Analysis of SCLC subtype markers ( ASCL1 , NEUROD1 , POU2F3 , YAP1 ), DLL3 , OTP, and TTF1 in 300 lung carcinoids and enteropancreatic neuroendocrine tumours

AIMS: ASCL1, NEUROD1, POU2F3 and YAP1 are recently described markers of transcriptional subtypes in small cell lung carcinoma (SCLC), while DLL3, regulated by ASCL1, is a target of novel therapeutic agents in various neuroendocrine neoplasms. The expression of these markers in lung carcinoids is not well established. METHODS AND RESULTS: We examined these markers in 109 lung carcinoids and compared their expression with that in 191 enteropancreatic neuroendocrine tumours (EP-NETs) and with lung carcinoid markers (OTP, TTF1). ASCL1, NEUROD1, OTP and TTF1 were positive in 56%, 0%, 84% and 35% of lung carcinoids, respectively. Of the OTP-negative lung carcinoids (n = 18), 4 (22%) were ASCL1-positive, of which one was TTF1-positive. In contrast, 59% of EP-NETs were NEUROD1-positive, whereas only rare tumours focally expressed ASCL1 (1.1%) and OTP (0.5%) and none expressed TTF1. DLL3 was positive in 57 (52%) lung carcinoids versus 5 (2.6%) EP-NETs. All lung carcinoids and EP-NETs were completely negative for POU2F3 and YAP1. We also analysed clinicopathologic correlates of ASCL1, OTP, TTF1 and DLL3 expression in lung carcinoids, expanding on several previously suggested associations, including ASCL1 and TTF1 with peripheral location, OTP with low Ki67 (P = 0.002) and low stage (P = 0.002) and DLL3 with high Ki67 (P = 0.002). CONCLUSION: Unlike SCLC, lung carcinoids and EP-NETs completely lack the expression of POU2F3 and YAP1, which offers diagnostic applications. Our findings also nominate ASCL1 and NEUROD1 as site of origin markers for lung versus digestive NETs/carcinoids, respectively. Finally, the divergent expression of DLL3 in lung carcinoids and EP-NETs has therapeutic implications.