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Uterus (excludes Cervix)

Stromal tumors

Malignant Mixed Mullerian Tumor (MMMT)


Reviewer: Mohamed Mokhtar Desouki, MD, PhD (see Reviewers page)
Revised: 29 December 2011, last major update September 2011
Copyright: (c) 2002-2011, PathologyOutlines.com, Inc.

Definition
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● Biphasic, high-grade tumor with malignant epithelial and stromal components
● Benign (both components): adenofibroma, adenomyoma and atypical polypoid adenomyoma
● Malignant (mesenchymal component): adenosarcoma
● Malignant (epithelial component): carcinofibroma
● Malignant (both components): MMMT (carcinosarcoma)

Terminology
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● Also called carcinosarcoma, sarcomatoid carcinoma, malignant mesodermal mixed tumor, metaplastic carcinoma

Epidemiology
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● Rare, almost always in postmenopausal women (median age 65 years), small number of women < age 40 years
● Constitutes half of all uterine sarcomas

Sites
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● Uterine corpus, cervix, ovaries, fallopian tubes, vagina, peritoneum; also extragenital sites

Etiology
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● Associated with chronic estrogen stimulation
● 30% with heterologous MMMT and 13% with homologous MMMT have history of radiation therapy (median 16 years previous, often pelvic)
● Other predisposing factors include nulliparity, diabetes, obesity
● Cases of tamoxifen associated uterine MMMTs have been reported

Clinical features
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● Vaginal bleeding, abdominal mass and pelvic pain are the usual presenting symptoms
● Usually elevated serum CA125
● Extrauterine spread in up to 1/3

Prognostic factors
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Highly aggressive:
● 5 year disease-free survival by stage is poor (stage I, 56%; stage II, 31%; stage III, 13%; stage IV, 0%) with most patients developing extrapelvic disease (J Clin Oncol 2010;28:2727)
● Cure possible only if tumor is restricted to inner half of myometrium
● Heterologous differentiation has no prognostic importance

Case reports
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● 54 year old woman with tamoxifen associated tumor (Indian J Pathol Microbiol 2010;53:886)

Treatment
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● TAHBSO with pelvic lymphadenectomy
● Radiotherapy and chemotherapy (initially chemosensitive, but relapse quickly)
● Recurs in lung and abdomen

Gross description
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● Fleshy, bulky, polypoid, may be friable
● May fill uterine cavity and protrude through cervical os
● Hemorrhage and necrosis common
● Usually extensive myoinvasion

Gross images
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Polypoid fleshy mass at fundus of uterus

Various images #1; #2; #3; #4; #5; #6

Micro description
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● Biphasic tumor with carcinomatous and sarcoma-like elements
● Most common epithelial component is glandular (endometrioid, clear cell, serous) and usually poorly differentiated
● Most common sarcomatous components are homologous (endometrial stromal sarcoma, leiomyosarcoma) or heterologous (muscle, cartilage, osteoid, fat)
● Angiolymphatic invasion common
● Peritoneal metastases may have scanty stromal component, psammoma bodies, and form papillary structures resembling ovarian serous carcinoma metastases
● Rarely neuroectodermal differentiation (Am J Surg Pathol 2008;32:219)

Micro images
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Various images

   
With rhabdomyosarcoma

   
With chrondrosarcoma

   
With osteosarcoma


H&E and immunostains

   
Left: biphasic pattern; right: sarcomatous elements

Various images #1; #2; #3; #4

Positive stains
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● Keratin (both components), p53 (usually positive or negative in both components), EMA (often both components)

EM description
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● Hybrid epithelial/stromal cells

Molecular description
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● p53 alteration occurs early before clonal expansion
● Loss of heterozygosity involving 17p, 17q, 11q, 15q and 21q
● Overexpression of c-myc
● Altered methylation of H19 gene
● Stromal and glandular cells may have same cell of origin; identical alleles are lost in epithelial and mesenchymal cells (J Pathol 1997;183:424)
● Mutations (loss of immunostaining): PTEN (39%), MLH1 (33%), MSH2 (22%), MSH6 (21%); p53 overexpression (38%, Mod Pathol 2011;24:1368)

Differential Diagnosis
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Teratoma: younger age, components include skin appendages, glia, thyroid; MMMT only rarely contains neuroectodermal elements
Botryoid rhabdomyosarcoma: children/teens, cervical or vaginal primaries, no carcinomatous component
Metastatic ovarian serous cystadenocarcinoma: papillae and psammoma bodies present; also anaplastic carcinoma; keratin may not be helpful

End of Uterus > Stromal tumors > Malignant Mixed Mullerian Tumor (MMMT)


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