Skip to main content
Top
Published in: Virchows Archiv 1/2021

01-01-2021 | Carcinoid Tumor | Review and Perspectives

Morphologic and molecular classification of lung neuroendocrine neoplasms

Authors: Jasna Metovic, Marco Barella, Fabrizio Bianchi, Paul Hofman, Veronique Hofman, Myriam Remmelink, Izidor Kern, Lina Carvalho, Linda Pattini, Angelica Sonzogni, Giulia Veronesi, Sergio Harari, Fabien Forest, Mauro Papotti, Giuseppe Pelosi

Published in: Virchows Archiv | Issue 1/2021

Login to get access

Abstract

Neuroendocrine neoplasms (NENs) of the lung encompass neuroendocrine tumors (NETs) composed of typical (TC) and atypical (AC) carcinoids and full-fledged carcinomas (NECs) inclusive of large cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCLC). NETs and NECs are thought to represent distinct and separate lesions with neither molecular overlap nor common developmental continuum. Two perspectives were addressed regarding the morphologic and molecular classification of lung NENs: (i) a supervised approach by browsing the traditional classification, the relevant gene alterations, and their clinical implications; and (ii) an unsupervised approach, by reappraising neoplasms according to risk factors and natural history of disease to construct an interpretation model relied on biological data. We herein emphasize lights and shadows of the current classification of lung NENs and provide an alternative outlook on these tumors focused on what we currently know about the biological determinants and the natural history of disease.
Literature
1.
go back to reference Abe H, Takase Y, Sadashima E, Fukumitsu C, Murata K, Ito T, Kawahara A, Naito Y, Akiba J (2019) Insulinoma-associated protein 1 is a novel diagnostic marker of small cell lung cancer in bronchial brushing and cell block cytology from pleural effusions: validity and reliability with cutoff value. Cancer Cytopathol 127:598–605PubMedCrossRef Abe H, Takase Y, Sadashima E, Fukumitsu C, Murata K, Ito T, Kawahara A, Naito Y, Akiba J (2019) Insulinoma-associated protein 1 is a novel diagnostic marker of small cell lung cancer in bronchial brushing and cell block cytology from pleural effusions: validity and reliability with cutoff value. Cancer Cytopathol 127:598–605PubMedCrossRef
2.
go back to reference Alcala N, Leblay N, Gabriel AAG, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J, Ghantous A, Delhomme TM, Chabrier A, Cuenin C, Abedi-Ardekani B, Boland A, Olaso R, Meyer V, Altmuller J, Le Calvez-Kelm F, Durand G, Voegele C, Boyault S, Moonen L, Lemaitre N, Lorimier P, Toffart AC, Soltermann A, Clement JH, Saenger J, Field JK, Brevet M, Blanc-Fournier C, Galateau-Salle F, Le Stang N, Russell PA, Wright G, Sozzi G, Pastorino U, Lacomme S, Vignaud JM, Hofman V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, Muscarella LA, Graziano P, Popper H, Stojsic J, Deleuze JF, Herceg Z, Viari A, Nuernberg P, Pelosi G, Dingemans AMC, Milione M, Roz L, Brcic L, Volante M, Papotti MG, Caux C, Sandoval J, Hernandez-Vargas H, Brambilla E, Speel EJM, Girard N, Lantuejoul S, McKay JD, Foll M, Fernandez-Cuesta L (2019) Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun 10:3407PubMedPubMedCentralCrossRef Alcala N, Leblay N, Gabriel AAG, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J, Ghantous A, Delhomme TM, Chabrier A, Cuenin C, Abedi-Ardekani B, Boland A, Olaso R, Meyer V, Altmuller J, Le Calvez-Kelm F, Durand G, Voegele C, Boyault S, Moonen L, Lemaitre N, Lorimier P, Toffart AC, Soltermann A, Clement JH, Saenger J, Field JK, Brevet M, Blanc-Fournier C, Galateau-Salle F, Le Stang N, Russell PA, Wright G, Sozzi G, Pastorino U, Lacomme S, Vignaud JM, Hofman V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, Muscarella LA, Graziano P, Popper H, Stojsic J, Deleuze JF, Herceg Z, Viari A, Nuernberg P, Pelosi G, Dingemans AMC, Milione M, Roz L, Brcic L, Volante M, Papotti MG, Caux C, Sandoval J, Hernandez-Vargas H, Brambilla E, Speel EJM, Girard N, Lantuejoul S, McKay JD, Foll M, Fernandez-Cuesta L (2019) Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids. Nat Commun 10:3407PubMedPubMedCentralCrossRef
3.
go back to reference Aslan DL, Gulbahce HE, Pambuccian SE, Manivel JC, Jessurun J (2005) Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact. Am J Clin Pathol 123:874–878PubMedCrossRef Aslan DL, Gulbahce HE, Pambuccian SE, Manivel JC, Jessurun J (2005) Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact. Am J Clin Pathol 123:874–878PubMedCrossRef
4.
go back to reference Baudin E, Hayes AR, Scoazec JY, Filosso PL, Lim E, Kaltsas G, Frilling A, Chen J, Kos-Kudla B, Gorbunova V, Wiedenmann B, Nieveen van Dijkum E, Cwikla JB, Falkerby J, Valle JW, Kulke MH, Caplin ME, Participants EMAB, Participants EMAB (2019) Unmet medical needs in pulmonary neuroendocrine (carcinoid) neoplasms. Neuroendocrinology 108:7–17PubMedCrossRef Baudin E, Hayes AR, Scoazec JY, Filosso PL, Lim E, Kaltsas G, Frilling A, Chen J, Kos-Kudla B, Gorbunova V, Wiedenmann B, Nieveen van Dijkum E, Cwikla JB, Falkerby J, Valle JW, Kulke MH, Caplin ME, Participants EMAB, Participants EMAB (2019) Unmet medical needs in pulmonary neuroendocrine (carcinoid) neoplasms. Neuroendocrinology 108:7–17PubMedCrossRef
5.
go back to reference Beasley MB, Lantuejoul S, Abbondanzo S, Chu WS, Hasleton PS, Travis WD, Brambilla E (2003) The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol 34:136–142PubMedCrossRef Beasley MB, Lantuejoul S, Abbondanzo S, Chu WS, Hasleton PS, Travis WD, Brambilla E (2003) The P16/cyclin D1/Rb pathway in neuroendocrine tumors of the lung. Hum Pathol 34:136–142PubMedCrossRef
6.
go back to reference Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD, participants Ecc (2015) Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 26:1604–1620PubMedCrossRef Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD, participants Ecc (2015) Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol 26:1604–1620PubMedCrossRef
7.
go back to reference Chen HJ, Poran A, Unni AM, Huang SX, Elemento O, Snoeck HW, Varmus H (2019) Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells. J Exp Med 216:674–687PubMedPubMedCentralCrossRef Chen HJ, Poran A, Unni AM, Huang SX, Elemento O, Snoeck HW, Varmus H (2019) Generation of pulmonary neuroendocrine cells and SCLC-like tumors from human embryonic stem cells. J Exp Med 216:674–687PubMedPubMedCentralCrossRef
8.
go back to reference Clinical Lung Cancer Genome P, Network Genomic M (2013) A genomics-based classification of human lung tumors. Sci Transl Med 5:209ra153 Clinical Lung Cancer Genome P, Network Genomic M (2013) A genomics-based classification of human lung tumors. Sci Transl Med 5:209ra153
9.
go back to reference Eldessouki I, Gaber O, Namad T, Wang J, Morris JC, Abdel Karim N (2018) Small or non-small cell lung cancer based therapy for treatment of large cell neuroendocrine cancer of the lung? University of Cincinnati Experience. J Oncol 2018:9761826PubMedPubMedCentralCrossRef Eldessouki I, Gaber O, Namad T, Wang J, Morris JC, Abdel Karim N (2018) Small or non-small cell lung cancer based therapy for treatment of large cell neuroendocrine cancer of the lung? University of Cincinnati Experience. J Oncol 2018:9761826PubMedPubMedCentralCrossRef
10.
go back to reference Fabbri A, Cossa M, Sonzogni A, Bidoli P, Canova S, Cortinovis D, Abbate MI, Calabrese F, Nannini N, Lunardi F, Rossi G, La Rosa S, Capella C, Tamborini E, Perrone F, Busico A, Capone I, Valeri B, Pastorino U, Albini A, Pelosi G (2017) Thymus neuroendocrine tumors with CTNNB1 gene mutations, disarrayed ss-catenin expression, and dual intra-tumor Ki-67 labeling index compartmentalization challenge the concept of secondary high-grade neuroendocrine tumor: a paradigm shift. Virchows Arch 471:31–47PubMedCrossRef Fabbri A, Cossa M, Sonzogni A, Bidoli P, Canova S, Cortinovis D, Abbate MI, Calabrese F, Nannini N, Lunardi F, Rossi G, La Rosa S, Capella C, Tamborini E, Perrone F, Busico A, Capone I, Valeri B, Pastorino U, Albini A, Pelosi G (2017) Thymus neuroendocrine tumors with CTNNB1 gene mutations, disarrayed ss-catenin expression, and dual intra-tumor Ki-67 labeling index compartmentalization challenge the concept of secondary high-grade neuroendocrine tumor: a paradigm shift. Virchows Arch 471:31–47PubMedCrossRef
11.
go back to reference Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G (2017) Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 470:153–164PubMedCrossRef Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G (2017) Ki-67 labeling index of neuroendocrine tumors of the lung has a high level of correspondence between biopsy samples and surgical specimens when strict counting guidelines are applied. Virchows Arch 470:153–164PubMedCrossRef
12.
go back to reference Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretic L, Seidal D, Zander T, Leenders F, George J, Muller C, Dahmen I, Pinther B, Bosco G, Konrad K, Altmuller J, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soltermann A, Brustugun OT, Helland A, Solberg S, Lund-Iversen M, Ansen S, Stoelben E, Wright GM, Russell P, Wainer Z, Solomon B, Field JK, Hyde R, Davies MP, Heukamp LC, Petersen I, Perner S, Lovly C, Cappuzzo F, Travis WD, Wolf J, Vingron M, Brambilla E, Haas SA, Buettner R, Thomas RK (2014) Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 5:3518PubMedCrossRef Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretic L, Seidal D, Zander T, Leenders F, George J, Muller C, Dahmen I, Pinther B, Bosco G, Konrad K, Altmuller J, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soltermann A, Brustugun OT, Helland A, Solberg S, Lund-Iversen M, Ansen S, Stoelben E, Wright GM, Russell P, Wainer Z, Solomon B, Field JK, Hyde R, Davies MP, Heukamp LC, Petersen I, Perner S, Lovly C, Cappuzzo F, Travis WD, Wolf J, Vingron M, Brambilla E, Haas SA, Buettner R, Thomas RK (2014) Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 5:3518PubMedCrossRef
13.
go back to reference Ferone G, Song JY, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij JP, Proost N, Gargiulo G, Berns A (2016) SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30:519–532PubMedPubMedCentralCrossRef Ferone G, Song JY, Sutherland KD, Bhaskaran R, Monkhorst K, Lambooij JP, Proost N, Gargiulo G, Berns A (2016) SOX2 is the determining oncogenic switch in promoting lung squamous cell carcinoma from different cells of origin. Cancer Cell 30:519–532PubMedPubMedCentralCrossRef
15.
go back to reference Fujino K, Motooka Y, Hassan WA, Ali Abdalla MO, Sato Y, Kudoh S, Hasegawa K, Niimori-Kita K, Kobayashi H, Kubota I, Wakimoto J, Suzuki M, Ito T (2015) Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am J Pathol 185:3164–3177PubMedCrossRef Fujino K, Motooka Y, Hassan WA, Ali Abdalla MO, Sato Y, Kudoh S, Hasegawa K, Niimori-Kita K, Kobayashi H, Kubota I, Wakimoto J, Suzuki M, Ito T (2015) Insulinoma-associated protein 1 is a crucial regulator of neuroendocrine differentiation in lung cancer. Am J Pathol 185:3164–3177PubMedCrossRef
16.
go back to reference Fujino K, Yasufuku K, Kudoh S, Motooka Y, Sato Y, Wakimoto J, Kubota I, Suzuki M, Ito K (2017) INSM1 is the best marker for the diagnosis of neuroendocrine tumors: comparison with CGA, SYP and CD56. Int J. Clin Exp Pathol 10:5393–5405 Fujino K, Yasufuku K, Kudoh S, Motooka Y, Sato Y, Wakimoto J, Kubota I, Suzuki M, Ito K (2017) INSM1 is the best marker for the diagnosis of neuroendocrine tumors: comparison with CGA, SYP and CD56. Int J. Clin Exp Pathol 10:5393–5405
17.
go back to reference Gazdar AF (2018) Morphologic and other forms of heterogeneity in small Cell lung cancer: what can we learn from them? J Thorac Oncol 13:148–150PubMedCrossRef Gazdar AF (2018) Morphologic and other forms of heterogeneity in small Cell lung cancer: what can we learn from them? J Thorac Oncol 13:148–150PubMedCrossRef
18.
go back to reference Gazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17:725–737PubMedCrossRef Gazdar AF, Bunn PA, Minna JD (2017) Small-cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 17:725–737PubMedCrossRef
19.
go back to reference George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G, Muller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Putzer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmuller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castanos-Velez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Kohler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansen S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nurnberg P, Reinhardt C, Perner S, Heukamp L, Buttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524:47–53PubMedPubMedCentralCrossRef George J, Lim JS, Jang SJ, Cun Y, Ozretic L, Kong G, Leenders F, Lu X, Fernandez-Cuesta L, Bosco G, Muller C, Dahmen I, Jahchan NS, Park KS, Yang D, Karnezis AN, Vaka D, Torres A, Wang MS, Korbel JO, Menon R, Chun SM, Kim D, Wilkerson M, Hayes N, Engelmann D, Putzer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmuller J, Yokota J, Kohno T, Iwakawa R, Tsuta K, Noguchi M, Muley T, Hoffmann H, Schnabel PA, Petersen I, Chen Y, Soltermann A, Tischler V, Choi CM, Kim YH, Massion PP, Zou Y, Jovanovic D, Kontic M, Wright GM, Russell PA, Solomon B, Koch I, Lindner M, Muscarella LA, la Torre A, Field JK, Jakopovic M, Knezevic J, Castanos-Velez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Kohler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansen S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nurnberg P, Reinhardt C, Perner S, Heukamp L, Buttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524:47–53PubMedPubMedCentralCrossRef
20.
go back to reference George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, Thomas RK (2018) Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9:1048PubMedPubMedCentralCrossRef George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Muller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmuller J, Becker C, Nurnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland A, Solberg S, Ansen S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sanger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Buttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, Thomas RK (2018) Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun 9:1048PubMedPubMedCentralCrossRef
21.
go back to reference Gridelli C, Rossi A, Airoma G, Bianco R, Costanzo R, Daniele B, Chiara GD, Grimaldi G, Irtelli L, Maione P, Morabito A, Piantedosi FV, Riccardi F (2013) Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. Cancer Treat Rev 39:466–472PubMedCrossRef Gridelli C, Rossi A, Airoma G, Bianco R, Costanzo R, Daniele B, Chiara GD, Grimaldi G, Irtelli L, Maione P, Morabito A, Piantedosi FV, Riccardi F (2013) Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. Cancer Treat Rev 39:466–472PubMedCrossRef
22.
go back to reference Hendifar AE, Marchevsky AM, Tuli R (2017) Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well-differentiated disease. J Thorac Oncol 12:425–436PubMedCrossRef Hendifar AE, Marchevsky AM, Tuli R (2017) Neuroendocrine tumors of the lung: current challenges and advances in the diagnosis and management of well-differentiated disease. J Thorac Oncol 12:425–436PubMedCrossRef
23.
go back to reference Horie M, Miyashita N, Mattsson JSM, Mikami Y, Sandelin M, Brunnstrom H, Micke P, Nagase T, Saito A (2018) An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer. J Pathol Horie M, Miyashita N, Mattsson JSM, Mikami Y, Sandelin M, Brunnstrom H, Micke P, Nagase T, Saito A (2018) An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer. J Pathol
24.
go back to reference Ibe T, Shimizu K, Nakano T, Kakegawa S, Kamiyoshihara M, Nakajima T, Kaira K, Takeyoshi I (2010) High-grade neuroendocrine carcinoma of the lung shows increased thymidylate synthase expression compared to other histotypes. J Surg Oncol 102:11–17PubMedCrossRef Ibe T, Shimizu K, Nakano T, Kakegawa S, Kamiyoshihara M, Nakajima T, Kaira K, Takeyoshi I (2010) High-grade neuroendocrine carcinoma of the lung shows increased thymidylate synthase expression compared to other histotypes. J Surg Oncol 102:11–17PubMedCrossRef
25.
go back to reference Kalemkerian GP, Loo BW, Akerley W, Attia A, Bassetti M, Boumber Y, Decker R, Dobelbower MC, Dowlati A, Downey RJ, Florsheim C, Ganti AKP, Grecula JC, Gubens MA, Hann CL, Hayman JA, Heist RS, Koczywas M, Merritt RE, Mohindra N, Molina J, Moran CA, Morgensztern D, Pokharel S, Portnoy DC, Rhodes D, Rusthoven C, Sands J, Santana-Davila R, Williams CC, Hoffmann KG, Hughes M (2018) NCCN guidelines insights: small cell lung cancer, Version 2.2018. J Natl Compr Cancer Netw 16:1171–1182CrossRef Kalemkerian GP, Loo BW, Akerley W, Attia A, Bassetti M, Boumber Y, Decker R, Dobelbower MC, Dowlati A, Downey RJ, Florsheim C, Ganti AKP, Grecula JC, Gubens MA, Hann CL, Hayman JA, Heist RS, Koczywas M, Merritt RE, Mohindra N, Molina J, Moran CA, Morgensztern D, Pokharel S, Portnoy DC, Rhodes D, Rusthoven C, Sands J, Santana-Davila R, Williams CC, Hoffmann KG, Hughes M (2018) NCCN guidelines insights: small cell lung cancer, Version 2.2018. J Natl Compr Cancer Netw 16:1171–1182CrossRef
26.
go back to reference Konala VM, Madhira BR, Ashraf S, Graziano S (2020) Use of immunotherapy in extensive-stage small cell lung cancer. Oncology:1–6 Konala VM, Madhira BR, Ashraf S, Graziano S (2020) Use of immunotherapy in extensive-stage small cell lung cancer. Oncology:1–6
27.
go back to reference Kontogianni K, Nicholson AG, Butcher D, Sheppard MN (2005) CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. J Clin Pathol 58:978–980PubMedPubMedCentralCrossRef Kontogianni K, Nicholson AG, Butcher D, Sheppard MN (2005) CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. J Clin Pathol 58:978–980PubMedPubMedCentralCrossRef
28.
go back to reference La Rosa S, Simbolo M, Franzi F, Uccella S, Imperatori A, Nardecchia E, Rotolo N, Dominioni L, Scarpa A, Sessa F (2018) Combined adenocarcinoma-atypical carcinoid of the lung. Targeted next-generation sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopathol 24:120–123CrossRef La Rosa S, Simbolo M, Franzi F, Uccella S, Imperatori A, Nardecchia E, Rotolo N, Dominioni L, Scarpa A, Sessa F (2018) Combined adenocarcinoma-atypical carcinoid of the lung. Targeted next-generation sequencing (NGS) suggests a monoclonal origin of the two components. Diagn Histopathol 24:120–123CrossRef
29.
go back to reference La Rosa S, Volante M, Uccella S, Maragliano R, Rapa I, Rotolo N, Inzani F, Siciliani A, Granone P, Rindi G, Dominioni L, Capella C, Papotti M, Sessa F, Imperatori A (2019) ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature. Virchows Arch 475:587–597PubMedCrossRef La Rosa S, Volante M, Uccella S, Maragliano R, Rapa I, Rotolo N, Inzani F, Siciliani A, Granone P, Rindi G, Dominioni L, Capella C, Papotti M, Sessa F, Imperatori A (2019) ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature. Virchows Arch 475:587–597PubMedCrossRef
30.
go back to reference Laddha SV, da Silva EM, Robzyk K, Untch BR, Ke H, Rekhtman N, Poirier JT, Travis WD, Tang LH, Chan CS (2019) Integrative genomic characterization identifies molecular subtypes of lung carcinoids. Cancer Res 79:4339–4347PubMedPubMedCentralCrossRef Laddha SV, da Silva EM, Robzyk K, Untch BR, Ke H, Rekhtman N, Poirier JT, Travis WD, Tang LH, Chan CS (2019) Integrative genomic characterization identifies molecular subtypes of lung carcinoids. Cancer Res 79:4339–4347PubMedPubMedCentralCrossRef
31.
go back to reference Lei Y, Feng H, Qiang H, Shang Z, Chang Q, Qian J, Zhang Y, Zhong R, Fan X, Chu T (2020) Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer 146:244–251PubMedCrossRef Lei Y, Feng H, Qiang H, Shang Z, Chang Q, Qian J, Zhang Y, Zhong R, Fan X, Chu T (2020) Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study. Lung Cancer 146:244–251PubMedCrossRef
32.
go back to reference Marchevsky AM, Wick MR (2015) Diagnostic difficulties with the diagnosis of small cell carcinoma of the lung. Semin Diagn Pathol 32:480–488PubMedCrossRef Marchevsky AM, Wick MR (2015) Diagnostic difficulties with the diagnosis of small cell carcinoma of the lung. Semin Diagn Pathol 32:480–488PubMedCrossRef
33.
go back to reference Meder L, Konig K, Ozretic L, Schultheis AM, Ueckeroth F, Ade CP, Albus K, Boehm D, Rommerscheidt-Fuss U, Florin A, Buhl T, Hartmann W, Wolf J, Merkelbach-Bruse S, Eilers M, Perner S, Heukamp LC, Buettner R (2016) NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer 138:927–938PubMedCrossRef Meder L, Konig K, Ozretic L, Schultheis AM, Ueckeroth F, Ade CP, Albus K, Boehm D, Rommerscheidt-Fuss U, Florin A, Buhl T, Hartmann W, Wolf J, Merkelbach-Bruse S, Eilers M, Perner S, Heukamp LC, Buettner R (2016) NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer 138:927–938PubMedCrossRef
34.
go back to reference Miyanaga A, Masuda M, Motoi N, Tsuta K, Nakamura Y, Nishijima N, Watanabe SI, Asamura H, Tsuchida A, Seike M, Gemma A, Yamada T (2020) Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence. Lung Cancer 145:85–94PubMedCrossRef Miyanaga A, Masuda M, Motoi N, Tsuta K, Nakamura Y, Nishijima N, Watanabe SI, Asamura H, Tsuchida A, Seike M, Gemma A, Yamada T (2020) Whole-exome and RNA sequencing of pulmonary carcinoid reveals chromosomal rearrangements associated with recurrence. Lung Cancer 145:85–94PubMedCrossRef
35.
go back to reference Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD (2002) Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 26:1184–1197PubMedCrossRef Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD (2002) Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 26:1184–1197PubMedCrossRef
36.
go back to reference Okazaki M, Sano Y, Soga Y, Katayama H, Sakao N, Shikatani Y, Yukumi S, Shigematsu H, Sugita A, Izutani H (2015) Combined atypical carcinoid tumour and squamous cell carcinoma of the lung. Intern Med 54:1385–1388PubMedCrossRef Okazaki M, Sano Y, Soga Y, Katayama H, Sakao N, Shikatani Y, Yukumi S, Shigematsu H, Sugita A, Izutani H (2015) Combined atypical carcinoid tumour and squamous cell carcinoma of the lung. Intern Med 54:1385–1388PubMedCrossRef
37.
go back to reference Ouadah Y, Rojas ER, Riordan DP, Capostagno S, Kuo CS, Krasnow MA (2019) Rare pulmonary neuroendocrine cells are stem cells regulated by Rb, p53, and Notch. Cell 179(403-416):e423 Ouadah Y, Rojas ER, Riordan DP, Capostagno S, Kuo CS, Krasnow MA (2019) Rare pulmonary neuroendocrine cells are stem cells regulated by Rb, p53, and Notch. Cell 179(403-416):e423
39.
go back to reference Owens CL, Fraire AE (2011) Combined carcinoid tumor and squamous cell carcinoma of lung: expanding the spectrum of combined tumors of lung. Int J Surg Pathol 19:273–275PubMedCrossRef Owens CL, Fraire AE (2011) Combined carcinoid tumor and squamous cell carcinoma of lung: expanding the spectrum of combined tumors of lung. Int J Surg Pathol 19:273–275PubMedCrossRef
40.
go back to reference Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Muller C, Di Cerbo V, Schildhaus HU, Altmuller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Bohm D, Ansen S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grutter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sanger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Buttner R, Wolf J, Nurnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104–1110PubMedPubMedCentralCrossRef Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, Plenker D, Leenders F, Sun R, Zander T, Menon R, Koker M, Dahmen I, Muller C, Di Cerbo V, Schildhaus HU, Altmuller J, Baessmann I, Becker C, de Wilde B, Vandesompele J, Bohm D, Ansen S, Gabler F, Wilkening I, Heynck S, Heuckmann JM, Lu X, Carter SL, Cibulskis K, Banerji S, Getz G, Park KS, Rauh D, Grutter C, Fischer M, Pasqualucci L, Wright G, Wainer Z, Russell P, Petersen I, Chen Y, Stoelben E, Ludwig C, Schnabel P, Hoffmann H, Muley T, Brockmann M, Engel-Riedel W, Muscarella LA, Fazio VM, Groen H, Timens W, Sietsma H, Thunnissen E, Smit E, Heideman DA, Snijders PJ, Cappuzzo F, Ligorio C, Damiani S, Field J, Solberg S, Brustugun OT, Lund-Iversen M, Sanger J, Clement JH, Soltermann A, Moch H, Weder W, Solomon B, Soria JC, Validire P, Besse B, Brambilla E, Brambilla C, Lantuejoul S, Lorimier P, Schneider PM, Hallek M, Pao W, Meyerson M, Sage J, Shendure J, Schneider R, Buttner R, Wolf J, Nurnberg P, Perner S, Heukamp LC, Brindle PK, Haas S, Thomas RK (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104–1110PubMedPubMedCentralCrossRef
41.
go back to reference Pelosi G, Rodriguez J, Viale G, Rosai J (2005) Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol 29:179–187PubMedCrossRef Pelosi G, Rodriguez J, Viale G, Rosai J (2005) Typical and atypical pulmonary carcinoid tumor overdiagnosed as small-cell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol 29:179–187PubMedCrossRef
42.
go back to reference Pelosi G, Sonzogni A, Galetta D, Perrone F, Braidotti P, Manzotti M, Fabbri A, Spaggiari L, Veronesi G, Viale G (2011) Combined small-cell carcinoma of the lung with quadripartite differentiation of epithelial, neuroendocrine, skeletal muscle, and myofibroblastic type. Virchows Arch 458:497–503PubMedCrossRef Pelosi G, Sonzogni A, Galetta D, Perrone F, Braidotti P, Manzotti M, Fabbri A, Spaggiari L, Veronesi G, Viale G (2011) Combined small-cell carcinoma of the lung with quadripartite differentiation of epithelial, neuroendocrine, skeletal muscle, and myofibroblastic type. Virchows Arch 458:497–503PubMedCrossRef
43.
go back to reference Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M (2012) DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 7:281–290PubMedCrossRef Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M (2012) DeltaNp63 (p40) and thyroid transcription factor-1 immunoreactivity on small biopsies or cellblocks for typing non-small cell lung cancer: a novel two-hit, sparing-material approach. J Thorac Oncol 7:281–290PubMedCrossRef
44.
go back to reference Pelosi G, Rossi G, Cavazza A, Righi L, Maisonneuve P, Barbareschi M, Graziano P, Pastorino U, Garassino M, de Braud F, Papotti M (2013) DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 21:229–239PubMedCrossRef Pelosi G, Rossi G, Cavazza A, Righi L, Maisonneuve P, Barbareschi M, Graziano P, Pastorino U, Garassino M, de Braud F, Papotti M (2013) DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 21:229–239PubMedCrossRef
45.
go back to reference Pelosi G, Papotti M, Rindi G, Scarpa A (2014) Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 25:151–164PubMedCrossRef Pelosi G, Papotti M, Rindi G, Scarpa A (2014) Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 25:151–164PubMedCrossRef
46.
go back to reference Pelosi G, Fabbri A, Papotti M, Rossi G, Cavazza A, Righi L, Tamborini E, Perrone F, Settanni G, Busico A, Testi MA, Maisonneuve P, De Braud F, Garassino M, Valeri B, Sonzogni A, Pastorino U (2015) Dissecting pulmonary large-cell carcinoma by targeted next generation sequencing of several cancer genes pushes genotypic-phenotypic correlations to emerge. J Thorac Oncol 10:1560–1569PubMedCrossRef Pelosi G, Fabbri A, Papotti M, Rossi G, Cavazza A, Righi L, Tamborini E, Perrone F, Settanni G, Busico A, Testi MA, Maisonneuve P, De Braud F, Garassino M, Valeri B, Sonzogni A, Pastorino U (2015) Dissecting pulmonary large-cell carcinoma by targeted next generation sequencing of several cancer genes pushes genotypic-phenotypic correlations to emerge. J Thorac Oncol 10:1560–1569PubMedCrossRef
47.
go back to reference Pelosi G, Scarpa A, Forest F, Sonzogni A (2016) The impact of immunohistochemistry on the classification of lung tumors. Expert Rev Respir Med 10:1105–1121PubMedCrossRef Pelosi G, Scarpa A, Forest F, Sonzogni A (2016) The impact of immunohistochemistry on the classification of lung tumors. Expert Rev Respir Med 10:1105–1121PubMedCrossRef
48.
go back to reference Pelosi G, Pattini L, Morana G, Fabbri A, Faccinetto A, Fazio N, Valeri B, Sonzogni A (2017) Grading lung neuroendocrine tumors: controversies in search of a solution. Histol Histopathol 32:223–241PubMed Pelosi G, Pattini L, Morana G, Fabbri A, Faccinetto A, Fazio N, Valeri B, Sonzogni A (2017) Grading lung neuroendocrine tumors: controversies in search of a solution. Histol Histopathol 32:223–241PubMed
49.
go back to reference Pelosi G, Sonzogni A, Harari S, Albini A, Bresaola E, Marchio C, Massa F, Righi L, Gatti G, Papanikolaou N, Vijayvergia N, Calabrese F, Papotti M (2017) Classification of pulmonary neuroendocrine tumors: new insights. Transl Lung Cancer Res 6:513–529PubMedPubMedCentralCrossRef Pelosi G, Sonzogni A, Harari S, Albini A, Bresaola E, Marchio C, Massa F, Righi L, Gatti G, Papanikolaou N, Vijayvergia N, Calabrese F, Papotti M (2017) Classification of pulmonary neuroendocrine tumors: new insights. Transl Lung Cancer Res 6:513–529PubMedPubMedCentralCrossRef
50.
go back to reference Pelosi G, Bianchi F, Dama E, Simbolo M, Mafficini A, Sonzogni A, Pilotto S, Harari S, Papotti M, Volante M, Fontanini G, Mastracci L, Albini A, Bria E, Calabrese F, Scarpa A (2018) Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. Virchows Arch 472:567–577PubMedCrossRef Pelosi G, Bianchi F, Dama E, Simbolo M, Mafficini A, Sonzogni A, Pilotto S, Harari S, Papotti M, Volante M, Fontanini G, Mastracci L, Albini A, Bria E, Calabrese F, Scarpa A (2018) Most high-grade neuroendocrine tumours of the lung are likely to secondarily develop from pre-existing carcinoids: innovative findings skipping the current pathogenesis paradigm. Virchows Arch 472:567–577PubMedCrossRef
51.
go back to reference Pelosi G, Bianchi F, Hofman P, Pattini L, Strobel P, Calabrese F, Naheed S, Holden C, Cave J, Bohnenberger H, Dinter H, Harari S, Albini A, Sonzogni A, Papotti M, Volante M, Ottensmeier CH (2019) Recent advances in the molecular landscape of lung neuroendocrine tumors. Expert Rev Mol Diagn 19:281–297PubMedCrossRef Pelosi G, Bianchi F, Hofman P, Pattini L, Strobel P, Calabrese F, Naheed S, Holden C, Cave J, Bohnenberger H, Dinter H, Harari S, Albini A, Sonzogni A, Papotti M, Volante M, Ottensmeier CH (2019) Recent advances in the molecular landscape of lung neuroendocrine tumors. Expert Rev Mol Diagn 19:281–297PubMedCrossRef
52.
go back to reference Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordonez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, Costa GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes MD, McKernan KJ, Stratton MR, Futreal PA, Campbell PJ (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463:184–190PubMedCrossRef Pleasance ED, Stephens PJ, O’Meara S, McBride DJ, Meynert A, Jones D, Lin ML, Beare D, Lau KW, Greenman C, Varela I, Nik-Zainal S, Davies HR, Ordonez GR, Mudie LJ, Latimer C, Edkins S, Stebbings L, Chen L, Jia M, Leroy C, Marshall J, Menzies A, Butler A, Teague JW, Mangion J, Sun YA, McLaughlin SF, Peckham HE, Tsung EF, Costa GL, Lee CC, Minna JD, Gazdar A, Birney E, Rhodes MD, McKernan KJ, Stratton MR, Futreal PA, Campbell PJ (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 463:184–190PubMedCrossRef
53.
go back to reference Pozo K, Kelenis DP, Minna JD, Johnson JE (2018) Different originating cells underlie intertumoral heterogeneity in lung neuroendocrine tumors. Cancer Discov 8:1216–1218PubMedPubMedCentralCrossRef Pozo K, Kelenis DP, Minna JD, Johnson JE (2018) Different originating cells underlie intertumoral heterogeneity in lung neuroendocrine tumors. Cancer Discov 8:1216–1218PubMedPubMedCentralCrossRef
55.
56.
go back to reference Puisieux A, Pommier RM, Morel AP, Lavial F (2018) Cellular pliancy and the multistep process of tumorigenesis. Cancer Cell 33:164–172PubMedCrossRef Puisieux A, Pommier RM, Morel AP, Lavial F (2018) Cellular pliancy and the multistep process of tumorigenesis. Cancer Cell 33:164–172PubMedCrossRef
57.
go back to reference Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, Halpenny DF, Wang H, Tian SK, Litvak AM, Paik PK, Drilon A, Socci N, Poirier JT, Shen R, Berger MF, Moreira AL, Travis WD, Rudin CM, Ladanyi M (2016) Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res 22:3618–3629PubMedPubMedCentralCrossRef Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, Halpenny DF, Wang H, Tian SK, Litvak AM, Paik PK, Drilon A, Socci N, Poirier JT, Shen R, Berger MF, Moreira AL, Travis WD, Rudin CM, Ladanyi M (2016) Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res 22:3618–3629PubMedPubMedCentralCrossRef
58.
go back to reference Rekhtman N, Pietanza CM, Sabari J, Montecalvo J, Wang H, Habeeb O, Kadota K, Adusumilli P, Rudin CM, Ladanyi M, Travis WD, Joubert P (2018) Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. Mod Pathol 31:111–121PubMedCrossRef Rekhtman N, Pietanza CM, Sabari J, Montecalvo J, Wang H, Habeeb O, Kadota K, Adusumilli P, Rudin CM, Ladanyi M, Travis WD, Joubert P (2018) Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. Mod Pathol 31:111–121PubMedCrossRef
59.
go back to reference Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M (2010) Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 17:977–987PubMedCrossRef Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M (2010) Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung. Endocr Relat Cancer 17:977–987PubMedCrossRef
60.
go back to reference Righi L, Volante M, Tavaglione V, Bille A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M (2010) Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol 21:548–555PubMedCrossRef Righi L, Volante M, Tavaglione V, Bille A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M (2010) Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol 21:548–555PubMedCrossRef
61.
go back to reference Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G (2014) Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 21:1–16PubMedCrossRef Rindi G, Klersy C, Inzani F, Fellegara G, Ampollini L, Ardizzoni A, Campanini N, Carbognani P, De Pas TM, Galetta D, Granone PL, Righi L, Rusca M, Spaggiari L, Tiseo M, Viale G, Volante M, Papotti M, Pelosi G (2014) Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 21:1–16PubMedCrossRef
62.
go back to reference Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, Fernandez-Cuesta L, Kloppel G, McCluggage WG, Moch H, Ohgaki H, Rakha EA, Reed NS, Rous BA, Sasano H, Scarpa A, Scoazec JY, Travis WD, Tallini G, Trouillas J, van Krieken JH, Cree IA (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 31:1770–1786PubMedPubMedCentralCrossRef Rindi G, Klimstra DS, Abedi-Ardekani B, Asa SL, Bosman FT, Brambilla E, Busam KJ, de Krijger RR, Dietel M, El-Naggar AK, Fernandez-Cuesta L, Kloppel G, McCluggage WG, Moch H, Ohgaki H, Rakha EA, Reed NS, Rous BA, Sasano H, Scarpa A, Scoazec JY, Travis WD, Tallini G, Trouillas J, van Krieken JH, Cree IA (2018) A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal. Mod Pathol 31:1770–1786PubMedPubMedCentralCrossRef
63.
go back to reference Rooper LM, Sharma R, Li QK, Illei PB, Westra WH (2017) INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol 41:1561–1569PubMedCrossRef Rooper LM, Sharma R, Li QK, Illei PB, Westra WH (2017) INSM1 demonstrates superior performance to the individual and combined use of synaptophysin, chromogranin and CD56 for diagnosing neuroendocrine tumors of the thoracic cavity. Am J Surg Pathol 41:1561–1569PubMedCrossRef
64.
go back to reference Rossi G, Bertero L, Marchio C, Papotti M (2018) Molecular alterations of neuroendocrine tumours of the lung. Histopathology 72:142–152PubMedCrossRef Rossi G, Bertero L, Marchio C, Papotti M (2018) Molecular alterations of neuroendocrine tumours of the lung. Histopathology 72:142–152PubMedCrossRef
65.
go back to reference Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, Massion PP, Minna JD, Oliver TG, Quaranta V, Sage J, Thomas RK, Vakoc CR, Gazdar AF (2019) Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19:289–297PubMedPubMedCentralCrossRef Rudin CM, Poirier JT, Byers LA, Dive C, Dowlati A, George J, Heymach JV, Johnson JE, Lehman JM, MacPherson D, Massion PP, Minna JD, Oliver TG, Quaranta V, Sage J, Thomas RK, Vakoc CR, Gazdar AF (2019) Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19:289–297PubMedPubMedCentralCrossRef
66.
67.
go back to reference Simbolo M, Mafficini A, Sikora KO, Fassan M, Barbi S, Corbo V, Mastracci L, Rusev B, Grillo F, Vicentini C, Ferrara R, Pilotto S, Davini F, Pelosi G, Lawlor RT, Chilosi M, Tortora G, Bria E, Fontanini G, Volante M, Scarpa A (2017) Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D. J Pathol 241:488–500PubMedCrossRef Simbolo M, Mafficini A, Sikora KO, Fassan M, Barbi S, Corbo V, Mastracci L, Rusev B, Grillo F, Vicentini C, Ferrara R, Pilotto S, Davini F, Pelosi G, Lawlor RT, Chilosi M, Tortora G, Bria E, Fontanini G, Volante M, Scarpa A (2017) Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D. J Pathol 241:488–500PubMedCrossRef
68.
go back to reference Simbolo M, Barbi S, Fassan M, Mafficini A, Ali G, Vicentini C, Sperandio N, Corbo V, Rusev B, Mastracci L, Grillo F, Pilotto S, Pelosi G, Pelliccioni S, Lawlor RT, Tortora G, Fontanini G, Volante M, Scarpa A, Bria E (2019) Gene expression profiling of lung atypical carcinoids and large cell neuroendocrine carcinomas identifies three transcriptomic subtypes with specific genomic alterations. J Thorac Oncol Simbolo M, Barbi S, Fassan M, Mafficini A, Ali G, Vicentini C, Sperandio N, Corbo V, Rusev B, Mastracci L, Grillo F, Pilotto S, Pelosi G, Pelliccioni S, Lawlor RT, Tortora G, Fontanini G, Volante M, Scarpa A, Bria E (2019) Gene expression profiling of lung atypical carcinoids and large cell neuroendocrine carcinomas identifies three transcriptomic subtypes with specific genomic alterations. J Thorac Oncol
69.
go back to reference Sonkin D, Thomas A, Teicher BA (2019) Are neuroendocrine negative small cell lung cancer and large cell neuroendocrine carcinoma with WT RB1 two faces of the same entity? Lung Cancer Manag 8:LMT13PubMedPubMedCentralCrossRef Sonkin D, Thomas A, Teicher BA (2019) Are neuroendocrine negative small cell lung cancer and large cell neuroendocrine carcinoma with WT RB1 two faces of the same entity? Lung Cancer Manag 8:LMT13PubMedPubMedCentralCrossRef
70.
go back to reference Sturm N, Lantuejoul S, Laverriere MH, Papotti M, Brichon PY, Brambilla C, Brambilla E (2001) Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol 32:918–925PubMedCrossRef Sturm N, Lantuejoul S, Laverriere MH, Papotti M, Brichon PY, Brambilla C, Brambilla E (2001) Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol 32:918–925PubMedCrossRef
71.
go back to reference Swarts DR, Henfling ME, Van Neste L, van Suylen RJ, Dingemans AM, Dinjens WN, Haesevoets A, Rudelius M, Thunnissen E, Volante M, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ (2013) CD44 and OTP are strong prognostic markers for pulmonary carcinoids. Clin Cancer Res 19:2197–2207PubMedCrossRef Swarts DR, Henfling ME, Van Neste L, van Suylen RJ, Dingemans AM, Dinjens WN, Haesevoets A, Rudelius M, Thunnissen E, Volante M, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ (2013) CD44 and OTP are strong prognostic markers for pulmonary carcinoids. Clin Cancer Res 19:2197–2207PubMedCrossRef
72.
go back to reference Swarts DR, Van Neste L, Henfling ME, Eijkenboom I, Eijk PP, van Velthuysen ML, Vink A, Volante M, Ylstra B, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ (2013) An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 34:2726–2737PubMedCrossRef Swarts DR, Van Neste L, Henfling ME, Eijkenboom I, Eijk PP, van Velthuysen ML, Vink A, Volante M, Ylstra B, Van Criekinge W, van Engeland M, Ramaekers FC, Speel EJ (2013) An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 34:2726–2737PubMedCrossRef
73.
go back to reference Swarts DR, Scarpa A, Corbo V, Van Criekinge W, van Engeland M, Gatti G, Henfling ME, Papotti M, Perren A, Ramaekers FC, Speel EJ, Volante M (2014) MEN1 gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids. J Clin Endocrinol Metab 99:E374–E378PubMedCrossRef Swarts DR, Scarpa A, Corbo V, Van Criekinge W, van Engeland M, Gatti G, Henfling ME, Papotti M, Perren A, Ramaekers FC, Speel EJ, Volante M (2014) MEN1 gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids. J Clin Endocrinol Metab 99:E374–E378PubMedCrossRef
74.
go back to reference Thunnissen E, Borczuk AC, Flieder DB, Witte B, Beasley MB, Chung JH, Dacic S, Lantuejoul S, Russell PA, den Bakker M, Botling J, Brambilla E, de Cuba E, Geisinger KR, Hiroshima K, Marchevsky AM, Minami Y, Moreira A, Nicholson AG, Yoshida A, Tsao MS, Warth A, Duhig E, Chen G, Matsuno Y, Travis WD, Butnor K, Cooper W, Mino-Kenudson M, Motoi N, Poleri C, Pelosi G, Kerr K, Aisner SC, Ishikawa Y, Buettner RH, Keino N, Yatabe Y, Noguchi M (2017) The use of immunohistochemistry improves the diagnosis of small cell lung cancer and its differential diagnosis. An International reproducibility study in a demanding set of cases. J Thorac Oncol 12:334–346PubMedCrossRef Thunnissen E, Borczuk AC, Flieder DB, Witte B, Beasley MB, Chung JH, Dacic S, Lantuejoul S, Russell PA, den Bakker M, Botling J, Brambilla E, de Cuba E, Geisinger KR, Hiroshima K, Marchevsky AM, Minami Y, Moreira A, Nicholson AG, Yoshida A, Tsao MS, Warth A, Duhig E, Chen G, Matsuno Y, Travis WD, Butnor K, Cooper W, Mino-Kenudson M, Motoi N, Poleri C, Pelosi G, Kerr K, Aisner SC, Ishikawa Y, Buettner RH, Keino N, Yatabe Y, Noguchi M (2017) The use of immunohistochemistry improves the diagnosis of small cell lung cancer and its differential diagnosis. An International reproducibility study in a demanding set of cases. J Thorac Oncol 12:334–346PubMedCrossRef
75.
go back to reference Travis W, Brambilla E, Burke A, Marx A, Nicholson A (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon Travis W, Brambilla E, Burke A, Marx A, Nicholson A (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC Press, Lyon
76.
go back to reference Tsuruoka K, Horinouchi H, Goto Y, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Asakura K, Nakagawa K, Sakurai H, Watanabe SI, Tsuta K, Ohe Y (2017) PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer 108:115–120PubMedCrossRef Tsuruoka K, Horinouchi H, Goto Y, Kanda S, Fujiwara Y, Nokihara H, Yamamoto N, Asakura K, Nakagawa K, Sakurai H, Watanabe SI, Tsuta K, Ohe Y (2017) PD-L1 expression in neuroendocrine tumors of the lung. Lung Cancer 108:115–120PubMedCrossRef
77.
go back to reference Uccella S, La Rosa S, Scaldaferri D, Monti L, Maragliano R, Sorrenti E, Gariboldi M, Taramelli R, Sessa F, Acquati F (2018) New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1alpha. Hum Pathol 79:66–76PubMedCrossRef Uccella S, La Rosa S, Scaldaferri D, Monti L, Maragliano R, Sorrenti E, Gariboldi M, Taramelli R, Sessa F, Acquati F (2018) New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1alpha. Hum Pathol 79:66–76PubMedCrossRef
78.
go back to reference Vollbrecht C, Werner R, Walter RF, Christoph DC, Heukamp LC, Peifer M, Hirsch B, Burbat L, Mairinger T, Schmid KW, Wohlschlaeger J, Mairinger FD (2015) Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. Br J Cancer 113:1704–1711PubMedPubMedCentralCrossRef Vollbrecht C, Werner R, Walter RF, Christoph DC, Heukamp LC, Peifer M, Hirsch B, Burbat L, Mairinger T, Schmid KW, Wohlschlaeger J, Mairinger FD (2015) Mutational analysis of pulmonary tumours with neuroendocrine features using targeted massive parallel sequencing: a comparison of a neglected tumour group. Br J Cancer 113:1704–1711PubMedPubMedCentralCrossRef
79.
go back to reference Warth A, Herpel E, Krysa S, Hoffmann H, Schnabel PA, Schirmacher P, Mechtersheimer G, Blaker H (2009) Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential. Exp Mol Med 41:349–353PubMedPubMedCentralCrossRef Warth A, Herpel E, Krysa S, Hoffmann H, Schnabel PA, Schirmacher P, Mechtersheimer G, Blaker H (2009) Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential. Exp Mol Med 41:349–353PubMedPubMedCentralCrossRef
80.
go back to reference Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, Granja JM, Jahchan NS, Lim JS, Kwok S, Kong CS, Berghoff AS, Schmitt A, Reinhardt HC, Park KS, Preusser M, Kundaje A, Greenleaf WJ, Sage J, Winslow MM (2018) Intertumoral heterogeneity in SCLC is influenced by the cell type of origin. Cancer Discov 8:1316–1331PubMedPubMedCentralCrossRef Yang D, Denny SK, Greenside PG, Chaikovsky AC, Brady JJ, Ouadah Y, Granja JM, Jahchan NS, Lim JS, Kwok S, Kong CS, Berghoff AS, Schmitt A, Reinhardt HC, Park KS, Preusser M, Kundaje A, Greenleaf WJ, Sage J, Winslow MM (2018) Intertumoral heterogeneity in SCLC is influenced by the cell type of origin. Cancer Discov 8:1316–1331PubMedPubMedCentralCrossRef
81.
go back to reference Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, Beasley MB, Thunnissen E, Pelosi G, Rekhtman N, Bubendorf L, Mino-Kenudson M, Yoshida A, Geisinger KR, Noguchi M, Chirieac LR, Bolting J, Chung JH, Chou TY, Chen G, Poleri C, Lopez-Rios F, Papotti M, Sholl LM, Roden AC, Travis WD, Hirsch FR, Kerr KM, Tsao MS, Nicholson AG, Wistuba I, Moreira AL (2019) Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol 14:377–407PubMedCrossRef Yatabe Y, Dacic S, Borczuk AC, Warth A, Russell PA, Lantuejoul S, Beasley MB, Thunnissen E, Pelosi G, Rekhtman N, Bubendorf L, Mino-Kenudson M, Yoshida A, Geisinger KR, Noguchi M, Chirieac LR, Bolting J, Chung JH, Chou TY, Chen G, Poleri C, Lopez-Rios F, Papotti M, Sholl LM, Roden AC, Travis WD, Hirsch FR, Kerr KM, Tsao MS, Nicholson AG, Wistuba I, Moreira AL (2019) Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol 14:377–407PubMedCrossRef
83.
go back to reference Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, Stastny V, Ghayee HK, Pacak K, Oliver TG, Minna JD, Gazdar AF (2018) Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 7:32–49PubMedPubMedCentralCrossRef Zhang W, Girard L, Zhang YA, Haruki T, Papari-Zareei M, Stastny V, Ghayee HK, Pacak K, Oliver TG, Minna JD, Gazdar AF (2018) Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes. Transl Lung Cancer Res 7:32–49PubMedPubMedCentralCrossRef
84.
go back to reference Zhou Z, Zhu L, Niu X, Shen S, Zhao Y, Zhang J, Ye J, Han-Zhang H, Liu J, Liu C, Lu S (2019) Comparison of genomic landscapes of large cell neuroendocrine carcinoma, small cell lung carcinoma, and large cell carcinoma. Thorac Cancer 10:839–847PubMedPubMedCentralCrossRef Zhou Z, Zhu L, Niu X, Shen S, Zhao Y, Zhang J, Ye J, Han-Zhang H, Liu J, Liu C, Lu S (2019) Comparison of genomic landscapes of large cell neuroendocrine carcinoma, small cell lung carcinoma, and large cell carcinoma. Thorac Cancer 10:839–847PubMedPubMedCentralCrossRef
Metadata
Title
Morphologic and molecular classification of lung neuroendocrine neoplasms
Authors
Jasna Metovic
Marco Barella
Fabrizio Bianchi
Paul Hofman
Veronique Hofman
Myriam Remmelink
Izidor Kern
Lina Carvalho
Linda Pattini
Angelica Sonzogni
Giulia Veronesi
Sergio Harari
Fabien Forest
Mauro Papotti
Giuseppe Pelosi
Publication date
01-01-2021
Publisher
Springer Berlin Heidelberg
Published in
Virchows Archiv / Issue 1/2021
Print ISSN: 0945-6317
Electronic ISSN: 1432-2307
DOI
https://doi.org/10.1007/s00428-020-03015-z

Other articles of this Issue 1/2021

Virchows Archiv 1/2021 Go to the issue