Phenotypic and Molecular Features of Somatically Derived “Yolk Sac Tumors”: Similarities and Differences With Counterparts of Germ Cell Origin

A subset of somatic carcinomas shows morphologic and immunophenotypic similarities to yolk sac tumor (YST) of germ cell origin, including fetal adenocarcinomas of the lung and somatic carcinomas with “YST”/enteroblastic differentiation. At least some of these tumors may result from reprogramming somatic cancer cells, leading to the acquisition of a “pluripotent” phenotype. Although these somatic tumors express markers such as SALL4, glypican 3, and alpha-fetoprotein, which are positive in germ cell-derived YST, it is currently uncertain to what degree their molecular features overlap with those of germ cell tumors (GCTs). We assessed i(12p) (fluorescence in situ hybridization) and levels of micro-RNA-371-373 (real-time PCR), hallmarks of germ cell neoplasia in situ (GCNIS)-derived GCTs, in a cohort of 11 somatically derived neoplasms with YST/enteroblastic phenotype (designated as “YST-like” tumors hereafter). In addition, we used immunohistochemistry to assess expression of FOXA2, a critical regulator of induction and maintenance of YST phenotype in GCTs. All YST-like tumors showed expression of FOXA2 and were negative for i(12p). Expression of miR-371a-3p (the most specific member of the miR-371-373 cluster) was detectable in 6 of 10 (60%) of YST-like tumors. Four samples showed levels in the gray zone of detection (ie, expression of uncertain clinical significance), and 2 samples (separate tumors from a single patient) showed positive levels similar to those found in nonteratoma GCNIS-derived GCTs. The remaining members of the micro-RNA cluster (miRs 372 and 373) followed the same patterns. Our results show that the overlap of somatically derived YST-like tumors and YSTs of germ cell origin goes beyond morphology, including expression of one of the master regulators of the YST phenotype and, in some cases, miR-371a-3p. However, these neoplasms lack a hallmark finding of GCNIS-derived GCTs (i[12p]) and show significant biologic and clinical differences with GCTs.