Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.
Abstract
Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.
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BibTeX
@article{centonze2026digital,
title = {{Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.}},
author = {Giovanni Centonze and Patrick Maisonneuve and Émilie Mathian and Federica Grillo and Giovanna Sabella and Vincenzo Lagano and Alessandro Mangogna and Sara Pusceddu and Paola Bossi and Paola Spaggiari and Alessandro del Gobbo and Stefano Ferrero and Luigi Rolli and Ugo Pastorino and Luisa Bercich and Andrea Tironi and Mauro Roberto Benvenuti and Maria Sole Gallazzi and Rosalia Romano and Alfredo Berruti and Luca Roz and Carlo Capella and Matthieu Foll and Massimo Milione},
journal = {Endocrine Pathology},
year = {2026},
month = oct,
doi = {10.1007/s12022-025-09886-9},
url = {https://hal.science/hal-05842059v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Digital Immunophenotyping of Lung Atypical Carcinoids and Large Cell Neuroendocrine Carcinomas Identifies Three Subtypes With Specific Tumor-Immune Microenvironment Features.
AU - Giovanni Centonze
AU - Patrick Maisonneuve
AU - Émilie Mathian
AU - Federica Grillo
AU - Giovanna Sabella
AU - Vincenzo Lagano
AU - Alessandro Mangogna
AU - Sara Pusceddu
AU - Paola Bossi
AU - Paola Spaggiari
AU - Alessandro del Gobbo
AU - Stefano Ferrero
AU - Luigi Rolli
AU - Ugo Pastorino
AU - Luisa Bercich
AU - Andrea Tironi
AU - Mauro Roberto Benvenuti
AU - Maria Sole Gallazzi
AU - Rosalia Romano
AU - Alfredo Berruti
AU - Luca Roz
AU - Carlo Capella
AU - Matthieu Foll
AU - Massimo Milione
PY - 2026
DA - 2026/10/28
JO - Endocrine Pathology
DO - 10.1007/s12022-025-09886-9
UR - https://hal.science/hal-05842059v1
AB - Atypical carcinoids (ACs) and large cell neuroendocrine carcinomas (LCNECs) are defined by the WHO as intermediate- and high-grade lung neuroendocrine neoplasms, respectively, based on morphological criteria; however, treatment strategies remain debated. Given the emerging role of the tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) in cancer prognosis and therapy response, this study aimed to characterize the immune landscape of ACs and LCNECs comprehensively. Immunohistochemistry for T-cell markers (CD3, CD8), immune checkpoints (PD-1, PD-L1), HLA molecules (HLA-DR, HLA-I), and fibroblasts (α-SMA) was performed on a re-evaluated cohort of 56 ACs and 104 LCNECs. Digital image analysis quantified intra-tumor (iTILs) and stromal (sTILs) CD3 and CD8 TILs in the whole slide and in specific tumor regions (invasive margin [IM] and central tumor [CT]). LCNECs exhibited significantly higher stromal T-cell infiltration, immune checkpoint expression, and HLA compared to ACs (p < 0.001), while α-SMA was more prominent in ACs. No ACs showed PD-L1 tumor expression. Digital quantification confirmed greater iTILs and sTILs in LCNECs across all regions, with moderate concordance to manual counts. Interestingly, TIL parameters were higher at the IM than in the CT (p < 0.001). Using Boruta feature selection algorithm, Principal Component Analysis and Hierarchical Clustering, three patient clusters were identified: Cluster 1 (mainly ACs, low TILs, favorable prognosis), Cluster 2 (mixed histology, intermediate TILs, moderate prognosis), and Cluster 3 (mostly LCNECs, high TILs, poor prognosis), with distinct TME marker profiles. PD-L1 tumor expression was strongly linked to Cluster 3. These findings suggest that ACs and LCNECs may be stratified into three distinct immune clusters, highlighting the heterogeneity of their tumor microenvironment and providing a rationale for further translational studies.
SN - 1046-3976
ER -