Uterus
Mixed epithelial and mesenchymal tumors
Müllerian adenosarcoma
Editorial Board Member: Carlos Parra-Herran, M.D.
Editor-in-Chief: Debra Zynger, M.D.
Topic Completed: 1 March 2018
Minor changes: 11 August 2020
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PubMed Search: Uterus stromal tumors adenosarcoma
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review answer #1Cite this page: Özen Ö. Müllerian adenosarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusadenosarcoma.html. Accessed August 14th, 2020.
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)
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:
Denuded malignant cells with variable sizes
Dense clusters of polymorphic tumor cells
Long oval, hyperchromatic nuclei with 1+ nucleoli (Pap)
Partly denuded tumor cells with fragile cytoplasm
Tumor cells have variable sizes
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
- Adenosarcoma of the female genital tract:
- 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 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.
