Uterus

Mixed epithelial and mesenchymal tumors

Müllerian adenosarcoma

Authors: Özlem Isiksacan Özen, M.D., Ayse Ayhan, M.D., Ph.D.

Editorial Board Member: Carlos Parra-Herran, M.D.

Editor-in-Chief: Debra L. Zynger, M.D.

Topic Completed: 1 March 2018

Minor changes: 12 August 2021

Copyright: 2003-2018, PathologyOutlines.com, Inc.

PubMed Search: Uterus stromal tumors adenosarcoma

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Table of Contents

Cite this page: Özen Ö. Müllerian adenosarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusadenosarcoma.html. Accessed November 27th, 2021.

Definition / general

A mixed epithelial and mesenchymal tumor in which the epithelial component is benign and the stromal component is malignant (IARC: WHO Classification of Tumours of the Female Reproductive Organs, 4th Edition, 2014)

Essential features

Mixed tumor with a neoplastic malignant mesenchymal component and an accompanying nonneoplastic (benign) epithelial component, as demonstrated in recent molecular studies (J Pathol 2016;238:381)

Terminology

Müllerian adenosarcoma first reported and described by Clement and Scully in 1974 as a mixed tumor of the uterus (Cancer 1974;34:1138)
In 1979, two additional cases were reported and the term Müllerian adenosarcoma became universally recognized (Cancer 1979;43:1439)
Three types of adenosarcoma have been described by Soslow and Longacre (Soslow: Uterine Pathology (Cambridge Illustrated Surgical Pathology), 1st Edition, 2012):
- Low grade adenosarcoma has a sarcomatous component that is uniformly low grade
- High grade adenosarcoma has a morphologically high grade sarcomatous component (definition below) (Am J Surg Pathol 2017;41:1513)
- Sarcomatous overgrowth is defined as pure sarcoma comprising 25% of tumor or more (Am J Surg Pathol 1989;13:28)

ICD coding

ICD-10: C55
WHO Blue Book: 8933/3

Epidemiology

6% of uterine sarcomas (Histopathology 2009;54:355)
No racial predilection (Gynecol Oncol 2004;93:204)
Incidence highest in perimenopausal or postmenopausal women but cases reported even in childhood (mean age 50 years, range 13 - 94) (Curr Oncol Rep 2016;18:68, Am J Surg Pathol 2009;33:278)

Sites

Uterine corpus is the most common primary site (Arch Pathol Lab Med 2016;140:286, Mutter: Pathology of the Female Reproductive Tract, 3rd Edition, 2014)
Also cervix, ovary, fallopian tube, vagina, peritoneum or outside the female genital tract arising from preexisting endometriosis (Adv Anat Pathol 2010;17:122, Am J Surg Pathol 2002;26:1243, Indian J Pathol Microbiol 2014;57:640, Int J Gynecol Pathol 2002;21:65)

Etiology

Pathogenesis and cell of origin unknown (Arch Pathol Lab Med 2016;140:286, Curr Oncol Rep 2016;18:68)
Endometriosis, previous pelvic radiotherapy, long term unopposed estrogen therapy and tamoxifen use may be risk factors (Curr Oncol Rep 2016;18:68, Clin Exp Obstet Gynecol 2004;31:302, Int J Gynecol Pathol 2001;20:133, Arch Gynecol Obstet 2000;264:105, Gynecol Oncol 1992;44:104, Histopathology 2000;36:91, J Gynecol Oncol 2010;21:269)

Clinical features

Can present with abnormal vaginal bleeding or pelvic pain but often discovered incidentally (Arch Pathol Lab Med 2016;140:286)
Prior history of recurrent endometrial polyps has been documented in some cases (Hum Pathol 1990;21:363)

Diagnosis

Obtain a sufficient endometrial biopsy (pipelle or D&C)
Apply routine histopathologic criteria; immunohistochemistry has a limited role

Prognostic factors

Survival is better compared to other sarcomas (Gynecol Oncol 2004;93:204)
Unlike other uterine sarcomas, staging of early stage (FIGO stage I, confined to the uterus) is based on presence and depth of myometrial invasion (IA – no myometrial invasion, IB – inner myometrial half, IC – outer myometrial half)
Good prognosis if confined to the endometrium – stage IA (Mod Pathol 2016;29:S78)
Poor prognostic factors:
- Myometrial invasion: risk of recurrence increases from 13% in noninvasive tumors to 46% in myoinvasive tumors (Clement: Atlas of Gynecologic Surgical Pathology, 3rd Edition, 2013)
- Sarcomatous overgrowth: usually associated with deep myometrial invasion or distant metastasis (Mod Pathol 2016;29:S78)
- Overall recurrence (70%), metastatic (40%) and death (60%) rates for adenosarcoma with stromal overgrowth are similar to other high grade uterine sarcomas (Mutter: Pathology of the Female Reproductive Tract, 3rd Edition, 2014)
- High grade: high grade adenosarcomas tend to present with extrauterine spread and rapid recurrences (Am J Surg Pathol 2017;41:1513)
- Advanced stage (FIGO stage II or greater): overall survival is ~60% with myoinvasion but less than 50% if metastases present (Gynecol Oncol 2010;119:305)
Recurrence usually occurs in the vagina, pelvis and abdomen, is seen in up to 30% of cases and is associated with a poor prognosis (Oncol Rep 1998;5:939)

Case reports

28 year old woman with sarcomatous overgrowth diagnosed as "a clear cell leiomyoma" (Int J Gynecol Pathol 2014;33:573)
28 year old woman treated by fertility preserving surgery and successfully delivered a child (Case Rep Obstet Gynecol 2017;2017:4187416)
39 year old woman with sarcomatous overgrowth and pelvic lymph node involvement (Int J Surg Case Rep 2016;27:155)
45 year old woman with postmenopausal bleeding (Case of the Week #451)
55 year old woman with sarcomatous overgrowth and brain metastasis (Brain Tumor Res Treat 2016;4:138)

Treatment

Total abdominal hysterectomy with bilateral salpingo-oophorectomy (Mod Pathol 2016;29:S78)
No standardized chemotherapy, hormonal therapy or radiation therapy (Arch Pathol Lab Med 2016;140:286, J Obstet Gynaecol 2017;37:93), chemotherapy may be considered in patients with recurrent or unresectable disease (Oncol Rep 1998;5:939)

Clinical images

Images hosted on other servers:

Mass protruding through cervix

Gross description

Usually forms polypoid masses ranging from 1 - 20 cm (mean 5 - 6.5 cm)
Typically fills the endometrial cavity and may project into the endocervical canal
Rarely mural and serosal
A cauliflower-like appearance may be seen
Cut surface is solid, white to tan in color with small cysts containing watery or mucoid fluid
Soft and fleshy with areas of hemorrhage or necrosis if sarcomatous overgrowth or high grade sarcoma is present

Gross images

Contributed by Aysha Mubeen, M.D.

Case #451

Images hosted on other servers:

Cut specimen of uterus and tumor

Endometrial polyp

Hysterectomy specimen

Microscopic (histologic) description

Low power reveals a biphasic tumor with intimally admixed glands and prominent stroma throughout
Morphologic features diagnostic of adenosarcoma are:
- Intraglandular growth with projections narrowing the glandular lumens, imparting a leaf-like (phyllodes-like) architecture
- Periglandular stromal condensation (cuffing)
- Rigid cystic dilation
- Mitotic activity ≥ 2 mitoses / 10 HPFs
- Stromal cytologic atypia
  - Low grade adenosarcomas have monotonous stromal nuclei with mild to moderate atypia (similar to that seen in low grade endometrial stromal sarcoma)
  - High grade adenosarcomas have pleomorphic, markedly atypical nuclei, noticeable at low power magnification and ≥ 2x the size of an endothelial cell nucleus (Am J Surg Pathol 2017;41:1513)
  - They are usually associated with sarcomatous overgrowth and heterologous (rhabdomyosarcoma) differentiation
At least 2 of these features must be present diffusely throughout the tumor in order to make the diagnosis of adenosarcoma
Epithelium of the glands is usually endometrioid but often shows mucinous, squamous or tubal metaplasia and may show mild to moderate atypia
Stroma may show hyalinization, elastosis, edema or myxoid change
Sarcomatous overgrowth: presence of sarcoma (without any epithelial component) in > 25% of the tumor, most frequently homologous high grade sarcoma, associated with deeper myometrial involvement and lymphovascular invasion
Heterologous elements, most commonly rhabdomyosarcoma, may be present, particularly in the setting of sarcomatous overgrowth and high grade morphology
Other types of heterologous differentiation, such as immature cartilage, sex cord-like differentiation or smooth muscle metaplasia may be present

Microscopic (histologic) images

Contributed by Ayse Ayhan, M.D., Ph.D.

Biphasic tumor

Periglandular cuff

Intraglandular papillae

Stromal mitoses

Squamous metaplasia

Sarcomatous overgrowth

Heterologous elements

Cytology images

Images hosted on other servers:

Mass protruding through cervix

Positive stains

Glandular component: AE1 / AE3, ER and PR; variable CD10
Mesenchymal component: vimentin, CD10, WT1, ER and PR; variable expression of muscle markers (smooth muscle actin and desmin), CD34 and cytokeratin
High grade adenosarcomas and those with sarcomatous overgrowth have high Ki67 and abnormal p53 (Arch Pathol Lab Med 2016;140:286, Am J Surg Pathol 2017;41:1513)

Negative stains

Glandular component: androgen receptor, p53
ATRX: negative in a subset of tumors with ATRX mutations (J Pathol 2016;238:381)

Molecular / cytogenetics description

Low level amplification of MDM2, unrelated to the presence of sarcomatous overgrowth (J Pathol 2016;238:381)
ATRX mutations and loss in a subset of tumors (J Pathol 2016;238:381)
Other recurrent mutations include FGFR2, KMT2C (J Pathol 2016;238:381)
DICER1 mutations present when there is rhabdomyosarcomatous differentiation (Gynecol Oncol Rep 2017;20:121, Am J Surg Pathol 2017;41:1513)
TP53 mutations are prevalent in high grade adenosarcoma (Am J Surg Pathol 2017;41:1513)
High level copy number gains of MYBL1 in a subset, usually associated with sarcomatous overgrowth (J Pathol 2015;235:37)

Differential diagnosis

Endometrial polyp: most adenosarcomas are polypoid, and can be mistaken for an endometrial polyp
Likewise, some endometrial polyps may display features suggestive of adenosarcoma
- Endometrial polyps are characterized by uniformly increased cellularity of the stroma lacking periglandular cuffing, cytologic atypia or mitotic activity
- Polyps with focal atypical features (leaf-like growth, periglandular condensation, atypia, mitoses) have an indolent outcome, and are referred currently as polyps with unusual features (Am J Surg Pathol 2015;39:116)
- Diagnosis of adenosarcoma requires the presence of diagnostic characteristics diffusely throughout the tumor
Adenofibroma: an exceedingly rare biphasic tumor that should be diagnosed only in a well sampled tumor removed totally
- Diffusely paucicellular stroma with no periglandular cuffing, no stromal atypia and absent or rare mitotic figures < 2 MF/10 HPF
Adenomyoma: grossly well circumscribed and the stromal component is made of smooth muscle cells that form fascicles identical to that of a leiomyoma
Atypical polypoid adenomyoma: stroma is fibromyomatous and glands have squamous metaplasia
Benign endometrial polyp: characterized by uniformly increased cellularity of the stroma lacking periglandular cuffing, cytologic atypia or mitotic activity
Carcinosarcoma: glandular component is frankly carcinomatous and high grade
- Phenomenon of carcinoma arising in an adenosarcoma has been described
- In these cases the carcinomatous component is localized, and the benign glandular component of adenosarcoma can be appreciated elsewhere
- Moreover, the carcinoma is usually low grade endometrioid, unlike carcinosarcoma (Mod Pathol 2018;31:418)
Embryonal rhabdomyosarcoma: most commonly occurs in the cervix of younger women and girls (mean 18 years)
- May contain entrapped glands which are surrounded by cuffs of tumor cells, resulting in a cambium layer
- Entrapped glands are confined to the surface and leaf-like pattern typical of adenosarcoma is absent
- Malignant stroma away from the cambium layer is hypocellular, edematous or myxoid alternating with small blue aggregates of neoplastic cells
Endometrial stromal sarcoma (when glandular elements or entrapped benign endometrial glands are present):
- Glands in endometrial stromal tumors are usually scant and towards the periphery of the tumor and lack the periglandular stromal condensation and uniform distribution throughout the tumor seen in adenosarcoma
- Neoplastic stroma permeates the myometrium with a tongue-like pattern in contrast to the destructive infiltration seen in adenosarcoma
- Immunohistochemistry is not helpful as it shows an overlapping profile
Polypoid endometriosis: composed of endometrial stroma and endometrial type glands that may be cystically dilated; it lacks the typical periglandular cuffs, intraglandular stromal papillae or stromal cytologic atypia

Board review style question #1

Differs from adenofibroma by showing marked cellularity (including periglandular cuffs), any degree of stromal cell atypia and ≥ 2 mitotic figures per 10 high powered fields.
Is associated with a good outcome even if myometrial invasion and sarcomatous overgrowth are present.
Is classified as an "adenosarcoma with sarcomatous overgrowth” if a high grade sarcoma is seen in > 10% of the tumor.
Is composed of glands with severe cytological atypia and a cellular low grade malignant stroma.
Never shows any heterologous component while almost half of carcinosarcomas show this feature.

Board review style answer #1

A. Differs from adenofibroma by showing marked cellularity (including periglandular cuffs), any degree of stromal cell atypia and ≥ 2 mitotic figures per 10 high powered fields. Adenosarcoma is a biphasic tumor composed of benign appearing epithelium and a cellular low grade malignant stroma. The main differential diagnosis includes adenofibroma and it differs from adenofibroma by showing marked cellularity (including periglandular cuffs), any degree of stromal cell atypia and ≥ 2 mitotic figures per 10 high powered fields. The tumor is classified as an adenosarcoma with sarcomatous overgrowth when at least 25% of the tumor is composed of pure sarcoma. Adenosarcoma is frequently associated with a good outcome if confined to the endometrium. Otherwise deep myometrial invasion, high grade cytomorphology and sarcomatous overgrowth predict a poor prognosis. Heterologous elements, most commonly rhabdomyosarcoma, may also be present especially in adenosarcoma with sarcomatous overgrowth.

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Reference: Müllerian adenosarcoma