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Pulmonale neuroendokrine Tumoren in der neuen WHO-Klassifikation 2015

Beginn eines Aufbruchs zu „neuen Ufern“?

Pulmonary neuroendocrine tumors in the new WHO 2015 classification

Start of breaking new grounds?

  • Schwerpunkt: Neuroendokrine Tumoren
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Zusammenfassung

Einteilung

In der kürzlich erschienenen 4. Auflage der WHO-Klassifikation von Tumoren der Lunge, der Pleura, des Thymus und des Herzens werden die neuroendokrinen Tumoren der Lunge (pNET) erstmalig in einem Kapitel gemeinsam nach den Adeno- und Plattenepithelkarzinomen sowie vor den großzelligen Karzinomen abgehandelt: High-grade-Tumoren, kleinzellige Lungenkarzinome (SCLC) und großzellige neuroendokrine Karzinome (LCNEC), Intermediate-grade-Tumoren, atypische Karzinoide (AC), Low-grade-Tumoren, typische Karzinoide (TC) und Vorläuferläsionen (DIPNECH). Bisher waren SCLC und Karzinoide jeweils in eigenen Kapiteln, LCNEC dagegen getrennt im Abschnitt der großzelligen Karzinome abgehandelt. Erstmalig gilt die neue WHO-Klassifikation auch für Biopsate.

Diagnostik

Üblicherweise ist allen pNET eine neuroendokrine Morphologie (soweit an kleinen Biopsaten erkennbar) sowie die Expression neuroendokriner (NE-)Marker (Chromogranin A, Synaptophysin, CD56/NCAM) gemeinsam. Der immunhistochemische Nachweis mindestens eines NE-Markers wurde bereits in der 3. Auflage der WHO-Klassifikation von 2004 (für Operationspräparate) nur für LCNEC gefordert. Unterscheidungsmerkmale sind: Eine klein- oder großzellige Zyto-/Histomorphologie, nukleäre Kriterien und die Mitoserate (für SCLC >10, mit einem Median von 80; für LCNEC >10, Median 70; für AC 2 – 10; für TC < 2, jeweils pro 2 mm2). Tumorzellnekrosen kommen meist bei SCLC und LCNEC, teilweise bei AC und nicht bei TC vor. Richtwerte für die Ki67-Proliferationsrate sind nach der neuen WHO-Klassifikation für SCLC 50–100 %, für LCNEC 40–80 %, für AC bis zu 20 % und für TC bis zu 5 %.

Molekularpathologie

Molekulare Alterationen treten jeweils bei SCLC und LCNEC zahlreich und sehr variabel, bei AC und TC wesentlich weniger und ähnlich auf.

Schlussfolgerung

Der direkte Vergleich aller pNET in einem Kapitel erleichtert die (Differenzial-)Diagnostik dieser Tumoren, schafft eine bessere Visibilität v. a. der LCNEC und macht eine weitere umfassende Entwicklung der klinisch-praktischen und wissenschaftlichen Beschäftigung mit pNET möglich und sinnvoll. Obwohl für die Lunge weiterhin eine eigene Terminologie der pNET beibehalten wird, ist doch eine „vorsichtige Annäherung“ an die gepNET festzustellen.

Abstract

Classification

In the recently published 4th edition of the World Health Organization (WHO) classification of tumors of the lungs, pleura, thymus and heart, all neuroendocrine tumors of the lungs (pNET) are presented for the first time in one single chapter following adenocarcinoma and squamous cell carcinoma and before large cell carcinoma. In this classification, high grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low grade typical carcinoids as well as from preinvasive lesions (DIPNECH). In the 3rd WHO classification from 2004, which dealt with resection specimens, SCLC and carcinoids each had a separate chapter and LCNEC was previously listed in the chapter on large cell carcinoma of the lungs. The new WHO classification is for the first time also applicable to lung biopsies.

Diagnostics

Normally, common features of all pNET are a neuroendocrine morphology (as far as detectable in small biopsies) and expression of the neuroendocrine (NE) markers (chromogranin A, synaptophysin and CD56/NCAM). An immunohistochemical positive staining of at least one NE marker was already recommended in the 3rd edition of the WHO classification (2004) only for LCNEC. Differentiating features are a small or large cell cytomorphology/histomorphology, nuclear criteria and the mitotic rate (for SCLC >10 with a median of 80, for LCNEC >10 median 70, for AC 2 - 10, for TC < 2 each per 2 mm2). Tumor cell necrosis usually occurs in SCLC and LCNEC, partially in AC and not in TC. The guideline Ki67 proliferation rates are given for the first time in the new WHO classification for SCLC as 50–100 %, for LCNEC 40–80 %, for AC up to 20 % and for TC up to 5 %.

Molecular pathology

Molecular alterations occur in SCLC and LCNEC in large numbers and are very variable in quality. In AC and TC they occur much less frequently and are relatively similar.

Conclusion

The direct comparison of all pNET in one chapter facilitates the differential diagnostics of these tumors, provides a better transparency especially of LCNEC and allows a further comprehensive development of the clinical practical and scientific evaluation of pNET. Although a separate terminology of pNET is maintained for the lungs, a careful approach towards the gastroentero-pancreatic NET (gepNET) can be observed.

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Literatur

  1. Ampollini L, Carbognani P, Rusca M, Bobbio A (2010) Resection of giant typical carcinoid tumor with cardiopulmonary bypass support. Thorac Cardiov Surg 58:494–502

    Article  Google Scholar 

  2. Beasley MB, Brambilla E, Chirieac LR, Austin JHM, Devesa SS, Hasleton P, Jett J, Marchevsky AM, Nicholson S, Papotti M, Pelosi G, Rami-Porta R, Scagliotti G, Thunnissen E, Travis WD, van Schil P, Yang P (2015) Carcinoid tumor. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Hrsg) WHO Classification of tumors of the lung, pleura, thymus and heart. IARC Press, Lyon, S 73–77

    Google Scholar 

  3. Bohle RM, Kim YJ, Schnabel PA (2015) Lungentumoren – Lehrserie Nr. 221, Internationale Akademie für Pathologie, Deutsche Abteilung e. V.

  4. Brambilla E, Beasley MB, Austin JHM, Capelozzi VL, Chirieac LR, Devesa SS, Frank GA, Gazdar A, Ishikawa Y, Jen J, Jett J, Marchevsky AM, Nicholson S, Pelosi G, Powell CA, Rami-Porta R, Scagliotti G, Thunissen E, Travis WD, van Schil P, Yang P (2015) Small cell carcinoma. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Hrsg) WHO classification of tumors of the lung, pleura, thymus and heart. IARC Press, Lyon, S 63–68

    Google Scholar 

  5. Brambilla E, Beasley MB, Chirieac LR, Austin JHM, Capelozzi VL Devesa SS, Gazdar A, Ishikawa Y, Jett J, Nicholson S, Pelosi G, Powell CA, Rami-Porta R, Riely G, Scagliotti G, Travis WD, van Schil P, Yang P, Yankelevitz D (2015) Large cell neuroendocrine carcinoma. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Hrsg) WHO classification of tumors of the lung, pleura, thymus and heart. IARC Press, Lyon, S 69–72

    Google Scholar 

  6. Brokx HAP, Paul MA, Postmus PE, Sutedja TG (2015) Long-term follow-up after first-line bronchoscopic therapy in patients with bronchial carcinoids. Thorax. (Epüb ahead of print)

  7. Collisson EA, Campbell JD, Brooks AN et al (2014) Comprehensive molecular profiling of lung adenocarcinoma. Cancer Genome Atlas Research Network. Nature 511:543–540

  8. Diakatou E, Alexandri KI, Tsolakis AV, Kontogeorgos G, Chatzellis E, Leonti A, Kaltsas GA (2015) Somatostatin and dopamine receptor expression in neuroendocrine neoplasms; correlation of immunohistochemical findings with somatostatin receptor scintigraphy visual scores. Clin Endocrinol (Oxf.). doi:10.1111/cen.12775. vv

  9. Dong HY, Liu W, Cohen P, Mahle CE, Zhang W (2005) B-cell specific activation protein encoded by the PAX-5 gene is commonly expressed in Merkel cell carcinoma and small cell carcinomas. Am J Surg Pathol 29:687–692

    Article  PubMed  Google Scholar 

  10. Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozrtic 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 MPA, 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

    Article  Google Scholar 

  11. Gazdar AF, Savage TK, Johnson JE, Berns A, Sage J, Linoilla RI, MacPherson D, McFadden DG, Farago A, Jacks T, Travis WD, Brambilla E (2015) The comparative pathology of genetically engineered mouse models for neuroendocrine carcinomas of the lung. J Thorac Oncol 10:553–564

    Article  CAS  PubMed  Google Scholar 

  12. Gosney JR, Austin JHM, Jett J, Nicholson AG, Nicholson S, Rami-Porta R, Travis WD, van Schil P (2015) Preinvasive leason – Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In: Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (Hrsg) WHO Classification of tumors of the lung, pleura, thymus and heart. IARC Press, Lyon, S 78–79

    Google Scholar 

  13. Gottschling S, Jensen K, Herth FJF, Thomas M, Schnabel PA, Herpel E (2013) Lack of prognostic significance of neuroendocrine differentiation and stem cell antigen co-expression in resected early-stage non-small cell lung cancer. Anticancer Res 33:981–990

    PubMed  Google Scholar 

  14. Grohé C (2014) Neuroendokrine Lungentumoren. Pneumologie 68:455–477

    Article  PubMed  Google Scholar 

  15. Hassan MM, Phan A, Li D, Dagohoy CG, Leary C, Yao JC (2008) Risk factors associated with neuroendocrine tumors: A U.S.-based case-control study. Int J Cancer 123:867–873

    Article  CAS  PubMed  Google Scholar 

  16. Helmbold P, Lahtz C, Herpel E, Schnabel PA, Dammann RH (2009) Frequent hypermethylation of RASSF1A tumour suppressor gene promoter and presence of Merkel cell polyomavirus in small cell lung cancer. Eur J Cancer 45:2207–2211

    Article  CAS  PubMed  Google Scholar 

  17. Huwer H, Kalweit G, Schäfer H, Eltze E (2011) Pulmonales Paragangliom: Fallbericht und Literaturübersicht. Pneumologie 65:742–744

    Article  CAS  PubMed  Google Scholar 

  18. Iyoda A, Jiang S-X, Travis WD, Kurouzu N, Ogawa F, Amano H, Sato Y, Rusch VW, Saegusa M, Satoh Y (2013) Clinicopathological features and the impact of the new TNM classification of malignant tumors in patients with pulmonary large cell neuroendocrine carcinoma. Mol Clin Oncol 1:437–443

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Johney EC, Pfannschmidt J, Rieker RJ, Schnabel PA, Mechtersheimer G, Dienemann H (2006) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasio and a typical carcinoid tumor. J Tharac Cardiovasc Surg 131:1207–1208

    Article  Google Scholar 

  20. Junker K, Länger F, Schnabel PA (2013) Update Pneumopathologie – Bericht der AG Pneumopathologie der Deutschen Gesellschaft für Pathologie. Pathologe 34(Suppl 2):304–307

    Article  PubMed  Google Scholar 

  21. Kaemmerer D, Specht E, Sänger J, Wirtz RM, Sayeg M, Schulz S, Lupp A (2015) Somatostatin receptors in bronchopulmonary neuroendocrine neoplasms: new diagnostic, prognostic, and therapeutic markers. J Clin Endocrinol Metab 100:831–840

    Article  CAS  PubMed  Google Scholar 

  22. Kanteti R, Nallasura V, Loganathan S, Tretiakova M, Kroll T, Krishnaswamy S, Faoro L, Cagle P, Husain AN, Vokes EE, Lang D, Salgia R (2009) PAX5 is expressed in small cell lung cancer and positively regulates c-Met transcription. Lab Invest 89:301–314

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Le Treut J, Sault MC, Lena H, Souquet PJ, Vergnenegre A, Le Caer H, Berard H, Boffa S, Monnet I, Damotte D, Chouaid C (2013) Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Ann Oncol 24:1548–1552

    Article  PubMed  Google Scholar 

  24. Mireskandari M, Abdirad A, Zhang Q, Dietel M, Petersen I (2013) Association of small foci of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) with adenocarcinoma of the lung. Path Res Pract 209:578–584

    Article  CAS  PubMed  Google Scholar 

  25. Nenekidis I, Stathopoulos GT, Anagnostakou V, Kokkori A, Dedeilias P, Kokotsakis J, Argiriou M, Zisis C (2011) Atypical pulmonary carcinoid tumour in a 28-year-old nonsmoker with Prader-Willi syndrome. Eur Respir J 38:1230–1233

    Article  CAS  PubMed  Google Scholar 

  26. Peifer M, Fernández-Cuesta L, Sos ML et al (2012) Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet 44:1104–1110

  27. 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

    Article  PubMed  Google Scholar 

  28. Petersen I, Schnabel PA (2011) Neues zur Lungenpathologie. Bericht der Arbeitsgemeinschaft Pneumopathologie der Deutschen Gesellschaft für Pathologie. Pathologe 32 (Suppl 2):351–357

    Article  PubMed  Google Scholar 

  29. Righi L, Volante M, Tavaglione V, Billè 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

    Article  CAS  PubMed  Google Scholar 

  30. Rindi R, Klersy C, Inzani F, Fellegara G, Ampolloni L, Ardizzoni A, Campanini N, Carbognani P, De Pas DM, 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. doi:10.1530/ERC-13-0246

  31. Rossi G, Mengoli MC, Cavazza A, Nicoli D, Barbareschi M, Cantaloni C, Papotti M, Tironi A, Graziano P, Paci M, Stefani A, Migaldi M, Sartori G, Pelosi G (2014) Large cell carcinoma of the lung: clinically oriented classification integrating immunohistochemistry and molecular biology. Virchows Arch 464:61–68

    Article  CAS  PubMed  Google Scholar 

  32. Sachithanandan N, Harle RA, Burgess JR (2005) Bronchopulmonary carcinoid in multiple endocrine neoplasia type 1. Cancer 103:509–515

    Article  PubMed  Google Scholar 

  33. Schnabel PA, Junker K (2014) Neuroendokrine Tumoren der Lunge – Vom kleinzelligen Lungenkarzinom bis zur diffusen idiopathischen pulmonalen neuroendokrinen Zellhyperplasie. Pathologe 35:557–564

    Article  CAS  PubMed  Google Scholar 

  34. Schnabel PA, Petersen I, Junker K (2012) Neueste Aktivitäten in der Pneumopathologie -Bericht der Arbeitgemeinschaft Pneumopathologie der Deutschen Gesellschaft für Pathologie. Pathologe 33(Suppl 2):351–354

    Article  PubMed  Google Scholar 

  35. Schnabel PA, Veith C, Zaharia C, Langer F, Seidel RM, Wehler TC, Bohle RM (2015) Co-occurrence of DIPNECH and of meningotheliosis with a pulmonary adenocarcinoma (pADC) in one lung lobe – Consequences for sampling. (Zur Publikation eingereicht)

  36. Seidel D, Zander T, Heukamp LC  et al (2013) A genomics-based classification of human lung tumors – Clinical Lung Cancer Genome Project (CLCGP); Network Genomic Medicine (NGM). Sci Transl Med 5(209):209ra153

  37. Sica G, Vazquez MF, Altorki N, Port J, Lee PC, Liu Y, Hyjek E, Saqi A (2008) PAX-5 expression in pulmonary neuroendocrine neoplasms. Am J Clin Pathol 129:556–562

    Article  PubMed  Google Scholar 

  38. Song J, Li M, Tretiakova M, Salgia R, Cagle PT, Husain AN (2010) Expression patterns of PAX5, c-MET and Paxillin in neuroendocrine tumors of the lung. Arch Pathol Lab Med 134:1702–1705

    PubMed Central  PubMed  Google Scholar 

  39. Sterlacci W, Fiegl M, Hilbe W, Auberger J, Mikuz G, Tzankov A (2009) Clinical relevance of neuroendocrine differentiation in non-small cell lung cancer assessed by immunohistochemistry: a retrospective study on 405 surgically resected cases. Virchows Arch 455:125–132

    Article  CAS  PubMed  Google Scholar 

  40. Travis WD, Brambilla E, Müller-Hermelink HK et al (2004) Tumors of the Lung, Pleura Thymus and Heart, World Health Organization classification of tumors. Pathology and genetics. IARC Press, Lyon

    Google Scholar 

  41. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) WHO Classification of tumors of the lung, pleura, thymus and heart. IARC Press, Lyon

    Google Scholar 

  42. Travis WD, Brambilla E, Noguchi M et al (2011) International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 6:244–285

    Article  PubMed  Google Scholar 

  43. Thunissen E, Kerr KM, Herth FJF, Lantuejoul S, Papotti M, Rintoul RC, Rossi G, Skov BG, Weynand B, Bubendorf L, Katrien G, Johansson L, López-Rios F, Ninane V, Olzewski W, Popper H, Jaume S, Schnabel PA, Thiberville L, Laenger F (2012) The challenge of NSCLC diagnosis and predictive analysis on small samples. Practical approach of a working group. Lung Cancer 76:1–18

    Article  Google Scholar 

  44. Volante M, Gatti G, Papotti M (2015) Classification of lung neuroendocrine tumors: lights and shadows. Endocrine. (Epub ahead of print)

  45. Walter RF, Mairinger FD, Werner R, Ting S, Vollbrecht C, Theegarten D, Christoph DC, Zarogoulidis K, Werner KW, Zarogoulidis P, Wohlschläger J (2015) SOX4, SOX11 and PAX6 mRNA expression was identified as a (prognostic) marker for the aggressiveness of neuroendocrine tumors of the lung by using next-generation expression analysis (NanoString). Future Oncol 7:1027–1036

    Article  Google Scholar 

  46. Warth A, Endris V, Penzel R, Weichert W (2014) Molecular pathology of lung cancer. State of the art 2014. Pathologe 35:565–573

    Article  CAS  PubMed  Google Scholar 

  47. Warth A, Fink L, Fisseler-Eckhoff A, Jonigk, Keller M, Ott G, Rieker RJ, Sinn P, Söder S, Soltermann A, Willenbrock K, Weichert W, on behalf of the Pulmonary Pathology Working Group of the German Society of Pathology (2013) Interobserver agreement if proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids. Virchows Arch 462:507–513

  48. Warth A, Herpel E, Krysa S, Hoffmann H, Schnabel PA, Schirmacher P, Mechtersheimer G, Bläker H (2009) Chromosomal instability is more frequent in metastasized than in non-metastasized pulmonary carcinoids but is not a reliable predictor of metastatic potential. Exp Mol Med 41:349–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Warth A, Herpel E, Schmähl A, Storz K, Schnabel PA (2008) Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) in association with an adenocarcinoma: a case report. J Medical Case Reprts 2:21–23

    Article  Google Scholar 

  50. Warth A, Krysa S, Zahel T, Hoffmann H, Schirmacher P, Schnabel PA, Herpel E (2010) S100 protein positive sustentacular cells in pulmonary carcinoids and thoracic paragangliomas: differential diagnostic and prognostic evaluation. Pathologe 31:379–384

    Article  CAS  PubMed  Google Scholar 

  51. Zahel T, Krysa S, Herpel E, Stenzinger A, Goeppert B, Schirmacher P, Schnabel PA, Warth A (2012) Phenoptyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch 460:299–308

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Institut für Allgemeine und Spezielle Pathologie, Universitätsklinikum des Saarlandes UKS, Gebäude 26, 66421, Homburg/Saar, Deutschland

    P.A. Schnabel

  2. Zentrum für Pathologie, Klinikum Bremen Mitte, Sankt-Jürgen-Str. 1, 28205, Bremen, Deutschland

    K. Junker

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Schnabel, P., Junker, K. Pulmonale neuroendokrine Tumoren in der neuen WHO-Klassifikation 2015. Pathologe 36, 283–292 (2015). https://doi.org/10.1007/s00292-015-0030-2

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