Definition/General
Introduction:
Endometrial mixed carcinoma is a malignant tumor containing two or more distinct histological types
It represents 5-10% of all endometrial carcinomas
The most common combination is endometrioid and serous carcinoma
Each component must comprise at least 10% of the tumor for recognition.
Origin:
Arises from endometrial epithelial cells with capacity for multiple differentiation pathways
May develop through divergent differentiation from common precursor
Dedifferentiation of one component into another possible
Represents tumor heterogeneity and clonal evolution.
Classification:
WHO classification recognizes mixed carcinoma as distinct entity
Common combinations include endometrioid + serous
Endometrioid + clear cell
Serous + clear cell
Adenosquamous carcinoma (endometrioid + squamous)
Grade determined by highest grade component.
Epidemiology:
Peak incidence in 6th-7th decades
Mean age 60-65 years
Age varies with histological components
Prognosis determined by most aggressive component
High-grade components (serous, clear cell) worsen prognosis
Stage at presentation often advanced.
Clinical Features
Presentation:
Postmenopausal bleeding (most common)
Rapidly growing uterine mass
Pelvic pressure or pain
Abnormal uterine bleeding (premenopausal)
Advanced stage at presentation common
Constitutional symptoms (weight loss, fatigue)
Ascites in serous component cases.
Symptoms:
Abnormal uterine bleeding (85-90%)
Pelvic pain and pressure
Bulky uterine mass
Vaginal discharge
Abdominal distension
Rapid symptom progression
Urinary or bowel symptoms
Paraneoplastic symptoms (rare).
Risk Factors:
Risk factors vary by predominant component
Endometrioid component: Obesity, diabetes, unopposed estrogen
Serous component: Age, p53 mutations, prior breast cancer
Clear cell component: Lynch syndrome, prior pelvic radiation
Mixed risk profile common.
Screening:
No specific screening for mixed carcinoma
Endometrial sampling for abnormal bleeding
Comprehensive sampling important to identify all components
Imaging studies (MRI helpful)
CA-125 often elevated (serous component)
Genetic counseling if Lynch syndrome suspected.
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Gross Description
Appearance:
Heterogeneous mass with variable consistency and coloration
Areas of different texture corresponding to different components
Soft, fleshy areas (endometrioid) mixed with firm, gray areas (serous)
Cut surface shows variegated appearance.
Characteristics:
Mixed consistency with soft and firm areas
Variable coloration (gray-white, tan, yellow)
Hemorrhage and necrosis common
May show papillary areas (serous component)
Cystic areas (clear cell component)
Solid areas (high-grade components).
Size Location:
Usually involves entire endometrial cavity
Size typically large (6-15 cm)
Different areas may show different growth patterns
Deep myometrial invasion common
Cervical extension frequent
Extrauterine spread common at presentation.
Multifocality:
Multifocal involvement common
Different components may show different distribution patterns
Lymphovascular invasion often extensive
Serous component predisposes to peritoneal spread
Synchronous ovarian involvement possible.
Microscopic Description
Histological Features:
Two or more distinct histological patterns
Endometrioid component: Glandular architecture, squamous morules
Serous component: Papillary architecture, high nuclear grade
Clear cell component: Clear cytoplasm, hobnail pattern
Transition zones between components may be seen.
Cellular Characteristics:
Features vary by component
Endometrioid: Columnar cells, variable nuclear grade
Serous: High nuclear grade, prominent nucleoli, high N:C ratio
Clear cell: Clear or eosinophilic cytoplasm, hobnail nuclei
Squamous: Keratinization, intercellular bridges
Mixed cellular populations.
Architectural Patterns:
Glandular patterns (endometrioid, clear cell)
Papillary patterns (serous)
Solid patterns (high-grade areas)
Squamous differentiation (adenosquamous)
Cribriform patterns
Complex architectural admixture
Different patterns in different tumor areas.
Grading Criteria:
Grade determined by highest grade component
Each component graded separately
Overall grade reflects most aggressive element
High-grade components (serous, clear cell, grade 3 endometrioid) determine final grade
Percentage of each component should be reported.
Immunohistochemistry
Positive Markers:
Endometrioid component: ER/PR positive, PAX8 positive, Vimentin positive
Serous component: p53 (mutant pattern), WT1 positive, p16 diffuse
Clear cell component: HNF-1β positive, Napsin A positive
Squamous component: p63 positive, CK5/6 positive
All components: PAX8 positive.
Negative Markers:
Variable depending on component
Serous component: ER/PR often negative
Clear cell component: ER/PR negative
Squamous component: ER/PR negative
High-grade components: Hormone receptors often negative
Component-specific negative markers.
Diagnostic Utility:
Essential for identifying individual components
p53 staining identifies serous areas
HNF-1β highlights clear cell areas
p63 confirms squamous differentiation
Hormone receptors help identify endometrioid areas
Molecular classification may require multiple markers.
Molecular Subtypes:
Molecular classification based on predominant component
p53-aberrant (serous component present)
Microsatellite instable (Lynch syndrome cases)
POLE-mutated (rare)
Copy number low (endometrioid component)
Mixed molecular features possible.
Molecular/Genetic
Genetic Mutations:
p53 mutations (serous component)
PTEN mutations (endometrioid component)
PIK3CA mutations (various components)
KRAS mutations (endometrioid)
Mismatch repair gene mutations (Lynch syndrome)
Different mutations in different components possible.
Molecular Markers:
p53 overexpression (serous areas)
PTEN loss (endometrioid areas)
Microsatellite instability (Lynch syndrome)
High Ki-67 in high-grade components
Chromosomal instability (serous component)
Molecular heterogeneity within tumor.
Prognostic Significance:
Prognosis determined by worst component
Serous component indicates poor prognosis
Clear cell component associated with poor outcome
High-grade endometrioid worsens prognosis
Stage more important than histological mix
Molecular subtype may predict treatment response.
Therapeutic Targets:
Chemotherapy tailored to high-grade component
Platinum-based therapy for serous component
Immunotherapy for microsatellite instable tumors
Hormone therapy if ER/PR positive areas present
Targeted therapy based on molecular profiling
Combination approaches may be needed.
Differential Diagnosis
Similar Entities:
Pure endometrioid carcinoma with squamous differentiation
Pure serous carcinoma
Pure clear cell carcinoma
Carcinosarcoma (malignant mixed müllerian tumor)
Metastatic carcinoma with mixed patterns
Adenosquamous carcinoma.
Distinguishing Features:
Mixed carcinoma: Multiple epithelial components
Mixed carcinoma: Each component >10%
Mixed carcinoma: No sarcomatous elements
Carcinosarcoma: Sarcomatous component present
Pure tumors: Single histological pattern
Adenosquamous: Endometrioid + squamous only
Metastatic: Primary tumor elsewhere.
Diagnostic Challenges:
Determining percentage of each component
Distinguishing from carcinosarcoma
Recognizing minor components (<10%)
Identifying transition zones
Separating from extensive sampling artifact
Molecular characterization of heterogeneous tumor.
Rare Variants:
Triple mixed carcinoma (three components)
Mixed with neuroendocrine component
Mixed with undifferentiated areas
Adenosquamous with clear cell features
Mixed carcinoma with trophoblastic differentiation.
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 mixed carcinoma
Classification
WHO Classification: Mixed carcinoma, Overall FIGO Grade: [based on highest grade component]
Histological Components
Component 1: [type] ([percentage]%, Grade [X]). Component 2: [type] ([percentage]%, Grade [X])
Predominant Component
[Component type] ([percentage]%)
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]
Special Studies
Component 1 IHC: [relevant markers and results]
Component 2 IHC: [relevant markers and results]
Molecular studies: [if performed]
FIGO Staging
FIGO Stage: [stage] ([staging criteria])
Prognostic Factors
Prognosis determined by [most aggressive component], Stage: [X]
Final Diagnosis
Endometrial mixed carcinoma ([components]), FIGO Stage [X]