Cancers (Sep 2022)
Combined Large Cell Neuroendocrine Carcinomas of the Lung: Integrative Molecular Analysis Identifies Subtypes with Potential Therapeutic Implications
- Michele Simbolo,
- Giovanni Centonze,
- Luca Giudice,
- Federica Grillo,
- Patrick Maisonneuve,
- Anastasios Gkountakos,
- Chiara Ciaparrone,
- Laura Cattaneo,
- Giovanna Sabella,
- Rosalba Giugno,
- Paola Bossi,
- Paola Spaggiari,
- Alessandro Del Gobbo,
- Stefano Ferrero,
- Luca Mastracci,
- Alessandra Fabbri,
- Martina Filugelli,
- Giovanna Garzone,
- Natalie Prinzi,
- Sara Pusceddu,
- Adele Testi,
- Valentina Monti,
- Luigi Rolli,
- Alessandro Mangogna,
- Luisa Bercich,
- Mauro Roberto Benvenuti,
- Emilio Bria,
- Sara Pilotto,
- Alfredo Berruti,
- Ugo Pastorino,
- Carlo Capella,
- Maurizio Infante,
- Michele Milella,
- Aldo Scarpa,
- Massimo Milione
Affiliations
- Michele Simbolo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
- Giovanni Centonze
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Luca Giudice
- Department of Computer Science, University of Verona, 37134 Verona, Italy
- Federica Grillo
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Patrick Maisonneuve
- Division of Epidemiology and Biostatistics, IEO, European Institute of Oncology IRCCS, 20132 Milan, Italy
- Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
- Chiara Ciaparrone
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
- Laura Cattaneo
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Giovanna Sabella
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Rosalba Giugno
- Department of Computer Science, University of Verona, 37134 Verona, Italy
- Paola Bossi
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, 20089 Milan, Italy
- Paola Spaggiari
- Pathology Department, Humanitas Clinical and Research Center, Humanitas Milan ENETS Center of Excellence, 20089 Milan, Italy
- Alessandro Del Gobbo
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Stefano Ferrero
- Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Luca Mastracci
- Unit of Pathology, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa and Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Alessandra Fabbri
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Martina Filugelli
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Giovanna Garzone
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Natalie Prinzi
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Sara Pusceddu
- Medical Oncology Department, Fondazione IRCCS, Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Adele Testi
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Valentina Monti
- 2nd Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- Luigi Rolli
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
- Alessandro Mangogna
- Institute for Maternal and Child Health, IRCCS Burlo Garofalo, 34137 Trieste, Italy
- Luisa Bercich
- Department of Pathology, ASST Spedali Civili of Brescia, 25123 Brescia, Italy
- Mauro Roberto Benvenuti
- Thoracic Surgery Unit, Department of Medical and Surgical Specialties Radiological Sciences and Public Health, Medical Oncology, University of Brescia, ASST Spedali Civili of Brescia, 25123 Brescia, Italy
- Emilio Bria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy
- Sara Pilotto
- Department of Medicine, Section of Oncology, University of Verona, 37134 Verona, Italy
- Alfredo Berruti
- Medical Oncology Unit, ASST Spedali Civili of Brescia, Department of Medical and Surgical Specialties, Radiological Science and Public Health, University of Brescia, 25123 Brescia, Italy
- Ugo Pastorino
- Thoracic Surgery Unit, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy
- Carlo Capella
- Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy
- Maurizio Infante
- Thoracic Surgery, University and Hospital Trust of Verona, 37134 Verona, Italy
- Michele Milella
- Department of Medicine, Section of Oncology, University of Verona, 37134 Verona, Italy
- Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy
- Massimo Milione
- 1st Pathology Division, Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
- DOI
- https://doi.org/10.3390/cancers14194653
- Journal volume & issue
-
Vol. 14,
no. 19
p. 4653
Abstract
Background: Combined large cell neuroendocrine carcinoma (CoLCNEC) is given by the association of LCNEC with adeno or squamous or any non-neuroendocrine carcinoma. Molecular bases of CoLCNEC pathogenesis are scant and no standardized therapies are defined. Methods: 44 CoLCNECs: 26 with adenocarcinoma (CoADC), 7 with squamous cell carcinoma (CoSQC), 3 with small cell carcinoma (CoSCLC), 4 with atypical carcinoid (CoAC) and 4 napsin-A positive LCNEC (NapA+), were assessed for alterations in 409 genes and transcriptomic profiling of 20,815 genes. Results: Genes altered included TP53 (n = 30), RB1 (n = 14) and KRAS (n = 13). Targetable alterations included six KRAS G12C mutations and ALK-EML4 fusion gene. Comparison of CoLCNEC transcriptomes with 86 lung cancers of pure histology (8 AC, 19 ADC, 19 LCNEC, 11 SCLC and 29 SQC) identified CoLCNEC as a separate entity of neuroendocrine tumours with three different molecular profiles, two of which showed a non-neuroendocrine lineage. Hypomethylation, activation of MAPK signalling and association to immunotherapy signature specifically characterized each of three CoLCNEC molecular clusters. Prognostic stratification was also provided. Conclusions: CoLCNECs are an independent histologic category. Our findings support the extension of routine evaluation of KRAS mutations, fusion genes and immune-related markers to offer new perspectives in the therapeutic management of CoLCNEC.
Keywords
- neuroendocrine carcinoma
- combined large cell neuroendocrine carcinoma
- next-generation sequencing
- transcriptomics
