Case 1 -
Low-Grade Mullerian Adenosarcoma Arising in Hepatic Endometriosis
Charles V. Biscotti
Cleveland Clinic Foundation
Click on each slide thumbnail image for an enlarged view
A 51-year-old presented for resection of a hepatic endometrioma diagnosed by tissue biopsy three years
prior. At that time, she had a significant response to leuprolide acetate: however, the mass recurred
approximately 2.5 years after discontinuing monthly injections. Repeat tissue biopsy was again
interpreted as endometriosis. This time, the patient had a poor response to leuprolide acetate. A
10x12x1.5 c.m. mass was excised.
Case 1 - Figure 1 - A variably thick capsule of soft tissue surrounds a central cavity containing blood clot and hemorrhagic soft tissue.
Case 1 - Figure 2 - Some of the periphery of the mass has endometrial tissue (left) a relatively hypocellular fibrous zone (center) and liver tissue (right).
Case 1 - Figure 3 - In this field, hypocellular fibrous stroma surrounds endometrial glands of varying size and shape.
Case 1 - Figure 4 - Some of the mass has more crowded and abnormally shaped endometrial glands surrounded by a more cellular stroma.
Case 1 - Figure 5 - This field represents an area of greatest stromal cellularity.
Low-Grade Mullerian Adenosarcoma Arising in Hepatic Endometriosis
Gross and Microscopic Examination
The mass presented grossly as a partially collapsed 10 x 12 x 1.5 cm cyst with an indurated reddish
gray capsule surrounding focally necrotic hemorrhagic soft tissue. Histologically, the capsule included
variably cellular fibrosis tissue and portions of diaphragm, liver capsule and hepatic parenchyma.
Centrally, the mass consisted of a variably cellular stroma, resembling a mixture of fibrous tissue and
endometrial stroma surrounding endometrial glands. The endometrial glandular architecture varied
including foci with crowded complex abnormally configured glands characteristic of complex endometrial
hyperplasia. The glandular epithelium lacked cytologic atypia. Stromal cellularity varied with much of
the tissue composed of relatively hypocellular fibrous stroma. A minor component had moderate and
focally marked stromal hypercellularity. Scattered inconspicuous foci of periglandular stromal
hypercellularity were identified along with intraglandular stromal protrusions imparting a phyllodes
pattern, albeit it extremely focally. Most of the tumor lacked appreciable stromal mitotic activity;
however, mitoses varied, up to 3 mitotic figures per 10 high magnification fields. Most of the tumor
also lacked stromal nuclear atypia; however, focal stromal atypia was identified. The stroma lacked
In addition to adenosarcoma, the differential diagnosis includes endometrioma or polypoid
endometriosis and mullerian adenofibroma. The gross appearance favors adenofibroma/adenosarcoma rather
than endometriosis. Endometriomas usually form cystic ovarian masses rather than solid and cystic
hepatic masses as in the current case . Endometriosis can form sizable polypoid masses simulating a
neoplasm, so called polypoid endometriosis ; although this occurs extremely infrequently. In
contrast, adenosarcomas characteristically form bulky solid and cystic masses. For example, in the
gastrointestinal tract three cases of adenosarcoma, complicating endometriosis, were 6.5 cm, 10.5 cm, and
15 cm in greatest dimension, respectively . In contrast, non-neoplastic endometriosis related masses
ranged from 1.0 to 4.5 cm in greatest dimension, mean 2.6 . Histologically, polypoid endometriosis
lacks stromal nuclear atypia, periglandular hypercellularity, and a phyllodes pattern . The current
case has stromal nuclear atypia and a well-developed phyllodes pattern, albeit focal. Resolving this
differential diagnosis requires extensive sampling and a high index of suspicion for any sizable mass of
Distinguishing the low end of the spectrum of adenosarcoma from adenofibroma can be problematic.
Adenofibromas have uniform stroma with infrequent mitoses and relatively low cellularity. Clement and
Scully diagnose adenosarcoma in the presence of one or more of the following criteria: > 2
mitotic figures per 10 high magnification fields, more than mild stromal nuclear atypia, or marked
stromal hypercellularity . The mitotic count criterion uses an average count based on 40 high
magnification fields in the most cellular zones . Periglandular stromal hypercellularity and
heterologous elements have also been cited as useful differential diagnostic criteria . The current
case has stromal nuclear atypia, periglandular stromal hypercellularity, marked stromal hypercellularity,
and up to 3 mitotic figures per 10 high magnification fields.
The clinicopathologic features of uterine mullerian adenosarcoma have been well-documented
Clement and Scully described uterine mullerian adenosarcoma in a 10 case series in 1974 and a follow-up
analysis of 100 cases
. In these series, the patients' ages varied but most were postmenopausal
(range 14 to 89 years, median 58) . The Gynecologic Oncology Group reported a similar age
distribution . In the largest series, 78% of patients presented with vaginal bleeding . Primary
sites of involvement included the endometrium (83%), endocervix (7%), myometrium (4%), or multiple sites
(7%) . Grossly, uterine adenosarcomas present as polypoid or papillary masses, often containing small
. In the largest series, tumors ranged from 1-17 cm (mean 5 cm) in maximum dimension .
A variety of epithelia line the glands, usually proliferative endometrioid cells followed by, in
decreasing order of infrequency, endocervical mucinous, squamous, serous, and secretory endometrioid
cells . Most cases have at least two epithelial cell types and some have three or four . In the
largest series 10% of cases had glandular crowding and architectural atypia. One third had mild to
marked nuclear atypia, always focal . One case had a small grade one endometrioid adenocarcinoma
The sarcomatous component of uterine tumors has distinctive histologic features. The sarcomatous
component usually resembles a low-grade homologous sarcoma, endometrial stromal sarcoma and/or
fibrosarcoma. Pure homologous sarcoma has been described in 78% of cases including high-grade homologous
sarcoma in 3 (4%) of 78 tumors without sarcomatous overgrowth and 2 (20%) of 10 tumors with sarcomatous
. The stromal cellularity commonly varies with hypocellular fibrous zones imparting a
benign appearance . This feature reinforces the importance of sampling to avoid misdiagnosis as
benign endometrial polyp or mullerian adenofibroma. Smooth muscle differentiation has been reported in
approximately six percent of cases . Heterologous sarcomatous differentiation almost always
rhabdomyosarcoma, occurs in approximately in 22% of uterine adenosarcomas . Stromal mitotic rates
vary. In the largest series, stromal mitotic counts, expressed as an average per 10 high magnification
fields based on 40 fields, varied from less than 1 to 40 (mean 9) . Other characteristic features of
the sarcomatous component include periglandular hypercellularity (80% of cases), phyllodes pattern (60%
of cases), moderate nuclear atypia (32% of cases), marked nuclear atypia (38% of cases), and sarcomatous
overgrowth (8% of cases)
. Pure sarcoma similar to or of higher grade than that of the underlying
adenosarcoma, occupying at least 25% of a well-sampled tumor defines sarcomatous overgrowth . In the
seminal study of mullerian adenosarcomas with sarcomatous overgrowth, the pure sarcomatous component was
of higher-grade in 7 of 10 cases .
Uterine mullerian adenosarcomas behave as low-grade malignancies except those tumors with sarcomatous
overgrowth. Only about 25% of mullerian adenosarcomas without sarcomatous overgrowth invade the
underlying myometrium (2,8) compared to 60% of those with sarcomatous overgrowth . More importantly,
recurrence affects approximately 26%  of patients without sarcomatous overgrowth compared to 76% of
patients with sarcomatous overgrowth
. In the series of Clement and Scully no tumor deaths occurred
in 95 patients without sarcomatous overgrowth
but tumor related deaths have been reported . In
contrast, 15 of 21 (71%) patients with sarcomatous overgrowth died of disease
overgrowth occurs in approximately eight percent of cases
. The pure sarcomatous component usually
has a higher-grade 
Other pathologic prognostic variables for uterine adenosarcoma include stage and myoinvasion
In one study tumors with vascular invasion and tumors with rhabdomyoblastic differentiation recurred more
often but the difference was not statistically significant .
The ovary is the second most common site for mullerian adenosarcoma accounting for 15% of cases in one
series . Ovarian mullerian adenosarcomas differ from their uterine counterparts with respect to some
clinical and pathologic features. Clinically, ovarian tumors affect younger patients, present at higher
stage and have a worse prognosis . Approximately half of the patients with ovarian adenosarcomas have
been less than 50 years of age
. In contrast, most uterine tumors affect post-menopausal patients
with a median age of 58 years in the largest series . Ovarian tumors appear to rupture easily as
evidenced by the fact that 75% of tumors were stage IC or greater . Thirty-five percent were stage II
or greater in the largest series . In a separate study both tumors had ruptured and one of these also
had peritoneal implants . Unlike uterine mullerian adenosarcomas most ovarian tumors recur (62%),
almost always within five years. Further, 38% of patients have died of disease, two thirds of these
within five years
. In contrast 31% of uterine tumors recur and six percent of patients die of
. Compared to their uterine counterparts, ovarian mullerian adenosarcomas more often have
sarcomatous overgrowth (30% versus 8%) and sex cord-like elements (15% versus 7%)
Interestingly, Eichhorn and colleagues observed some differences in pathologic prognostic variables.
Specifically, high-grade and the presence of a high-grade sarcomatous overgrowth component were
associated with recurrence in ovarian tumors . The presence or amount of sarcomatous overgrowth was
not associated with recurrence provided that the sarcomatous overgrowth component was low-grade .
Mullerian adenosarcomas complicate endometriosis, albeit infrequently. The prevalence of
endometriosis has been estimated at 15% among pre-menopausal women and 2-5% among post-menopausal women
. Malignant transformation occurs rarely with estimates ranging from 0.3 to 0.8% for surgical series
of ovarian endometriosis . In one study 78.7% of endometriosis-associated malignancies arose in the
ovary . The histologic types of malignant neoplasms differ between ovarian and extraovarian sites.
Carcinomas, almost always endometrioid or clear cell, predominate in both the ovary and extraovarian
sites. However, sarcomas are relatively more common in extraovarian sites, accounting for 25% of
malignancies compared to 11.6% of malignancies associated with all sites of endometriosis combined .
In one study, adenosarcoma accounted for three of 15 neoplasms involving extraovarian endometriosis
compared to 0 of 27 neoplasms associated with ovarian endometriosis . Mullerian adenosarcomas
accounted for four of 17  and one of six  neoplasms arising in gastrointestinal endometriosis.
Mullerian adenosarcomas have been linked to endometriosis at other sites including the vagina
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