Molecular studies of lung neuroendocrine neoplasms uncover new concepts and entities.
Abstract
Lung neuroendocrine neoplasms (NENs) account for up to 25% of all lung cancers and can be subdivided into poorly differentiated, high-grade neuroendocrine carcinomas (NECs) including small cell lung carcinoma (SCLC, 20%) and large-cell neuroendocrine carcinomas (LCNEC, 3%), and well-differentiated neuroendocrine tumours (NETs, 2%) including the low-and intermediate-grade typical and atypical carcinoids, respectively (1).Each of these lung NEN subtypes shows different behaviour in terms of clinical presentation, prognosis and aetiology: whereas SCLC and LCNEC are smoking-related very aggressive, highly metastatic tumours with poor prognosis, typical and atypical carcinoids have thus far unclear association with smoking and are less aggressive, with longer survival expectancy (2).The distinction between lung NETs and NECs is crucial for the clinical management of these diseases; surgical resection is the treatment of choice for localized tumours-mostly NETs-while systemic treatment and, more recently, immunotherapy are preferred for disseminated NECs.However, cytotoxic agents are mostly ineffective in these tumours (3). Molecular landscape of lung NENsNECs and NETs have very distinct molecular characteristics and it is widely accepted that they are different diseases and not simply a continuum of neoplasms with a common pathogenesis (4,5): both typical and atypical pulmonary carcinoids show low mutation rate and frequent alterations in chromatin-remodelling genes (6,7) with very rare mutations in TP53 and RB1 genes.These latter two genes are, conversely, universally inactivated in SCLC (8,9).The molecular spectrum of LCNEC is more heterogeneous, with two well-distinguished large groups of samples: type-I LCNEC, with frequent alterations in TP53, STK11 and KEAP1, and type-II LCNEC, with alterations in both TP53 and RB1 (10,11) (Figure 1).While the nomenclature given by Rekhtman and colleagues (NSCLC-like and SCLClike LCNEC for type-I and type-II, respectively) is accurate in terms of mutational patterns, it does not reflect the expression patterns: type-I LCNECs have the mutational characteristics of NSCLCs, but expression profiles similar to SCLC, while type-II LCNECs have mutational characteristics of SCLC but low neuroendocrine expression profiles similar to NSCLCs (10).Recent studies on molecular subtypes of SCLC point to distinct expression profiles marked by the differential expression of key transcription factors (13) (Figure 1).With regard to the strong similarities of LCNEC and SCLC, and the difficulties in distinguishing these cancer types in cell culture and by histology, it remains to be understood how many of these SCLC subtypes may rather reflect similarities to LCNEC.
Related
- A molecular map of lung neuroendocrine neoplasms
- Spotlight on Small-Cell Lung Cancer and Other Lung Neuroendocrine Neoplasms.
- Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
- Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms
- Diagnostic pitfalls and unmet needs in neuroendocrine neoplasms: The added value of collegial expert pathology review through the national TENpath network
BibTeX
@article{fernandezcuesta2026molecular,
title = {{Molecular studies of lung neuroendocrine neoplasms uncover new concepts and entities.}},
author = {Lynnette Fernandez-Cuesta and Matthieu Foll},
journal = {Translational Lung Cancer Research},
year = {2026},
month = oct,
doi = {10.21037/tlcr.2019.11.08},
url = {https://hal.science/hal-05842043v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Molecular studies of lung neuroendocrine neoplasms uncover new concepts and entities.
AU - Lynnette Fernandez-Cuesta
AU - Matthieu Foll
PY - 2026
DA - 2026/10/28
JO - Translational Lung Cancer Research
DO - 10.21037/tlcr.2019.11.08
UR - https://hal.science/hal-05842043v1
AB - Lung neuroendocrine neoplasms (NENs) account for up to 25% of all lung cancers and can be subdivided into poorly differentiated, high-grade neuroendocrine carcinomas (NECs) including small cell lung carcinoma (SCLC, 20%) and large-cell neuroendocrine carcinomas (LCNEC, 3%), and well-differentiated neuroendocrine tumours (NETs, 2%) including the low-and intermediate-grade typical and atypical carcinoids, respectively (1).Each of these lung NEN subtypes shows different behaviour in terms of clinical presentation, prognosis and aetiology: whereas SCLC and LCNEC are smoking-related very aggressive, highly metastatic tumours with poor prognosis, typical and atypical carcinoids have thus far unclear association with smoking and are less aggressive, with longer survival expectancy (2).The distinction between lung NETs and NECs is crucial for the clinical management of these diseases; surgical resection is the treatment of choice for localized tumours-mostly NETs-while systemic treatment and, more recently, immunotherapy are preferred for disseminated NECs.However, cytotoxic agents are mostly ineffective in these tumours (3). Molecular landscape of lung NENsNECs and NETs have very distinct molecular characteristics and it is widely accepted that they are different diseases and not simply a continuum of neoplasms with a common pathogenesis (4,5): both typical and atypical pulmonary carcinoids show low mutation rate and frequent alterations in chromatin-remodelling genes (6,7) with very rare mutations in TP53 and RB1 genes.These latter two genes are, conversely, universally inactivated in SCLC (8,9).The molecular spectrum of LCNEC is more heterogeneous, with two well-distinguished large groups of samples: type-I LCNEC, with frequent alterations in TP53, STK11 and KEAP1, and type-II LCNEC, with alterations in both TP53 and RB1 (10,11) (Figure 1).While the nomenclature given by Rekhtman and colleagues (NSCLC-like and SCLClike LCNEC for type-I and type-II, respectively) is accurate in terms of mutational patterns, it does not reflect the expression patterns: type-I LCNECs have the mutational characteristics of NSCLCs, but expression profiles similar to SCLC, while type-II LCNECs have mutational characteristics of SCLC but low neuroendocrine expression profiles similar to NSCLCs (10).Recent studies on molecular subtypes of SCLC point to distinct expression profiles marked by the differential expression of key transcription factors (13) (Figure 1).With regard to the strong similarities of LCNEC and SCLC, and the difficulties in distinguishing these cancer types in cell culture and by histology, it remains to be understood how many of these SCLC subtypes may rather reflect similarities to LCNEC.
SN - 2218-6751
SN - 2226-4477
ER -