Pseudoneoplastic Lesions of the Female Genital Tract
Fabiola Medeiros, MD; Debra A. Bell, MD
NContext.—Numerous benign, proliferative, or reactive
processes, often related to hormone stimulation or inflam-
mation, occur throughout the female genital tract and may
mimic benign or malignant tumors. Several of the more
common pseudoneoplastic lesions are discussed in this
article, including microglandular hyperplasia of the cervix
mimicking well-differentiated endometrial adenocarcinoma,
reactive epithelial changes in the fallopian tubes mimicking
adenocarcinoma or carcinoma in situ, and pregnancy
changes in the ovary including pregnancy luteoma and large
solitary luteinized follicular cyst of pregnancy and puerperi-
um that may mimic ovarian neoplasms.
Objectives.—To discuss and illustrate several common
lesions of the female genital tract that mimic neoplasms.
Data Sources.—Material derived from consultation
cases and review of the literature.
Conclusions.—Many benign hyperplastic or reactive
processes that occur in the female genital tract may be
mistaken for neoplasms both clinically and pathologically.
Awareness of the features of such lesions will aid in their
correct diagnosis and prevent overtreatment of benign
(Arch Pathol Lab Med. 2010;134:393–403)
stimulation may mimic neoplasms throughout the female
genital tract. Although many of these proliferative
processes are difficult to distinguish from neoplasms,
frequently their morphologic features allow their identi-
fication. Several such entities are discussed in this review,
including microglandular hyperplasia of the cervix
mimicking well-differentiated endometrial and endocer-
vical adenocarcinoma, reactive epithelial changes in the
fallopian tubes mimicking adenocarcinoma or carcinoma
in situ, atypical and hyperplastic changes in endometri-
osis, and pregnancy changes in the ovary including
pregnancy luteoma and large solitary luteinized follicular
cyst of pregnancy and puerperium. Recognition of these
pseudoneoplastic entities is of crucial importance in
preventing overtreatment of such lesions that often occur
in young women of reproductive age.
variety of reactive and hyperplastic processes due to
inflammation or repair and hormone or gonadotropin
The distinction between benign endocervical glandular
proliferations and adenocarcinoma in both endocervical
and endometrial specimens continues to represent a
diagnostic challenge. Several entities have been recog-
nized as mimics of malignancy; amongst those, micro-
glandular hyperplasia probably represents the most
This entity was first recognized in a study of cervical
changes in pregnant women.1The term microglandular
hyperplasia was first used by Kyriakos and coworkers2in
1968 for a cohort of patients taking oral contraceptives.
Surprisingly, 1 year before this landmark publication, the
lesion was already recognized as bearing histopathologic
resemblance with endocervical adenocarcinoma.3Cur-
rently, it is controversial whether microglandular hyper-
plasia bears true association with endogenous or exoge-
nous hormones.4,5The lesion usually occurs in women of
reproductive age, but a small percentage of patients are
Microglandular hyperplasia is frequently an incidental
finding but can present as a polyp or erosion. At low-
power view, the architecture is variable; the lesion can be
polypoid or not, single or multifocal, superficial or deeply
located. Characteristically, it is composed of closely
packed, small tubular or irregular glands with areas of
cystic dilatation (Figure 1, A). There is scant intervening
stroma and no sharp separation between glands and
stroma (Figure 1, B). Admixed acute and chronic inflam-
mation is typically associated with the lesion and is often
present within the luminal secretions (Figure 1, C). The
lining epithelium is cuboidal or low columnar and
mucinous, with variable degrees of squamous metaplasia
and reserve cell hyperplasia (Figure 1, D). Cytoplasmic
vacuoles are common and are characteristically subnucle-
ar, but supranuclear vacuoles are also encountered. In
most instances, the nuclei are bland; when present, atypia
is usually focal (Figure 1, C). Mitotic figures are rare or
The typical histopathologic features of microglandular
hyperplasia are well established, but uncommon patterns
can pose problems in the differential diagnosis. These
include solid, sheetlike proliferations of cells, pseudoinfil-
trative growth, signet ring cells, hobnail-like cells,
increased nuclear atypia, and mitotic figures7,8(Figure 2,
A and B). We have recently encountered an example of
florid microglandular hyperplasia in a pregnant patient,
associated with Arias-Stella reaction, that closely simulat-
Accepted for publication October 21, 2009.
From the Department of Laboratory Medicine and Pathology, Mayo
Clinic, Rochester, Minnesota.
The authors have no relevant financial interest in the products or
companies described in this article.
Reprints: Debra A. Bell, MD, Department of Laboratory Medicine and
Pathology, Mayo Clinic, Hilton Bldg 11th floor, 200 First St SW,
Rochester, MN 55905 (e-mail: firstname.lastname@example.org).
Arch Pathol Lab Med—Vol 134, March 2010Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell393
demarcation between glands and stroma. C, Reserve cell hyperplasia and squamous metaplasia is associated with the glands D, Bland cuboidal
mucinous cells without nuclear atypia and mitosis; also note the inflammatory infiltrate (hematoxylin-eosin, original magnifications 3100 [A], 3200
[B and C], and 3400 [D]).
Typical histopathologic features of microglandular hyperplasia. A, Low-power view of crowded glands with focal cystification. B, Poor
hyperplasia with solid growth pattern (hematoxylin-eosin, original magnifications 3400 [A] and 3200 [B]).
Unusual morphologic variants of microglandular hyperplasia. A, Nuclear atypia in microglandular hyperplasia. B, Microglandular
394 Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell
ed adenocarcinoma. Importantly, these unusual patterns
merge with areas of typical microglandular hyperplasia,
thus facilitating the correct diagnosis in well-sampled
specimens. However, a greater diagnostic challenge is
faced in small and fragmented biopsy samples.
The difficult distinction of endocervical microglandular
hyperplasia and well-differentiated endometrial adeno-
carcinoma in biopsy and curettage specimensis a common
reason for consultation in gynecologic pathology. Partic-
ularly concerning are well-differentiated endometrial
adenocarcinomas with mucinous differentiation, either
in pure form or, more commonly, intermixed with
endometrioid adenocarcinoma. The architectural pattern
can be confusingly similar and can feature small crowded
glands. The presence of nuclear atypia and mitotic figures
is certainly helpful in favoring endometrial adenocarci-
noma; yet the latter may be deceptively bland. Both
conditions may display associated squamous differentia-
tion, in the form of central squamous morules in
endometrioid adenocarcinoma and immature squamous
metaplasia in microglandular hyperplasia. Intraluminal
mucin and polymorphonuclear infiltration can be seen in
both conditions.9It is often very helpful to characterize the
normal epithelium in the same fragment as the lesion in
question; if endometrial or endocervical, as an indication
of endometrial adenocarcinoma or microglandular hyper-
plasia, respectively. Table 1 and Figure 3, A through D,
provide a comparison between endocervical microgland-
ular hyperplasia and endometrial adenocarcinoma and
demonstrate the difficulty in this distinction. Above all,
considering the age of the patient is of major importance.
The diagnosis of microglandular hyperplasia in endome-
trial samples of postmenopausal women should be
exercised with extreme caution.9,10Overall, the presence
of even mild nuclear atypia or mitotic activity in a
complex glandular proliferation in a sample confirmed
to be from the endometrium (by the presence of
endometrial tissue) in a perimenopausal or postmeno-
pausal woman should raise the concern of well-differen-
tiated adenocarcinoma and prompt further investiga-
Microglandular hyperplasia may also simulate invasive
endocervical adenocarcinoma.7,11As in the differential
with endometrial carcinoma, the presence of nuclear
atypia and mitotic activity strongly favors malignancy.
Architecturally, invasive adenocarcinomas tend to have
more irregular and haphazardly arranged glands with
surrounding desmoplastic stroma. Identification of adja-
cent adenocarcinoma in situ would be consistent with a
neoplastic process in a questionable focus. Finally, if
morphologic examination does not suffice, p16 immuno-
staining or human papilloma virus in situ hybridization
may be used; positivity would be diagnostic of neoplasia
in this particular setting. Some studies12,13have explored
the application of immunohistochemistry for carcinoem-
bryonic antigen as an adjunct to the morphologic
diagnosis. They report more frequent and diffuse expres-
sion in adenocarcinoma versus microglandular hyperpla-
sia. Despite the positive results, these studies comprised a
few cases. This may be the reason why, to our knowledge,
this complementary method has not been widely used in
the differential diagnosis of microglandular hyperplasia.
The diagnosis of clear cell carcinomas may be enter-
tained in rare instances. This tumor typically occurs in
older women in contrast to the predominantly reproduc-
tive-age population for microglandular hyperplasia. Clear
cell carcinoma shows marked cytologic atypia and numer-
ous mitotic figures, at least focally. Both lesions may
contain tubular, cystic, and solid patterns but the papillary
growth seen in some clear cell carcinomas is not found in
microglandular hyperplasia. The solid growth of clear cell
carcinoma displays cells with abundant clear cytoplasm,
while the cells in microglandular hyperplasia tend to be
smaller and have bland nuclei, containing subnuclear
vacuoles and lacking intracytoplasmic glycogen.
Microglandular hyperplasia is a reactive process of
endocervical glands that occurs most commonly in
women of reproductive age. The importance of its
recognition lies in the distinction from malignant process-
es, primarily endometrial and endocervical adenocarci-
nomas. The examination of scant biopsy specimens
remains a challenge.
FALLOPIAN TUBE LESIONS
The fallopian tube has a limited variety of neoplastic
and pseudoneoplastic processes when compared to other
organs of the female genital tract and has traditionally
received modest interest regarding histopathologic find-
ings. However, it has become a focus of greater attention
during the last few years, after the recognition of its role in
the development of serous carcinoma in women with
germline BRCA mutations who undergo risk-reducing
salpingo-oophorectomy.14,15Recent contributions have
progressively pinpointed the tubal epithelium as the
potential origin of tubal, ovarian, and peritoneal carcino-
mas, not only in the BRCA mutation setting but also in
sporadic adnexal epithelial tumors.16–18This knowledge
has led pathologists to heighten their index of suspicion
regarding tubal atypia and has resulted in an appreciation
of subtle neoplastic changes occurring in the fallopian
tube epithelium, as well as the propensity of reactive
atypia to mimic serous carcinoma in situ. BRCA-related
neoplasms are usually clinically and grossly occult, often
microscopic, and in situ, leading to difficulty in differen-
tial diagnosis with reactive changes.19The distinction is of
major importance and guides decisions regarding staging,
surgery, chemotherapy, and follow-up.20,21
Table 1. Comparison of Endocervical Microglandular Hyperplasia (MGH) and Well-Differentiated Endometrioid
Mucinous with subnuclear vacuoles
Absent or rare
Perimenopausal or postmenopausal
Benign or hyperplastic endometrium
Endometrioid and/or mucinous
Arch Pathol Lab Med—Vol 134, March 2010Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell395
appearance with closely packed glands. However, the glands of endometrial adenocarcinoma tend to be more irregularly shaped (A) than those in
microglandular hyperplasia (B). The cells of endometrial adenocarcinoma have greater pleomorphism and irregular chromatin (C), while in
microglandular hyperplasia, the nuclei are bland and regular (D). Also note the mitotic figure (C, arrow) in the endometrial adenocarcinoma
(hematoxylin-eosin, original magnifications 3100 [A and B] and 3400 [C and D]).
A and C, Endometrial adenocarcinoma (left). B and D, Microglandular hyperplasia (right). Both lesions have a similar low-power
are taller with oval nuclei (hematoxylin-eosin, original magnification 3400).
Normal fallopian tube epithelium showing the ciliated cells with clear cytoplasm and round nuclei and intermixed secretory cells; they
ratio and, more importantly, the cilia. Mitoses are absent (hematoxylin-eosin, original magnification 3400).
Reactive tubal epithelial changes. Note that despite the severe nuclear enlargement and atypia, the cells maintain nuclear to cytoplasmic
396 Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell
The fallopian tube epithelium shows morphologic
changes in response to hormonal status.22–24During the
estrogenic phase of the menstrual cycle, the tubal ciliated
cells show increased height and number, and mitotic
figures are slightly more frequent. Despite these features,
mitotic figures are extremely rare in normal tubal
epithelium.23Normal tubal lining cells have scant cyto-
plasm and can appear dark and crowded at low-power
view. However, the nuclear features are bland (Figure 4).
Mild degree of mucosal epithelial proliferation is frequent
in fallopian tubes removed for a diversity of reasons, and
it can be found in up to 66% of tubal ligations.25
More prominent reactive changes involving the fallopi-
an tube have been referred to as atypical or adenomatous
hyperplasia.25–27They can be encountered in association
with a variety of conditions, including inflammation,
hyperestrogenic states, and neoplastic processes involving
other gynecologic sites.28–30These findings have been
reported in 7% to 16% of unselected salpingectomy
Reactive tubal epithelial changes are
characterized by mucosal hyperplasia with crowding
and stratification of the epithelium, tufting, and nuclear
atypia (Figure 5). The nuclear atypia is mild to moderate,
but can be focally severe. Mitotic figures are infrequent
and often absent. The cells maintain the nuclear to
cytoplasmic ratio and cilia.
Early tubal carcinoma is typically of serous type and
arises most commonly in the fimbriae but other histologic
variants have been described and other fallopian tube
segments may be affected.17Serous carcinoma in situ of
the fallopian tube reveals a hypercellular stratified
epithelium with nuclear crowding, enlargement and
hyperchromasia, loss of polarity, increased nuclear to
cytoplasmic ratio, and often numerous mitotic figures
(Figure 6, A).
Factors classically used in the distinction of a malignant
versus a pseudoneoplastic process, such as young age,
absence of gross tumor, and lack of solid areas, are not as
helpful in the BRCA era. Therefore, this differentiation has
to rely on a constellation of clinicopathologic features
(Table 2). In reactive changes, the nuclear atypia is less
alarming than in tubal serous carcinoma in situ that
displays severe nuclear atypia in all cells comprising the
lesion. The identification of cilia and terminal bars in the
apical surface of the cells in question is very helpful, as
those are invariably absent in high-grade serous carcino-
ma. A high mitotic activity has been regarded by some as
the only single diagnostic criteria for carcinomas, as
mitotic figures are absent or infrequent in reactive
In a simplistic way, the diagnosis of serous carcinoma in
situ requires unequivocal cytologic atypia that cannot be
explained by a reactive process. In case of doubt,
immunostains for MIB-1 and p53 can be applied. The
nuclearpositivity for p53shouldbe strong and diffuse and
MIB-1 proliferation index should be high to support a
diagnosis of serous carcinoma.18It is often useful to
compare the area in question to the rest of the epithelium
(Figure 6, A through F).
According to the literature and also in our experience,
patients with BRCA mutations frequently have epithelial
atypia that does not reach the criteria for carcinoma.33,34It
is conceivable that these lesions could progress to
carcinoma, but currently this is merely speculation. It is
very important to strictly apply the criteria. Only
carcinomas in situ should be considered diagnosable
lesions until a general consensus is reached for the
diagnostic features of the earlier morphologically recog-
nizable stages of tubal carcinogenesis, such as dysplasia.
These alterations are of uncertain significance at this point;
only time and growing experience will reveal their
A more florid example of reactive change in the
fallopian tube that mimics invasive adenocarcinoma has
been termed pseudocarcinomatous hyperplasia.35,36It may be
encountered in tuberculous salpingitis and nontubercu-
lous salpingitis. It is characterized by crowding and
stratification of the epithelium, apparent gland formation
or cribriforming, tufting, and nuclear atypia (Figure 7, A
through C). This is associated with glandular infiltration
of the muscularis propria with desmoplastic reaction and
pseudoglandular hyperplasia of tubal serosal mesothelial
cells, mimicking transmural extension of carcinoma.
However, florid tubal epithelial hyperplasia almost
invariably is accompanied by marked chronic and
sometimes acute inflammation. Mitotic activity in tubal
hyperplasia generally is low. It must be emphasized that
inflammation can be occasionally present in tubal carci-
nomas, highlighting again the importance of the cytologic
features in the differential diagnosis.
Metaplastic papillary tumor is a peculiar and uncom-
mon incidental finding in the fallopian tube during
pregnancy or postpartum period. The lesion is micro-
scopic and composed of papillary structures lined by large
epithelial cells, with abundant eosinophilic cytoplasm
with mild nuclear atypia (Figure 8). Because of its distinct
appearance, it is easily differentiated from borderline
tumors or adenocarcinoma.36,37
The histopathologic diagnosis of endometriosis is
usually straightforward and is based on the recognition
of endometriotic glands and stroma in aberrant sites.
However, several unusual aspects may raise concern for a
neoplasm, including atypical endometriosis, mass-form-
ing lesions, polypoid growth, lymphovascular or perineu-
ral involvement, and necrotic pseudoxanthomatous nod-
ules, all of which will be discussed below.
The pathogenic mechanisms of endometriosis have not
been completely elucidated and are probably multifacto-
rial. Many investigators38,39have shown clonality in
endometriotic cysts, and a wide range of cytogenetics
and molecular genetic alterations have been described,
including partial or total chromosomal losses and
gains.40,41For the purpose of this review, endometriosis
and associated lesions will be considered pseudoneoplas-
tic, pertinent to the focus of this article; however, future
investigations mayprove a true neoplasticnature for some
of these tissue processes.
Atypical endometriosis refers to the presence of
cytologic atypia within the glandular epithelial cells,
particularly within the lining of endometriotic cysts. The
frequency has been reported to be between 12% and 22%,
depending on the criteria for atypia.42,43The cells are
enlarged, and have varied amounts of dense eosinophilic
cytoplasm and atypical hyperchromatic nuclei. They are
usually arranged in a single layer but can, on occasion, be
stratified or form small papillary structures. A hobnail
appearance is common. The presence of cytologic atypia
in endometriotic cysts does not appear to have a negative
Arch Pathol Lab Med—Vol 134, March 2010Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell 397
impact on prognosis.44However, it has been documented
adjacent to endometrioid or clear cell carcinomas arising
within endometriotic cysts, suggesting that it may
potentially be a precursor occasionally prone to malignant
transformation45(Figure 9). Clear cell carcinoma repre-
sents the main differential diagnosis for atypical endome-
triosis because of the nuclear atypia, hobnail appearance,
and association with endometriotic cysts. Distinguishing
features are absence of a mass, infiltration of the cyst wall,
or mitotic activity in atypical endometriosis.
same case. Immunohistochemistry for p53 shows strong and diffuse nuclear staining in the in situ carcinoma (C) and focal weak staining in the
normal tubal epithelium (D). MIB-1 immunostain shows higher proliferation index in the in situ carcinoma (E) compared to the normal tubal
epithelium (F) (hematoxylin-eosin, original magnifications 3400 [A and B]; original magnifications 3200 [C through F]).
A, Tubal serous carcinoma in situ showing stratification, loss of polarity, and severe nuclear atypia. B, Normal tubal epithelium from the
398 Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell
Polypoid endometriosis shows histopathologic findings
very similar to those of endometrial polyps occurring
within the endometrial cavity and featuring irregular and
often cystic endometrial glands, fibrotic endometrial
stroma, and prominent, thick-walled blood vessels.
Reported sites include the walls of endometriotic cysts,
omentum, serosal surfaces of the bowel and uterus, and
mucosal surfaces of the vagina and bowel, among others.46
These lesions are most commonly associated with usual
endometriosis and have been linked to estrogenic stimu-
lation, including tamoxifen use.46,47The main differential
diagnosis is mu ¨llerian adenosarcoma, which characteris-
tically shows leaflike glandular architecture, periglandu-
lar stromal hypercellularity, and atypical stromal cells,
features absent in polypoid endometriosis.
Intestinal endometriosis is believed to affect about one-
third of patients with endometriosis.48On occasion, it
forms mass lesions or infiltrates the bowel wall, mimick-
ing a neoplasm, primarily colonic adenocarcinoma. Useful
features that distinguish endometriosis from malignancy
are the predominantly mural location with an outward to
inward growth, minimal or absent mucosal involvement,
and the identification of endometrial stroma and old
hemorrhage. Immunostains are certainly helpful in this
differentiation, as large intestinal epithelium is usually
positive for CK20 and CDX2, and mu ¨llerian epithelium is
usually negative for these markers but positive for CK7
and estrogen receptor protein. Although most examples of
endometriosis involving the digestive tract occur in the
small bowel and colon, it has been described in other sites.
We recently encountered a case of very extensive
decidualized endometriosis in a pregnant patient that
formed a large abdominal mass, infiltrating the stomach
Endometrial tissue can be encountered within lymphat-
ic and blood vessels, unrelated to menstruation, leading to
the differential of lymphovascular involvement by carci-
noma. It has been reported in the myometrium, urethra,
and ovary and almost invariably is concurrent with
adenomyosis or endometriosis.50,51The bland cytologic
features of the focus in question and the absence of
malignancy elsewhere strongly argue against adenocarci-
noma. Perineural involvement by nonneoplastic endome-
trial glands has also been described and is not considered
to be evidence of malignancy.52
Necrotic pseudoxanthomatous nodules are composed
of an area of central necrosis, surrounded by histiocytes
and hyalinization (Figure 10). The histiocytes have abun-
dant foamy or granular cytoplasm, often pigmented,
thereby the denomination pseudoxanthomatous. More typ-
ical foci of endometriosis are not usually found adjacent to
these areas but often in other sites in the same patient.53
Rarely, these cases may raise the question of a neoplasm
because of the presence of necrosis, but any other features
suggestive of malignancy are absent.
Finally, a wide range of mu ¨llerian neoplasms are know
to arise in association with endometriosis, including
endometrioid and clear cell carcinoma, endometrial
stromal tumors, adenosarcoma, and carcinosarcoma54,55;
these diagnostic possibilities must be excluded in cases of
Several pseudoneoplastic conditions occur in the ovary
duringpregnancyas aresultof stimulationofstromal orsex
cord elements, or both, by pregnancy hormones. Two such
entities that may be mistaken clinically and pathologically
for neoplasms are pregnancy luteoma and solitary lutein-
ized follicle cyst of pregnancy and the puerperium.56
Pregnancy luteoma is a benign, hyperplastic lesion that
may be mistaken for a neoplasm, thus leading to
unnecessary oophorectomy. Between 100 and 200 cases
have been reported in the literature, although the true
incidence is probably underestimated, as most of these
lesions likely remain undetected.56–66Pregnancy luteoma
occurs in the second half of pregnancy, often among
African American women, and is usually an incidental
finding at cesarean delivery or during postpartum tubal
ligation.56,58–60In rare cases, a pelvic mass has been
detected or the lesion has become symptomatic because
of torsion, rupture, or obstruction of the pelvic outlet
during labor.61,62Recently, cases have been detected
sonographically63,64or by magnetic resonance imaging.65
Pregnancy luteomas are associated with virilization of the
mother in about 25% of cases, and female infants are
virilized as well in 60% to 70% of cases.64–66
Macroscopically, pregnancy luteomas are solid masses
that may be mistaken for ovarian neoplasms because of
this feature. Bilateral masses are present in approximately
one-third of cases and multiple nodules are present within
the ovary in about 50% of patients. Pregnancy luteomas
range in size from microscopic up to 20 cm in maximal
diameter, with a mean diameter of 7 cm in 1 study.59The
cut surfaces reveal 1 or more solid, brown, reddish, or tan
nodules with a pushing margin. Foci of hemorrhage are
nodules of steroid hormone–producing cells, intermediate
in size between luteinized granulosa cells and luteinized
theca interna cells. The cells are arranged in sheets,
trabeculae, and follicle-like structures (Figure 11, A). The
cells are polygonal with round, centrally located nuclei,
which often contain a prominent nucleolus. Nuclear atypia
may be present. Mitotic figures are often present, with a
mitotic count of up to 7 mitotic figures per 10 high-power
fields (Figure 11, B). Rarely, colloid droplets similar to those
seen in the corpus luteum of pregnancy are identified.56,59
Reticulum invests nests and groups of cells.
Table 2.Comparison of Reactive Epithelial Atypia and Serous Carcinoma In Situ of the Fallopian Tube
Serous Carcinoma In Situ Reactive Epithelial Changes
Type of surgery
Salpingectomy was part of surgery for other reasons
Mild to moderate, can be focally severe
Arch Pathol Lab Med—Vol 134, March 2010Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell 399
epithelium within the muscular wall. C, Mesothelial hyperplasia with a focus of transitional cell metaplasia (Walthard cell rest) (hematoxylin-eosin,
original magnifications 3400 [A and C]; and 3200 [B]).
Pseudocarcinomatous hyperplasia. A, Prominent mucosal proliferation with architectural complexity and cellular stratification. B, Tubal
nuclei (hematoxylin-eosin, original magnification 3400).
Metaplastic papillary tumor featuring papillary structures lined by large epithelial cells with abundant eosinophilic cytoplasm and bland
Figure 9. Well-differentiated endometrioid adenocarcinoma arising in a focus of endometriosis (hematoxylin-eosin, original magnification 3400).
(hematoxylin-eosin, original magnification 3200).
Necrotic pseudoxanthomatous nodule characterized by a central area of necrosis surrounded by hemosiderin-laden histiocytes
400Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell
Pregnancy luteomas are generally thought to arise from
nodular hyperplasia of theca interna cells (theca-lutein
hyperplasia),59,67,69although others56have proposed an
origin from stromal cells. More recently, it has been
suggested that these tumorlike lesions may be clonal
proliferations that have a growth advantage in pregnancy.70
The differential diagnosis includes sex cord–stromal
tumors such as luteinized thecoma, steroid cell tumor, and
hilus cell tumor and metastatic neoplasms such as
carcinomas and melanoma. Sex cord–stromal tumors are
occasionally seen in pregnancy and often become at least
partially luteinized. They differ from pregnancy luteoma
in that they are usually unilateral and solitary, as opposed
to the multinodular and bilateral lesions seen in pregnan-
cy luteoma. Microscopically, luteinized thecomas gener-
ally have at least focal residual spindle cell areas even in
pregnancy. Reticulum stains invest single cells in theco-
mas rather than groups of cells, as seen in pregnancy
luteoma. Several features that may aid in distinguishing
pregnancy luteoma from steroid cell tumors include the
presence of multiple nodules and numerous mitotic
figures in pregnancy luteomas, features that are not
usually seen in steroid cell tumors. Steroid cell tumors
often have a distinctive prominent vascular pattern
(Figure 12). Despite these features, the 2 entities may be
impossible to distinguish morphologically in many cases.
For practical purposes, a solid, lipid-poor, steroid hor-
mone cell–type tumor in pregnancy should be considered
a pregnancy luteoma56unless there is substantial data to
the contrary. Metastatic carcinomas are often multinodu-
lar and bilateral and may present in pregnancy; however,
they would show a greater degree of nuclear atypia than is
seen in pregnancy luteomas. Immunostains are helpful in
distinguishing primary and metastatic carcinomas from
pregnancy luteoma. Carcinomas, either primary or met-
astatic, are positive for keratins and epithelial membrane
antigen and for other respective antigens based on their
primary site of origin, and they are negative for inhibin.
Pregnancy luteomas are positive for inhibin and may be
positive for Melan-A, but are negative for HMB-45 and
S100, which would differentiate them from malignant
are polygonal with round, centrally located nuclei and prominent nucleoli (hematoxylin-eosin, original magnifications 3200 [A] and 3400 [B]).
A, Pregnancy luteoma showing nodules of steroid hormone–producing cells arranged in sheets and follicle-like structures. B, The cells
pregnancy. Ovarian steroid cell tumors often have a more prominent vascular pattern as seen here (hematoxylin-eosin, original magnification 3400).
Ovarian stromal luteoma is very similar in appearance to the luteoma of pregnancy and the two may sometimes be indistinguishable in
cytoplasm. Scattered cells are large with enlarged, hyperchromatic, bizarre nuclei (hematoxylin-eosin, original magnification 3400).
Large, solitary luteinized follicle cyst of pregnancy and the puerperium. The cyst is lined by polygonal cells with a moderate amount of
Arch Pathol Lab Med—Vol 134, March 2010 Pseudoneoplastic Lesions of Female Genital Tract—Medeiros & Bell401
Since pregnancy luteomas usually spontaneously re-
gress within weeks of delivery, and the ovaries return to
normal size,56,59minimal intervention is appropriate. Solid
nodules with radiologic findings of pregnancy luteoma
(solid nodules, multinodularity, and bilaterality) discov-
ered in the second half of pregnancy have been followed
clinically.64When encountered during surgery at the time
of cesarean delivery or postpartum tubal ligation, a biopsy
to determine the pathologic diagnosis is sufficient.
Large Solitary Luteinized Follicle Cyst of Pregnancy
Another benign lesion of the ovary that occurs during
pregnancy and may be mistaken for a neoplasm is an
uncommon, large, unilocular cyst first described by
Clement and Scully71in 1980 as large solitary luteinized
follicle cyst of pregnancy and puerperium.
The patients with this lesion are young, with an average
age of 26 years.71
The cysts are often discovered
incidentally on routine physical or ultrasound examina-
tions during pregnancy or puerperium, or as incidental
findings during cesarean delivery. They have been
detected from the third month of pregnancy to the third
month postpartum, and in rare cases, seemed to have
developed or enlarged after delivery.71,72Neither the
patients nor their infants have shown endocrinologic
Macroscopically, the cysts are unilateral and large, with
smooth external surfaces; they measure from 8 to 55 cm in
greatest diameter. The cysts are unilocular, with thin walls
measuring up to 5 mm in thickness, and contain clear,
serosanguinous or mucoid fluid. The inner cyst lining is
Microscopic examination reveals 1 to 10 layers of
luteinized cells, presumably granulosa cells, without a
clear distinction between the granulosa and theca lutein
layers. The cells are polygonal and may be uniform or
highly variable in size, with eosinophilic to clear cyto-
plasm. Most of the cells have uniform, round nuclei and
often have a single prominent nucleolus. A characteristic
feature is the presence focally of enlarged, hyperchromat-
ic, bizarre nuclei in 10% to 50% of the cyst-lining cells.
Mitotic figures are not seen (Figure 13). The lining cells
may desquamate into the cyst lumen, and the wall in these
areas is fibrous or lined by fibrin. Luteinized cells are also
often seen in the underlying fibrous wall of the cyst. Call-
Exner bodies or colloid bodies are not identified. The
histologic features of the cysts are similar when resected
during pregnancy, at term, or during the puerperium.71–76
Although the pathogenesis of these cysts is unknown,
the timing of their development would suggest that
human chorionic gonadotropin stimulation is involved
in their development. High levels of gonadotropins
during postpartum may play a role, as well as for those
lesions that develop or enlarge in the postpartum period.71
The presence of large cysts lined by atypical cells raises
the possibility of a neoplasm both clinically and patho-
logically. The major neoplasms in the differential diagno-
sis are cystic granulosa cell tumor and cystic serous or
mucinous neoplasms. The cystic granulosa cell tumor is a
rare variant that presents as a unilocular or paucilocular
cyst lined by multiple layers of granulosa cells. The
granulosa cells are smaller, more uniform, and without
pleomorphism and are usually not strikingly luteinized;
they form Call-Exner bodies and have grooved nuclei
when of adult type. Although granulosa cell tumors often
become luteinized during pregnancy, the luteinization is
usuallynot as pronounced as inthe solitary luteinized cyst
of pregnancy, and Call-Exner bodies have not been
reported in the latter entity. Although the stroma of
mucinous epithelial neoplasms may be extensively lutein-
ized in pregnancy, the mucin-containing columnar lining
cells are usually unaffected. On the other hand, the lining
cells of benign and borderline serous tumors may become
polygonal or hobnail shaped, with abundant eosinophilic
cytoplasm and enlarged hyperchromatic nuclei. Features
that allow the recognition of serous neoplasms are the
presence of cilia on some cells, the uniform single layer of
cells lining the cysts in a cystadenoma, and the presence of
the distinctive architecture of serous borderline tumors,
whereas solitary luteinized follicle cysts of pregnancy are
usually at least focally lined by stratified polygonal cells.
Immunostains are also helpful; the cells of solitary
luteinized follicle cyst of pregnancy are positive for
inhibin and calretinin.
A number of benign entities may be difficult to
distinguish from neoplasms in the female genital tract.
Being aware of the spectrum of such lesions may allow
their correct diagnosis and prevent overdiagnosis and
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