Immunohistochemical characterization of somatically derived “yolk sac tumors”: analysis of a multi-institutional case series

A rare subset of somatic tumors shows a striking resemblance to yolk sac tumors (YSTs) of germ cell origin, including somatic carcinomas with YST/enteroblastic differentiation, fetal lung adenocarcinomas (FLACs), and YSTs in older (≥ 40 years) females. These somatic tumors express markers such as SALL4, glypican 3 (GPC 3) and alpha-fetoprotein (αFP). However, it is currently unclear to what extent they express FOXA2, HNF1β, and SOX17, which are pioneer transcription factors and key drivers of YST differentiation and stain the vast majority of chemotherapy-naïve YSTs of germ cell origin. Therefore, a multi-institutional series of seven somatically derived "YST-like" tumors was assembled and evaluated with a comprehensive panel of YST related markers (SALL4, FOXA2, HNF1β, SOX17, αFP, GATA3, and CDX2), to evaluate the potential involvement of FOXA2, HNF1β, and SOX17 in the biology of these tumors. FOXA2 and HNF1β were positive in all (7/7, 100%) YST-like tumors, followed by CDX2 (6/7, 85.7%) and SALL4 (5/7, 71.4%). In contrast, SOX17, GATA3, αFP, and GPC3 were positive in fewer cases, and showed lower percentages and intensities. Four of seven (57.1%) YST-like tumors showed synchronous/accompanying somatic neoplastic components: one clear cell carcinoma of the ovary, two urothelial carcinomas of the bladder, and one invasive non-mucinous (conventional) adenocarcinoma of the lung. HNF1β stained all these components (4/4, 100%), and all of them (4/4, 100%) stained for at least two of the YST markers evaluated (range: 2-4). In conclusion, our results support the use of an immunohistochemical panel to diagnose YST-like tumors, considering not only the most frequently expressed makers (FOXA2 and HNF1β), but also the potential expression (particularly of HNF1β) by the associated somatic neoplastic components lacking an overt YST phenotype. The consistent expression of FOXA2 and HNF1β (but not SOX17) in our cohort underscores the phenotypic overlap between YST-like tumors and YSTs of germ cell origin (type II), including shared expression of multiple pioneer transcription factors which drive the YST phenotype.