NPNs within the cyst locules. potential resemblance to cortical epithelial inclusion cysts
Additionally, Zotalis et al104 described a 35 cm omental (Fig. 6A), and their often subtle cuffs of endometriotic
mass that consisted of an admixture of endometriosis, stroma may not be distinguishable from ovarian stroma
peritoneal inclusion cysts, and nodules of smooth muscle unless examined at high-power magnification.
(peritoneal leiomyomatosis, as discussed below). Helpful diagnostic features are the tendency for
endometriotic stromal cells to be less spindled than
Liesegang Rings ovarian stromal cells and for the latter not to condense
Liesegang rings are a rare microscopic finding and around glands as in endometriosis. Ovarian stromal cells
are typically encountered within or adjacent to necrotic, often have fascicular or storiform arrangements that are
inflamed, or fibrotic tissue. They take the form of not a feature of endometriotic stroma. Other findings, as
eosinophilic, PAS-positive, acellular, variably-sized, ring- noted earlier, that should suggest the diagnosis of
like structures (Fig. 5F). Six of the 8 reported cases of endometriosis are the presence of numerous arterioles
Liesegang rings in the female genital tract were associated (some of which may be distended with erythrocytes),
with endometriosis, usually within the walls and lumens of stromal hemorrhage, and foamy or pigmented histiocytes.
endometriotic cysts (5 of the cases) or less commonly The latter may form aggregates only loosely attached to,
within endometriotic implants (1 case).105,106 These struc- or even seemingly detached from, the ovarian surface.
tures have been histologically confused with, and should be Immunoreactivity of the stromal cells for CD10 can also
distinguished from, parasites and foreign material. be helpful distinguishing endometriotic stromal cells from
ovarian stromal cells (Fig. 6D), which are CD10-
negative,12–14 although immunostaining for this marker
SELECTED SITE-RELATED ISSUES
should rarely be needed.
Endometriosis on or Close to the
Ovarian Surface Superficial Endometriosis of the Uterine Cervix
The ovary is the most common site for endome- Cervical endometriosis may be superficial (mucosal)
or deep.107,108 Superficial cervical endometriosis is fre-
triosis, where its presence is usually obvious owing to
appreciable foci within the ovarian parenchyma that quently localized to areas of prior biopsy or cautery,
contain obvious endometriotic glands or cysts and suggesting implantation of menstrual endometrium or
trauma-induced metaplasia.108 Deep cervical endometrio-
endometriotic stroma. In contrast, endometriosis con-
fined to the ovarian surface or superficial cortex may be sis is usually an extension of cul-de-sac involvement
under-diagnosed not only because of the often micro- associated with typical pelvic endometriosis.
scopic size of the foci but also because endometriotic Superficial endometriosis is usually an incidental
stroma and glands are easily misinterpreted as ovarian microscopic finding, but occasionally it can cause a
stroma and epithelial inclusion glands (Figs. 6A–C). thickened, granular, or hemorrhagic mucosa, or be
Surface ovarian endometriosis is often embedded within responsible for an abnormal cervicovaginal smear. The
adhesions or may form thin plaques or tiny tear- lesion is almost always found beneath the surface
drop–shaped surface polypoid projections (Fig. 6B). Both epithelium and/or admixed with the normal endocervical
endometriotic glands and stroma are usually present but glands (Figs. 6E, F). The endometriotic glands are
one component may predominate. When endometriotic typically well spaced and round to oval but occasionally
foci occupy the most superficial cortical stroma, the may show irregularity in size and shape and crowding.
FIGURE 6. A, Endometriosis on the ovarian surface. The cystically dilated endometriotic glands are separated by endometriotic
stroma, the appearance of which differs from that of the underlying ovarian stroma (bottom). B, Endometriosis on the ovarian
surface. Polypoid projections are composed predominantly of endometriotic stroma that is congested and hemorrhagic, differing
in appearance from the underlying ovarian stroma at the bottom of the field. Two cystic endometriotic glands are also present
and can be potentially confused with ovarian inclusion glands, one of which is partly represented in the extreme bottom of the
field. C, Endometriosis in superficial ovarian cortex. A single endometriotic gland is surrounded by endometriotic stroma that
merges with ovarian stroma at the extreme left and extreme right of the figure. In a small focus such as this, the endometriotic
gland 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 ovarian
stroma is CD10 negative. E, Superficial endometriosis of uterine cervix. Endometriotic glands are subjacent to the normal cervical
squamous epithelium and are separated by scanty endometriotic stroma that contains congested blood vessels. The
endometriotic 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 the
endometriotic nature of the focus is not recognized. The glands are separated by endometriotic stromal cells, the features of
which 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 are
dilated lymphatics. H, Endometriosis intimately admixed with peritoneal leiomyomatosis, two nodules of which are seen on the
right side of the field.
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16. Clement Adv Anat Pathol Volume 14, Number 4, July 2007
They most commonly resemble the glands of a prolif- with endometriosis in other sites. Deep endometriosis is
erative or weakly proliferative endometrium, including more common, and is typically located in the posterior
the presence of occasional mitotic figures (Fig. 6F). fornix. The latter may represent extension of cul-de-sac
Occasionally they have a secretory appearance. An disease, and may be associated with involvement of the
rectovaginal septum.114
endometriotic stromal component is obvious in most
Staats et al,115 in a recent study of 18 cases of
cases, usually as periglandular collections of cells with
small uniform, dark, naked, oval to round nuclei. In some vaginal endometrioid adenocarcinoma, found a strong
cases, however, the stromal cells are difficult to appreciate association with vaginal endometriosis, the latter being
because they are sparse and/or obscured by edema, identified in 14 cases. Ten tumors were located at the
hemorrhage, inflammation, or combinations thereof vaginal apex. The tumors contained an exclusive or
(Figs. 6E, F). The presence of the characteristic small predominant component of endometrioid carcinoma;
arterioles and extravasated erythrocytes can aid the unusual findings in some of the tumors included
recognition of the stromal component in such cases. squamous metaplasia, mucinous metaplasia, and promi-
nent small nonvillous papillae.116 As noted at the very
Rarely, superficial cervical endometriosis is composed
only of endometriotic stroma (stromal endometriosis) beginning of this review, the presence of endometriosis
(Fig. 4D), as considered earlier.73 adjacent to a mullerian-type neoplasm can be very helpful
The diagnosis of superficial cervical endometriosis in indicating that the tumor is likely primary in that site.
and its distinction from the otherwise similar finding of This observation is particularly important in establishing
tuboendometrioid metaplasia of the endocervical a vaginal origin for endometrioid carcinomas because of
glands108 requires the recognition of endometriotic their rarity compared to other sites in the female genital
stroma and its distinction from endocervical stroma. This tract and because the vagina is a common site of
recognition can be facilitated by reticulin and trichrome recurrence of endometrial adenocarcinoma.
staining, endometriotic stroma having dense reticulin but
Tubal Endometriosis
sparse collagen with the opposite findings in normal
endocervical stroma.109 McCluggage et al13 found that An unadorned diagnosis of ‘‘tubal endometriosis’’ is
normal endocervical stromal cells are immunoreactive for ambiguous as it has been applied to 3 different lesions of
CD10, especially those around endocervical glands, the fallopian tube. The most common is endometriosis
limiting the usefulness of this marker in the diagnosis of involving the tubal serosa or subserosa; it is usually
cervical endometriosis. In the study of Barroeta et al,110 associated with endometriosis elsewhere in the pelvis.
Sheldon et al,117 in a study of 23 such cases, found that
however, endocervical stromal cells were predominantly
CD34+/CD À (‘‘CD34 dominant phenotype’’), whereas the foci were confined to the serosa in 16 cases, with the
endometrial stromal cells were predominantly CD34 À / remainder showing some downgrowth into the subserosal
CD10+ (‘‘CD10 dominant phenotype’’). Additionally, tissues; surprisingly, the myosalpinx was not involved in
Orlandi et al111 found that cellular retinol-binding any of the cases. Ovarian endometriosis was present in
protein-1 is a more specific marker for endometrial half the cases.
stromal cells than CD10 and could be helpful in this The mucosa of the interstitial portion of one or both
context because it does not stain endocervical stromal tubes can be of endometrial type in as many as 25% of
cells. women in the general population; the corresponding
When superficial cervical endometriosis is over- frequency of endometrial-type lining in the isthmic and/or
ampullary portions of the tube is 10%.118,119 The
looked on microscopic examination, reactive atypia and/
or mitotic activity in the endometriotic glands and their endometrial-type lining in these cases can be diffuse or
occasional immunoreactivity for p16 and a high MIB1 interspersed with tubal-type mucosa. These findings are
index112 can result in a misdiagnosis of endocervical considered to represent a normal morphologic variation,
glandular dysplasia or even AIS.107 An absence of both but it is not clear if the ectopic endometrial tissue in these
the marked nuclear atypia and the numerous apoptotic cases is developmental, metaplastic, or a result of direct or
bodies of AIS and recognition of the endometriotic embolic spread of eutopic endometrium. The ectopic
nature of at least some of the stromal cells facilitate the endometrial tissue may give rise to a variety of lesions,
including endometrial-type polyps,118 tubal adenomyosis
diagnosis. Negative or only focal p16-immunoreactivity
(analogous to salpingitis isthmica nodosa),119 and in-
also favors endometriosis in this context, although more
extensive staining does not exclude the diagnosis.112 traluminal endometriosis with occlusion of one or both
tubal lumens (Fig. 6G).120,121 Intraluminal endometriosis,
Vaginal Endometriosis which may or may not be associated with endometriosis
The vagina is not a common location for endome- elsewhere, accounts for about 15% of tubal-related
triosis; Stern et al5 found that only 2% of over 1000 cases infertility and may be associated with tubal pregnancy.120
of endometriosis were vaginal. As in the cervix, vaginal The third type of tubal endometriosis, ‘‘postsalpin-
endometriosis can be superficial or deep.113,114 The gectomy endometriosis,’’ occurs in the tip of the proximal
former most commonly involves the vaginal vault and tubal stump, typically 1 to 4 years after tubal liga-
tion.122,123 It otherwise resembles tubal adenomyosis
shares with its more common cervical counterpart an
apparent relation to trauma and a lack of association (see above), and may be admixed with salpingitis isthmica
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17. Adv Anat Pathol Volume 14, Number 4, July 2007 The Pathology of Endometriosis
matosis have been reported (Fig. 6H)104,132,133; in 1 case,
nodosa. Endometrial glands and stroma extend from the
admixed peritoneal inclusion cysts were also present.104
endosalpinx into the myosalpinx and sometimes to the
serosa. Hysterosalpingography or India ink injection in Two of the patients had taken oral contraceptives.
some cases can demonstrate tuboperitoneal fistulae, Although the combination of endometriosis and perito-
which can lead to postligation pregnancies. Postsalpin- neal leiomyomatosis might be coincidental, the intimate
gectomy endometriosis has been found in 20% to 50% of relationship of the two lesions suggests a multidirectional
tubes examined after ligation. It is more common with metaplasia, consistent with the mullerian potential of the
peritoneum (‘‘secondary mullerian system’’).134
long postligation intervals, the electrocautery method of
ligation, and with short proximal stumps. Three cases of peritoneal gliomatosis in which the
glial implants contained foci of endometriosis have been
Intestinal Endometriosis described.135–137 In each case, the peritoneal lesions were
The typical pathologic features of intestinal endo- found a decade or more after removal of an ovarian
metriosis have been reviewed elsewhere,2,3,124 and only teratoma that was immature in at least two of the cases.
more recent observations will be highlighted here. The The foci of endometriosis were confined to the glial
lesions can vary macroscopically from small, clinically implants in each case. Intriguingly, 2 recent studies138,139
insignificant serosal or mural lesions to large tumorlike have suggested that the glial implants of peritoneal
mural masses that can cause kinking of the bowel gliomatosis are genetically unrelated to the associated
and luminal obstruction. Endometriosis, including its teratoma and are likely of metaplastic origin. The
polypoid variant, can also involve the colonic mucosa, presence of endometriotic tissue within the glial tissue in
potentially simulating a primary colonic adenocarcinoma these cases provides some support for this hypothesis.
on gross examination. The histologic diagnosis of
intestinal endometriosis is usually straightforward, but ACKNOWLEDGMENT
occasionally it may induce a variety of histologic changes The author thanks Dr Robert H. Young who offered
that can mimic primary bowel disease, such as colitis, constructive criticism of the manuscript that was most
mucosal prolapse, solitary rectal ulcer, and ischemic and helpful.
adenomatous lesions.124–126 Thus caution is warranted in
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