What are the histological differences between endometrioid (endometrial cancer) carcinoma, serous carcinoma, and mucinous carcinoma in endometrial cancer?

Histological Differences Between Endometrioid, Serous, and Mucinous Endometrial Carcinomas

Endometrioid carcinoma comprises approximately 80% of endometrial cancers and demonstrates glandular architecture with varying degrees of solid growth, while serous carcinoma (5-10% of cases) exhibits papillary architecture with marked nuclear atypia and p53 abnormalities, and mucinous carcinoma (rare subtype) shows mucin-producing glands with intracellular mucin. 1

Endometrioid Carcinoma: Architectural and Molecular Features

Histological Architecture:

• Endometrioid tumors display glandular patterns resembling normal endometrial glands, with grading based on solid growth pattern percentage 1
• Grade 1 (G1): ≤5% non-squamous, non-morular solid growth pattern 1
• Grade 2 (G2): 5-50% solid growth pattern 1
• Grade 3 (G3): >50% solid growth pattern 1
• Notable nuclear atypia inappropriate for architectural grade raises the tumor grade by one 1

Molecular Characteristics:

• The majority (65%) of endometrioid carcinomas are copy number-low/microsatellite stable (MSS) tumors with frequent PTEN (77%), PIK3CA (53%), CTNNB1 (53%), and KRAS (15%) mutations 1
• 30% are hypermutated/MSI-high tumors with mismatch repair deficiency 1
• 7% are POLE-mutated ultramutated tumors with excellent prognosis despite high-grade features 1
• Increased progesterone receptor expression in copy number-low tumors suggests potential responsiveness to progestin therapy 1

Clinical Behavior:

• Endometrioid histology is associated with low-risk disease when presenting as stage IA/IB, grade 1 or 2 1
• These tumors are estrogen-dependent and commonly present in younger women with early-stage disease 2, 3

Serous Carcinoma: Aggressive Histology with Distinct Molecular Profile

Histological Architecture:

• Serous carcinomas exhibit complex papillary architecture with cellular budding, marked nuclear pleomorphism, and prominent nucleoli 1, 4
• Nuclear features show high-grade atypia regardless of architectural pattern 5
• 70% of serous carcinomas have already spread outside the uterus at presentation, with frequent intraperitoneal disease even without myometrial invasion 1

Molecular Characteristics:

• Serous carcinomas are predominantly copy number-high tumors (26% of all endometrial cancers) with TP53 mutations in the vast majority of cases 1
• These tumors exhibit low mutational frequency but extensive chromosomal instability 1
• HER2 amplification is highest in serous carcinomas compared to other histologic subtypes 6
• p53 immunohistochemistry shows aberrant staining (either diffuse strong positivity or complete absence) 1, 5

Clinical Behavior:

• Serous histology confers poor prognosis at any given stage compared to grade 1 or 2 endometrioid tumors 1, 2
• These are estrogen-independent tumors presenting in older women at advanced stages 4, 3
• Omentectomy is specifically recommended for serous carcinomas during surgical staging 1
• 5-year survival for serous histology is 53% compared to 83% for endometrioid 7

Mucinous Carcinoma: Rare Subtype with Distinct Features

Histological Architecture:

• Mucinous carcinomas demonstrate glands lined by cells with intracellular mucin, resembling endocervical or intestinal epithelium 1
• This is a rare established subtype accounting for a small percentage of endometrial cancers 1

Molecular Characteristics:

• Mucinous carcinomas show the highest PD-L1 expression among all endometrial cancer subtypes 6
• EGFR mutations are seen exclusively in mucinous endometrial carcinomas 6
• KRAS mutations are common in mucinous histology 6
• c-MET overexpression is elevated in mucinous tumors 6

Clinical Behavior:

• Mucinous carcinomas are classified as an established subtype with distinct biological behavior 1
• ER/PR expression is common in mucinous histology 6

Critical Diagnostic Pitfalls

Distinguishing Low-Grade Endometrioid from Serous:

• Histomorphologic assessment has poor reproducibility, particularly among high-grade carcinomas, and mixed histology is not infrequent 1
• Preoperative histological diagnosis based on endometrial sampling is changed at final evaluation in up to 25% of cases 1
• Immunohistochemical markers including p53, PTEN, ER, p16, and molecular testing improve diagnostic accuracy 1, 5
• Misdiagnosing serous carcinoma as endometrioid has significant therapeutic consequences 5

Grading Considerations:

• Notable nuclear atypia inappropriate for architectural grade raises a grade 1 or 2 endometrioid tumor by one grade 1
• This grading system applies specifically to endometrioid histology and not to serous or other non-endometrioid subtypes 1

Prognostic Implications by Histologic Type

Risk Stratification:

• Histological type is an established independent prognostic factor alongside FIGO stage, grade, depth of myometrial invasion, age, and lymphovascular space invasion 1
• Stage IA/IB grade 1-2 endometrioid histology defines low-risk disease 1, 8
• Any stage with serous, clear cell, or undifferentiated histology is classified as high-risk regardless of other factors 1, 8

Molecular Classification Impact:

• POLE-mutated tumors have the best progression-free survival despite frequently presenting as high-grade endometrioid histology 1, 9
• Copy number-high/p53-abnormal tumors (predominantly serous) have the worst prognosis and almost always require chemotherapy 1, 9