Uterus
Carcinoma
Carcinosarcoma (MMMT)
Authors: Joana Ferreira, M.D., Ana Félix, M.D., Ph.D.
Editor-in-Chief: Debra Zynger, M.D.
Minor changes: 27 October 2020
Copyright: 2002-2020, PathologyOutlines.com, Inc.
PubMed search: malignant mixed Müllerian tumor (carcinosarcoma) uterus
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Positive stains | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Board review style question #1 | Board review answer #1Cite this page: Ferreira J, Félix A. Carcinosarcoma (MMMT). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/uterusmmmt.html. Accessed October 29th, 2020.
Definition / general
- Biphasic, malignant tumor with high grade epithelial and stromal components
- Sarcomatous component is derived from the carcinomatous component as a result of metaplasia / transdifferentiation (epithelial to mesenchymal transition)
Essential features
- Rare, aggressive neoplasm
- Occurs in postmenopausal women, most frequently in the uterine corpus
- Biphasic tumor with malignant epithelial (more frequently high grade carcinoma) and stromal (can be homologous and heterologous) components
- Staged like endometrial carcinomas according to the International Federation of Gynecology and Obstetrics and the American Joint Committee on Cancer staging classifications
Terminology
- Malignant mixed Müllerian tumor, malignant mesodermal mixed tumor, metaplastic carcinoma
ICD coding
- ICD-O: 8980/3 - Carcinosarcoma, NOS
Epidemiology
- Rare (< 5% of gynecological carcinomas)
- Almost always in postmenopausal women (mean age: 65 years)
- Higher incidence in black women
- References: J Gynecol Oncol 2018;29:e22, Gynecol Oncol 2004;93:204
Sites
- More frequent in the uterine corpus
- Can also arise in the cervix, ovaries, fallopian tubes, vagina, peritoneum and extragenital sites
Pathophysiology
- 4 theories have been proposed (J Clin Pathol 2002;55:321):
- Collision theory: the sarcomatous and carcinomatous are two independent neoplasms
- Combination theory: both components are derived from a single stem cell that undergoes divergent differentiation early in the evolution of the tumor
- Conversion theory: the sarcomatous element derives from the carcinomatous element during the evolution of the tumor
- Composition theory: the spindle cell component is a pseudosarcomatous stromal reaction to the carcinoma
- The Cancer Genome Atlas (TCGA) data supports the conversion and combination theories (Nat Commun 2019;10:4965, Cancer Cell 2017;31:411)
- Carcinomatous cells convert themselves to sarcomatous cells via epithelial to mesenchymal transition; this is supported by high epithelial to mesenchymal transition gene signature scores and is likely due to epigenetic alterations at microRNA promoters and histone gene mutations and amplifications (Cancer Cell 2017;31:411, Proc Natl Acad Sci U S A 2016;113:12238)
Etiology
- Almost all are sporadic
- Tamoxifen use and pelvic radiation therapy have been associated with an increased incidence
- Other predisposing factors include chronic estrogen exposure, nulliparity, diabetes and obesity
- References: Gynecol Oncol 2017;144:329, Cancer 1980;45:1625
Clinical features
- Vaginal bleeding, abdominal mass and pelvic pain are the usual presenting symptoms
- Usually elevated serum CA125
- 10% of patients have distant metastasis at presentation
- Extrauterine spread in up to 45% of patients at presentation (Ann Oncol 2016;27:1257)
Diagnosis
- Frequently only rendered after surgical resection
Prognostic factors
- 5 year survival rate is approximately 30% (stage I - II: 59%; stage III: 25%; stage IV: 9%) (Gynecol Oncol 2010;116:419)
- This is a much more aggressive prognosis than high grade endometrial carcinoma in which 5 year survival rate for stage I disease is over 80% (Am J Surg Pathol 2007;31:979)
- Stage is the most consistent independent predictor of outcome
- Presence of heterologous elements is a poor prognostic factor in early stage disease but its significance remains to be determined in advanced stage disease (Am J Surg Pathol 2007;31:1653)
- Metastatic component frequently of carcinomatous type but can be of sarcomatous component or of combinations of both; carcinoma components tended to spread lymphatically, while sarcoma components tended to spread locoregionally (Ann Oncol 2016;27:1257)
- Compared with other high grade endometrial carcinomas, lung metastasis are more frequent (Gynecol Oncol 2005;98:274)
Case reports
- 64 year old woman with carcinosarcoma of the uterine cervix (BMJ Case Rep 2019;12:e227050)
- 76 and 81 year old women with primary peritoneal carcinosarcomas (Taiwan J Obstet Gynecol 2019;58:288)
- 78 year old woman with a primary mesenteric carcinosarcoma with neuroendocrine differentiation (Mod Pathol 2001;14:515)
Treatment
- Total abdominal hysterectomy bilateral salpingo-oophorectomy with pelvic lymphadenectomy
- Radiotherapy or chemotherapy
Gross description
- Polypoid lesions
- Fleshy, bulky and friable
- Hemorrhage and necrosis common
- May fill uterine cavity and protrude through cervical os
- Usually extensive myoinvasion and often extends beyond the uterus
- Reference: Semin Diagn Pathol 2010;27:274
Gross images
Contributed by Joana Ferreira, M.D. and Ana Félix, M.D., Ph.D.
Uterus macroscopy
Tumor polypoid growth
Images hosted on other servers:
Polypoid fleshy mass at fundus of uterus
Infiltrating partially necrotic tumor
Serosal and vaginal invasion
Polypoid tumor with superficial myometrial invasion
Microscopic (histologic) description
- Biphasic tumor with carcinomatous and sarcomatous elements, both of high grade (Int J Gynecol Pathol 1990;9:1)
- Carcinomatous and sarcomatous components are juxtaposed, often with a leaf-like phyllodes type morphology
- Carcinomatous elements:
- Often high grade endometrioid or serous carcinoma, frequently admixed
- More uncommonly clear cell carcinoma
- 50 - 75% of cases have serous or mixed serous and high grade endometrioid carcinoma (Am J Surg Pathol 2007;31:1653)
- Hybrid morphology between endometrioid and serous carcinoma is frequent, as is undifferentiated carcinoma (Mod Pathol 2010;23:781)
- Other components that can be rarely found are squamous, mucinous and neuroendocrine
- Sarcomatous elements:
- Often high grade spindle and pleomorphic
- 50% contain heterologous elements (most commonly rhabdomyosarcoma and chondrosarcoma) (Am J Surg Pathol 2007;31:1653)
- Osteosarcomatous, liposarcomatous and angiosarcomatous differentiation are less common (Semin Diagn Pathol 1988;5:199, Arch Pathol Lab Med 1991;115:583, Int J Gynecol Pathol 2017;36:140)
- Central nervous system type and peripheral type neuroectodermal components as well as yolk sac tumor differentiation have been reported (Histopathology 1996;29:565, Am J Surg Pathol 2017;41:761, Int J Gynecol Pathol 2008;27:515)
- Carcinomatous elements:
- Angiolymphatic invasion common, more commonly of the carcinomatous component
Microscopic (histologic) images
Contributed by Joana Ferreira, M.D. and Ana Félix, M.D., Ph.D.
Large polypoid tumor, small myometrial invasion
Highly atypical cells, types of matrix
Necrosis, squamous differentiation
Highly pleomorphic carcinoma
Chondrosarcomatous area
Pleomorphic sarcomatous area
Fusocellular sarcomatous area
Carcinoma area
Osteosarcomatous area
Striated muscle sarcomatous area
Cytology description
- Cytologic findings have been described on cervicovaginal smears, endometrial and peritoneal aspirates (Diagn Cytopathol 2019;47:547)
- Fine needle aspiration can be especially useful documenting recurrent or metastatic disease; demonstration of both sarcomatous and carcinomatous components can be difficult
Positive stains
- Immunohistochemistry is not necessary to establish the diagnosis
- Can be useful to demonstrate heterologous differentiation (skeletal muscle)
- Immunohistochemical loss of mismatch repair (MMR) proteins can occur but is infrequent (Am J Surg Pathol 2020;44:782)
- Some are HER2 positive (Mod Pathol 2020;33:118)
- Aberrant neuroendocrine markers expression is frequent (Pathology 2019;51:369)
- Carcinomatous component:
- PAX8, EMA, cytokeratin positive
- Both serous and high grade endometrioid carcinomas show aberrant p53 expression (Int J Gynecol Pathol 2017;36:412)
- Endometrioid components can show ER, PR, vimentin positivity
- Sarcomatous component:
- Often shows aberrant p53 expression (Int J Gynecol Pathol 2017;36:412)
- Often expresses cytokeratins (more frequently focal)
- Rhabdomyosarcoma: desmin and myogenin
- Liposarcoma and chondrosarcoma: S100
Molecular / cytogenetics description
- Genomic analysis has identified 4 molecular subtypes that resemble those described in endometrial carcinoma, compared with endometrial carcinoma TCGA (Nat Commun 2019;10:4965):
- Proportions of POLE and MSI subtypes are similar
- Copy number high (CNH) are much more common in carcinosarcomas and copy number low (CNL) less so
- Most share common features with high grade serous ovarian and serous endometrial carcinomas, although a minority has features consistent with an endometrioid subtype
- TP53 is frequently mutated
- Mutations in the phosphatidylinositol3-kinase pathway genes (PIK3CA, PTEN, PIK3R1) are also very common
- Other significantly mutated genes include FBXW7, PPP2R1, CDH4, KRAS, ARID1A, ARHGAP35, SPOP, RB1, U2AF1, ZBTB7B (Cancer Cell 2017;31:411)
Sample pathology report
- Uterus, total hysterectomy and bilateral salpingo-oophorectomy:
- Uterine carcinosarcoma with a heterologous component (see synoptic report and comment)
- Comment: There is a malignant biphasic cell proliferation composed by carcinomatous elements: high grade serous carcinoma intimately admixed with sarcomatous elements - chondrosarcoma and osteosarcoma. The constellation of morphological features strongly supports the diagnosis of carcinosarcoma (malignant mixed Müllerian tumor). This belongs to the malignant epithelial tumors of the uterus and behaves as a high grade carcinoma.
Differential diagnosis
- Endometrial carcinoma with spindle cell differentiation and corded and hyalinized endometrial carcinoma (Am J Surg Pathol 2005;29:157):
- No high grade malignant nuclear spindle cell differentiation
- Smooth transition between the malignant epithelial to spindle cell component
- Undifferentiated and dedifferentiated carcinoma (Surg Pathol Clin 2019;12:343):
- No sarcomatous areas
- No recognizable glandular, trabecular, nested (if undifferentiated carcinoma) areas
- Well or moderate differentiated endometroid carcinoma as the only epithelial component juxtaposed (if dedifferentiated carcinoma)
- Desmoplastic stromal reaction in high grade endometrial or undifferentiated carcinoma:
- Atypical fibromyxoid areas associated with inflammatory cells
- No merging between malignant areas and stromal reaction
- Endometrioid adenocarcinoma with metaplastic osteoid elements (Am J Surg Pathol 2005;29:157):
- No cytological atypia in cells surrounded by osteoid type of matrix
- Müllerian adenosarcoma (Hum Pathol 1990;21:363):
- Epithelial component is benign
- Malignant stroma predominantly in a periglandular cuffing (Phyllodes architecture)
- Low grade sarcoma except in areas of stromal overgrowth
- Combined adenocarcinoma and neuroendocrine carcinoma (Am J Surg Pathol 2016;40:577):
- Neuroendocrine markers positive
- No sarcomatous areas, especially heterologous elements
- Mesonephric carcinomas / carcinosarcomas (Am J Surg Pathol 2020;44:429, Am J Surg Pathol 2004;28:601):
- Undifferentiated uterine sarcoma (Surg Pathol Clin 2019;12:363):
- No recognizable epithelial areas
- Epithelial markers negative
Board review style question #1
A 75 year old woman presents with vaginal bleeding. A hysterectomy is performed (see images above). What is the diagnosis?
- Carcinosarcoma with heterologous differentiation
- Carcinosarcoma with homologous differentiation
- Serous endometrial carcinoma
- Rhabdomyosarcoma
Board review answer #1
