Definition/General
Introduction:
Endometrial carcinosarcoma, also known as malignant mixed müllerian tumor (MMMT), is a rare and highly aggressive malignant neoplasm
It represents 2-5% of all uterine malignancies
It is composed of both malignant epithelial and mesenchymal components
It has a poor prognosis with high propensity for metastasis.
Origin:
Arises from pluripotent müllerian stem cells or represents transdifferentiation of carcinoma
The conversion theory suggests epithelial-to-mesenchymal transition
Molecular studies support monoclonal origin from epithelial cells
The sarcomatous component represents dedifferentiation of carcinomatous elements.
Classification:
Classified as homologous or heterologous based on mesenchymal component
Homologous: Contains tissue native to uterus (smooth muscle, stromal sarcoma)
Heterologous: Contains tissue foreign to uterus (cartilage, bone, skeletal muscle)
WHO classification includes both under mixed epithelial and mesenchymal tumors.
Epidemiology:
Peak incidence in 6th-7th decades
Mean age 65-70 years
Risk factors include nulliparity
Previous pelvic irradiation
Tamoxifen therapy
Obesity
Diabetes mellitus
African-American women have higher incidence
Represents 40-50% of uterine sarcomas.
Clinical Features
Presentation:
Postmenopausal bleeding (most common)
Pelvic mass
Abdominal distension
Uterine enlargement
Pelvic pain
Prolapsing mass through cervix
Constitutional symptoms (weight loss, fatigue)
Advanced cases may present with distant metastases.
Symptoms:
Abnormal uterine bleeding (90%)
Pelvic pressure
Lower abdominal pain
Rapidly enlarging uterus
Vaginal discharge (may be purulent)
Bowel or bladder symptoms
Paraneoplastic syndromes (rare)
Ascites in advanced cases.
Risk Factors:
Advanced age (>60 years)
Prior pelvic radiation
Tamoxifen therapy
Nulliparity
Obesity (BMI >30)
Diabetes mellitus
Lynch syndrome
Previous endometrial hyperplasia
Unopposed estrogen therapy.
Screening:
No specific screening guidelines
Endometrial sampling for postmenopausal bleeding
Imaging studies (ultrasound, MRI)
Hysteroscopy may reveal polypoid mass
CA-125 may be elevated
Genetic counseling for Lynch syndrome patients.
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Gross Description
Appearance:
Large, polypoid, bulky mass filling uterine cavity
Gray-white to tan cut surface with areas of hemorrhage and necrosis
Size ranges from 5-20 cm
Cut surface shows heterogeneous appearance with firm and soft areas.
Characteristics:
Soft, fleshy consistency with areas of firm tissue
Extensive necrosis and hemorrhage
Calcifications may be present in heterologous types
Surface may be ulcerated
May show myometrial invasion on gross examination.
Size Location:
Usually involves entire endometrial cavity
Average size 8-12 cm
May extend to cervix
Myometrial invasion common
May involve serosa and adnexa
Extrauterine extension frequent at presentation.
Multifocality:
Usually unifocal but extensive
May have satellite nodules
Lymphovascular invasion common
Peritoneal implants frequent
Ovarian metastases in 10-15% cases
Synchronous ovarian carcinosarcoma possible.
Microscopic Description
Histological Features:
Biphasic tumor with intimately admixed carcinomatous and sarcomatous elements
Carcinomatous component usually high-grade endometrioid or serous adenocarcinoma
Sarcomatous component shows high-grade spindle cell morphology
Transition zones between components may be seen.
Cellular Characteristics:
Carcinomatous cells show high nuclear grade
Pleomorphic nuclei with prominent nucleoli
High mitotic activity
Sarcomatous cells are spindle-shaped
Marked nuclear pleomorphism
Numerous atypical mitoses
Areas of necrosis common.
Architectural Patterns:
Glandular pattern in carcinomatous component
Solid sheets and fascicles in sarcomatous areas
Heterologous elements (cartilage, bone, skeletal muscle) in 50% cases
May show rhabdomyoblastic differentiation
Vascular invasion frequently present.
Grading Criteria:
All carcinosarcomas considered high-grade tumors
Grade based on worst component
Carcinomatous component graded by FIGO system
Sarcomatous component assessed for mitotic count and pleomorphism
Presence of heterologous elements noted.
Immunohistochemistry
Positive Markers:
Carcinomatous component: Cytokeratins (CK7, CK8/18)
EMA
p53 (often mutant pattern)
PAX8
WT1 (serous type)
Sarcomatous component: Vimentin
p53 (shared mutations)
Desmin (smooth muscle)
MyoD1 (rhabdomyosarcoma).
Negative Markers:
Sarcomatous component: Cytokeratins (usually negative)
EMA (usually negative)
Carcinomatous component: Vimentin (usually negative)
Muscle markers (usually negative)
CD117
DOG1
Hormone receptors often negative.
Diagnostic Utility:
Essential for confirming biphasic nature
p53 shows concordant staining pattern supporting monoclonal origin
PAX8 positivity supports müllerian origin
Muscle markers identify heterologous elements
Cytokeratins highlight epithelial component.
Molecular Subtypes:
p53-aberrant type (most common, poor prognosis)
p53-wild type (rare, better prognosis)
Microsatellite instability (Lynch syndrome cases)
POLE-mutated (rare)
Copy number high subtype most common.
Molecular/Genetic
Genetic Mutations:
p53 mutations (70-90%)
PIK3CA mutations (20-30%)
PTEN mutations (20%)
KRAS mutations (15-25%)
PPP2R1A mutations (10%)
FBXW7 mutations
Shared mutations in both components support monoclonal origin.
Molecular Markers:
p53 overexpression (mutant pattern)
High Ki-67 proliferation index (>50%)
Loss of PTEN expression
PIK3CA overexpression
Chromosomal instability (aneuploidy)
DNA repair defects in Lynch syndrome cases.
Prognostic Significance:
p53 mutation associated with poor prognosis
Microsatellite instability may predict better response to immunotherapy
POLE mutations associated with better prognosis
High tumor mutational burden in some cases
Copy number alterations correlate with aggressive behavior.
Therapeutic Targets:
p53 pathway: MDM2 inhibitors
PI3K/AKT pathway: PI3K inhibitors
PARP inhibitors for homologous recombination deficiency
Immunotherapy for microsatellite instable tumors
Anti-angiogenic therapy
CDK4/6 inhibitors under investigation.
Differential Diagnosis
Similar Entities:
Endometrial stromal sarcoma (low-grade, CD10 positive)
Leiomyosarcoma (smooth muscle markers positive)
Adenosarcoma (low-grade, benign epithelial component)
Metastatic carcinoma with stromal reaction
Dedifferentiated carcinoma (lacks true sarcomatous differentiation).
Distinguishing Features:
Carcinosarcoma: High-grade carcinomatous component
Carcinosarcoma: True sarcomatous differentiation
Carcinosarcoma: p53 mutations common
Adenosarcoma: Benign epithelial component
Adenosarcoma: Low-grade sarcomatous stroma
ESS: CD10 positive
ESS: Low-grade morphology
Leiomyosarcoma: Smooth muscle differentiation only.
Diagnostic Challenges:
Distinguishing carcinosarcoma from adenosarcoma (grade of epithelial component)
Identifying heterologous elements
Separating from dedifferentiated carcinoma
Recognition of minimal sarcomatous component
Distinction from carcinoma with spindle cell metaplasia.
Rare Variants:
Embryonal rhabdomyosarcoma component (very rare)
Osteosarcomatous differentiation
Chondrosarcomatous elements
Angiosarcomatous areas
Liposarcomatous differentiation
Mixed heterologous elements.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Hysterectomy specimen measuring [X x Y x Z] cm, weighing [X] grams
Diagnosis
Endometrial carcinosarcoma ([homologous/heterologous])
Classification
WHO Classification: Malignant mixed müllerian tumor, FIGO Grade: High-grade
Histological Features
Biphasic tumor with carcinomatous component showing [type] and sarcomatous component with [differentiation]
Size and Extent
Tumor size: [X] cm, myometrial invasion: [depth/total thickness], [percent]%
Margins
Margins: [involved/uninvolved], closest margin: [X] mm
Lymphovascular Invasion
Lymphovascular invasion: [present/absent]
Cervical Involvement
Cervical involvement: [present/absent], [stromal/surface]
Adnexal Involvement
Ovaries: [involved/uninvolved], Fallopian tubes: [involved/uninvolved]
Special Studies
IHC: Cytokeratins: [positive in carcinomatous component], Vimentin: [positive in sarcomatous component], p53: [pattern]
Molecular studies: [if performed]
Peritoneal Cytology
Peritoneal washings: [positive/negative/not submitted]
FIGO Staging
FIGO Stage: [stage] ([staging criteria])
Prognostic Factors
High-grade tumor, Stage: [X], Lymphovascular invasion: [present/absent], p53 status: [pattern]
Final Diagnosis
Endometrial carcinosarcoma, [homologous/heterologous], FIGO Stage [X]