Endometrial Carcinoma of Gastrointestinal-type (EMCG): Incidence, Molecular Features, and Distinction From Other Endometrial Cancers With Gastrointestinal Marker Immunoexpression

Endometrial carcinoma of gastrointestinal-type (EMCG) is an aggressive endometrial cancer characterized by gastric and/or intestinal-type mucinous morphology, absent/minimal estrogen receptor expression, and at least focal gastrointestinal marker immunoexpression. We herein present a clinicopathologic characterization of 4 EMCG: 2 were prospectively diagnosed, and 2 found on retrospective screening of 274 endometrial carcinomas performed to identify undetected EMCG and characterize gastrointestinal marker expression within our endometrial carcinoma population. All 4 EMCG expressed CDX2 and were negative for SATB2; CK20 was diffuse in one, focal in another, and absent in 2. None showed strong membranous Claudin-18. One was MMR-deficient; 2 had PTEN loss. Sequencing revealed a variety of molecular events, including pathogenic/likely pathogenic variants KRAS, PIK3CA, POLE, PTEN, SMARCA4, and TP53. Thirty-six percent of retrospectively screened endometrial carcinomas expressed at least one gastrointestinal marker; however, the majority had strong ER co-expression, precluding EMCG classification. Other than the 2 cases of true EMCG identified on screening, only one screen-positive tumor had convincing gastrointestinal-type morphology in concert with ER negativity; this case showed SALL4 and AFP expression consistent with a somatically derived yolk sac tumor. These data provide an expanded understanding of the molecular underpinnings of EMCG-including the first description of a SMARCA4 frameshift variant in this entity-and demonstrate that while gastrointestinal marker immunoexpression is relatively common among endometrial carcinomas, strictly defined EMCG remains rare (<1%). As awareness of this entity grows, pathologists should take care not to over-interpret gastrointestinal marker expression as stand-alone evidence of an EMCG diagnosis.