Analysis of ASCL1/NEUROD1/POU2F3/YAP1 Yields Novel Insights for the Diagnosis of Olfactory Neuroblastoma and Identifies Sinonasal Tuft Cell-Like Carcinoma.

The diagnosis and treatment of sinonasal small round epithelial/neuroepithelial malignancies depend on the expression of conventional neuroendocrine markers (NEMs), such as synaptophysin, chromogranin A, INSM1, and CD56/NCAM1. However, these tumors remain diagnostically challenging because of overlapping histologic and immunohistochemical features. The transcriptional regulators ASCL1, NEUROD1, POU2F3, and YAP1 are novel NEM (nNEM) used for the subtyping of small-cell lung cancer (SCLC). Here, we assessed the immunoexpression of nNEM in 76 sinonasal malignancies, including 27 olfactory neuroblastomas (ONB), 14 small-cell neuroendocrine carcinomas (SCNEC), 2 large-cell neuroendocrine carcinomas, 12 sinonasal undifferentiated carcinomas (SNUC), 7 olfactory carcinomas (OC), 11 SWI/SNF-deficient carcinomas, and 3 neuroendocrine tumors. We correlated nNEM expression with the extent of neuroendocrine (NE) differentiation, as defined by averaged conventional NEM expression (NE-high: H-score, ≥150; NE-low: H-score, <150). Dominant NE subtypes were defined by the nNEM with the highest H-score. Coexpression of 2 nNEM with <100 H-score difference defined a codominant NE subtype. NE differentiation positively correlated with NEUROD1 and negatively with YAP1 expression (P < .0001). ONB were NE-high (96%), and all were NEUROD1-dominant/POU2F3-negative/ASCL1-negative (low)/YAP1-negative (low). In contrast to ONB, all OC were NE-low, mostly (71%) codominant subtypes, NEUROD1-low (negative) (100%, P = .0001), and YAP1 high (71%; P = .0001). Most notably, all SNUC were POU2F3-(co)dominant/NEUROD1-negative irrespective of the IDH2 mutations. Sinonasal tumors with high POU2F3 expression showed enrichment for "tuft cell carcinoma" and tuft cell signatures (P = .009). Similar to SCLC, SCNEC was heterogeneous in terms of nNEM expression comprising several molecular subtypes, including ASCL1-(co)dominant (43%) cases. All SWI/SNF-deficient carcinomas were consistently ASCL1/NEUROD1/POU2F3-negative and YAP1-positive. ASCL1/NEUROD1/POU2F3/YAP1 are useful markers in the differential diagnosis of ONB, SNUC, OC, and SWI/SNF-deficient carcinomas. Subsets of SNUC and large-cell neuroendocrine carcinomas may represent tuft cell-like carcinomas, suggesting that the tuft cell could be explored as the cell of origin for these tumors. The therapeutic vulnerabilities associated with POU2F3 expression in SCLC suggest that a similar approach might be considered for POU2F3-positive carcinomas of the sinonasal tract. Given their diagnostic and possible therapeutic relevance, nNEM have the potential to transform the way we approach the diagnosis and management of sinonasal small round epithelial/neuroepithelial malignancies.