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. 2025 Apr;20(4):451-464.
doi: 10.1016/j.jtho.2024.11.018. Epub 2024 Nov 22.

Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids

Daphne J G Leunissen  1 , Laura Moonen  1 , Jan H von der Thüsen  2 , Michael A den Bakker  3 , Lisa M Hillen  1 , Tijmen J J van Weert  1 , Axel Zur Hausen  1 , Thierry P P van den Bosch  2 , Lisa M V Lap  1 , Ronald A Damhuis  4 , Niki L Reynaert  5 , Esther C van den Broek  6 ; PALGA group  6 ; Lynnette Fernandez-Cuesta  7 , Matthieu Foll  7 , Nicolas Alcala  7 , Alexandra Sexton-Oates  7 , Anne-Marie C Dingemans  8 , Ernst-Jan M Speel  9 , Jules L Derks  10
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Free article

Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids

Daphne J G Leunissen et al. J Thorac Oncol. 2025 Apr.
Free article

Abstract

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: OTP, ASCL1, and HNF1A reported similar IHC and mRNA expression patterns in the matched primary samples. In the national cohort, IHC separated PCs into subgroups A1 (n = 224 [53%], OTPhigh-ASCL1high-HNF1Alow), A2 (n = 161 [38%], OTPhigh-ASCL1low-HNF1Ahigh), and B (n = 37 [9%], OTPlow-ASCL1low-HNF1Ahigh). 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.

Keywords: Immunohistochemistry; Molecular subgroups; OTP; Pulmonary carcinoid; Therapy.

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Conflict of interest statement

Disclosure Dr. Speel reports grants from the Dutch Cancer Society, AstraZeneca, and Bayer, and participated in the advisory board of AstraZeneca, GSK, Janssen-Cilag, and Merck, outside the submitted work. Dr. Dingemans reports grants from Dutch Cancer Society, HANARTH, and Amgen, consulting fees from Sanofi, Amgen, Bayer, Roche, Janssen, AstraZeneca, Boehringer-Ingelheim, Honoraria from Eli Lilly, Pfizer, Janssen, Takeda and AstraZeneca, participated in the advisory board of Roche and Takeda, and is chair of the EORTC lung cancer group, outside the submitted work. Although authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policies, or views of the International Agency for Research on Cancer/WHO. The remaining authors declare no conflict of interest.

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