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 style answer #1Cite this page: Özen Ö. Müllerian adenosarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/uterusadenosarcoma.html. Accessed January 19th, 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)
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)
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
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
Cytology images
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 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.