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INTRODUCTION: Multi-omic studies have identified three molecular separated pulmonary carcinoid (PC) subgroups (A1, A2, B) with distinctive mRNA expression profiles (e.g., orthopedia homeobox protein OTP, achaete-scute homolog ASCL1, and hepatocyte nuclear factor 1 homeobox A HNF1A). We aimed to establish an immunohistochemical (IHC) biomarker panel that enables subgroup identification, and assessment of its potential clinical relevance. METHODS: All patients with resected pulmonary carcinoids (2003-2012) were identified from the Dutch Cancer/Pathology Registry, and tumors were revised. The IHC expression of OTP, ASCL1, and HNF1A was scored in a blinded fashion in a mRNA-profiled (n = 5 per subgroup) and national carcinoid cohort (N = 478). The expression of potential therapeutic targets (somatostatin receptor type 2a SSTR2A and delta-like canonical Notch ligand 3 DLL3) was assessed. Immunohistochemistry was assessed using H-scoring. RESULTS: ). In 12% of PCs, no distinct classification could be provided. Patients with A1 were enriched for older age (83% > 50 y), female individuals (83%), and peripheral location (55%) with low SSTR2A (median = 10) and high DLL3 (median = 52) expression. A2 included younger patients (34% < 40 y) and endobronchial/central (87%) tumors with high SSTR2A (median = 160), but low DLL3 (median 0) expression. Group B included more male individuals (59%) and recurrence was more frequent (19%) than in groups A1 (8%) and A2 (6%). Neuroendocrine cell hyperplasia was enriched in A1 (25%) compared with A2 (3%) and B (0%). CONCLUSIONS: An OTP, ASCL1, and HNF1A IHC panel enables the identification of molecular-defined pulmonary carcinoid subgroups with distinct clinical phenotypes and diverging therapeutic vulnerabilities that require further prospective evaluation.
Leunissen et al. (Fri,) studied this question.