Primary Endometrial Gastric (Gastrointestinal)-type Mucinous Adenocarcinoma

Endometrial gastric (gastrointestinal)-type mucinous adenocarcinoma (EmGA) is rare and was introduced as a new entity in the latest World Health Organization (WHO) classification of female genital tumors. Herein, we report a detailed clinicopathologic, immunohistochemical, and molecular study of 27 EmGA, the largest published series to date. The cohort consisted of 27 patients (median age 69 y; range 42 to 87 years). Histologically all cases showed gastric/gastrointestinal differentiation with foamy apical cytoplasm with distinct cell borders (n=21), goblet cells (n=9), signet ring cells (n=4), and Paneth cells (n=1). Using FIGO grading, 5 were grade 1, 14 grade 2, and 8 grade 3. Tumors were positive for MUC6 (10/21), CK7 (22/24), CK20 (16/24), CDX2 (24/26), and Claudin 18 (9/12). In all, 12/27 exhibited aberrant p53 expression and 3/26 showed MLH1 and PMS2 loss, including 2 with confirmed MLH1 gene promoter methylation. Next-generation sequencing showed pathogenic variants in TP53 (13/20), KRAS (7/20), PIK3CA (5/20), BRCA2 (4/20), SMAD4 (3/20), and POLE (1/20). Using TCGA classification (based on cases with available molecular results), 1/20 was POLE mutated, 2/20 were mismatch repair deficient (MMRd), 4/20 were no specific molecular profile (NSMP), and 13/20 were TP53 abnormal. FIGO stage (2009 staging system) ranged from IA to IVB. Outcome data (21 patients; follow-up of 2 to 77 mo) showed that 2 patients died of disease at 14 and 46 months after diagnosis, 1 patient died from other causes at 28 months, 8 were alive with disease, and 10 were alive with no evidence of disease. Like the cervical counterpart, primary EmGA has a distinctive morphologic appearance, harbors frequent TP53 mutations, and can be associated with adverse outcomes despite low-grade morphology and/or low-stage at presentation. They may be represented in all 4 TCGA molecular groups.