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The Spectrum of Neuroendocrine Neoplasia pp 151–206Cite as

Thoracic (Lung/Thymus) Neuroendocrine Neoplasms

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Abstract

Thoracic neuroendocrine neoplasms include pulmonary and thymic tumors. Well-differentiated neuroendocrine tumors are currently classified as typical and atypical carcinoids based on mitotic index and presence of necrosis. Large cell neuroendocrine carcinoma (LCNEC) accounts for 3% or less of all lung cancers, but its prevalence is destined to increase due to heightened diagnostic awareness and increased use of immunohistochemistry for refining poorly differentiated tumors. Small cell lung carcinoma (SCLC) accounts for about 15% of all lung carcinomas worldwide and for most neuroendocrine neoplasms arising in the lung. Neuroendocrine neoplasms of the thymus account for 2–5% of all thymic tumors. The pathological features of pulmonary neuroendocrine cell alterations in nonneoplastic and preinvasive conditions encompass a spectrum of morphological changes ranging from linear hyperplasia to tumorlets. The role of these lesions as precursors of lung neuroendocrine neoplasms is postulated for well differentiated neuroendocrine tumors, mainly those in peripheral location that may be associated with neuroendocrine cell hyperplasia in up to 75% of cases. By contrast, these lesions are probably not associated with the development of high-grade small and large cell carcinomas whose origin seems to be more complex and possibly linked also to other cell types (including type II alveolar cells).

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References

  1. Linnoila RI. Functional facets of the pulmonary neuroendocrine system. Lab Invest. 2006;86(5):425–44.

    Article  CAS  PubMed  Google Scholar 

  2. Franks TJ, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Engelhardt J, Frid M, Herzog E, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, Serge J, Sunday ME, Voynow JA, Weinstein BM, Whitsett J, Williams MC. Resident cellular components of the human lung: current knowledge and goals for research on cell phenotyping and function. Proc Am Thorac Soc. 2008;5(7):763–6.

    Article  PubMed  Google Scholar 

  3. Brouns I, Van Genechten J, Hayashi H, Gajda M, Gomi T, Burnstock G, Timmermans JP, Adriaensen D. Dual sensory innervation of pulmonary neuroepithelial bodies. Am J Respir Cell Mol Biol. 2003;28(3):275–85.

    Article  CAS  PubMed  Google Scholar 

  4. Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature. 1993;365(6442):153–5.

    Article  CAS  PubMed  Google Scholar 

  5. Evans AM, Hardie DG, Peers C, Mahmoud A. Hypoxic pulmonary vasoconstriction: mechanisms of oxygen-sensing. Curr Opin Anaesthesiol. 2011;24(1):13–20.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I, WHO Panel. The 2015 World Health Organization classification of lung tumors: impact of genetic, clinical and radiologic advances since the 2004 classification. J Thorac Oncol. 2015;10(9):1243–60.

    Article  PubMed  Google Scholar 

  7. Swarts DR, van Suylen RJ, den Bakker MA, van Oosterhout MF, Thunnissen FB, Volante M, Dingemans AM, Scheltinga MR, Bootsma GP, Pouwels HM, van den Borne BE, Ramaekers FC, Speel EJ. Interobserver variability for the WHO classification of pulmonary carcinoids. Am J Surg Pathol. 2014;38(10):1429–36.

    Article  PubMed  Google Scholar 

  8. Rizvi SM, Goodwill J, Lim E, Yap YK, Wells AU, Hansell DM, Davis P, Selim AG, Goldstraw P, Nicholson AG. The frequency of neuroendocrine cell hyperplasia in patients with pulmonary neuroendocrine tumours and non-neuroendocrine cell carcinomas. Histopathology. 2009;55(3):332–7.

    Article  PubMed  Google Scholar 

  9. Derks JL, Leblay N, Lantuejoul S, Dingemans AC, Speel EM, Fernandez-Cuesta L. New insights into the molecular characteristics of pulmonary carcinoids and large cell neuroendocrine carcinomas, and the impact on their clinical management. J Thorac Oncol. 2018;13(6):752–66.

    Article  CAS  PubMed  Google Scholar 

  10. Carr LL, Kern JA, Deutsch GH. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and neuroendocrine hyperplasia of infancy. Clin Chest Med. 2016;37(3):579–87.

    Article  PubMed  Google Scholar 

  11. Spielberg DR, Brody AS, Baker ML, Woods JC, Towe CT. Ground-glass burden as a biomarker in neuroendocrine cell hyperplasia of infancy. Pediatr Pulmonol. 2019;54(6):822–7.

    Article  PubMed  Google Scholar 

  12. Gosney JR, Sissons MC, Allibone RO, Blakey AF. Pulmonary endocrine cells in chronic bronchitis and emphysema. J Pathol. 1989;157(2):127–33.

    Article  CAS  PubMed  Google Scholar 

  13. Shyu S, Heath JE, Burke AP. Neuroendocrine cell proliferations in lungs explanted for fibrotic interstitial lung disease and emphysema. Pathology. 2018;50(7):699–702.

    Article  CAS  PubMed  Google Scholar 

  14. Song H, Yao E, Lin C, Gacayan R, Chen MH, Chuang PT. Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis. Proc Natl Acad Sci U S A. 2012;109(43):17531–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ferolla P, Daddi N, Urbani M, Semeraro A, Ribacchi R, Giovenali P, Ascani S, De Angelis V, Crinò L, Puma F, Daddi G, Regional Multidisciplinary Group for the Diagnosis and Treatment of Neuroendocrine Tumors, CRO, Umbria Region Cancer Network, Italy. Tumorlets, multicentric carcinoids, lymph-nodal metastases, and long-term behavior in bronchial carcinoids. J Thorac Oncol. 2009;4(3):383–7.

    Article  PubMed  Google Scholar 

  16. 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. ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature. Virchows Arch. 2019;475(5):587–97.

    Article  PubMed  CAS  Google Scholar 

  17. Swarts DR, Ramaekers FC, Speel EJ. Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta. 2012;1826(2):255–71.

    CAS  PubMed  Google Scholar 

  18. Pelosi G, Nesa F, Taietti D, Servillo SP, Papanikolaou N, Zompatori M, Meroni A, Harari S, Incarbone M. Spread of hyperplastic pulmonary neuroendocrine cells into air spaces (S.H.I.P.M.E.N.T.S): a proof for artifact. Lung Cancer. 2019;137:43–7.

    Article  PubMed  Google Scholar 

  19. Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Tumours of the lung, pleura, thymus and heart. Pathology & Genetics. In: World Health Organization classification of tumours. Lyon: IARC Press; 2004.

    Google Scholar 

  20. Aguayo SM, Miller YE, Waldron JA Jr, Bogin RM, Sunday ME, Staton GW Jr, Beam WR, King TE Jr. Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med. 1992;327(18):1285–8.

    Article  CAS  PubMed  Google Scholar 

  21. Rossi G, Cavazza A, Spagnolo P, Sverzellati N, Longo L, Jukna A, Montanari G, Carbonelli C, Vincenzi G, Bogina G, Franco R, Tiseo M, Cottin V, Colby TV. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia syndrome. Eur Respir J. 2016;47(6):1829–41.

    Article  CAS  PubMed  Google Scholar 

  22. Mengoli MC, Rossi G, Cavazza A, Franco R, Marino FZ, Migaldi M, Gnetti L, Silini EM, Ampollini L, Tiseo M, Lococo F, Fournel L, Spagnolo P, Cottin V, Colby TV. Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) syndrome and carcinoid tumors with/without nech: a clinicopathologic, radiologic, and immunomolecular comparison study. Am J Surg Pathol. 2018;42(5):646–55.

    Article  PubMed  Google Scholar 

  23. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM, Sheppard MN, Nicholson AG. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an under-recognised spectrum of disease. Thorax. 2007;62(3):248–52.

    Article  PubMed  Google Scholar 

  24. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM, Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: a systematic overview. Am J Respir Crit Care Med. 2011;184(1):8–16.

    Article  PubMed  Google Scholar 

  25. Cameron CM, Roberts F, Connell J, Sproule MW. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: an unusual cause of cyclical ectopic adrenocorticotrophic syndrome. Br J Radiol. 2011;84(997):e14–7.

    Article  CAS  PubMed  Google Scholar 

  26. Chassagnon G, Favelle O, Marchand-Adam S, De Muret A, Revel MP. DIPNECH: when to suggest this diagnosis on CT. Clin Radiol. 2015;70(3):317–25.

    Article  CAS  PubMed  Google Scholar 

  27. Marchevsky AM, Wirtschafter E, Walts AE. The spectrum of changes in adults with multifocal pulmonary neuroendocrine proliferations: what is the minimum set of pathologic criteria to diagnose DIPNECH? Hum Pathol. 2015;46(2):176–81.

    Article  CAS  PubMed  Google Scholar 

  28. Jayaschandran V, Gjorgova-Gjeorgjievski S, Siddique H. An uncommon cause of miliary pattern of pulmonary nodules-diffuse pulmonary meningotheliomatosis. Respirol Case Rep. 2017;5(4):e00238.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Yao JC, Hassan M, Phan A, Dagohoy C, Leary C, Mares JE, Abdalla EK, Fleming JB, Vauthey JN, Rashid A, Evans DB. One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol. 2008;26(18):3063–72.

    Article  PubMed  Google Scholar 

  30. Naalsund A, Rostad H, Strøm EH, Lund MB, Strand TE. Carcinoid lung tumors--incidence, treatment and outcomes: a population-based study. Eur J Cardiothorac Surg. 2011;39(4):565–9.

    Article  PubMed  Google Scholar 

  31. Sachithanandan N, Harle RA, Burgess JR. Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer. 2005;103(3):509–15.

    Article  PubMed  Google Scholar 

  32. Papaxoinis G, Lamarca A, Quinn AM, Mansoor W, Nonaka D. Clinical and pathologic characteristics of pulmonary carcinoid tumors in central and peripheral locations. Endocr Pathol. 2018;29(3):259–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fink G, Krelbaum T, Yellin A, Bendayan D, Saute M, Glazer M, Kramer MR. Pulmonary carcinoid: presentation, diagnosis, and outcome in 142 cases in Israel and review of 640 cases from the literature. Chest. 2001;119(6):1647–51.

    Article  CAS  PubMed  Google Scholar 

  34. Halperin DM, Shen C, Dasari A, Xu Y, Chu Y, Zhou S, Shih YT, Yao JC. Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study. Lancet Oncol. 2017;18(4):525–34.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kyriakakis N, Trouillas J, Dang MN, Lynch J, Belchetz P, Korbonits M, Murray RD. Diagnostic challenges and management of a patient with acromegaly due to ectopic growth hormone-releasing hormone secretion from a bronchial carcinoid tumour. Endocrinol Diabetes Metab Case Rep. 2017;2017. pii: 16-0104.

    Google Scholar 

  36. Caplin ME, Baudin E, Ferolla P, Filosso P, Garcia-Yuste M, Lim E, Oberg K, Pelosi G, Perren A, Rossi RE, Travis WD, ENETS consensus conference participants. Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids. Ann Oncol. 2015;26(8):1604–20.

    Article  CAS  PubMed  Google Scholar 

  37. Krenning EP, Kwekkeboom DJ, Bakker WH, Breeman WA, Kooij PP, Oei HY, van Hagen M, Postema PT, de Jong M, Reubi JC, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716–31.

    Article  CAS  PubMed  Google Scholar 

  38. Jiang Y, Hou G, Cheng W. The utility of 18F-FDG and 68Ga-DOTA-Peptide PET/CT in the evaluation of primary pulmonary carcinoid: a systematic review and meta-analysis. Medicine (Baltimore). 2019;98(10):e14769.

    Article  CAS  Google Scholar 

  39. Kneuertz PJ, Kamel MK, Stiles BM, Lee BE, Rahouma M, Harrison SW, Altorki NK, Port JL. Incidence and prognostic significance of carcinoid lymph node metastases. Ann Thorac Surg. 2018;106(4):981–8.

    Article  PubMed  Google Scholar 

  40. Chen X, Pang Z, Wang Y, Bie F, Zeng Y, Wang G, Du J. The role of surgery for atypical bronchopulmonary carcinoid tumor: development and validation of a model based on Surveillance, Epidemiology, and End Results (SEER) database. Lung Cancer. 2019;139:94–102.

    Article  PubMed  Google Scholar 

  41. Wegner RE, Abel S, Hasan S, Horne ZD, Colonias A, Weksler B, Verma V. The role of adjuvant therapy for atypical bronchopulmonary carcinoids. Lung Cancer. 2019;131:90–4.

    Article  PubMed  Google Scholar 

  42. Melosky B. Advanced typical and atypical carcinoid tumours of the lung: management recommendations. Curr Oncol. 2018;25(Suppl 1):S86–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Dermawan JK, Farver CF. The prognostic significance of the 8th edition TNM staging of pulmonary carcinoid tumors: a single institution study with long-term follow-up. Am J Surg Pathol. 2019;43(9):1291–6.

    Article  PubMed  Google Scholar 

  44. Sheppard MN. Nuclear pleomorphism in typical carcinoid tumours of the lung: problems in frozen section interpretation. Histopathology. 1997;30(5):478–80.

    Article  CAS  PubMed  Google Scholar 

  45. Gupta R, Dastane A, McKenna RJ Jr, Marchevsky AM. What can we learn from the errors in the frozen section diagnosis of pulmonary carcinoid tumors? An evidence-based approach. Hum Pathol. 2009;40(1):1–9.

    Article  PubMed  Google Scholar 

  46. Stoll LM, Johnson MW, Burroughs F, Li QK. Cytologic diagnosis and differential diagnosis of lung carcinoid tumors a retrospective study of 63 cases with histologic correlation. Cancer Cytopathol. 2010;118(6):457–67.

    Article  PubMed  Google Scholar 

  47. Arrigoni MG, Woolner LB, Bernatz PE. Atypical carcinoid tumors of the lung. J Thorac Cardiovasc Surg. 1972;64(3):413–21.

    Article  CAS  PubMed  Google Scholar 

  48. Altinay S, Metovic J, Massa F, Gatti G, Cassoni P, Scagliotti GV, Volante M, Papotti M. Spread through air spaces (STAS) is a predictor of poor outcome in atypical carcinoids of the lung. Virchows Arch. 2019;475(3):325–34.

    Article  CAS  PubMed  Google Scholar 

  49. Aly RG, Rekhtman N, Li X, Takahashi Y, Eguchi T, Tan KS, Rudin CM, Adusumilli PS, Travis WD. Spread Through Air Spaces (STAS) is prognostic in atypical carcinoid, large cell neuroendocrine carcinoma, and small cell carcinoma of the lung. J Thorac Oncol. 2019;14(9):1583–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tsuta K, Kalhor N, Raso MG, Wistuba II, Moran CA. Oncocytic neuroendocrine tumors of the lung: histopathologic spectrum and immunohistochemical analysis of 15 cases. Hum Pathol. 2011;42(4):578–85.

    Article  PubMed  Google Scholar 

  51. Nannini N, Bertolini F, Cavazza A, Casali C, Mengoli MC, Rossi G. Atypical carcinoid with prominent mucinous stroma: a hitherto unreported variant of pulmonary neuroendocrine tumor. Endocr Pathol. 2010;21(2):120–4.

    Article  PubMed  Google Scholar 

  52. Gaffey MJ, Mills SE, Frierson HF Jr, Askin FB, Maygarden SJ. Pulmonary clear cell carcinoid tumor: another entity in the differential diagnosis of pulmonary clear cell neoplasia. Am J Surg Pathol. 1998;22(8):1020–5.

    Article  CAS  PubMed  Google Scholar 

  53. Grazer R, Cohen SM, Jacobs JB, Lucas P. Melanin-containing peripheral carcinoid of the lung. Am J Surg Pathol. 1982;6(1):73–8.

    Article  CAS  PubMed  Google Scholar 

  54. Churg A. Large spindle cell variant of peripheral bronchial carcinoid tumor. Arch Pathol Lab Med. 1977;101(4):216–8.

    CAS  PubMed  Google Scholar 

  55. Uccella S, La Rosa S, Volante M, Papotti M. Immunohistochemical biomarkers of gastrointestinal, pancreatic, pulmonary, and thymic neuroendocrine neoplasms. Endocr Pathol. 2018;29(2):150–68.

    Article  PubMed  Google Scholar 

  56. Sica G, Vazquez MF, Altorki N, Port J, Lee PC, Liu Y, Hyjek E, Saqi A. PAX-5 expression in pulmonary neuroendocrine neoplasms: its usefulness in surgical and fine-needle aspiration biopsy specimens. Am J Clin Pathol. 2008;129(4):556–62.

    Article  PubMed  Google Scholar 

  57. Vesterinen T, Leijon H, Mustonen H, Remes S, Knuuttila A, Salmenkivi K, Vainio P, Arola J, Haglund C. Somatostatin receptor expression is associated with metastasis and patient outcome in pulmonary carcinoid tumors. J Clin Endocrinol Metab. 2019;104(6):2083–93.

    Article  PubMed  Google Scholar 

  58. Jiang SX, Kameya T, Asamura H, Umezawa A, Sato Y, Shinada J, Kawakubo Y, Igarashi T, Nagai K, Okayasu I. hASH1 expression is closely correlated with endocrine phenotype and differentiation extent in pulmonary neuroendocrine tumors. Mod Pathol. 2004;17(2):222–9.

    Article  CAS  PubMed  Google Scholar 

  59. La Rosa S, Marando A, Gatti G, Rapa I, Volante M, Papotti M, Sessa F, Capella C. Achaete-scute homolog 1 as a marker of poorly differentiated neuroendocrine carcinomas of different sites: a validation study using immunohistochemistry and quantitative real-time polymerase chain reaction on 335 cases. Hum Pathol. 2013;44(7):1391–9.

    Article  PubMed  CAS  Google Scholar 

  60. Mukhopadhyay S, Dermawan JK, Lanigan CP, Farver CF. Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections. Mod Pathol. 2019;32(1):100–9.

    Article  CAS  PubMed  Google Scholar 

  61. La Rosa S, Chiaravalli AM, Placidi C, Papanikolaou N, Cerati M, Capella C. TTF1 expression in normal lung neuroendocrine cells and related tumors: immunohistochemical study comparing two different monoclonal antibodies. Virchows Arch. 2010;457(4):497–507.

    Article  PubMed  CAS  Google Scholar 

  62. Du EZ, Goldstraw P, Zacharias J, Tiffet O, Craig PJ, Nicholson AG, Weidner N, Yi ES. TTF-1 expression is specific for lung primary in typical and atypical carcinoids: TTF-1-positive carcinoids are predominantly in peripheral location. Hum Pathol. 2004;35(7):825–31.

    Article  CAS  PubMed  Google Scholar 

  63. Vahidi S, Stewart J, Amin K, Racila E, Li F. Metastatic medullary thyroid carcinoma or calcitonin-secreting carcinoid tumor of lung? A diagnostic dilemma in a patient with lung mass and thyroid nodule. Diagn Cytopathol. 2018;46(4):345–8.

    Article  PubMed  Google Scholar 

  64. Nonaka D, Papaxoinis G, Mansoor W. Diagnostic utility of orthopedia homeobox (OTP) in pulmonary carcinoid tumors. Am J Surg Pathol. 2016;40(6):738–44.

    Article  PubMed  Google Scholar 

  65. Viswanathan K, Borczuk AC, Siddiqui MT. Orthopedia homeobox protein (OTP) is a sensitive and specific marker for primary pulmonary carcinoid tumors in cytologic and surgical specimens. J Am Soc Cytopathol. 2019;8(1):39–46.

    Article  PubMed  Google Scholar 

  66. Huang X, Liang QL, Jiang L, Liu QL, Ou WT, Li DH, Zhang HJ, Yuan GL. Primary pulmonary paraganglioma: a case report and review of literature. Medicine (Baltimore). 2015;94(31):e1271.

    Article  Google Scholar 

  67. Galván JA, Astudillo A, Vallina A, Crespo G, Folgueras MV, González MV. Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors. BMC Cancer. 2014;14:855.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Kaemmerer D, Reimann C, Specht E, Wirtz RM, Sayeg M, Baum RP, Schulz S, Lupp A. Differential expression and prognostic value of the chemokine receptor CXCR4 in bronchopulmonary neuroendocrine neoplasms. Oncotarget. 2015;6(5):3346–58.

    Article  PubMed  Google Scholar 

  69. Del Gobbo A, Vaira V, Guerini Rocco E, Palleschi A, Bulfamante G, Ricca D, Fiori S, Bosari S, Ferrero S. The oncofetal protein IMP3: a useful marker to predict poor clinical outcome in neuroendocrine tumors of the lung. J Thorac Oncol. 2014;9(11):1656–61.

    Article  PubMed  CAS  Google Scholar 

  70. 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. CD44 and OTP are strong prognostic markers for pulmonary carcinoids. Clin Cancer Res. 2013;19(8):2197–207.

    Article  CAS  PubMed  Google Scholar 

  71. Papaxoinis G, Nonaka D, O’Brien C, Sanderson B, Krysiak P, Mansoor W. Prognostic significance of CD44 and orthopedia homeobox protein (OTP) expression in pulmonary carcinoid tumours. Endocr Pathol. 2017;28(1):60–70.

    Article  CAS  PubMed  Google Scholar 

  72. Naranjo Gómez JM, Bernal JF, Arranz PG, Fernández SL, Roman JJ. Alterations in the expression of p53, KLF4, and p21 in neuroendocrine lung tumors. Arch Pathol Lab Med. 2014;138(7):936–42.

    Article  PubMed  Google Scholar 

  73. Marchevsky AM, Hendifar A, Walts AE. The use of Ki-67 labeling index to grade pulmonary well-differentiated neuroendocrine neoplasms: current best evidence. Mod Pathol. 2018;31(10):1523–31.

    Article  PubMed  Google Scholar 

  74. Swarts DR, Rudelius M, Claessen SM, Cleutjens JP, Seidl S, Volante M, Ramaekers FC, Speel EJ. Limited additive value of the Ki-67 proliferative index on patient survival in World Health Organization-classified pulmonary carcinoids. Histopathology. 2017;70(3):412–22.

    Article  PubMed  Google Scholar 

  75. 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. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer. 2013;21(1):1–16.

    Article  PubMed  Google Scholar 

  76. Fabbri A, Cossa M, Sonzogni A, Papotti M, Righi L, Gatti G, Maisonneuve P, Valeri B, Pastorino U, Pelosi G. 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. 2017;470(2):153–64.

    Article  CAS  PubMed  Google Scholar 

  77. Dermawan JKT, Farver CF. The role of histologic grading and Ki-67 index in predicting outcomes in pulmonary carcinoid tumors. Am J Surg Pathol. 2020;44:224–31.

    Article  PubMed  Google Scholar 

  78. Marchiò C, Gatti G, Massa F, Bertero L, Filosso P, Pelosi G, Cassoni P, Volante M, Papotti M. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch. 2017;471(6):713–20.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Kasajima A, Konukiewitz B, Oka N, Suzuki H, Sakurada A, Okada Y, Kameya T, Ishikawa Y, Sasano H, Weichert W, Klöppel G. Clinicopathological profiling of lung carcinoids with a Ki67 index > 20. Neuroendocrinology. 2019;108(2):109–20.

    Article  CAS  PubMed  Google Scholar 

  80. Rekhtman N, Desmeules P, Litvak AM, Pietanza MC, Santos-Zabala ML, Ni A, Montecalvo J, Chang JC, Beras A, Preeshagul IR, Sabari JK, Rudin CM, Ladanyi M, Klimstra DS, Travis WD, Lai WC. Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices. Mod Pathol. 2019;32(8):1106–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T. Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg. 2007;84(2):702–7.

    Article  PubMed  Google Scholar 

  82. Yang Q, Xu Z, Chen X, Zheng L, Yu Y, Zhao X, Chen M, Luo B, Wang J, Sun J. Clinicopathological characteristics and prognostic factors of pulmonary large cell neuroendocrine carcinoma: a large population-based analysis. Thorac Cancer. 2019;10(4):751–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Naidoo J, Santos-Zabala ML, Iyriboz T, Woo KM, Sima CS, Fiore JJ, Kris MG, Riely GJ, Lito P, Iqbal A, Veach S, Smith-Marrone S, Sarkaria IS, Krug LM, Rudin CM, Travis WD, Rekhtman N, Pietanza MC. Large cell neuroendocrine carcinoma of the lung: clinico-pathologic features, treatment, and outcomes. Clin Lung Cancer. 2016;17(5):e121–9.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Fasano M, Della Corte CM, Papaccio F, Ciardiello F, Morgillo F. Pulmonary large-cell neuroendocrine carcinoma: from epidemiology to therapy. J Thorac Oncol. 2015;10(8):1133–41.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Hayashi N, Fujita A, Saikai T, Takabatake H, Sotoshiro M, Sekine K, Kawana A. Large cell neuroendocrine carcinoma harboring an anaplastic lymphoma kinase (ALK) rearrangement with response to alectinib. Intern Med. 2018;57(5):713–6.

    Article  PubMed  Google Scholar 

  86. Zhou F, Hou L, Ding T, Song Q, Chen X, Su C, Li W, Gao G, Ren S, Wu F, Fan J, Wu C, Zhang J, Zhou C. Distinct clinicopathologic features, genomic characteristics and survival of central and peripheral pulmonary large cell neuroendocrine carcinoma: from different origin cells? Lung Cancer. 2018;116:30–7.

    Article  PubMed  Google Scholar 

  87. De Pas TM, Giovannini M, Manzotti M, Trifirò G, Toffalorio F, Catania C, Spaggiari L, Labianca R, Barberis M. Large-cell neuroendocrine carcinoma of the lung harboring EGFR mutation and responding to gefitinib. J Clin Oncol. 2011;29(34):e819–22.

    Article  PubMed  CAS  Google Scholar 

  88. Pelosi G, Bianchi F, Hofman P, Pattini L, Ströbel 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. Recent advances in the molecular landscape of lung neuroendocrine tumors. Expert Rev Mol Diagn. 2019;19(4):281–97.

    Article  CAS  PubMed  Google Scholar 

  89. Verma R, Lambert A, Katz HH, Benson SJ. Ectopic ACTH-producing large cell neuroendocrine Pancoast tumour presenting as Horner syndrome. BMJ Case Rep. 2017;2017:bcr2016219156.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Grommes C, Preston DC, Al-Kadhimi Z, Alshekhlee A. Lambert-Eaton syndrome with large-cell neuroendocrine carcinoma of the lung. Muscle Nerve. 2008;37(6):786–9.

    Article  PubMed  Google Scholar 

  91. Nakamura T, Fujisaka Y, Tamura Y, Tsuji H, Matsunaga N, Yoshida S, Imanishi M, Fujita K, Ikeda S, Oku H, Goto I, Ikeda T, Hanafusa T. Large cell neuroendocrine carcinoma of the lung with cancer-associated retinopathy. Case Rep Oncol. 2015;8(1):153–8.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol. 2006;24(1):70–6.

    Article  PubMed  Google Scholar 

  93. Jones MH, Virtanen C, Honjoh D, Miyoshi T, Satoh Y, Okumura S, Nakagawa K, Nomura H, Ishikawa Y. Two prognostically significant subtypes of high-grade lung neuroendocrine tumours independent of small-cell and large-cell neuroendocrine carcinomas identified by gene expression profiles. Lancet. 2004;363(9411):775–81.

    Article  CAS  PubMed  Google Scholar 

  94. Lee KW, Lee Y, Oh SW, Jin KN, Goo JM. Large cell neuroendocrine carcinoma of the lung: CT and FDG PET findings. Eur J Radiol. 2015;84(11):2332–8.

    Article  PubMed  Google Scholar 

  95. Righi L, Volante M, Tavaglione V, Billè A, Daniele L, Angusti T, Inzani F, Pelosi G, Rindi G, Papotti M. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 'clinically aggressive’ cases. Ann Oncol. 2010;21(3):548–55.

    Article  CAS  PubMed  Google Scholar 

  96. Derks JL, Dingemans AC, van Suylen RJ, den Bakker MA, Damhuis RAM, van den Broek EC, Speel EJ, Thunnissen E. Is the sum of positive neuroendocrine immunohistochemical stains useful for diagnosis of large cell neuroendocrine carcinoma (LCNEC) on biopsy specimens? Histopathology. 2019;74(4):555–66.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Travis WD, Brambilla E, Nicholson AG. Testing for neuroendocrine immunohistochemical markers should not be performed in poorly differentiated NSCCs in the absence of neuroendocrine morphologic features according to the 2015 WHO classification. J Thorac Oncol. 2016;11(2):e26–7.

    Article  PubMed  Google Scholar 

  98. Hiroshima K, Abe S, Ebihara Y, Ogura S, Kikui M, Kodama T, Komatsu H, Saito Y, Sagawa M, Sato M, Tagawa Y, Nakamura S, Nakayama T, Baba M, Hanzawa S, Hirano T, Horai T. Cytological characteristics of pulmonary large cell neuroendocrine carcinoma. Lung Cancer. 2005;48(3):331–7.

    Article  PubMed  Google Scholar 

  99. Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB Jr, Nieman L, Chrousos G, Pass H, Doppman J. Neuroendocrine tumors of the lung with proposed criteria for large-cell neuroendocrine carcinoma. An ultrastructural, immunohistochemical, and flow cytometric study of 35 cases. Am J Surg Pathol. 1991;15(6):529–53.

    Article  CAS  PubMed  Google Scholar 

  100. Warren WH, Gould VE, Faber LP, Kittle CF, Memoli VA. Neuroendocrine neoplasms of the bronchopulmonary tract. A classification of the spectrum of carcinoid to small cell carcinoma and intervening variants. J Thorac Cardiovasc Surg. 1985;89(6):819–25.

    Article  CAS  PubMed  Google Scholar 

  101. Gould VE, Linnoila RI, Memoli VA, Warren WH. Neuroendocrine components of the bronchopulmonary tract: hyperplasias, dysplasias, and neoplasms. Lab Invest. 1983;49(5):519–37.

    CAS  PubMed  Google Scholar 

  102. Caruso RA, Branca G, Fedele F, Irato E, Finocchiaro G, Parisi A, Ieni A. Mechanisms of coagulative necrosis in malignant epithelial tumors (review). Oncol Lett. 2014;8(4):1397–402.

    Article  PubMed  PubMed Central  Google Scholar 

  103. den Bakker MA, Willemsen S, Grünberg K, Noorduijn LA, van Oosterhout MF, van Suylen RJ, Timens W, Vrugt B, Wiersma-van Tilburg A, Thunnissen FB. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability. Histopathology. 2010;56(3):356–63.

    Article  Google Scholar 

  104. Marchevsky AM, Gal AA, Shah S, Koss MN. Morphometry confirms the presence of considerable nuclear size overlap between “small cells” and “large cells” in high-grade pulmonary neuroendocrine neoplasms. Am J Clin Pathol. 2001;116(4):466–72.

    Article  CAS  PubMed  Google Scholar 

  105. Howe MC, Chapman A, Kerr K, Dougal M, Anderson H, Hasleton PS. Neuroendocrine differentiation in non-small cell lung cancer and its relation to prognosis and therapy. Histopathology. 2005;46(2):195–201.

    Article  CAS  PubMed  Google Scholar 

  106. Pelosi G, Pasini F, Sonzogni A, Maffini F, Maisonneuve P, Iannucci A, Terzi A, De Manzoni G, Bresaola E, Viale G. Prognostic implications of neuroendocrine differentiation and hormone production in patients with stage I nonsmall cell lung carcinoma. Cancer. 2003;97(10):2487–97.

    Article  PubMed  Google Scholar 

  107. Sterlacci W, Fiegl M, Hilbe W, Auberger J, Mikuz G, Tzankov A. Clinical relevance of neuroendocrine differentiation in non-small cell lung cancer assessed by immunohistochemistry: a retrospective study on 405 surgically resected cases. Virchows Arch. 2009;455(2):125–32.

    Article  CAS  PubMed  Google Scholar 

  108. Meder L, König K, Ozretić 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. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer. 2016;138(4):927–38.

    Article  CAS  PubMed  Google Scholar 

  109. 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. Best practices recommendations for diagnostic immunohistochemistry in lung cancer. J Thorac Oncol. 2019;14(3):377–407.

    Article  CAS  PubMed  Google Scholar 

  110. 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. 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. 2017;12(2):334–46.

    Article  PubMed  Google Scholar 

  111. Rooper LM, Sharma R, Li QK, Illei PB, Westra WH. 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. 2017;41(11):1561–9.

    Article  PubMed  Google Scholar 

  112. Rekhtman N, Pietanza CM, Sabari J, Montecalvo J, Wang H, Habeeb O, Kadota K, Adusumilli P, Rudin CM, Ladanyi M, Travis WD, Joubert P. Pulmonary large cell neuroendocrine carcinoma with adenocarcinoma-like features: napsin A expression and genomic alterations. Mod Pathol. 2018;31(1):111–21.

    Article  CAS  PubMed  Google Scholar 

  113. Pelosi G, Rossi G, Cavazza A, Righi L, Maisonneuve P, Barbareschi M, Graziano P, Pastorino U, Garassino M, de Braud F, Papotti M. ΔNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol. 2013;21(3):229–39.

    Article  PubMed  CAS  Google Scholar 

  114. Oronsky B, Reid TR, Oronsky A, Carter CA. What’s new in SCLC? Rev Neoplasia. 2017;19(10):842–7.

    Article  CAS  Google Scholar 

  115. Radzikowska E, Głaz P, Roszkowski K. Lung cancer in women: age, smoking, histology, performance status, stage, initial treatment and survival. Population-based study of 20 561 cases. Ann Oncol. 2002;13(7):1087–93.

    Article  CAS  PubMed  Google Scholar 

  116. Abdel-Rahman O. Changing epidemiology of elderly small cell lung cancer patients over the last 40 years; a SEER database analysis. Clin Respir J. 2018;12(3):1093–9.

    Article  PubMed  Google Scholar 

  117. Jiang S, Hao X, Li J, Hu X, Xiao Z, Wang H, Wang Y, Sun Y, Shi Y. Small cell lung cancer in the young: characteristics, diagnosis and outcome data. Clin Respir J. 2019;13(2):98–104.

    Article  CAS  PubMed  Google Scholar 

  118. Pesatori AC, Carugno M, Consonni D, Hung RJ, Papadoupolos A, Landi MT, Brenner H, Müller H, Harris CC, Duell EJ, Andrew AS, McLaughlin JR, Schwartz AG, Wenzlaff AS, Stucker I. Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO). Br J Cancer. 2013;109(7):1954–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Roengvoraphoj O, Eze C, Niyazi M, Li M, Hildebrandt G, Fietkau R, Belka C, Manapov F. Prognostic role of patient gender in limited-disease small-cell lung cancer treated with chemoradiotherapy. Strahlenther Onkol. 2017;193(2):150–5.

    Article  PubMed  Google Scholar 

  120. Shirasawa M, Fukui T, Kusuhara S, Hiyoshi Y, Ishihara M, Kasajima M, Nakahara Y, Otani S, Igawa S, Yokoba M, Mitsufuji H, Kubota M, Katagiri M, Sasaki J, Naoki K. Prognostic significance of the 8th edition of the TNM classification for patients with extensive disease small cell lung cancer. Cancer Manag Res. 2018;10:6039–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Huang R, Wei Y, Hung RJ, Liu G, Su L, Zhang R, Zong X, Zhang ZF, Morgenstern H, Brüske I, Heinrich J, Hong YC, Kim JH, Cote M, Wenzlaff A, Schwartz AG, Stucker I, Mclaughlin J, Marcus MW, Davies MP, Liloglou T, Field JK, Matsuo K, Barnett M, Thornquist M, Goodman G, Wang Y, Chen S, Yang P, Duell EJ, Andrew AS, Lazarus P, Muscat J, Woll P, Horsman J, Teare MD, Flugelman A, Rennert G, Zhang Y, Brenner H, Stegmaier C, van der Heijden EH, Aben K, Kiemeney L, Barros-Dios J, Pérez-Ríos M, Ruano-Ravina A, Caporaso NE, Bertazzi PA, Landi MT, Dai J, Hongbing Shen H, Fernandez-Tardon G, Rodriguez-Suarez M, Tardon A, Christiani DC. Associated links among smoking, chronic obstructive pulmonary disease, and small cell lung cancer: a pooled analysis in the international lung cancer consortium. EBioMedicine. 2015;2(11):1677–85.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Liu X, Lin XJ, Wang CP, Yan KK, Zhao LY, An WX, Liu XD. Association between smoking and p53 mutation in lung cancer: a meta-analysis. Clin Oncol (R Coll Radiol). 2014;26(1):18–24.

    Article  CAS  Google Scholar 

  123. Liu X, Jiang T, Li W, Li X, Zhao C, Shi J, Zhao S, Jia Y, Qiao M, Zhang L, Luo J, Gao G, Zhou F, Wu F, Chen X, He Y, Ren S, Su C, Zhou C. Characterization of never-smoking and its association with clinical outcomes in Chinese patients with small-cell lung cancer. Lung Cancer. 2018;115:109–15.

    Article  PubMed  Google Scholar 

  124. Lüchtenborg M, Riaz SP, Lim E, Page R, Baldwin DR, Jakobsen E, Vedsted P, Lind M, Peake MD, Mellemgaard A, Spicer J, Lang-Lazdunski L, Møller H. Survival of patients with small cell lung cancer undergoing lung resection in England, 1998–2009. Thorax. 2014;69(3):269–73.

    Article  PubMed  Google Scholar 

  125. 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, Klöppel 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. 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. 2018;31(12):1770–86.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Miret M, Horváth-Puhó E, Déruaz-Luyet A, Sørensen HT, Ehrenstein V. Potential paraneoplastic syndromes and selected autoimmune conditions in patients with non-small cell lung cancer and small cell lung cancer: a population-based cohort study. PLoS One. 2017;12(8):e0181564.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Raspotnig M, Vedeler C, Storstein A. Paraneoplastic neurological syndromes in lung cancer patients with or without onconeural antibodies. J Neurol Sci. 2015;348(1-2):41–5.

    Article  CAS  PubMed  Google Scholar 

  128. Gandhi L, Johnson BE. Paraneoplastic syndromes associated with small cell lung cancer. J Natl Compr Canc Netw. 2006;4(6):631–8.

    Article  PubMed  Google Scholar 

  129. Mitchell MD, Aggarwal C, Tsou AY, Torigian DA, Treadwell JR. Imaging for the pretreatment staging of small cell lung cancer: a systematic review. Acad Radiol. 2016;23(8):1047–56.

    Article  PubMed  Google Scholar 

  130. Rusthoven CG, Kavanagh BD. Prophylactic cranial irradiation (PCI) versus active MRI surveillance for small cell lung cancer: the case for equipoise. J Thorac Oncol. 2017;12(12):1746–54.

    Article  PubMed  Google Scholar 

  131. Pinsky PF, Church TR, Izmirlian G, Kramer BS. The National Lung Screening Trial: results stratified by demographics, smoking history, and lung cancer histology. Cancer. 2013;119(22):3976–83.

    Article  PubMed  Google Scholar 

  132. Genestreti G, Bongiovanni A, Burgio MA, Burgio SL, Musto A, Rossi A, Monti M, Scarpi E, Ulivi P, Bravaccini S, Dubini A, Matteucci F, Gavelli G. 111In-Pentetreotide (OctreoScan) scintigraphy in the staging of small-cell lung cancer: its accuracy and prognostic significance. Nucl Med Commun. 2015;36(2):135–42.

    Article  PubMed  Google Scholar 

  133. Strimpakos A, Politi E, Kainis E, Grapsa D, Siolos S, Tsagouli S, Trigidou R, Syrigos K. The clinical significance of cytology versus histology-based diagnosis in small cell lung cancer: a retrospective study. Lung Cancer. 2014;85(2):186–90.

    Article  PubMed  Google Scholar 

  134. Gansler T, Fedewa SA, Lin CC, Jemal A, Ward EM. Variations in cancer centers’ use of cytology for the diagnosis of small cell lung carcinoma in the National Cancer Data Base. Cancer Cytopathol. 2016;124(1):44–52.

    Article  PubMed  Google Scholar 

  135. Metovic J, Righi L, Delsedime L, Volante M, Papotti M. Role of immunocytochemistry in the cytological diagnosis of pulmonary tumors. Acta Cytol. 2019;15:1–14.

    Google Scholar 

  136. Pelosi G, Rodriguez J, Viale G, Rosai J. 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. 2005;29(2):179–87.

    Article  PubMed  Google Scholar 

  137. Nicholson SA, Beasley MB, Brambilla E, Hasleton PS, Colby TV, Sheppard MN, Falk R, Travis WD. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol. 2002;26(9):1184–97.

    Article  PubMed  Google Scholar 

  138. Azzopardi JG. Oat-cell carcinoma of the bronchus. J Pathol Bacteriol. 1959;78:513–9.

    Article  CAS  PubMed  Google Scholar 

  139. Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N, Kato H. Phase II trial of postoperative adjuvant cisplatin and etoposide in patients with completely resected stage I-IIIa small cell lung cancer: the Japan Clinical Oncology Lung Cancer Study Group Trial (JCOG9101). J Thorac Cardiovasc Surg. 2005;129(5):977–83.

    Article  CAS  PubMed  Google Scholar 

  140. Rekhtman N, Pietanza MC, Hellmann MD, Naidoo J, Arora A, Won H, Halpenny DF, Wang H, Tian SK, Litvak AM, Paik PK, Drilon AE, Socci N, Poirier JT, Shen R, Berger MF, Moreira AL, Travis WD, Rudin CM, Ladanyi M. Next-generation sequencing of pulmonary large cell neuroendocrine carcinoma reveals small cell carcinoma-like and non-small cell carcinoma-like subsets. Clin Cancer Res. 2016;22(14):3618–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Müller 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, Altmüller J, Becker C, Nürnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, JD MK, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland Å, Solberg S, Ansén S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sänger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Büttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L, Thomas RK. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9(1):1048.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Sturm N, Rossi G, Lantuéjoul S, Laverrière MH, Papotti M, Brichon PY, Brambilla C, Brambilla E. 34BetaE12 expression along the whole spectrum of neuroendocrine proliferations of the lung, from neuroendocrine cell hyperplasia to small cell carcinoma. Histopathology. 2003;42(2):156–66.

    Article  CAS  PubMed  Google Scholar 

  143. Kontogianni K, Nicholson AG, Butcher D, Sheppard MN. CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact. J Clin Pathol. 2005;58(9):978–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. 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. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer. 2019;19(5):289–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Broers JL, Carney DN, de Ley L, Vooijs GP, Ramaekers FC. Differential expression of intermediate filament proteins distinguishes classic from variant small-cell lung cancer cell lines. Proc Natl Acad Sci U S A. 1985;82(13):4409–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. McColl K, Wildey G, Sakre N, Lipka MB, Behtaj M, Kresak A, Chen Y, Yang M, Velcheti V, Fu P, Dowlati A. Reciprocal expression of INSM1 and YAP1 defines subgroups in small cell lung cancer. Oncotarget. 2017;8(43):73745–56.

    Article  PubMed  PubMed Central  Google Scholar 

  147. Švajdler M, Mezencev R, Šašková B, Ondič O, Mukenšnábl P, Michal M. Triple marker composed of p16, CD56, and TTF1 shows higher sensitivity than INSM1 for diagnosis of pulmonary small cell carcinoma: proposal for a rational immunohistochemical algorithm for diagnosis of small cell carcinoma in small biopsy and cytology specimens. Hum Pathol. 2019;85:58–64.

    Article  PubMed  CAS  Google Scholar 

  148. Kaufmann O, Dietel M. Expression of thyroid transcription factor-1 in pulmonary and extrapulmonary small cell carcinomas and other neuroendocrine carcinomas of various primary sites. Histopathology. 2000;36(5):415–20.

    Article  CAS  PubMed  Google Scholar 

  149. Horie M, Miyashita N, Mattsson JSM, Mikami Y, Sandelin M, Brunnström H, Micke P, Nagase T, Saito A. An integrative transcriptome analysis reveals a functional role for thyroid transcription factor-1 in small cell lung cancer. J Pathol. 2018;246(2):154–65.

    Article  CAS  PubMed  Google Scholar 

  150. Pelosi G, Fabbri A, Bianchi F, Maisonneuve P, Rossi G, Barbareschi M, Graziano P, Cavazza A, Rekhtman N, Pastorino U, Scanagatta P, Papotti M. ΔNp63 (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. 2012;7(2):281–90.

    Article  PubMed  Google Scholar 

  151. Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, Hong SM, Schwartz BE, Cameron MJ, Rubin MA, Chang MC, Aster JC, French CA. Diagnosis of NUT midline carcinoma using a NUT-specific monoclonal antibody. Am J Surg Pathol. 2009;33(7):984–91.

    Article  PubMed  PubMed Central  Google Scholar 

  152. Sholl LM, Nishino M, Pokharel S, Mino-Kenudson M, French CA, Janne PA, Lathan C. Primary pulmonary NUT midline carcinoma: clinical, radiographic, and pathologic characterizations. J Thorac Oncol. 2015;10(6):951–9.

    Article  PubMed  PubMed Central  Google Scholar 

  153. Bari MF, Brown H, Nicholson AG, Kerr KM, Gosney JR, Wallace WA, Soomro I, Muller S, Peat D, Moore JD, Ward LA, Freidin MB, Lim E, Vatish M, Snead DR. BAI3, CDX2 and VIL1: a panel of three antibodies to distinguish small cell from large cell neuroendocrine lung carcinomas. Histopathology. 2014;64(4):547–56.

    Article  PubMed  Google Scholar 

  154. Dosaka-Akita H, Cagle PT, Hiroumi H, Fujita M, Yamashita M, Sharma A, Kawakami Y, Benedict WF. Differential retinoblastoma and p16(INK4A) protein expression in neuroendocrine tumors of the lung. Cancer. 2000;88(3):550–6.

    Article  CAS  PubMed  Google Scholar 

  155. Khalifa M, Hruby G, Ehrlich L, Danjoux C, Perez-Ordoñez B. Combined large cell neuroendocrine carcinoma and spindle cell carcinoma of the lung. Ann Diagn Pathol. 2001;5(4):240–5.

    Article  CAS  PubMed  Google Scholar 

  156. Zhao X, McCutcheon JN, Kallakury B, Chahine JJ, Pratt D, Raffeld M, Chen Y, Wang C, Giaccone G. Combined small cell carcinoma of the lung: is it a single entity? J Thorac Oncol. 2018;13(2):237–45.

    Article  CAS  PubMed  Google Scholar 

  157. Olofson AM, Tafe LJ. A case of a primary lung cancer comprised of adenocarcinoma and atypical carcinoid tumor with both components harboring BRAF p.V600E mutation. Exp Mol Pathol. 2018;104(1):26–8.

    Article  CAS  PubMed  Google Scholar 

  158. Shao Y, Zhong DS. Histological transformation after acquired resistance to epidermal growth factor tyrosine kinase inhibitors. Int J Clin Oncol. 2018;23(2):235–42.

    Article  CAS  PubMed  Google Scholar 

  159. Lin MW, Su KY, Su TJ, Chang CC, Lin JW, Lee YH, Yu SL, Chen JS, Hsieh MS. Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer. Lung Cancer. 2018;125:282–90.

    Article  PubMed  Google Scholar 

  160. Volante M, Monica V, Birocco N, Brizzi MP, Busso S, Daniele L, La Rosa S, Righi L, Sapino A, Berruti A, Scagliotti GV, Papotti M. Expression analysis of genes involved in DNA repair or synthesis in mixed neuroendocrine/nonneuroendocrine carcinomas. Neuroendocrinology. 2015;101(2):151–60.

    Article  CAS  PubMed  Google Scholar 

  161. Soga J, Yakuwa Y, Osaka M. Evaluation of 342 cases of mediastinal/thymic carcinoids collected from literature: a comparative study between typical carcinoids and atypical varieties. Ann Thorac Cardiovasc Surg. 1999;5(5):285–92.

    CAS  PubMed  Google Scholar 

  162. Gaur P, Leary C, Yao JC. Thymic neuroendocrine tumors: a SEER database analysis of 160 patients. Ann Surg. 2010;251(6):1117–21.

    Article  PubMed  Google Scholar 

  163. Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, Jaffe ES, Kurrer MO, Marom EM, Moreira AL, Mukai K, Orazi A, Ströbel P. The 2015 World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol. 2015;10(10):1383–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Moran CA, Suster S. Neuroendocrine carcinomas (carcinoid tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol. 2000;114(1):100–10.

    Article  CAS  PubMed  Google Scholar 

  165. de Perrot M, Spiliopoulos A, Fischer S, Totsch M, Keshavjee S. Neuroendocrine carcinoma (carcinoid) of the thymus associated with Cushing’s syndrome. Ann Thorac Surg. 2002;73(2):675–81.

    Article  PubMed  Google Scholar 

  166. Ferolla P, Falchetti A, Filosso P, Tomassetti P, Tamburrano G, Avenia N, Daddi G, Puma F, Ribacchi R, Santeusanio F, Angeletti G, Brandi ML. Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series. J Clin Endocrinol Metab. 2005;90(5):2603–9.

    Article  CAS  PubMed  Google Scholar 

  167. Goudet P, Murat A, Cardot-Bauters C, Emy P, Baudin E, du Boullay Choplin H, Chapuis Y, Kraimps JL, Sadoul JL, Tabarin A, Vergès B, Carnaille B, Niccoli-Sire P, Costa A, Calender A, GTE Network (Groupe des Tumeurs Endocrines). Thymic neuroendocrine tumors in multiple endocrine neoplasia type 1: a comparative study on 21 cases among a series of 761 MEN1 from the GTE (Groupe des Tumeurs Endocrines). World J Surg. 2009;33(6):1197–207.

    Article  PubMed  Google Scholar 

  168. Christakis I, Qiu W, Silva Figueroa AM, Hyde S, Cote GJ, Busaidy NL, Williams M, Grubbs E, Lee JE, Perrier ND. Clinical features, treatments, and outcomes of patients with thymic carcinoids and multiple endocrine neoplasia type 1 syndrome at MD Anderson Cancer Center. Horm Cancer. 2016;7(4):279–87.

    Article  CAS  PubMed  Google Scholar 

  169. Kamp K, Alwani RA, Korpershoek E, Franssen GJ, de Herder WW, Feelders RA. Prevalence and clinical features of the ectopic ACTH syndrome in patients with gastroenteropancreatic and thoracic neuroendocrine tumors. Eur J Endocrinol. 2016;174(3):271–80.

    Article  CAS  PubMed  Google Scholar 

  170. Yoshikawa T, Noguchi Y, Matsukawa H, Kondo J, Matsumoto A, Nakatani Y, Kitamura H, Ito T. Thymus carcinoid producing parathyroid hormone (PTH)-related protein: report of a case. Surg Today. 1994;24(6):544–7.

    Article  CAS  PubMed  Google Scholar 

  171. Jansson JO, Svensson J, Bengtsson BA, Frohman LA, Ahlman H, Wängberg B, Nilsson O, Nilsson M. Acromegaly and Cushing’s syndrome due to ectopic production of GHRH and ACTH by a thymic carcinoid tumour: in vitro responses to GHRH and GHRP-6. Clin Endocrinol (Oxf). 1998;48(2):243–50.

    Article  CAS  Google Scholar 

  172. Davis M, Ravenel JG. Paraneoplastic limbic encephalitis due to thymic carcinoid. J Thorac Oncol. 2008;3(12):1484–6.

    Article  PubMed  Google Scholar 

  173. Fratalia L, Larner AJ. Late onset myasthenia gravis and carcinoid tumour: paraneoplastic syndrome? Br J Hosp Med (Lond). 2017;78(10):588–9.

    Article  CAS  Google Scholar 

  174. Wang DY, Kuo SH, Chang DB, Yang PC, Lee YC, Hsu HC, Luh KT. Fine needle aspiration cytology of thymic carcinoid tumor. Acta Cytol. 1995;39(3):423–7.

    CAS  PubMed  Google Scholar 

  175. Zhao Y, Gu H, Fan L, Han K, Yang J, Zhao H. Comparison of clinical features and survival between thymic carcinoma and thymic carcinoid patients. Eur J Cardiothorac Surg. 2017;52(1):33–8.

    Article  PubMed  Google Scholar 

  176. Weissferdt A, Kalhor N, Liu H, Rodriguez J, Fujimoto J, Tang X, Wistuba II, Moran CA. Thymic neuroendocrine tumors (paraganglioma and carcinoid tumors): a comparative immunohistochemical study of 46 cases. Hum Pathol. 2014;45(12):2463–70.

    Article  PubMed  Google Scholar 

  177. Moran CA, Suster S. Angiomatoid neuroendocrine carcinoma of the thymus: report of a distinctive morphological variant of neuroendocrine tumor of the thymus resembling a vascular neoplasm. Hum Pathol. 1999;30(6):635–9.

    Article  CAS  PubMed  Google Scholar 

  178. 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. 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. 2017;471(1):31–47.

    Article  CAS  PubMed  Google Scholar 

  179. Hishima T, Fukayama M, Hayashi Y, Fujii T, Arai K, Shiozawa Y, Funata N, Koike M. Neuroendocrine differentiation in thymic epithelial tumors with special reference to thymic carcinoma and atypical thymoma. Hum Pathol. 1998;29(4):330–8.

    Article  CAS  PubMed  Google Scholar 

  180. Weissferdt A, Tang X, Wistuba II, Moran CA. Comparative immunohistochemical analysis of pulmonary and thymic neuroendocrine carcinomas using PAX8 and TTF-1. Mod Pathol. 2013;26(12):1554–60.

    Article  CAS  PubMed  Google Scholar 

  181. Moll UM, Lane BL, Robert F, Geenen V, Legros JJ. The neuroendocrine thymus. Abundant occurrence of oxytocin-, vasopressin-, and neurophysin-like peptides in epithelial cells. Histochemistry. 1988;89(4):385–90.

    Article  CAS  PubMed  Google Scholar 

  182. Geenen V, Bodart G, Henry S, Michaux H, Dardenne O, Charlet-Renard C, Martens H, Hober D. Programming of neuroendocrine self in the thymus and its defect in the development of neuroendocrine autoimmunity. Front Neurosci. 2013;7:187.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Batanero E, de Leeuw FE, Jansen GH, van Wichen DF, Huber J, Schuurman HJ. The neural and neuro-endocrine component of the human thymus. II. Hormone immunoreactivity. Brain Behav Immun. 1992;6(3):249–64.

    Article  CAS  PubMed  Google Scholar 

  184. Lauriola L, Erlandson RA, Rosai J. Neuroendocrine differentiation is a common feature of thymic carcinoma. Am J Surg Pathol. 1998;22(9):1059–66.

    Article  CAS  PubMed  Google Scholar 

  185. Lauriola L, Maggiano N, Serra FG, Nori S, Tardio ML, Capelli A, Piantelli M, Ranelletti FO. Immunohistochemical and in situ hybridization detection of growth-hormone-producing cells in human thymoma. Am J Pathol. 1997;151(1):55–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Paties C, Zangrandi A, Vassallo G, Rindi G, Solcia E. Multidirectional carcinoma of the thymus with neuroendocrine and sarcomatoid components and carcinoid syndrome. Pathol Res Pract. 1991;187(2–3):170–7.

    Article  CAS  PubMed  Google Scholar 

  187. Moran CA, Suster S. Thymic neuroendocrine carcinomas with combined features ranging from well-differentiated (carcinoid) to small cell carcinoma. A clinicopathologic and immunohistochemical study of 11 cases. Am J Clin Pathol. 2000;113(3):345–50.

    Article  CAS  PubMed  Google Scholar 

  188. Lecomte P, Binquet C, Le Bras M, Tabarin A, Cardot-Bauters C, Borson-Chazot F, Lombard-Bohas C, Baudin E, Delemer B, Klein M, Vergès B, Aparicio T, Cosson E, Beckers A, Caron P, Chabre O, Chanson P, Du Boullay H, Guilhem I, Niccoli P, Rohmer V, Guigay J, Vulpoi C, Scoazec JY, Goudet P. Histologically proven bronchial neuroendocrine tumors in MEN1: a GTE 51-case cohort study. World J Surg. 2018;42(1):143–52.

    Article  CAS  PubMed  Google Scholar 

  189. Oliveira AM, Tazelaar HD, Wentzlaff KA, Kosugi NS, Hai N, Benson A, Miller DL, Yang P. Familial pulmonary carcinoid tumors. Cancer. 2001;91(11):2104–9.

    Article  CAS  PubMed  Google Scholar 

  190. Thevenon J, Bourredjem A, Faivre L, Cardot-Bauters C, Calender A, Le Bras M, Giraud S, Niccoli P, Odou MF, Borson-Chazot F, Barlier A, Lombard-Bohas C, Clauser E, Tabarin A, Pasmant E, Chabre O, Castermans E, Ruszniewski P, Bertherat J, Delemer B, Christin-Maitre S, Beckers A, Guilhem I, Rohmer V, Goichot B, Caron P, Baudin E, Chanson P, Groussin L, Du Boullay H, Weryha G, Lecomte P, Schillo F, Bihan H, Archambeaud F, Kerlan V, Bourcigaux N, Kuhn JM, Vergès B, Rodier M, Renard M, Sadoul JL, Binquet C, Goudet P. Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study. Eur J Endocrinol. 2015;173(6):819–26.

    Article  CAS  PubMed  Google Scholar 

  191. Kamilaris CDC, Stratakis CA. Multiple endocrine neoplasia type 1 (MEN1): an update and the significance of early genetic and clinical diagnosis. Front Endocrinol (Lausanne). 2019;10:339.

    Article  Google Scholar 

  192. Zhang C, Yang AI, Vasconcelos L, Moon S, Yang C, Nesvick CL, Saidkhodjaeva L, Abdullaev Z, Pack SD, Ghosh A, Chittiboina P, Heiss JD, Zhuang Z, Quezado MM, Zaghloul KA. Von Hippel-Lindau disease associated pulmonary carcinoid with cranial metastasis. J Clin Endocrinol Metab. 2014;99(8):2633–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Mathew P, Roberts JA, Zwischenberger J, Haque AK. Mediastinal atypical carcinoid and neurofibromatosis type 1. Arch Pathol Lab Med. 2000;124(2):319–21.

    Article  CAS  PubMed  Google Scholar 

  194. Zhang Z, Wang M. PI3K/AKT/mTOR pathway in pulmonary carcinoid tumours. Oncol Lett. 2017;14(2):1373–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  195. Debelenko LV, Swalwell JI, Kelley MJ, Brambilla E, Manickam P, Baibakov G, Agarwal SK, Spiegel AM, Marx SJ, Chandrasekharappa SC, Collins FS, Travis WD, Emmert-Buck MR. MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chromosomes Cancer. 2000;28(1):58–65.

    Article  CAS  PubMed  Google Scholar 

  196. 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. 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. 2017;241(4):488–500.

    Article  CAS  PubMed  Google Scholar 

  197. Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretić L, Seidal D, Zander T, Leenders F, George J, Müller C, Dahmen I, Pinther B, Bosco G, Konrad K, Altmüller J, Nürnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soltermann A, Brustugun OT, Helland Å, Solberg S, Lund-Iversen M, Ansén 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. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014;5:3518.

    Article  PubMed  CAS  Google Scholar 

  198. George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G, Leenders F, Lu X, Fernández-Cuesta L, Bosco G, Müller 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, Pützer B, Bos M, Michels S, Vlasic I, Seidel D, Pinther B, Schaub P, Becker C, Altmüller 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, Castaños-Vélez E, Roz L, Pastorino U, Brustugun OT, Lund-Iversen M, Thunnissen E, Köhler J, Schuler M, Botling J, Sandelin M, Sanchez-Cespedes M, Salvesen HB, Achter V, Lang U, Bogus M, Schneider PM, Zander T, Ansén S, Hallek M, Wolf J, Vingron M, Yatabe Y, Travis WD, Nürnberg P, Reinhardt C, Perner S, Heukamp L, Büttner R, Haas SA, Brambilla E, Peifer M, Sage J, Thomas RK. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524(7563):47–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. 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. Gene expression profiling of lung atypical carcinoids and large cell neuroendocrine carcinomas identifies three transcriptomic subtypes with specific genomic alterations. J Thorac Oncol. 2019;14(9):1651–61.

    Article  CAS  PubMed  Google Scholar 

  200. Mollaoglu G, Guthrie MR, Böhm S, Brägelmann J, Can I, Ballieu PM, Marx A, George J, Heinen C, Chalishazar MD, Cheng H, Ireland AS, Denning KE, Mukhopadhyay A, Vahrenkamp JM, Berrett KC, Mosbruger TL, Wang J, Kohan JL, Salama ME, Witt BL, Peifer M, Thomas RK, Gertz J, Johnson JE, Gazdar AF, Wechsler-Reya RJ, Sos ML, Oliver TG. MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to aurora kinase inhibition. Cancer Cell. 2017;31(2):270–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Lim JS, Ibaseta A, Fischer MM, Cancilla B, O’Young G, Cristea S, Luca VC, Yang D, Jahchan NS, Hamard C, Antoine M, Wislez M, Kong C, Cain J, Liu YW, Kapoun AM, Garcia KC, Hoey T, Murriel CL, Sage J. Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature. 2017;545(7654):360–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Saber A, Hiltermann TJN, Kok K, Terpstra MM, de Lange K, Timens W, Groen HJM, van den Berg A. Mutation patterns in small cell and non-small cell lung cancer patients suggest a different level of heterogeneity between primary and metastatic tumors. Carcinogenesis. 2017;38(2):144–51.

    CAS  PubMed  Google Scholar 

  203. Pelosi G, Fumagalli C, Trubia M, Sonzogni A, Rekhtman N, Maisonneuve P, Galetta D, Spaggiari L, Veronesi G, Scarpa A, Malpeli G, Viale G. Dual role of RASSF1 as a tumor suppressor and an oncogene in neuroendocrine tumors of the lung. Anticancer Res. 2010;30(10):4269–81.

    CAS  PubMed  Google Scholar 

  204. Chaussade L, Eymin B, Brambilla E, Gazzeri S. Expression of p15 and p15.5 products in neuroendocrine lung tumours: relationship with p15(INK4b) methylation status. Oncogene. 2001;20(45):6587–96.

    Article  CAS  PubMed  Google Scholar 

  205. Li F, Ye B, Hong L, Xu H, Fishbein MC. Epigenetic modifications of histone h4 in lung neuroendocrine tumors. Appl Immunohistochem Mol Morphol. 2011;19(5):389–94.

    Article  CAS  PubMed  Google Scholar 

  206. Rapa I, Votta A, Felice B, Righi L, Giorcelli J, Scarpa A, Speel EJ, Scagliotti GV, Papotti M, Volante M. Identification of MicroRNAs differentially expressed in lung carcinoid subtypes and progression. Neuroendocrinology. 2015;101(3):246–55.

    Article  CAS  PubMed  Google Scholar 

  207. Pan CC, Jong YJ, Chen YJ. Comparative genomic hybridization analysis of thymic neuroendocrine tumors. Mod Pathol. 2005;18(3):358–64.

    Article  CAS  PubMed  Google Scholar 

  208. Ströbel P, Zettl A, Shilo K, Chuang WY, Nicholson AG, Matsuno Y, Gal A, Laeng RH, Engel P, Capella C, Marino M, Chan JK, Rosenwald A, Travis W, Franks TJ, Ellenberger D, Schaefer IM, Marx A. Tumor genetics and survival of thymic neuroendocrine neoplasms: a multi-institutional clinicopathologic study. Genes Chromosomes Cancer. 2014;53(9):738–49.

    Article  PubMed  CAS  Google Scholar 

  209. Dinter H, Bohnenberger H, Beck J, Bornemann-Kolatzki K, Schütz E, Küffer S, Klein L, Franks TJ, Roden A, Emmert A, Hinterthaner M, Marino M, Brcic L, Popper H, Weis CA, Pelosi G, Marx A, Ströbel P. Molecular classification of neuroendocrine tumors of the thymus. J Thorac Oncol. 2019;14(8):1472–83.

    Article  CAS  PubMed  Google Scholar 

  210. Hubaux R, Thu KL, Coe BP, MacAulay C, Lam S, Lam WL. EZH2 promotes E2F-driven SCLC tumorigenesis through modulation of apoptosis and cell-cycle regulation. J Thorac Oncol. 2013;8(8):1102–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. 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. 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. 2018;472(4):567–77.

    Article  PubMed  Google Scholar 

  212. Pelosi G, Massa F, Gatti G, Righi L, Volante M, Birocco N, Maisonneuve P, Sonzogni A, Harari S, Albini A, Papotti M. Ki-67 evaluation for clinical decision in metastatic lung carcinoids: a proof of concept. Clin Pathol. 2019;12:2632010X19829259.

    Article  PubMed  PubMed Central  Google Scholar 

  213. Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG, Ohrling K, Birkemeyer E, Thiis-Evensen E, Biagini M, Gronbaek H, Soveri LM, Olsen IH, Federspiel B, Assmus J, Janson ET, Knigge U. Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Ann Oncol. 2013;24(1):152–60.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Oncology, Aou San Luigi and University of Turin, Orbassano, Turin, Italy

    Marco Volante

  2. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Giuseppe Pelosi

  3. Inter-hospital Pathology Division, Science & Technology Park, IRCCS MultiMedica, Milan, Italy

    Giuseppe Pelosi

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  1. Marco Volante
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  1. University Hospitals Cleveland Medical Center, Case Western Reserve University, Cleveland, OH, USA

    Sylvia L. Asa

  2. Institute of Pathology, University Hospital of Lausanne, Lausanne, Vaud, Switzerland

    Stefano La Rosa

  3. Department of Pathology, University Health Network, Toronto, ON, Canada

    Ozgur Mete

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Volante, M., Pelosi, G. (2021). Thoracic (Lung/Thymus) Neuroendocrine Neoplasms. In: Asa, S.L., La Rosa, S., Mete, O. (eds) The Spectrum of Neuroendocrine Neoplasia. Springer, Cham. https://doi.org/10.1007/978-3-030-54391-4_9

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