Uterus
Carcinoma
Carcinosarcoma (MMMT)


Minor changes: 27 October 2020

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PubMed search: malignant mixed Müllerian tumor (carcinosarcoma) uterus

Joana Ferreira, M.D.
Ana Félix, M.D., Ph.D.
Page views in 2019: 23,289
Page views in 2020 to date: 20,247
Cite 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
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
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
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
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
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?

  1. Carcinosarcoma with heterologous differentiation
  2. Carcinosarcoma with homologous differentiation
  3. Serous endometrial carcinoma
  4. Rhabdomyosarcoma
Board review answer #1
A. Carcinosarcoma with heterologous differentiation

Comment Here

Reference: Carcinosarcoma (MMMT)
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