Müllerian adenosarcoma is an uncommon biphasic tumor composed of malignant stromal and benign epithelial components. Morphologically, adenosarcoma is characterized by a broad leaflike architecture, reminiscent of phyllodes tumors of the breast. Periglandular cuffing of the stromal cells around the compressed or cystically dilated glands is characteristic. The mesenchymal component is typically a low-grade spindle cell sarcoma, whereas the epithelial counterpart is commonly endometrioid with frequent squamous or mucinous metaplasia and may, in some circumstances, show mild to moderate atypia. In all cases, it is important to assess for the presence of sarcomatous overgrowth and myometrial invasion, which are the prognostic factors. In this brief review, we present the clinical, histopathologic, and immunohistochemical features of adenosarcoma, as well as updates on the molecular biology of this neoplasm.

In 1974, Clement and Scully1  reported a series of tumors of the female genital tract that were described as “... mixed tumors of the uterus, in which the stromal component has been malignant, but the epithelial elements, benign,” and proposed naming these tumors adenosarcoma. A subsequent study,2  in 1979, added a few cases to the original series, and the term Müllerian adenosarcoma has since become universally recognized.

Müllerian adenosarcoma is an uncommon biphasic malignant mesenchymal tumor composed of a benign glandular component and a malignant, but generally low-grade, stromal component. With a growing number of cases reported (now considerably more than 200) in the literature, the spectrum of morphologies and clinical behavior is fairly well understood. The molecular pathogenesis of these tumors, however, remains to be elucidated.

Although uncommon, adenosarcoma affects women of a broad age range. The incidence is highest in perimenopausal or postmenopausal women, but cases have been reported in children as young as 10 years.3  Patients may present clinically with abnormal vaginal bleeding and/or pelvic pain or, in a large percentage of cases, with no symptoms. Although the uterine corpus is by far the most common primary site, adenosarcoma may also arise in the cervix, ovary, fallopian tube, or vagina.4  Adenosarcoma occurring outside the female genital tract likely represents tumors arising from preexisting endometriosis.57  Some studies suggest that the use of tamoxifen may have a role in the pathogenesis of adenosarcoma.811 

The prognosis of adenosarcoma greatly depends on stage and the presence of sarcomatous overgrowth.12  A small series of cases13  found that the 2-year progression-free and overall survival rates for tumors with sarcomatous overgrowth were 20% compared with 100% for adenosarcoma lacking sarcomatous overgrowth. Another study14  demonstrated that 36% of adenosarcoma with myometrial invasion recurred, and the risk of recurrence in the absence of myoinvasion was only 7%. Overall survival is around 60% for tumors with myoinvasion and less than 50% for tumors with associated metastasis.15  Tumors that arise in the ovary or extrauterine sites tend to have a higher recurrence rate secondary to lack of a physical barrier to spread within the pelvis and abdomen. A new FIGO (International Federation of Gynecology and Obstetrics) staging system for adenosarcoma, identical to that for endometrial stromal sarcoma (ESS), has been devised recently16  (Table 1).

Table 1. 

The FIGO (International Federation of Gynecology and Obstetrics) Staging System for Uterine Adenosarcoma

The FIGO (International Federation of Gynecology and Obstetrics) Staging System for Uterine Adenosarcoma
The FIGO (International Federation of Gynecology and Obstetrics) Staging System for Uterine Adenosarcoma

MACROSCOPIC FEATURES

The uterine cavity is typically filled with an exophytic and polypoid mass, which may project through the cervix. The average size is 5 cm, although tumors up to 50 cm have been reported.17  The cut surface shows variably cystic and solid areas, and papillary or polypoid projections into cystic spaces can often be appreciated macroscopically (Figure 1). Focal hemorrhage and necrosis may also be present. When sarcomatous overgrowth is present, the mass may acquire a more fleshy appearance commonly seen in other types of sarcoma.18,19 

Figure 1. 

Gross image of Müllerian adenosarcoma of the uterus. The mass has a yellow-tan, exophytic appearance, which fills the entire endometrial cavity and extends to the cervix. In this case, sarcomatous overgrowth was present.

Figure 2.Section of endomyometrium showing a large, polypoid mass replacing the endometrium. Note the phyllodes architecture and cleftlike spaces at scanning magnification (hematoxylin-eosin; original magnification ×10).

Figure 3.The resemblance with phyllodes tumor of the breast is evident in a section of adenosarcoma at low power. The leaflike appearance with compressed epithelium is characteristic of these tumors (hematoxylin-eosin; original magnification ×200).

Figure 4.Rigid cyst formation is an architectural pattern also frequently seen in adenosarcoma. Large cystic spaces lined by benign epithelium are surrounded by low-grade malignant stroma (hematoxylin-eosin; original magnification ×200).

Figure 1. 

Gross image of Müllerian adenosarcoma of the uterus. The mass has a yellow-tan, exophytic appearance, which fills the entire endometrial cavity and extends to the cervix. In this case, sarcomatous overgrowth was present.

Figure 2.Section of endomyometrium showing a large, polypoid mass replacing the endometrium. Note the phyllodes architecture and cleftlike spaces at scanning magnification (hematoxylin-eosin; original magnification ×10).

Figure 3.The resemblance with phyllodes tumor of the breast is evident in a section of adenosarcoma at low power. The leaflike appearance with compressed epithelium is characteristic of these tumors (hematoxylin-eosin; original magnification ×200).

Figure 4.Rigid cyst formation is an architectural pattern also frequently seen in adenosarcoma. Large cystic spaces lined by benign epithelium are surrounded by low-grade malignant stroma (hematoxylin-eosin; original magnification ×200).

MICROSCOPIC FEATURES

Histologically, adenosarcoma is composed of benign-appearing epithelium and malignant stroma. Many of the diagnostic features are best appreciated at low-power magnification and may reflect the gross appearance of this tumor (Figure 2). The architecture often demonstrates a broad leaflike appearance, formed by the malignant stroma compressing the benign epithelium, somewhat resembling a phyllodes tumor of the breast (Figure 3). “Rigid cyst” formation is another architectural pattern in which large, dilated, cystic structures, lined by benign epithelium, are surrounded tightly by malignant stroma (Figure 4). Periglandular cuffing of the stromal cells condensing under the epithelium is characteristic and can also be appreciated from low-power microscopic examination. The epithelial or glandular component is usually endometrioid and frequently demonstrates metaplasia (squamous and mucinous are most common)12  and may show mild to moderate atypia. The malignant stroma can have a varied appearance but is classically a low-grade spindle cell sarcoma, frequently with myxoid foci, with no specific line of differentiation, although some consider it to resemble ESS. Mitoses are essentially required for the diagnosis (at least 2 per 10 high-power fields). The mitoses are usually most pronounced in areas of periglandular cuffing. Atypical mitotic figures are generally absent except in the presence of sarcomatous overgrowth.17  Sex cord-like differentiation can be seen, which has no effect on prognosis.4 

The presence or absence of sarcomatous overgrowth is an important prognostic factor and should be assessed in all tumors.20  Sarcomatous overgrowth is defined as the presence of pure sarcoma (without any epithelial component) comprising at least 25% of the tumor. Morphologic features of sarcomatous overgrowth are typically high grade (Figure 5) and include severe cytologic atypia, brisk mitotic activity, and necrosis; however, high-grade stroma is not a requisite for the diagnosis of sarcomatous overgrowth. When high-grade stroma is present but comprises less than 25% of the tumor, it should be mentioned but no definitive data exist on the prognostic significance. Of course, additional tumor should be sampled and examined histologically if possible. Not uncommonly, adenosarcoma with sarcomatous overgrowth may demonstrate low- to intermediate-grade atypia with a myxoid appearance (Figure 6). Sarcomatous overgrowth is associated with deeper myometrial involvement and lymphovascular invasion.4  Heterologous elements, most notably rhabdomyoblastic differentiation, have no prognostic significance alone, although they occur most commonly in the presence of sarcomatous overgrowth.

Figure 5. 

An example of sarcomatous overgrowth, in which the mesenchymal component comprises at least 25% of tumor with no associated epithelium. This example demonstrates high-grade stroma with cytologic atypia and frequent mitoses (hematoxylin-eosin, original magnification ×400).

Figure 6.Sarcomatous overgrowth with low-grade stroma. Mild cytologic atypia is present. Myxoid stroma, as shown here, can be seen in cases of sarcomatous overgrowth (hematoxylin-eosin, original magnification ×200).

Figure 7.Immunohistochemistry for CD10 highlighting the periglandular “cuffing” of malignant stromal cells (original magnification ×200).

Figure 5. 

An example of sarcomatous overgrowth, in which the mesenchymal component comprises at least 25% of tumor with no associated epithelium. This example demonstrates high-grade stroma with cytologic atypia and frequent mitoses (hematoxylin-eosin, original magnification ×400).

Figure 6.Sarcomatous overgrowth with low-grade stroma. Mild cytologic atypia is present. Myxoid stroma, as shown here, can be seen in cases of sarcomatous overgrowth (hematoxylin-eosin, original magnification ×200).

Figure 7.Immunohistochemistry for CD10 highlighting the periglandular “cuffing” of malignant stromal cells (original magnification ×200).

IMMUNOHISTOCHEMISTRY

Diffuse or multifocal expression of CD10 in the stromal compartment is seen in most adenosarcomas and often highlights the periglandular cuffing (Figure 7). Immunoreactivity for estrogen and progesterone receptors is also seen in most cases, both in the glandular and stromal components. However, expression of these markers is significantly decreased in adenosarcoma with sarcomatous overgrowth.14,21  Mesenchymal markers, such as smooth muscle actin (SMA), desmin, and CD34 can have variable positivity in the stromal component. More than one-half of tumors exhibit expression of SMA and/or desmin, whereas the percentage of CD34+ tumors is smaller.14,21  Cytokeratins may rarely be focally positive in the sarcomatous component.21,22  For an expanded summary of the immunohistochemical profile of adenosarcoma, refer to Table 2.

Table 2. 

Immunohistochemical Staining Patterns in Uterine Adenosarcomaa

Immunohistochemical Staining Patterns in Uterine Adenosarcomaa
Immunohistochemical Staining Patterns in Uterine Adenosarcomaa

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of adenosarcoma is broad and consists predominantly of tumors that also have a biphasic (epithelial and mesenchymal) appearance. The particular entities considered in the differential diagnosis vary with the type of adenosarcoma. At the very low end of the spectrum, the differential diagnosis includes primarily benign entities, such as the so-called adenofibroma, adenomyoma (benign), endometrial polyps with unusual features, and atypical polypoid adenomyoma. In the presence of high-grade sarcoma and/or sarcomatous overgrowth, the main diagnosis to rule out is carcinosarcoma, although undifferentiated uterine sarcoma, ESS, and leiomyosarcoma should also be considered in the differential diagnosis.

Differential Diagnosis of Adenosarcoma Without Sarcomatous Overgrowth

Endometrial polyps, adenofibroma, and adenomyoma are tumors in which both the epithelial and stromal components are morphologically benign. So-called adenofibroma has the architectural features of adenosarcoma, but the stroma is typically hypocellular and fibrotic. Mitoses should be absent or rare. Indeed, adenofibroma may represent the far “low-grade” end of the spectrum of adenosarcoma, and thus, a diagnosis of adenofibroma should be rendered with extreme caution, if at all.14,19  Occasionally, benign uterine polyps may display features suggestive of adenosarcoma; however, those features are subdiagnostic, typically subtle, and only partially involve the polyp.23  Endometrial polyps with myomatous stroma can resemble adenosarcoma, but the stromal component is made of smooth muscle cells that form fascicles. Fascicular growth of the stromal component in adenosarcoma is unusual. Atypical polypoid adenomyoma is characterized by endometrial glands frequently displaying mild cytologic and architectural atypia and often diffuse or focal squamous morular metaplasia. The myofibromatous stroma is cellular but lacks the leaflike architecture of adenosarcoma.

Differential Diagnosis of Adenosarcoma With Sarcomatous Overgrowth

Perhaps the most challenging differential diagnosis is carcinosarcoma. As the name implies, both elements of these neoplasms are malignant, but adenosarcoma can demonstrate cytologic atypia in the epithelial component; thus, the distinction from a small carcinoma can be difficult. To further complicate this differential diagnosis, epithelial malignancies may arise in the setting of adenosarcoma, and carcinosarcomas can focally demonstrate areas mimicking adenosarcoma.4  In most carcinosarcomas, the sarcomatous component is not predominant; nevertheless, extensive sampling may be required to distinguish adenosarcoma with sarcomatous overgrowth from carcinosarcomas composed predominantly of sarcoma.

When the tumor cells are markedly high grade and do not recapitulate normal endometrial stroma, undifferentiated uterine sarcoma should be considered. If entrapped glands are present, it can mimic adenosarcoma. These tumors are composed of pleomorphic, undifferentiated, malignant cells with high mitotic index. In the absence of classic features of adenosarcoma, undifferentiated uterine sarcoma should be diagnosed, with the understanding that a subset of these heterogenous tumors may represent extensive sarcomatous overgrowth of an adenosarcoma.

Low-grade ESS may resemble adenosarcoma with sarcomatous overgrowth, particularly if glandular elements and/or entrapped benign endometrial glands are present. In ESS, the tumor cells are monomorphic and have fusiform, round to ovoid nuclei and fine chromatin. The cell borders are indistinct, and cytoplasm is scant. Delicate vasculature is characteristic of these tumors, which is composed of thin-walled blood vessels surrounded by whorling of tumor cells. Because CD10 immunostain is positive in both adenosarcoma and ESS, it is not helpful in distinguishing between these tumors. Many ESSs have a t(7;17) translocation resulting in JAZF1-SUZ12 gene fusion, and cytogenetic studies may be used in difficult cases.

A high-grade ESS has also been described,24  which is characterized by malignant cells with uniform atypia and high mitotic index. The immunohistochemical profile varies, but these tumors are generally nonreactive for CD10, estrogen receptor, and progesterone receptor, in contrast to adenosarcoma. High-grade ESSs are positive for cyclin D1, which indirectly reflects the presence of a YWHAE-FAM22 gene fusion product created by the characteristic translocation t(10;17).24 

Given its frequency among mesenchymal tumors of the gynecologic tract, leiomyosarcoma may also be considered. Leiomyosarcoma may uncommonly entrap benign endometrial glands but does not demonstrate features characteristic for adenosarcoma. The presence of typical fascicular architecture and immunohistochemical positivity for smooth muscle markers, particularly caldesmon, is diagnostic of leiomyosarcoma.

MOLECULAR DIAGNOSTICS

The precise molecular mechanism of tumorigenesis in adenosarcoma remains unclear. One reported karyotype of adenosarcoma with sarcomatous overgrowth revealed a hyperdiploid karyotype with multiple structural and numerical abnormalities involving chromosomes 2, 8, 10, 13, 19, and 21.25  Some studies have found low rates of TP53 mutations,2628  and others have described low-level amplification of MDM2 and other genes on band 12q14-15.26,27  Recently described alterations in adenosarcoma include MYBL1 amplification and ATRX mutation, which are each present in 50% of adenosarcomas with sarcomatous overgrowth.27  MYBL1 is a transcription factor that regulates cell proliferation and is amplified in subsets of other types of tumors, including 10% of uterine carcinosarcoma (http://www.cbioportal.org; accessed January 14, 2015). ATRX regulates DNA methylation and chromatin remodeling; loss-of-function mutations in ATRX have prognostic significance in other tumor types.29 

TREATMENT

Total abdominal or laparoscopic-assisted vaginal hysterectomy is the treatment of choice for uterine adenosarcoma, with or without bilateral salpingo-oophorectomy. One study13  did not identify any ovarian metastases in patients who underwent bilateral salpingo-oophorectomy for uterine adenosarcoma. However, given the frequent positivity of estrogen and progesterone receptors in adenosarcoma, removal of the ovaries could potentially benefit patients, even in the absence of metastatic disease—but that benefit needs to be weighed against the age of the patient and cost of surgical menopause.

There is no standardized chemotherapy, hormonal therapy, or radiation therapy in adenosarcoma, but standard sarcoma chemotherapy regimens, such as doxorubicin, ifosfamide, or gemcitabine/docetaxel, and newer drugs, such as trabectedin, appear to have some efficacy in adenosarcoma with sarcomatous overgrowth.13,30,31 

CONCLUSION

Müllerian adenosarcoma is a relatively uncommon entity in gynecologic pathology that has distinctive clinical and histologic characteristics. It is important for pathologists to be aware of the morphologic features of these neoplasms to distinguish them from other biphasic (epithelial and mesenchymal) tumors, both benign and malignant. Adenosarcoma is of generally low malignant potential, except when accompanied by sarcomatous overgrowth and myoinvasion. Patients with adenosarcoma lacking these 2 histopathologic features have an excellent prognosis.

References

References
1.
Clement
PB
,
Scully
RE.
Müllerian adenosarcoma of the uterus: a clinicopathologic analysis of ten cases of a distinctive type of müllerian mixed tumor
.
Cancer
.
1974
;
34
(
4
):
1138
1149
.
2.
Valdez
VA
,
Planas
AT
,
Lopez
VF
,
Goldberg
M
,
Herrera
NE.
Adenosarcoma of uterus and ovary: a clinicopathologic study of two cases
.
Cancer
.
1979
;
43
(
4
):
1439
1447
.
3.
Fleming
NA
,
Hopkins
L
,
de Nanassy
J
,
Senterman
M
,
Black
AY.
Mullerian adenosarcoma of the cervix in a 10-year-old girl: case report and review of the literature
.
J Pediatr Adolesc Gynecol
.
2009
;
22
(
4
):
45
51
.
4.
McCluggage
WG.
Mullerian adenosarcoma of the female genital tract
.
Adv Anat Pathol
.
2010
;
17
(
2
):
122
129
.
5.
Gollard
R
,
Kosty
M
,
Bordin
G
,
Wax
A
,
Lacey
C.
Two unusual presentations of müllerian adenosarcoma: case reports, literature review, and treatment considerations
.
Gynecol Oncol
.
1995
;
59
(
3
):
412
422
.
6.
N'Senda
P
,
Wendum
D
,
Balladur
P
,
Dahan
H
,
Tubiana
JM
,
Arrive
L.
Adenosarcoma arising in hepatic endometriosis
.
Eur Radiol
.
2000
;
10
(
8
):
1287
1289
.
7.
Yantiss
RK
,
Clement
PB
,
Young
RH.
Neoplastic and pre-neoplastic changes in gastrointestinal endometriosis: a study of 17 cases
.
Am J Surg Pathol
.
2000
;
24
(
4
):
513
524
.
8.
Arici
DS
,
Aker
H
,
Yildiz
E
,
Tasyurt
A.
Mullerian adenosarcoma of the uterus associated with tamoxifen therapy
.
Arch Gynecol Obstet
.
2000
;
264
(
2
):
105
107
.
9.
Bocklage
T
,
Lee
KR
,
Belinson
JL.
Uterine mullerian adenosarcoma following adenomyoma in a woman on tamoxifen therapy
.
Gynecol Oncol
.
1992
;
44
(
1
):
104
109
.
10.
Clement
PB
,
Oliva
E
,
Young
RH.
Mullerian adenosarcoma of the uterine corpus associated with tamoxifen therapy: a report of six cases and a review of tamoxifen-associated endometrial lesions
.
Int J Gynecol Pathol
.
1996
;
15
(
3
):
222
229
.
11.
Jessop
FA
,
Roberts
PF.
Müllerian adenosarcoma of the uterus in association with tamoxifen therapy
.
Histopathol
.
2000
;
36
(
1
):
91
92
.
12.
Clement
PB
,
Scully
RE.
Mullerian adenosarcoma of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature
.
Hum Pathol
.
1990
;
21
(
4
):
363
381
.
13.
Tanner
EJ
,
Toussaint
T
,
Leitao
MM
Jr,
et al
.
Management of uterine adenosarcomas with and without sarcomatous overgrowth
.
Gynecol Oncol
.
2013
;
129
(
1
):
140
144
.
14.
Gallardo
A
,
Prat
J.
Mullerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma
.
Am J Surg Pathol
.
2009
;
33
(
2
):
278
288
.
15.
Arend
R
,
Bagaria
M
,
Lewin
SN
,
et al
.
Long-term outcome and natural history of uterine adenosarcomas
.
Gynecol Oncol
.
2010
;
119
(
2
):
305
308
.
16.
Prat
J.
FIGO staging for uterine sarcomas
.
Int J Gynaecol Obstet
.
2009
;
104
(
3
):
177
178
.
17.
Eichhorn
JH
,
Young
RH
,
Clement
PB
,
Scully
RE.
Mesodermal (müllerian) adenosarcoma of the ovary: a clinicopathologic analysis of 40 cases and a review of the literature
.
Am J Surg Pathol
.
2002
;
26
(
10
):
1243
1258
.
18.
Oliva
E.
Mullerian Adenosarcoma, Corpus
.
Diagnostic Pathology: Gynecological
.
Vol
1
.
1st ed
.
Altona, Manitoba, Canada
:
Amirsys
;
2014
:(
3
)
224
229
.
19.
Zaloudek
CJ
,
Norris
HJ.
Adenofibroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases
.
Cancer
.
1981
;
48
(
2
):
354
366
.
20.
Clarke
BA
,
Mulligan
AM
,
Irving
JA
,
McCluggage
WG
,
Oliva
E.
Müllerian adenosarcomas with unusual growth patterns: staging issues
.
Int J Gynecol Pathol
.
2011
;
30
(
4
):
340
347
.
21.
Soslow
RA
,
Ali
A
,
Oliva
E.
Mullerian adenosarcomas: an immunophenotypic analysis of 35 cases
.
Am J Surg Pathol
.
2008
;
32
(
7
):
1013
1021
.
22.
Abeler
VM
,
Nenodovic
M.
Diagnostic immunohistochemistry in uterine sarcomas: a study of 397 cases
.
Int J Gynecol Pathol
.
2011
;
30
(
3
):
236
243
.
23.
Howitt
BE
,
Quade
BJ
,
Nucci
MR.
Uterine polyps with features overlapping with those of müllerian adenosarcoma: a clinicopathologic analysis of 29 cases emphasizing their likely benign nature
.
Am J Surg Pathol
.
2015
;
39
(
1
):
116
126
.
24.
Lee
CH
,
Ali
RH
,
Rouzbahman
M
,
et al
.
Cyclin D1 as a diagnostic immunomarker for endometrial stromal sarcoma with YWHAE-FAM22 rearrangement
.
Am J Surg Pathol
.
2012
;
36
(
10
):
1562
1570
.
25.
Chen
Z
,
Hong
B
,
Drozd-Borysiuk
E
,
Coffin
C
,
Albritton
K.
Molecular cytogenetic characterization of a case of Müllerian adenosarcoma
.
Cancer Genet Cytogenet
.
2004
;
148
(
2
):
129
132
.
26.
Blom
R
,
Guerrieri
C.
Adenosarcoma of the uterus: a clinicopathologic, DNA flow cytometric, p53 and mdm-2 analysis of 11 cases
.
Int J Gynecol Cancer
.
1999
;
9
(
1
):
37
43
.
27.
Howitt
BE
,
Sholl
LM
,
Dal Cin
P
,
et al
.
Targeted genomic analysis of Müllerian Adenosarcoma
.
J Pathol
.
2015
;
235
(
1
):
37
49
.
28.
Swisher
EM
,
Gown
AM
,
Skelly
M
,
et al
.
The expression of epidermal growth factor receptor, HER-2/Neu, p53, and Ki-67 antigen in uterine malignant mixed mesodermal tumors and adenosarcoma
.
Gynecol Oncol
.
1996
;
60
(
1
):
81
88
.
29.
Marinoni
I
,
Kurrer
AS
,
Vassella
E
,
et al
.
Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors
.
Gastroenterology
.
2014
;
146
(
2
):
453
460.e5
. doi:.
30.
Schöffski
P
,
Taron
M
,
Jimeno
J
,
et al
.
Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study
.
Eur J Cancer
.
2011
;
47
(
7
):
1006
1012
.
31.
Schroeder
B
,
Pollack
SM
,
Jones
RL.
Systemic therapy in advanced uterine adenosarcoma with sarcomatous overgrowth
.
Gynecol Oncol
.
2014
;
132
(
2
):
513
.

Author notes

The authors have no relevant financial interest in the products or companies described in this article.