SOX2 Is the Most Sensitive Biomarker in Testicular and Gynecologic Embryonic-type Neuroectodermal Tumors (ENT) Based on a Comprehensive Evaluation of Biomarker Expression

Embryonic-type neuroectodermal tumor (ENT; previously referred to as primitive neuroectodermal tumor, PNET) of the testis and gynecologic tract share morphologic features with small round blue cell tumors, including Ewing sarcoma (ES), yet are biologically, therapeutically, and prognostically distinct. The diagnosis of ENT can be challenging, and it is unclear if there are reliable biomarkers that can be used to confirm this diagnosis. This study characterized 50 ENTs arising from the testis (n=38) and gynecologic tract (n=12; 7 ovary/5 uterus) with 27 biomarkers (AE1/AE3, ATRX, CD99, chromogranin-A, Cyclin D1, Fli-1, GFAP, GLUT-1, IDH1/2, INSM1, MTAP, NANOG, Nestin, neurofilament, NKX2.2, NSE, OCT3/4, OLIG2, p16, PAX6, PHOX2B, S100, SALL4, SOX2, SOX10, SOX17, synaptophysin). Expression was evaluated for extent (0, negative; 1, ≤10% positive; 2, 11% to 50% positive; 3, >50% positive) and intensity (1, weak; 2, moderate; 3, strong) of staining to obtain a combined score (CS) of 0-9; a CS ≥4 was considered "significant staining." SOX2 was the most sensitive biomarker for ENT, as 85% of the tumors demonstrated CS=9. GLUT-1, Fli-1, SALL4, and Cyclin D1 also showed CS ≥4 in more than half of the ENTs; however, only a minority demonstrated CS=9. All other biomarkers showed CS ≥4 in fewer than half of the ENTs, including synaptophysin (38%), GFAP (15%), S100 (15%), and chromogranin-A (14%). NKX2.2, CD99, and SOX17 showed CS ≥4 in 7%, 0%, and 3% of tumors, respectively. Overall, we found that in the appropriate clinicopathologic context, utilizing a panel of SOX2, OCT3/4 (to exclude embryonal carcinoma), AE1/AE3, NKX2.2, CD99, and SOX17 could be helpful in the diagnosis of ENT; many other traditional diagnostic biomarkers show limited utility.