Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids
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: ). 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.
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BibTeX
@article{leunissen2026identification,
title = {{Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids}},
author = {Daphne J. G. Leunissen and Laura Moonen and Jan H. von Der Thüsen and Michael A. Den Bakker and Lisa M. Hillen and Tijmen J. J. Van Weert and Axel Zur Hausen and Thierry P. P. van Den Bosch and Lisa M. V. Lap and Ronald A. Damhuis and Niki L. Reynaert and Esther C. van Den Broek and Lynnette Fernandez-Cuesta and Matthieu Foll and Nicolas Alcala and Alexandra Sexton-Oates and Anne-Marie C. Dingemans and Ernst-Jan M. Speel and Jules L. Derks},
journal = {Journal of Thoracic Oncology},
year = {2026},
month = oct,
doi = {10.1016/j.jtho.2024.11.018},
url = {https://hal.science/hal-05842060v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Identification of Defined Molecular Subgroups on the Basis of Immunohistochemical Analyses and Potential Therapeutic Vulnerabilities of Pulmonary Carcinoids
AU - Daphne J. G. Leunissen
AU - Laura Moonen
AU - Jan H. von Der Thüsen
AU - Michael A. Den Bakker
AU - Lisa M. Hillen
AU - Tijmen J. J. Van Weert
AU - Axel Zur Hausen
AU - Thierry P. P. van Den Bosch
AU - Lisa M. V. Lap
AU - Ronald A. Damhuis
AU - Niki L. Reynaert
AU - Esther C. van Den Broek
AU - Lynnette Fernandez-Cuesta
AU - Matthieu Foll
AU - Nicolas Alcala
AU - Alexandra Sexton-Oates
AU - Anne-Marie C. Dingemans
AU - Ernst-Jan M. Speel
AU - Jules L. Derks
PY - 2026
DA - 2026/10/28
JO - Journal of Thoracic Oncology
DO - 10.1016/j.jtho.2024.11.018
UR - https://hal.science/hal-05842060v1
AB - 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.
SN - 1556-0864
SN - 1556-1380
ER -