Sarcomas of the Female Genital Tract
Moderator: Dr. Marisa Nucci
Case 4 -
Low-grade mesodermal adenosarcoma with sarcomatous overgrowth arising in the
Esther Oliva, M.D.
Massachusetts General Hospital
Boston, MA, USA
A 50-year-old woman presented with blood in stool. On colonoscopy a 9 x 5
cm polypoid mass was found to protrude into the lumen showing focal ulceration. Relevant prior clinical
history included previous hysterectomy and bilateral salpingo-oophorectomy for leiomyomas and resection
of extensive pelvic endometriosis 5 years ago. The initial colon biopsy only showed benign colonic
mucosa. The patient underwent segmental resection of the rectosigmoid colon.
Case 4 - Slide 1
Low-grade mesodermal adenosarcoma with sarcomatous overgrowth arising in the
Müllerian adenosarcoma (AS) belongs to the category of mixed mullerian tumors and represents
approximately 8% of all uterine sarcomas. Outside the uterus these tumors are rare and they are
designated mesodermal adenosarcomas. Clement and Scully first described the features of 10 ASs arising
in the uterus in 1974. Soon after, Roth and colleagues described a similar tumor in the cervix (1976)
and two years later Clement and Scully first reported 5 histologically identical tumors arising at
extrauterine sites. Among all extrauterine sites, mesodermal adenosarcomas are more often seen in the
ovary, followed by peritoneum, intestine, cervix, vagina, liver, bladder and fallopian tube.
Uterine tumors typically occur in postmenopausal women (median 60 years),
but in contrast to malignant mixed müllerian tumors, approximately 30% are found in-patients below 50
years of age. However, extrauterine ASs typically occur at a younger age (median 44 years) when compared
to their uterine counterpart. An occasional association with hyperestrinism, prior pelvic radiation or
tamoxifen therapy with both, uterine and extrauterine ASs, may suggest their possible etiologic role in
some cases. Patients with uterine tumors present most commonly with abnormal vaginal bleeding, often
accompanied by lower abdominal or pelvic pain whereas patients with extrauterine ASs present with a wide
variety of symptoms and signs depending on tumor location, vaginal bleeding being by far much less
common. Patients with tumors originating in the gastrointestinal tract often present with chronic
abdominal pain, obstructive symptoms or even bleeding as described in the current case. Pelvic
examination typically reveals an enlarged uterus, and in about half the cases, tumor protruding through
the external os; a palpable pelvic or abdominal mass in ovarian tumors while tumors in other locations
may be more difficult to evaluate. Patients with typical uterine ASs are almost always stage I at
presentation and the presence of extrauterine tumor in this setting suggests multicentricity or
metastases from an adenosarcoma with sarcomatous overgrowth. In contrast, in the ovary, 75% of the
tumors where stage IC or higher at the time of diagnosis in the largest series reported up to date while
outside the ovary these tumors are infrequently well circumscribed and exhibit more than one tumor
- IN THE
UTERUS: Occasional patients have presented on two or more occasions with lesions misinterpreted
microscopically as benign polyps. Recurrent endocervical or endometrial polyps are uncommon,
particularly in young women, and their occurrence should therefore suggest the possibility of
- OUTSIDE THE
UTERUS: If the lesion is only biopsied, it may be misinterpreted as endometriosis. Persistent or
worsening symptomatology should raise the possibility of malignancy and the patient should undergo
Gross features :
Adenosarcomas typically form polypoid or villous broad-based masses;
frequently with secondary prolapse through the external os when they arise from the endometrium (90%).
Approximately 10% of the tumors originate in the endocervix. Uterine tumors have a mean size of 5 cm
(range from 1 to 17 cm), which contrast with ovarian ASs, typically larger with a mean size of 14 cm
(range 5.5 to 50 cm). This difference in size is probably related to the fact that ovarian ASs have more
space to grow before they are associated with clinical manifestations. Tumors at other sites vary much
more in size depending on their location. In the gastrointestinal tract they are frequently centered in
the serosa but they may infiltrate the muscularis wall and even appear as ulcerated polyps. Their cut
surface is frequently spongy, with cystic spaces filled with watery or mucoid fluid, surrounded by white
to tan tissue. At extrauterine locations ASs may be mostly solid, predominantly cystic, or may also
rarely show polypoid projections on their external surfaces.
- IN THE UTERUS, myometrial invasion, which is present in approximately one-sixth of adenosarcomas, may be
- IN THE OVARY it is
not infrequent that the tumor is ruptured during or before surgery
- IN OTHER EXTAUTERINE SITES, poorly defined
tumors may be difficult to resect
Microscopic features :
component has frequently cystically dilated glands scattered throughout the mesenchymal
component. Occasionally a villous pattern, with the neoplastic epithelium lining thin papillae or broad
polypoid fronds, and only a minor component of glands may be seen. The glands are lined more commonly by
proliferative-endometrial type epithelium, although endocervical (mucinous), tubal (ciliated),
secretory-endometrial (with subnuclear vacuoles), hobnail, clear or indifferent epithelia may also be
seen. Metaplastic squamous epithelium, typically nonkeratinizing, is often present. In approximately
one-third of adenosarcomas, the glandular epithelium exhibits focal architectural or cytological atypia,
and small foci of endometrial adenocarcinoma may be rarely encountered. The frequent mitotic activity of
the epithelial component, the variety of epithelial cell types, the extensive distribution of glands
throughout the stromal component and the occasional presence of glands within recurrent adenosarcoma are
evidence of the neoplastic nature of the epithelial component of the tumor.
The stromal component typically has the
appearance of a low-grade sarcoma, usually an endometrial stromal sarcoma, fibrosarcoma, or combinations
thereof. The stroma is more cellular around the glands, creating a cuff-like appearance which may be
more prominent in uterine tumors than in extrauterine ASs. Intraluminal polypoid or papillary stromal
projections of cellular stroma are a common finding. The stroma at a distance from the glands is often
less cellular, and in some tumors, the stroma is predominantly hypocellular, myxoid or extensively
hyalinized, imparting a deceptively benign appearance. The stromal cells exhibit mild or moderate
nuclear atypia, but occasionally may be highly atypical. Mitotic activity is an almost constant finding,
and >80% of tumors exhibit a mitotic rate of ³4 MFs/10HPFs, however, some uterine and extrauterine ASs
may show less than 2 MFs/10HPFs. Foci of smooth muscle differentiation have been described and
multinucleated giant cells, xanthoma cells and inflammatory cells may be seen. . In the ovary stromal
luteinization or ectopic decidua have been reported. In the uterus, approximately 1/6 of ASs invade the
myometrium; although in only 20% of such cases the invasion extends beyond the inner half of the
Other microscopic features
- Heterologous elements are seen in approximately
20% of ASs, varying from minor foci of fat, cartilage, or rhabdomyoblasts to embryonal rhabdomyosarcoma
occupying most or all of the stroma. Some of the cases with the latter type of stroma have also
contained nodules of fetal-type cartilage similar to those occurring in some cases of embryonal
rhabdomyosarcoma of the vagina and cervix.
- Foci of sex cord-like elements (SCLEs) within the stromal component. The SCLEs, which account for 5-50% of the
tumors, are composed of benign-appearing epithelial type cells arranged in solid nests, trabeculae, and
solid or hollow tubules. The cells may contain abundant eosinophilic or foamy, lipid-rich cytoplasm.
The appearance of the SCLEs is similar to that of those encountered in some endometrial stromal tumors
and in the rare uterine tumors resembling ovarian sex cord tumors.
- Sarcomatous overgrowth of the stromal component
occurs more frequently in extrauterine ASs ("müllerian/mesodermal adenosarcoma with sarcomatous
overgrowth") (MASO). To establish the diagnosis of MASO, the
area of pure sarcoma should occupy at least 25% of the tumor volume or one low-power field in one
slide. The sarcoma in most cases is high-grade with a destructive growth, but it can have a
similar appearance to the low-grade sarcoma of the conventional AS.
Useful criteria in diagnosing müllerian/mesodermal AS
include in general:
- Two or more stromal mitotic figures/10 HPFs
- Marked stromal cellularity
- Significant stromal cell atypia
Modified criteria for ovarian ASs
- Conspicuous non-invasive müllerian-type glands within predominant malignant stromal component, either
homologous or heterologous
- Periglandular cuffs or intraglandular protrusions of cellular stroma, or both
- Usually at least mild stromal atypia
- Stromal mitotic count variable, but may be very low
Immunohistochemical profile :
The stromal component is typically positive for vimentin, WT1,
CD10, estrogen, and progesterone receptors (ER and PR) with variable expression of cytokeratin, muscle
actin and androgen receptor, an immunohistologic profile that overlaps with that of endometrial stromal
neoplasms. Areas of MASO are typically CD10, ER and PR negative.
Differential Diagnosis :
Adenofibroma. Although it may have a similar
gross appearance in the uterus or at extrauterine sites, on microscopic examination the stromal component
of the tumor is cytologically benign, with cells resembling fibroblasts or endometrial stromal cells
exhibiting no or minimal nuclear atypia and no mitotic activity. Zaloudek and Norris reported stromal
mitotic rate as the most reliable criterion in this differential diagnosis in uterine tumors, and
concluded that only tumors with stromal mitotic counts ³ 4 MFs/10 HPFs should be diagnosed as AS.
However, almost half of their clinically malignant ASs, had mitotic rates of only 4 or 5/10HPFs; while a
"benign" count was that of 3MFs/10 HPFs, this subtle difference is within interobserver variation and
also related to variations in cellularity. In contrast, Clement and Scully encountered a number of ASs
with 2 or 3 MFs/10HPF that either had extrauterine disease at the time of presentation or recurred after
hysterectomy, while Eichhorn and colleagues found that ovarian ASs with 2 or less mitoses/10HPFs also
behaved in a malignant fashion. Thus, it appears that almost any measurable degree of stromal mitotic
activity can be associated with a malignant behavior and that the diagnosis should rely upon other
morphologic findings including absence of heterologous elements, periglandular condensation of the
stromal cells and invasion in adenofibromas.
Benign endometrial polyp
. The stroma typically resemble that of the adjacent endometrium or it is less cellular and often
sclerotic, but even when cellular it is typically inactive. Bizarre stromal cells may be seen in an
otherwise typical endometrial polyp and should not be misinterpreted as cytologic atypia, however, the
same atypical ("bizarre") cells may be seen in ASs. If the stromal component is unusually cellular or
mitotically active, if its glandular cells differ in appearance from those of the adjacent endometrium,
or if periglandular cuffing or intraglandular stromal papillae are present, the diagnosis of AS should be
- We diagnose
as adenosarcoma tumors with 2 or more MFs/10HPFs, a mitotic rate that will detect almost all tumors with
a malignant potential.
rare essentially amitotic tumors with marked stromal cellularity, stromal atypia or both have recurred,
we also consider tumors with these features low-grade adenosarcomas.
sampling is required to exclude foci exhibiting mitotic activity, marked cellularity, or stromal cell
Atypical polypoid adenomyoma when the AS has a prominent smooth muscle component. The predominant stromal
component is smooth muscle arranged in fascicles that may be cellular and mitotically active. The
glandular component is less cystic and generally more atypical than that of an AS and usually contains
prominent numbers of squamous morules that may contain central areas of necrosis. There is absence of
intraglandular polypoid projections or periglandular cuffing.
Endometrial/ioid stromal sarcoma (ESS). Both
entities share a similar appearance of the stromal component,
both tumors may have sex cord-like differentiation, and rarely, ESSs may show focal
prominent glandular differentiation. However, ESS typically lacks the typical epithelium/stroma
relationship seen in AS and unlike ASs, it typically has highly infiltrative borders with extensive
invasion and vascular permeation.
Polypoid endometriosis may enter in the
differential diagnosis of extrauterine lesions. However, this lesion has an appearance similar to that
of endometrial polyps or endometrial hyperplasia, but stromal atypia, periglandular cuffing and true
intraluminal stromal protrusions are not seen.
Embryonal rhabdomyosarcoma. Both tumors occur
at a younger age than AS arising in the corpus and share the polypoid gross appearance and the presence
of cartilage and rhabdomyoblasts. However, in contrast to embryonal rhabdomyosarcoma, cervical AS has
more glands, they often show the characteristic intraluminal polypoid projections and there is a variety
of müllerian-type epithelium.
Fibrosarcoma, endometrial stromal sarcoma, diffuse adult
granulosa cell tumor (in the ovary) or even gastrointestinal stromal tumor (in the peritoneum) when MASO
is present. Thorough sampling is very important in these cases.
Uterine ASs arise from the malignant transformation of the endometrial stromal
cells, however the histogenesis of ovarian and extrauterine non-ovarian ASs is unknown. It has been
postulated that these tumors arise from preexisting endometriosis, as these tumors are more often
encountered in regions where endometriosis is common, however, endometriosis is only found in a minority
of cases. Possibly, most ovarian ASs arise directly from the surface epithelium and ovarian stroma,
while extrauterine extraovarian ASs arise from pluripotential mesothelial and mesenchymal cells.
Uterine adenosarcomas present with vaginal or abdominopelvic recurrence in
approximately 1/4 of cases, while hematogenous spread occurs in less than 5%. Even in clinically
malignant cases, the recurrent tumor is commonly indolent. The tumors often recur 5 or more years after
hysterectomy. In the ovary, extraovarian spread and high-grade of the tumor are associated with higher
rates of recurrence, and even so, recurrence was seen in 63% of stage I low-grade tumors in the largest
series of ovarian ASs. In that study it was concluded that age <53, tumor rupture and high-grade
might appeared to be associated with recurrence, especially in stage I tumors and overall these tumors
have a poorer prognosis than uterine ASs with early recurrences and a 5-, 10-, and 15-year survival of
64%, 46% and 30% respectively. Experience with extrauterine extraovarian ASs is limited, however, a 60%
recurrence rate (early recurrence) and a 33% frequency of hematogenous spread have been reported, and
patients die from their tumors despite adjuvant therapy. The recurrent tumor is a pure sarcoma in the
majority of cases, an AS in almost 30% and rarely as carcinosarcoma and blood-borne metastases have been
- The risk of recurrence in UTERINE AS correlates
with the presence of myometrial invasion.
- MASO correlates with an increased recurrence
risk in UTERINE AND EXTRAUTERINE ASs, having a behavior similar to that of other high-grade
- OVARIAN ASs recur in almost 2/3of cases and
need additional therapy most often surgical.
- EXTRAUTERINE EXTRAOVARIAN ASs are also
associated with poor prognosis despite aggressive treatment.
- The presence of heterologous elements is not
associated with an increased risk of recurrence.
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