Endocrine Pathology

, Volume 25, Issue 2, pp 151–164

Unraveling Tumor Grading and Genomic Landscape in Lung Neuroendocrine Tumors

  • Giuseppe Pelosi
  • Mauro Papotti
  • Guido Rindi
  • Aldo Scarpa
Article

Abstract

Currently, grading in lung neuroendocrine tumors (NETs) is inherently defined by the histological classification based on cell features, mitosis count, and necrosis, for which typical carcinoids (TC) are low-grade malignant tumors with long life expectation, atypical carcinoids (AC) intermediate-grade malignant tumors with more aggressive clinical behavior, and large cell NE carcinomas (LCNEC) and small cell lung carcinomas (SCLC) high-grade malignant tumors with dismal prognosis. While Ki-67 antigen labeling index, highlighting the proportion of proliferating tumor cells, has largely been used in digestive NETs for assessing prognosis and assisting therapy decisions, the same marker does not play an established role in the diagnosis, grading, and prognosis of lung NETs. Next generation sequencing techniques (NGS), thanks to their astonishing ability to process in a shorter timeframe up to billions of DNA strands, are radically revolutionizing our approach to diagnosis and therapy of tumors, including lung cancer. When applied to single genes, panels of genes, exome, or the whole genome by using either frozen or paraffin tissues, NGS techniques increase our understanding of cancer, thus realizing the bases of precision medicine. Data are emerging that TC and AC are mainly altered in chromatin remodeling genes, whereas LCNEC and SCLC are also mutated in cell cycle checkpoint and cell differentiation regulators. A common denominator to all lung NETs is a deregulation of cell proliferation, which represents a biological rationale for morphologic (mitoses and necrosis) and molecular (Ki-67 antigen) parameters to successfully serve as predictors of tumor behavior (i.e., identification of pathological entities with clinical correlation). It is envisaged that a novel grading system in lung NETs based on the combined assessment of mitoses, necrosis, and Ki-67 LI may offer a better stratification of prognostic classes, realizing a bridge between molecular alterations, morphological features, and clinical behavior.

Keywords

Lung Neuroendocrine Tumors Carcinoma Carcinoid Typical Atypical LCNEC SCLC Grading Next generation sequencing Cell cycle Chromatin Remodeling Prognosis Survival 

References

  1. 1.
    Travis W, Brambilla E, Muller-Hermelink H, Harris C (2004) Tumours of the lung, pleura, thymus and heart. IARC Press, Lyon.Google Scholar
  2. 2.
    Franks TJ, Galvin JR (2008) Lung tumors with neuroendocrine morphology: essential radiologic and pathologic features. Arch Pathol Lab Med 132: 1055–1061.PubMedGoogle Scholar
  3. 3.
    Travis WD, Rush W, Flieder DB, Falk R, Fleming MV, Gal AA, Koss MN (1998) Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 22: 934–944.PubMedGoogle Scholar
  4. 4.
    Travis WD, Linnoila RI, Tsokos MG, Hitchcock CL, Cutler GB, Jr., Nieman L, Chrousos G, Pass H, Doppman J (1991) 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 15: 529–553.PubMedGoogle Scholar
  5. 5.
    Asamura H, Kameya T, Matsuno Y, Noguchi M, Tada H, Ishikawa Y, Yokose T, Jiang SX, Inoue T, Nakagawa K, Tajima K, Nagai K (2006) Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 24: 70–76.PubMedGoogle Scholar
  6. 6.
    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: 548–555.PubMedGoogle Scholar
  7. 7.
    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: 1–16.PubMedGoogle Scholar
  8. 8.
    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: 466–472.PubMedGoogle Scholar
  9. 9.
    Beasley MB, Thunnissen FB, Brambilla E, Hasleton P, Steele R, Hammar SP, Colby TV, Sheppard M, Shimosato Y, Koss MN, Falk R, Travis WD (2000) Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 31: 1255–1265.PubMedGoogle Scholar
  10. 10.
    Filosso PL, Rena O, Donati G, Casadio C, Ruffini E, Papalia E, Oliaro A, Maggi G (2002) Bronchial carcinoid tumors: surgical management and long-term outcome. J Thorac Cardiovasc Surg 123: 303–309.PubMedGoogle Scholar
  11. 11.
    Filosso PL, Ruffini E, Di Gangi S, Guerrera F, Bora G, Ciccone G, Galassi C, Solidoro P, Lyberis P, Oliaro A, Sandri A (2013) Prognostic factors in neuroendocrine tumours of the lung: a single-centre experience. Eur J Cardiothorac Surg 45:521–526.PubMedGoogle Scholar
  12. 12.
    Garcia-Yuste M, Matilla JM, Alvarez-Gago T, Duque JL, Heras F, Cerezal LJ, Ramos G (2000) Prognostic factors in neuroendocrine lung tumors: a Spanish Multicenter Study. Spanish Multicenter Study of Neuroendocrine Tumors of the Lung of the Spanish Society of Pneumonology and Thoracic Surgery (EMETNE-SEPAR). Ann Thorac Surg 70: 258–263.PubMedGoogle Scholar
  13. 13.
    Garcia-Yuste M, Matilla JM, Cueto A, Paniagua JM, Ramos G, Canizares MA, Muguruza I (2007) Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung. Eur J Cardiothorac Surg 31: 192–197.PubMedGoogle Scholar
  14. 14.
    den Bakker MA, Willemsen S, Grunberg K, Noorduijn LA, van Oosterhout MF, van Suylen RJ, Timens W, Vrugt B, Wiersma-van Tilburg A, Thunnissen FB (2010) Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability. Histopathology 56: 356–363.Google Scholar
  15. 15.
    Ha SY, Han J, Kim WS, Suh BS, Roh MS (2012) Interobserver variability in diagnosing high-grade neuroendocrine carcinoma of the lung and comparing it with the morphometric analysis. Korean J Pathol 46: 42–47.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Iyoda A, Hiroshima K, Nakatani Y, Fujisawa T (2007) Pulmonary large cell neuroendocrine carcinoma: its place in the spectrum of pulmonary carcinoma. Ann Thorac Surg 84: 702–707.PubMedGoogle Scholar
  17. 17.
    Marchevsky AM, Gal AA, Shah S, Koss MN (2001) 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 116: 466–472.PubMedGoogle Scholar
  18. 18.
    Huang Q, Muzitansky A, Mark EJ (2002) Pulmonary neuroendocrine carcinomas. A review of 234 cases and a statistical analysis of 50 cases treated at one institution using a simple clinicopathologic classification. Arch Pathol Lab Med 126: 545–553.PubMedGoogle Scholar
  19. 19.
    Moran CA, Suster S, Coppola D, Wick MR (2009) Neuroendocrine carcinomas of the lung: a critical analysis. Am J Clin Pathol 131: 206–221.PubMedGoogle Scholar
  20. 20.
    Axiotis C. The neuroendocrine lung. In: Li Volsi V, Asa S, editors. Endocrine Pathology. New York Edinburgh: Churchill Livingstone; 2002. p. 261–296.Google Scholar
  21. 21.
    Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN (1998) Reproducibility of neuroendocrine lung tumor classification. Hum Pathol 29: 272–279.PubMedGoogle Scholar
  22. 22.
    Veronesi G, Morandi U, Alloisio M, Terzi A, Cardillo G, Filosso P, Rea F, Facciolo F, Pelosi G, Gandini S, Calabro F, Casali C, Marulli G, Spaggiari L (2006) Large cell neuroendocrine carcinoma of the lung: a retrospective analysis of 144 surgical cases. Lung Cancer 53: 111–115.PubMedGoogle Scholar
  23. 23.
    Grand B, Cazes A, Mordant P, Foucault C, Dujon A, Guillevin EF, Barthes Fle P, Riquet M (2013) High grade neuroendocrine lung tumors: pathological characteristics, surgical management and prognostic implications. Lung Cancer 81: 404–409.PubMedGoogle Scholar
  24. 24.
    Niemiec J, Adamczyk A, Malecki K, Ambicka A, Rys J (2013) Tumor grade and matrix metalloproteinase 2 expression in stromal fibroblasts help to stratify the high-risk group of patients with early breast cancer identified on the basis of st Gallen recommendations. Clin Breast Cancer 13: 119–128.PubMedGoogle Scholar
  25. 25.
    Zumsteg ZS, Spratt DE, Pei I, Zhang Z, Yamada Y, Kollmeier M, Zelefsky MJ (2013) A new risk classification system for therapeutic decision making with intermediate-risk prostate cancer patients undergoing dose-escalated external-beam radiation therapy. Eur Urol 64: 895–902.PubMedGoogle Scholar
  26. 26.
    Procopio G, Verzoni E, Iacovelli R, Biasoni D, Testa I, Porcu L, De Braud F (2012) Prognostic factors for survival in patients with metastatic renal cell carcinoma treated with targeted therapies. Br J Cancer 107: 1227–1232.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Ueno H, Hase K, Hashiguchi Y, Shimazaki H, Tanaka M, Miyake O, Masaki T, Shimada Y, Kinugasa Y, Mori Y, Kishimoto M, Kameoka S, Sato Y, Matsuda K, Nakadoi K, Shinto E, Nakamura T, Sugihara K (2014) Site-specific Tumor Grading System in Colorectal Cancer: Multicenter Pathologic Review of the Value of Quantifying Poorly Differentiated Clusters. Am J Surg Pathol 38: 197–204.PubMedGoogle Scholar
  28. 28.
    Capelle L, Fontaine D, Mandonnet E, Taillandier L, Golmard JL, Bauchet L, Pallud J, Peruzzi P, Baron MH, Kujas M, Guyotat J, Guillevin R, Frenay M, Taillibert S, Colin P, Rigau V, Vandenbos F, Pinelli C, Duffau H (2013) Spontaneous and therapeutic prognostic factors in adult hemispheric World Health Organization Grade II gliomas: a series of 1097 cases: clinical article. J Neurosurg 118: 1157–1168.PubMedGoogle Scholar
  29. 29.
    Travis WD1, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D (2011) International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6: 244–285PubMedGoogle Scholar
  30. 30.
    Kadota K, Suzuki K, Kachala SS, Zabor EC, Sima CS, Moreira AL, Yoshizawa A, Riely GJ, Rusch VW, Adusumilli PS, Travis WD (2012) A grading system combining architectural features and mitotic count predicts recurrence in stage I lung adenocarcinoma. Mod Pathol 25: 1117–1127.PubMedGoogle Scholar
  31. 31.
    Sica G, Yoshizawa A, Sima CS, Azzoli CG, Downey RJ, Rusch VW, Travis WD, Moreira AL (2010) A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. Am J Surg Pathol 34: 1155–1162.PubMedGoogle Scholar
  32. 32.
    von der Thusen JH, Tham YS, Pattenden H, Rice A, Dusmet M, Lim E, Nicholson AG (2013) Prognostic significance of predominant histologic pattern and nuclear grade in resected adenocarcinoma of the lung: potential parameters for a grading system. J Thorac Oncol 8: 37–44.PubMedGoogle Scholar
  33. 33.
    Kadota K, Colovos C, Suzuki K, Rizk NP, Dunphy MP, Zabor EC, Sima CS, Yoshizawa A, Travis WD, Rusch VW, Adusumilli PS (2012) FDG-PET SUVmax combined with IASLC/ATS/ERS histologic classification improves the prognostic stratification of patients with stage I lung adenocarcinoma. Ann Surg Oncol 19: 3598–3605.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Cerilli LA, Ritter JH, Mills SE, Wick MR (2001) Neuroendocrine neoplasms of the lung. Am J Clin Pathol 116 Suppl: S65-96.PubMedGoogle Scholar
  35. 35.
    Wick MR (2000) Neuroendocrine neoplasia. Current concepts. Am J Clin Pathol 113: 331–335.PubMedGoogle Scholar
  36. 36.
    Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G (1994) Revised classification of neuroendocrine tumors of the lung, pancreas and gut. Digestion 55 Suppl 3: 11–23.PubMedGoogle Scholar
  37. 37.
    Capella C, Heitz PU, Hofler H, Solcia E, Kloppel G (1995) Revised classification of neuroendocrine tumours of the lung, pancreas and gut. Virchows Arch 425: 547–560.PubMedGoogle Scholar
  38. 38.
    Stadler ZK, Schrader KA, Vijai J, Robson ME, Offit K (2014) Cancer Genomics and Inherited Risk. J Clin Oncol 32:687–98.PubMedGoogle Scholar
  39. 39.
    Hagemann IS, Cottrell CE, Lockwood CM (2013) Design of targeted, capture-based, next generation sequencing tests for precision cancer therapy. Cancer Genet 206:420–431.PubMedGoogle Scholar
  40. 40.
    Hawkins RD, Hon GC, Ren B (2010) Next-generation genomics: an integrative approach. Nat Rev Genet 11: 476–486.PubMedCentralPubMedGoogle Scholar
  41. 41.
    Watson IR, Takahashi K, Futreal PA, Chin L (2013) Emerging patterns of somatic mutations in cancer. Nat Rev Genet 14: 703–718.PubMedCentralPubMedGoogle Scholar
  42. 42.
    Sanger F, Nicklen S, Coulson AR (1977) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A 74: 5463–5467.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Rossi G, Graziano P, Leone A, Migaldi M, Califano R (2013) The role of molecular analyses in the diagnosis and treatment of non-small-cell lung carcinomas. Semin Diagn Pathol 30: 298–312.PubMedGoogle Scholar
  44. 44.
    Chen Y, Shi JX, Pan XF, Feng J, Zhao H (2013) Identification of candidate genes for lung cancer somatic mutation test kits. Genet Mol Biol 36: 455–464.PubMedCentralPubMedGoogle Scholar
  45. 45.
    Daniels MG, Bowman RV, Yang IA, Govindan R, Fong KM (2013) An emerging place for lung cancer genomics in 2013. J Thorac Dis 5: S491-S497.PubMedCentralPubMedGoogle Scholar
  46. 46.
    Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling DJ, Watson M, Mardis ER, Wilson RK (2012) Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150: 1121–1134.PubMedCentralPubMedGoogle Scholar
  47. 47.
    Imielinski M, Berger AH, Hammerman PS, Hernandez B, Pugh TJ, Hodis E, Cho J, Suh J, Capelletti M, Sivachenko A, Sougnez C, Auclair D, Lawrence MS, Stojanov P, Cibulskis K, Choi K, de Waal L, Sharifnia T, Brooks A, Greulich H, Banerji S, Zander T, Seidel D, Leenders F, Ansen S, Ludwig C, Engel-Riedel W, Stoelben E, Wolf J, Goparju C, Thompson K, Winckler W, Kwiatkowski D, Johnson BE, Janne PA, Miller VA, Pao W, Travis WD, Pass HI, Gabriel SB, Lander ES, Thomas RK, Garraway LA, Getz G, Meyerson M (2012) Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150: 1107–1120.PubMedCentralPubMedGoogle Scholar
  48. 48.
    Kim SC, Jung Y, Park J, Cho S, Seo C, Kim J, Kim P, Seo J, Park S, Jang I, Kim N, Yang JO, Lee B, Rho K, Keum J, Lee J, Han J, Kang S, Bae S, Choi SJ, Kim S, Lee JE, Kim W, Lee S (2013) A high-dimensional, deep-sequencing study of lung adenocarcinoma in female never-smokers. PLoS One 8: e55596.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Li T, Kung HJ, Mack PC, Gandara DR (2013) Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies. J Clin Oncol 31: 1039–1049.PubMedCentralPubMedGoogle Scholar
  50. 50.
    Liu J, Lee W, Jiang Z, Chen Z, Jhunjhunwala S, Haverty PM, Gnad F, Guan Y, Gilbert HN, Stinson J, Klijn C, Guillory J, Bhatt D, Vartanian S, Walter K, Chan J, Holcomb T, Dijkgraaf P, Johnson S, Koeman J, Minna JD, Gazdar AF, Stern HM, Hoeflich KP, Wu TD, Settleman J, de Sauvage FJ, Gentleman RC, Neve RM, Stokoe D, Modrusan Z, Seshagiri S, Shames DS, Zhang Z (2012) Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Res 22: 2315–2327.PubMedCentralPubMedGoogle Scholar
  51. 51.
    Cancer Genome Atlas Research Network (Hammerman PS, Lawrence MS, Voet D, Jing R, Cibulskis K, Sivachenko A, Stojanov P, McKenna A, Lander ES, Gabriel S, Getz G, Sougnez C, Imielinski M, Helman E, Hernandez B, Pho NH, Meyerson M, Chu A, Chun HJ, Mungall AJ, Pleasance E, Robertson A, Sipahimalani P, Stoll D, Balasundaram M, Birol I, Butterfield YS, Chuah E, Coope RJ, Corbett R, Dhalla N, Guin R, He A, Hirst C, Hirst M, Holt RA, Lee D, Li HI, Mayo M, Moore RA, Mungall K, Nip KM, Olshen A, Schein JE, Slobodan JR, Tam A, Thiessen N, Varhol R, Zeng T, Zhao Y, Jones SJ, Marra MA, Saksena G, Cherniack AD, Schumacher SE, Tabak B, Carter SL, Pho NH, Nguyen H, Onofrio RC, Crenshaw A, Ardlie K, Beroukhim R, Winckler W, Hammerman PS, Getz G, Meyerson M, Protopopov A, Zhang J, Hadjipanayis A, Lee S, Xi R, Yang L, Ren X, Zhang H, Shukla S, Chen PC, Haseley P, Lee E, Chin L, Park PJ, Kucherlapati R, Socci ND, Liang Y, Schultz N, Borsu L, Lash AE, Viale A, Sander C, Ladanyi M, Auman T, Hoadley KA, Wilkerson MD, Shi Y, Liquori C, Meng S, Li L, Turman YJ, Topal MD, Tan D, Waring S, Buda E, Walsh J, Jones CD, Mieczkowski PA, Singh D, Wu J, Gulabani A, Dolina P, Bodenheimer T, Hoyle AP, Simons JV, Soloway MG, Mose LE, Jefferys SR, Balu S, O’Connor BD, Prins JF, Liu J, Chiang DY, Hayes D, Perou CM, Cope L, Danilova L, Weisenberger DJ, Maglinte DT, Pan F, Van Den Berg DJ, Triche T Jr, Herman JG, Baylin SB, Laird PW, Getz G, Noble M, Voet D, Saksena G, Gehlenborg N, DiCara D, Zhang J, Zhang H, Wu CJ, Liu SY, Lawrence MS, Zou L, Sivachenko A, Lin P, Stojanov P, Jing R, Cho J, Nazaire MD, Robinson J, Thorvaldsdottir H, Mesirov J, Park PJ, Chin L, Schultz N, Sinha R, Ciriello G, Cerami E, Gross B, Jacobsen A, Gao J, Aksoy B, Weinhold N, Ramirez R, Taylor BS, Antipin Y, Reva B, Shen R, Mo Q, Seshan V, Paik PK, Ladanyi M, Sander C, Akbani R, Zhang N, Broom BM, Casasent T, Unruh A, Wakefield C, Cason R, Baggerly KA, Weinstein JN, Haussler D, Benz CC, Stuart JM, Zhu J, Szeto C, Scott GK, Yau C, Ng S, Goldstein T, Waltman P, Sokolov A, Ellrott K, Collisson EA, Zerbino D, Wilks C, Ma S, Craft B, Wilkerson MD, Auman J, Hoadley KA, Du Y, Cabanski C, Walter V, Singh D, Wu J, Gulabani A, Bodenheimer T, Hoyle AP, Simons JV, Soloway MG, Mose LE, Jefferys SR, Balu S, Marron J, Liu Y, Wang K, Liu J, Prins JF, Hayes D, Perou CM, Creighton CJ, Zhang Y, Travis WD, Rekhtman N, Yi J, Aubry MC, Cheney R, Dacic S, Flieder D, Funkhouser W, Illei P, Myers J, Tsao MS, Penny R, Mallery D, Shelton T, Hatfield M, Morris S, Yena P, Shelton C, Sherman M, Paulauskis J, Meyerson M, Baylin SB, Govindan R, Akbani R, Azodo I, Beer D, Bose R, Byers LA, Carbone D, Chang LW, Chiang D, Chu A, Chun E, Collisson E, Cope L, Creighton CJ, Danilova L, Ding L, Getz G, Hammerman PS, Hayes D, Hernandez B, Herman JG, Heymach J, Ida C, Imielinski M, Johnson B, Jurisica I, Kaufman J, Kosari F, Kucherlapati R, Kwiatkowski D, Ladanyi M, Lawrence MS, Maher CA, Mungall A, Ng S, Pao W, Peifer M, Penny R, Robertson G, Rusch V, Sander C, Schultz N, Shen R, Siegfried J, Sinha R, Sivachenko A, Sougnez C, Stoll D, Stuart J, Thomas RK, Tomaszek S, Tsao MS, Travis WD, Vaske C, Weinstein JN, Weisenberger D, Wheeler D, Wigle DA, Wilkerson MD, Wilks C, Yang P, Zhang JJ, Jensen MA, Sfeir R, Kahn AB, Chu AL, Kothiyal P, Wang Z, Snyder EE, Pontius J, Pihl TD, Ayala B, Backus M, Walton J, Baboud J, Berton DL, Nicholls MC, Srinivasan D, Raman R, Girshik S, Kigonya PA, Alonso S, Sanbhadti RN, Barletta SP, Greene JM, Pot DA, Tsao MS, Bandarchi-Chamkhaleh B, Boyd J, Weaver J, Wigle DA, Azodo IA, Tomaszek SC, Aubry MC, Ida CM, Yang P, Kosari F, Brock MV, Rodgers K, Rutledge M, Brown T, Lee B, Shin J, Trusty D, Dhir R, Siegfried JM, Potapova O, Fedosenko KV, Nemirovich-Danchenko E, Rusch V, Zakowski M, Iacocca MV, Brown J, Rabeno B, Czerwinski C, Petrelli N, Fan Z, Todaro N, Eckman J, Myers J, Rathmell W, Thorne LB, Huang M, Boice L, Hill A, Penny R, Mallery D, Curley E, Shelton C, Yena P, Morrison C, Gaudioso C, Bartlett JM, Kodeeswaran S, Zanke B, Sekhon H, David K, Juhl H, Van Le X, Kohl B, Thorp R, Nguyen VT, Nguyen VB, Sussman H, Phu BD, Hajek R, Nguyen PH, Khan KZ, Muley T, Shaw KR, Sheth M, Yang L, Buetow K, Davidsen T, Demchok JA, Eley G, Ferguson M, Dillon LA, Schaefer C, Guyer MS, Ozenberger BA, Palchik JD, Peterson J, Sofia HJ, Thomson E ) (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489: 519–525.Google Scholar
  52. 52.
    Stead LF, Egan P, Devery A, Conway C, Daly C, Berri S, Wood H, Belvedere O, Papagiannopoulos K, Ryan A, Rabbitts P (2013) An integrated inspection of the somatic mutations in a lung squamous cell carcinoma using next-generation sequencing. PLoS One 8: e78823.PubMedCentralPubMedGoogle Scholar
  53. 53.
    Wu K, Huang RS, House L, Cho WC (2013) Next-generation sequencing for lung cancer. Future Oncol 9: 1323–1336.PubMedGoogle Scholar
  54. 54.
    Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba, II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455: 1069–1075.PubMedCentralPubMedGoogle Scholar
  55. 55.
    Marchetti A, Del Grammastro M, Filice G, Felicioni L, Rossi G, Graziano P, Sartori G, Leone A, Malatesta S, Iacono M, Guetti L, Viola P, Mucilli F, Cuccurullo F, Buttitta F (2012) Complex mutations & subpopulations of deletions at exon 19 of EGFR in NSCLC revealed by next generation sequencing: potential clinical implications. PLoS One 7: e42164.PubMedCentralPubMedGoogle Scholar
  56. 56.
    Lee W, Jiang Z, Liu J, Haverty PM, Guan Y, Stinson J, Yue P, Zhang Y, Pant KP, Bhatt D, Ha C, Johnson S, Kennemer MI, Mohan S, Nazarenko I, Watanabe C, Sparks AB, Shames DS, Gentleman R, de Sauvage FJ, Stern H, Pandita A, Ballinger DG, Drmanac R, Modrusan Z, Seshagiri S, Zhang Z (2010) The mutation spectrum revealed by paired genome sequences from a lung cancer patient. Nature 465: 473–477.PubMedGoogle Scholar
  57. 57.
    Lazar V, Suo C, Orear C, van den Oord J, Balogh Z, Guegan J, Job B, Meurice G, Ripoche H, Calza S, Hasmats J, Lundeberg J, Lacroix L, Vielh P, Dufour F, Lehtio J, Napieralski R, Eggermont A, Schmitt M, Cadranel J, Besse B, Girard P, Blackhall F, Validire P, Soria JC, Dessen P, Hansson J, Pawitan Y (2013) Integrated molecular portrait of non-small cell lung cancers. BMC Med Genomics 6: 53.PubMedGoogle Scholar
  58. 58.
    Scarpa A, Sikora K, Fassan M, Rachiglio AM, Cappellesso R, Antonello D, Amato E, Mafficini A, Lambiase M, Esposito C, Bria E, Simonato F, Scardoni M, Turri G, Chilosi M, Tortora G, Fassina A, Normanno N (2013) Molecular typing of lung adenocarcinoma on cytological samples using a multigene next generation sequencing panel. PLoS One 8: e80478.PubMedCentralPubMedGoogle Scholar
  59. 59.
    de Biase D, Visani M, Malapelle U, Simonato F, Cesari V, Bellevicine C, Pession A, Troncone G, Fassina A, Tallini G (2013) Next-Generation Sequencing of Lung Cancer EGFR Exons 18–21 Allows Effective Molecular Diagnosis of Small Routine Samples (Cytology and Biopsy). PLoS One 8: e83607.PubMedCentralPubMedGoogle Scholar
  60. 60.
    Crowley E, Di Nicolantonio F, Loupakis F, Bardelli A (2013) Liquid biopsy: monitoring cancer-genetics in the blood. Nat Rev Clin Oncol 10: 472–484.PubMedGoogle Scholar
  61. 61.
    Moskalev EA, Stohr R, Rieker R, Hebele S, Fuchs F, Sirbu H, Mastitsky SE, Boltze C, Konig H, Agaimy A, Hartmann A, Haller F (2013) Increased detection rates of EGFR and KRAS mutations in NSCLC specimens with low tumour cell content by 454 deep sequencing. Virchows Arch 462: 409–419.PubMedCentralPubMedGoogle Scholar
  62. 62.
    Tuononen K, Maki-Nevala S, Sarhadi VK, Wirtanen A, Ronty M, Salmenkivi K, Andrews JM, Telaranta-Keerie AI, Hannula S, Lagstrom S, Ellonen P, Knuuttila A, Knuutila S (2013) Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutations on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma-superiority of NGS. Genes Chromosomes Cancer 52: 503–511.PubMedGoogle Scholar
  63. 63.
    Luchini C, Capelli P, Fassan M, Simbolo M, Mafficini A, Pedica F, Ruzzenente A, Guglielmi A, Corbo V, Scarpa A (2014) Next-Generation Histopathologic Diagnosis: A Lesson From a Hepatic Carcinosarcoma. J Clin Oncol doi:10.1200/JCO.2012.47.5855; published online ahead of print at www.jco.org on February 3, 2014
  64. 64.
    Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, Kim YT, Kim JI, Kang JH, Seo JS (2012) A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 22: 436–445.PubMedCentralPubMedGoogle Scholar
  65. 65.
    Majewski IJ, Mittempergher L, Davidson NM, Bosma A, Willems SM, Horlings HM, de Rink I, Greger L, Hooijer GK, Peters D, Nederlof PM, Hofland I, de Jong J, Wesseling J, Kluin RJ, Brugman W, Kerkhoven R, Nieboer F, Roepman P, Broeks A, Muley TR, Jassem J, Niklinski J, van Zandwijk N, Brazma A, Oshlack A, van den Heuvel M, Bernards R (2013) Identification of recurrent FGFR3 fusion genes in lung cancer through kinome-centred RNA sequencing. J Pathol 230: 270–276.PubMedGoogle Scholar
  66. 66.
    Jia P, Jin H, Meador CB, Xia J, Ohashi K, Liu L, Pirazzoli V, Dahlman KB, Politi K, Michor F, Zhao Z, Pao W (2013) Next-generation sequencing of paired tyrosine kinase inhibitor-sensitive and -resistant EGFR mutant lung cancer cell lines identifies spectrum of DNA changes associated with drug resistance. Genome Res 23: 1434–1445.PubMedCentralPubMedGoogle Scholar
  67. 67.
    Huang D, Kim DW, Kotsakis A, Deng S, Lira P, Ho SN, Lee NV, Vizcarra P, Cao JQ, Christensen JG, Kim TM, Sun JM, Ahn JS, Ahn MJ, Park K, Mao M (2013) Multiplexed deep sequencing analysis of ALK kinase domain identifies resistance mutations in relapsed patients following crizotinib treatment. Genomics 102: 157–162.PubMedGoogle Scholar
  68. 68.
    Bosman F, Carneiro F, Hruban R, Theise N (2010) WHO classification of tumours of the digestive system. IARC Press, Lyon.Google Scholar
  69. 69.
    Rindi G, Falconi M, Klersy C, Albarello L, Boninsegna L, Buchler MW, Capella C, Caplin M, Couvelard A, Doglioni C, Delle Fave G, Fischer L, Fusai G, de Herder WW, Jann H, Komminoth P, de Krijger RR, La Rosa S, Luong TV, Pape U, Perren A, Ruszniewski P, Scarpa A, Schmitt A, Solcia E, Wiedenmann B (2012) TNM staging of neoplasms of the endocrine pancreas: results from a large international cohort study. J Natl Cancer Inst 104: 764–777.PubMedGoogle Scholar
  70. 70.
    Yang Z, Tang LH, Klimstra DS (2013) Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues. Semin Diagn Pathol 30: 186–196.PubMedGoogle Scholar
  71. 71.
    Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (2010) The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 39: 707–712.PubMedGoogle Scholar
  72. 72.
    Travis W, Colby T, Corrin B, Shimosato Y, Brambilla E (1999) Histological typing of lung and pleural tumours. Springer Verlag, Berlin Heidelberg New York.Google Scholar
  73. 73.
    Jones MH, Virtanen C, Honjoh D, Miyoshi T, Satoh Y, Okumura S, Nakagawa K, Nomura H, Ishikawa Y (2004) 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 363: 775–781.PubMedGoogle Scholar
  74. 74.
    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: 1184–1197.PubMedGoogle Scholar
  75. 75.
    Tsuchiya R, Suzuki K, Ichinose Y, Watanabe Y, Yasumitsu T, Ishizuka N, Kato H (2005) 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 129: 977–983.PubMedGoogle Scholar
  76. 76.
    Brock MV, Hooker CM, Syphard JE, Westra W, Xu L, Alberg AJ, Mason D, Baylin SB, Herman JG, Yung RC, Brahmer J, Rudin CM, Ettinger DS, Yang SC (2005) Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come. J Thorac Cardiovasc Surg 129: 64–72.PubMedGoogle Scholar
  77. 77.
    Rea F, Callegaro D, Favaretto A, Loy M, Paccagnella A, Fantoni U, Festi G, Sartori F (1998) Long term results of surgery and chemotherapy in small cell lung cancer. Eur J Cardiothorac Surg 14: 398–402.PubMedGoogle Scholar
  78. 78.
    Bastrurk O, Yang Z, Tang L, Hruban R, McCall C, Adsay V, Krasinkas A, Jang K-T, Bellizzi A, Shi C, Klimstra D (2013) Increased (>20%) Ki-67 proliferation index in morphologically well differentiated pancreatic neuroendocrine tumors (PanNETs) correlates with decreased overall survival (abstract #1761). Mod Pathol 26: 423A.Google Scholar
  79. 79.
    Basturk O, Tang L, Hruban RH, Adsay V, Yang Z, Krasinskas AM, Vakiani E, La Rosa S, Jang KT, Frankel WL, Liu X, Zhang L, Giordano TJ, Bellizzi AM, Chen JH, Shi C, Allen P, Reidy DL, Wolfgang CL, Saka B, Rezaee N, Deshpande V, Klimstra DS (2014) Poorly Differentiated Neuroendocrine Carcinomas of the Pancreas: A Clinicopathologic Analysis of 44 Cases. Am J Surg Pathol 38:437–447.PubMedGoogle Scholar
  80. 80.
    Oberg K, Knigge U, Kwekkeboom D, Perren A (2012) Neuroendocrine gastro-entero-pancreatic tumors: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23 Suppl 7: vii124-130.PubMedGoogle Scholar
  81. 81.
    Tsutsumi K, Ohtsuka T, Fujino M, Nakashima H, Aishima S, Ueda J, Takahata S, Nakamura M, Oda Y, Tanaka M (2013) Analysis of risk factors for recurrence after curative resection of well-differentiated pancreatic neuroendocrine tumors based on the new grading classification. J Hepatobiliary Pancreat Sci Oct 20. doi:10.1002/jhbp.47. [Epub ahead of print]
  82. 82.
    Welin S, Sorbye H, Sebjornsen S, Knappskog S, Busch C, Oberg K (2011) Clinical effect of temozolomide-based chemotherapy in poorly differentiated endocrine carcinoma after progression on first-line chemotherapy. Cancer 117: 4617–4622.PubMedGoogle Scholar
  83. 83.
    Klimstra DS, Modlin IR, Adsay NV, Chetty R, Deshpande V, Gonen M, Jensen RT, Kidd M, Kulke MH, Lloyd RV, Moran C, Moss SF, Oberg K, O’Toole D, Rindi G, Robert ME, Suster S, Tang LH, Tzen CY, Washington MK, Wiedenmann B, Yao J (2010) Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 34: 300–313.PubMedGoogle Scholar
  84. 84.
    Moran CA, Suster S (2007) Neuroendocrine carcinomas (carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma): current concepts. Hematol Oncol Clin North Am 21: 395–407; vii.PubMedGoogle Scholar
  85. 85.
    Pelosi G, Rindi G, Travis WD, Papotti M (2014) Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol 9: 273–284.PubMedGoogle Scholar
  86. 86.
    Pelosi G, Bresaola E, Bogina G, Pasini F, Rodella S, Castelli P, Iacono C, Serio G, Zamboni G (1996) Endocrine tumors of the pancreas: Ki-67 immunoreactivity on paraffin sections is an independent predictor for malignancy: a comparative study with proliferating-cell nuclear antigen and progesterone receptor protein immunostaining, mitotic index, and other clinicopathologic variables. Hum Pathol 27: 1124–1134.PubMedGoogle Scholar
  87. 87.
    Pelosi G, Zamboni G (1996) Proliferation Markers and Their Uses in the Study of Endocrine Tumors. Endocr Pathol 7: 103–119.PubMedGoogle Scholar
  88. 88.
    Pelosi G, Zamboni G, Doglioni C, Rodella S, Bresaola E, Iacono C, Serio G, Iannucci A, Scarpa A (1992) Immunodetection of proliferating cell nuclear antigen assesses the growth fraction and predicts malignancy in endocrine tumors of the pancreas. Am J Surg Pathol 16: 1215–1225.PubMedGoogle Scholar
  89. 89.
    Morin E, Cheng S, Mete O, Serra S, Araujo PB, Temple S, Cleary S, Gallinger S, Greig PD, McGilvray I, Wei A, Asa SL, Ezzat S (2013) Hormone profiling, WHO 2010 grading, and AJCC/UICC staging in pancreatic neuroendocrine tumor behavior. Cancer Med 2: 701–711.PubMedCentralPubMedGoogle Scholar
  90. 90.
    Fernandez-Figueras MT, Puig L, Musulen E, Gilaberte M, Ferrandiz C, Lerma E, Ariza A (2005) Prognostic significance of p27Kip1, p45Skp2 and Ki67 expression profiles in Merkel cell carcinoma, extracutaneous small cell carcinoma, and cutaneous squamous cell carcinoma. Histopathology 46: 614–621.PubMedGoogle Scholar
  91. 91.
    Han B, Sun JM, Ahn JS, Park K, Ahn MJ (2013) Clinical outcomes of atypical carcinoid tumors of the lung and thymus: 7-year experience of a rare malignancy at single institute. Med Oncol 30: 479.PubMedGoogle Scholar
  92. 92.
    Rindi G, Kloppel G, Alhman H, Caplin M, Couvelard A, de Herder WW, Erikssson B, Falchetti A, Falconi M, Komminoth P, Korner M, Lopes JM, McNicol AM, Nilsson O, Perren A, Scarpa A, Scoazec JY, Wiedenmann B (2006) TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449: 395–401.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Zahel T, Krysa S, Herpel E, Stenzinger A, Goeppert B, Schirmacher P, Hoffmann H, Schnabel PA, Warth A (2012) Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch 460: 299–308.PubMedGoogle Scholar
  94. 94.
    Grimaldi F, Muser D, Beltrami CA, Machin P, Morelli A, Pizzolitto S, Talmassons G, Marciello F, Colao AA, Monaco R, Monaco G, Faggiano A (2011) Partitioning of bronchopulmonary carcinoids in two different prognostic categories by ki-67 score. Front Endocrinol (Lausanne) Vol. 2, Article 20, Pages 1–6Google Scholar
  95. 95.
    Costes V, Marty-Ane C, Picot MC, Serre I, Pujol JL, Mary H, Baldet P (1995) Typical and atypical bronchopulmonary carcinoid tumors: a clinicopathologic and KI-67-labeling study. Hum Pathol 26: 740–745.PubMedGoogle Scholar
  96. 96.
    Rugge M, Fassan M, Clemente R, Rizzardi G, Giacomelli L, Pennelli G, Mescoli C, Segat D, Rea F (2008) Bronchopulmonary carcinoid: phenotype and long-term outcome in a single-institution series of Italian patients. Clin Cancer Res 14: 149–154.PubMedGoogle Scholar
  97. 97.
    Walts AE, Ines D, Marchevsky AM (2012) Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol 25: 1258–1264.PubMedGoogle Scholar
  98. 98.
    Granberg D, Wilander E, Oberg K, Skogseid B (2000) Prognostic markers in patients with typical bronchial carcinoid tumors. J Clin Endocrinol Metab 85: 3425–3430.PubMedGoogle Scholar
  99. 99.
    Helpap B, Kollermann J (2001) Immunohistochemical analysis of the proliferative activity of neuroendocrine tumors from various organs. Are there indications for a neuroendocrine tumor-carcinoma sequence? Virchows Arch 438: 86–91.PubMedGoogle Scholar
  100. 100.
    Igarashi T, Jiang SX, Kameya T, Asamura H, Sato Y, Nagai K, Okayasu I (2004) Divergent cyclin B1 expression and Rb/p16/cyclin D1 pathway aberrations among pulmonary neuroendocrine tumors. Mod Pathol 17: 1259–1267.PubMedGoogle Scholar
  101. 101.
    Laitinen KL, Soini Y, Mattila J, Paakko P (2000) Atypical bronchopulmonary carcinoids show a tendency toward increased apoptotic and proliferative activity. Cancer 88: 1590–1598.PubMedGoogle Scholar
  102. 102.
    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: 179–187.PubMedGoogle Scholar
  103. 103.
    Skov BG, Holm B, Erreboe A, Skov T, Mellemgaard A (2010) ERCC1 and Ki67 in small cell lung carcinoma and other neuroendocrine tumors of the lung: distribution and impact on survival. J Thorac Oncol 5: 453–459.PubMedGoogle Scholar
  104. 104.
    Warth A, Fink L, Fisseler-Eckhoff A, Jonigk D, Keller M, Ott G, Rieker RJ, Sinn P, Soder S, Soltermann A, Willenbrock K, Weichert W (2013) Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids. Virchows Arch 462: 507–513.PubMedGoogle Scholar
  105. 105.
    McCall CM, Shi C, Cornish TC, Klimstra DS, Tang LH, Basturk O, Mun LJ, Ellison TA, Wolfgang CL, Choti MA, Schulick RD, Edil BH, Hruban RH (2013) Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 37: 1671–1677.PubMedGoogle Scholar
  106. 106.
    Clinical Lung Cancer Genome Project (CLCGP); Network Genomic Medicine (NGM) (Seidel D, Zander T, Heukamp LC, Peifer M, Bos M, Fernández-Cuesta L, Leenders F, Lu X, Ansén S, Gardizi M, Nguyen C, Berg J, Russell P, Wainer Z, Schildhaus HU, Rogers TM, Solomon B, Pao W, Carter SL, Getz G, Hayes D, Wilkerson MD, Thunnissen E, Travis WD, Perner S, Wright G, Brambilla E, Büttner R, Wolf J, Thomas RK, Gabler F, Wilkening I, Müller C, Dahmen I, Menon R, König K, Albus K, Merkelbach-Bruse S, Fassunke J, Schmitz K, Kuenstlinger H, Kleine MA, Binot E, Querings S, Altmüller J, Bäßmann I, Nürnberg P, Schneider PM, Bogus M, Büttner R, Perner S, Russell P, Thunnissen E, Travis WD, Brambilla E, Soltermann A, Moch H, Brustugun OT, Solberg S, Lund-Iversen M, Helland Å, Muley T, Hoffmann H, Schnabel PA, Chen Y, Groen H, Timens W, Sietsma H, Clement JH, Weder W, Sänger J, Stoelben E, Ludwig C, Engel-Riedel W, Smit E, Heideman DA, Snijders PJ, Nogova L, Sos ML, Mattonet C, Töpelt K, Scheffler M, Goekkurt E, Kappes R, Krüger S, Kambartel K, Behringer D, Schulte W, Galetke W, Randerath W, Heldwein M, Schlesinger A, Serke M, Hekmat K, Frank KF, Schnell R, Reiser M, Hünerlitürkoglu AN, Schmitz S, Meffert L, Ko YD, Litt-Lampe M, Gerigk U, Fricke R, Besse B, Brambilla C, Lantuejoul S, Lorimier P, Moro-Sibilot D, Cappuzzo F, Ligorio C, Damiani S, Field JK, Hyde R, Validire P, Girard P, Muscarella LA, Fazio VM, Hallek M, Soria JC, Carter SL, Getz G, Hayes D, Wilkerson MD, Achter V, Lang U, Seidel D, Zander T, Heukamp LC, Peifer M, Bos M, Pao W, Travis WD, Brambilla E, Büttner R, Wolf J, Thomas RK, Büttner R, Wolf J, Thomas RK) (2013). A genomics-based classification of human lung tumors. Sci Transl Med 5: 209ra153.Google Scholar
  107. 107.
    Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretić L, Seidel 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 A, 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 CM, 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 5:3518. doi:10.1038/ncomms4518.PubMedGoogle Scholar
  108. 108.
    Iwakawa R, Takenaka M, Kohno T, Shimada Y, Totoki Y, Shibata T, Tsuta K, Nishikawa R, Noguchi M, Sato-Otsubo A, Ogawa S, Yokota J (2013) Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer. Genes Chromosomes Cancer 52: 802–816.PubMedCentralPubMedGoogle Scholar
  109. 109.
    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: 1104–1110.PubMedGoogle Scholar
  110. 110.
    Rudin CM, Durinck S, Stawiski EW, Poirier JT, Modrusan Z, Shames DS, Bergbower EA, Guan Y, Shin J, Guillory J, Rivers CS, Foo CK, Bhatt D, Stinson J, Gnad F, Haverty PM, Gentleman R, Chaudhuri S, Janakiraman V, Jaiswal BS, Parikh C, Yuan W, Zhang Z, Koeppen H, Wu TD, Stern HM, Yauch RL, Huffman KE, Paskulin DD, Illei PB, Varella-Garcia M, Gazdar AF, de Sauvage FJ, Bourgon R, Minna JD, Brock MV, Seshagiri S (2012) Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44: 1111–1116.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Karpathakis A, Dibra H, Thirlwell C (2013) Neuroendocrine tumours: cracking the epigenetic code. Endocr Relat Cancer 20: R65-82.PubMedGoogle Scholar
  112. 112.
    Chadwick LH (2012) The NIH Roadmap Epigenomics Program data resource. Epigenomics 4: 317–324.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Swarts DR, Ramaekers FC, Speel EJ (2012) Molecular and cellular biology of neuroendocrine lung tumors: Evidence for separate biological entities. Biochim Biophys Acta 1826: 255–271.PubMedGoogle Scholar
  114. 114.
    Cakir M, Grossman A (2011) The molecular pathogenesis and management of bronchial carcinoids. Expert Opin Ther Targets 15: 457–491.PubMedGoogle Scholar
  115. 115.
    Navin N, Kendall J, Troge J, Andrews P, Rodgers L, McIndoo J, Cook K, Stepansky A, Levy D, Esposito D, Muthuswamy L, Krasnitz A, McCombie WR, Hicks J, Wigler M (2011) Tumour evolution inferred by single-cell sequencing. Nature 472: 90–94.PubMedGoogle Scholar
  116. 116.
    Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS, Ritchey JK, Young MA, Lamprecht T, McLellan MD, McMichael JF, Wallis JW, Lu C, Shen D, Harris CC, Dooling DJ, Fulton RS, Fulton LL, Chen K, Schmidt H, Kalicki-Veizer J, Magrini VJ, Cook L, McGrath SD, Vickery TL, Wendl MC, Heath S, Watson MA, Link DC, Tomasson MH, Shannon WD, Payton JE, Kulkarni S, Westervelt P, Walter MJ, Graubert TA, Mardis ER, Wilson RK, DiPersio JF (2012) Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481: 506–510.PubMedCentralPubMedGoogle Scholar
  117. 117.
    Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366: 883–892.PubMedGoogle Scholar
  118. 118.
    Proskuryakov SY, Gabai VL (2010) Mechanisms of tumor cell necrosis. Curr Pharm Des 16: 56–68.PubMedGoogle Scholar
  119. 119.
    Francis JM, Kiezun A, Ramos AH, Serra S, Pedamallu CS, Qian ZR, Banck MS, Kanwar R, Kulkarni AA, Karpathakis A, Manzo V, Contractor T, Philips J, Nickerson E, Pho N, Hooshmand SM, Brais LK, Lawrence MS, Pugh T, McKenna A, Sivachenko A, Cibulskis K, Carter SL, Ojesina AI, Freeman S, Jones RT, Voet D, Saksena G, Auclair D, Onofrio R, Shefler E, Sougnez C, Grimsby J, Green L, Lennon N, Meyer T, Caplin M, Chung DC, Beutler AS, Ogino S, Thirlwell C, Shivdasani R, Asa SL, Harris CR, Getz G, Kulke M, Meyerson M (2013) Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 45: 1483–1486.PubMedGoogle Scholar
  120. 120.
    Papadopoulos A, Guida F, Leffondre K, Cenee S, Cyr D, Schmaus A, Radoi L, Paget-Bailly S, Carton M, Menvielle G, Woronoff AS, Tretarre B, Luce D, Stucker I (2014) Heavy smoking and lung cancer: Are women at higher risk? Result of the ICARE study. Br J Cancer 110: 1385–1391.PubMedGoogle Scholar
  121. 121.
    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: 136–142.PubMedGoogle Scholar
  122. 122.
    Swarts DR, Claessen SM, Jonkers YM, van Suylen RJ, Dingemans AM, de Herder WW, de Krijger RR, Smit EF, Thunnissen FB, Seldenrijk CA, Vink A, Perren A, Ramaekers FC, Speel EJ (2011) Deletions of 11q22.3-q25 are associated with atypical lung carcinoids and poor clinical outcome. Am J Pathol 179: 1129–1137.PubMedCentralPubMedGoogle Scholar
  123. 123.
    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: E374-378.PubMedGoogle Scholar
  124. 124.
    Marchetti A, Felicioni L, Pelosi G, Del Grammastro M, Fumagalli C, Sciarrotta M, Malatesta S, Chella A, Barassi F, Mucilli F, Camplese P, D’Antuono T, Sacco R, Buttitta F (2008) Frequent mutations in the neurotrophic tyrosine receptor kinase gene family in large cell neuroendocrine carcinoma of the lung. Hum Mutat 29: 609–616.PubMedGoogle Scholar
  125. 125.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, Bergethon K, Shaw AT, Gettinger S, Cosper AK, Akhavanfard S, Heist RS, Temel J, Christensen JG, Wain JC, Lynch TJ, Vernovsky K, Mark EJ, Lanuti M, Iafrate AJ, Mino-Kenudson M, Engelman JA (2011) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 3: 75ra26.PubMedCentralPubMedGoogle Scholar
  126. 126.
    Brambilla E, Moro D, Gazzeri S, Brichon PY, Nagy-Mignotte H, Morel F, Jacrot M, Brambilla C (1991) Cytotoxic chemotherapy induces cell differentiation in small-cell lung carcinoma. J Clin Oncol 9: 50–61.PubMedGoogle Scholar
  127. 127.
    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: 184–190.PubMedCentralPubMedGoogle Scholar
  128. 128.
    George J, Peifer M, Fernandez-Cuesta L, Thomas RK. Comprehensive genome and transcriptome analyses on small cell lung cancer (abstract #1542). AACR Annual Meeting of the American Association of Cancer Research. San Diego (CA); 2014.Google Scholar
  129. 129.
    Coe BP, Lee EH, Chi B, Girard L, Minna JD, Gazdar AF, Lam S, MacAulay C, Lam WL (2006) Gain of a region on 7p22.3, containing MAD1L1, is the most frequent event in small-cell lung cancer cell lines. Genes Chromosomes Cancer 45: 11–19.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Giuseppe Pelosi
    • 1
    • 2
    • 7
  • Mauro Papotti
    • 3
  • Guido Rindi
    • 4
  • Aldo Scarpa
    • 5
    • 6
  1. 1.Department of Pathology and Laboratory MedicineFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  2. 2.Department of Biomedical and Clinical Sciences Luigi SaccoUniversità degli StudiMilanItaly
  3. 3.Department of OncologyUniversità degli Studi of Turin at San Luigi HospitalOrbassanoItaly
  4. 4.Institute of Anatomic PathologyGemelli Hospital and Università Cattolica del Sacro CuoreRomeItaly
  5. 5.Department of Pathology and DiagnosticsUniversità degli StudiVeronaItaly
  6. 6.ARC-NET Research CentreUniversità degli StudiVeronaItaly
  7. 7.Dipartimento di Patologia Diagnostica e LaboratorioFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly

Personalised recommendations