Primary vulvar and vaginal adenocarcinomas of intestinal-type are closer to colorectal adenocarcinomas than to carcinomas of Müllerian origin.

Primary vulvar and vaginal adenocarcinomas of intestinal-type (VVAIts) are very rare tumors, displaying morphological and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Herein, we studied a series of 4 vulvar and 4 vaginal adenocarcinomas of intestinal-type using a large panel of immunohistochemistry, and DNA and RNA sequencing with clustering analyses. All tumors shared a similar morphology with colorectal adenocarcinomas and diffuse CK20 and CDX2 expression. SATB2 diffuse positivity was observed in 62.5% of tumors and CK7 in 82.5%, while PAX8, SOX17, p16, estrogen and progesterone receptors were always negative. A p53 mutated-type expression was observed in 75% of tumors. All tumors were MMR proficient. No HPV DNA nor pathogenic transcript fusions were detected. The most frequent molecular alterations were TP53 and KRAS variants in 71.4% and 42.9%, respectively. The transcriptomic analysis highlighted a robust VVAIts cluster distinct from endocervical, ovarian, lung, thyroid, salivary glands, breast, and renal carcinomas, but failed to differentiate vulvar from vaginal intestinal-type tumors. On two different clustering analyses, VVAIts clustered altogether, very close to colorectal adenocarcinomas. Compared to endocervical adenocarcinomas of intestinal-type, VVAIts had a significantly lower expression of SOX17 and epithelial-mesenchymal transition (EMT) genes, and a higher MAP-Kinase pathway gene expression. These results suggest that Müllerian structures leading to cervical adenocarcinomas may undergo intestinal-type transdifferentiation via an EMT phenomenon. Conversely, MAP-Kinase pathway activation in VVAIts, which plays a major role in colorectal adenocarcinomas, may indicate a close relationship in the carcinogenesis of these tumors. Our results indicate that adenocarcinomas of intestinal-type, in distal vagina or vestibular vulva, might be a unique and single entity, probably originating from cloacogenic embryonic remnants and/or ectopic colorectal mucosae inclusions. An open question would be to explore the efficacy of systemic drugs prescribed in colorectal cancers, in VVAIts.