Нейроэндокринные опухоли легкого: современная классификация и алгоритм морфологической диагностики

Нейроэндокринные опухоли (НЭО) бронхолегочной локализации объединяют одну из наиболее распространенных категорий, входящих в гетерогенную группу нейроэндокринных новообразований человека. Опухоли данного типа часто встречаются в практической диагностической работе морфолога, однако их классификация и гистологическая градация не являются точным повторением подходов, разработанных для НЭО желудочно-кишечного тракта и поджелудочной железы. Номенклатура НЭО легких до сих пор основана на использовании термина «карциноид». В последней классификации опухолей легких Всемирной организации здравоохранения, опубликованной в 2015 г., все НЭО данной локализации впервые представлены в одной общей главе. В соответствии с данной классификационной схемой в группу нейроэндокринных пролиферативных процессов входят карциноидные опухоли (включая типичный и атипичный карциноиды), крупноклеточный нейроэндокринный рак, мелкоклеточный рак легкого и диффузная идиопатическая гиперплазия нейроэндокринных клеток как преинвазивное поражение, которое может предшествовать развитию карциноидных опухолей. Каждый вариант НЭО легких имеет характерные морфологические и иммуногистохимические признаки, которые являются ключевыми критериями для диагностики этих опухолей. Морфологические параметры определения степени злокачественности НЭО легких остались неизменными в новой редакции. Однако имеются противоречивые моменты в отношении роли антигена Ki-67 в системе градации НЭО легких при анализе резецированных образцов и малого диагностического материала. Данный обзор обобщает основные ключевые вопросы в области классификации и морфологической диагностики бронхопульмональных НЭО, ответы на которые все еще не являются окончательными. Таким образом, необходимы дополнительные исследования для того, чтобы улучшить наши представления о НЭО данной локализации.

легкое, нейроэндокринная опухоль, рак, карциноид, крупноклеточный нейроэндокринный рак, мелкоклеточный рак, классификация, диагностика, иммуногистохимия

1. Travis W.D. Pathology and diagnosis of neuroendocrine tumors: lung neuroendocrine. Thorac Surg Clin 2014;24(3):257–66.

2. Asamura H., Kameya T., Matsuno Y. et al. Neuroendocrine neoplasms of the lung: a prognostic spectrum. J Clin Oncol 2006;24(1):70–6.

3. Swarts D.R., Ramaekers F.C., Speel E.J. Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta 2012;1826(2): 255–71.

4. Wick M.R. Neuroendocrine neoplasia. Current concepts. Am J Clin Pathol 2000;113(3):331–5.

5. Huang Q., Muzitansky A., Mark E.J. 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 2002;126(5):545–53.

6. Rekhtman N. Neuroendocrine tumors of the lung: an update. Arch Pathol Lab Med 2010;134(11):1628–38.

7. Travis W.D. Advances in neuroendocrine lung tumors. Ann Oncol 2010; 21(Suppl 7):65–71.

8. Travis W.D., Brambilla E., Nicholson A.G. et al. 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.

9. Righi L., Volante M., Rapa I. et al. Neuroendocrine tumours of the lung. A review of relevant pathological and molecular data. Virchows Arch 2007;451(Suppl 1):S51–9.

10. Moran C.A., Suster S. Neuroendocrine carcinomas (carcinoid, atypical carcinoid, small cell carcinoma, and large cell neuroendocrine carcinoma): current concepts. Hematol Oncol Clin North Am 2007;21(3):395–407.

11. den Bakker M.A., Thunnissen F.B. Neuroendocrine tumours – challenges in the diagnosis and classification of pulmonary neuroendocrine tumours. J Clin Pathol 2013;66(10):862–9.

12. Travis W.D., Brambilla E., Burke A.P. et al. WHO classification of tumours of the lung, pleura, thymus and heart. 4th edn. Lyon: IARC Press, 2015.

13. Caplin M.E., Baudin E., Ferolla P. et al. 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.

14. Travis W., Colby T., Corrin B. et al. Hystological typing of lung and pleural tumours. Berlin, Heidelberg, New York: Springer Verlag, 1999.

15. Travis W., Brambilla E., MullerHermelink H., Harris C. Tumours of the lung, pleura, thymus and heart. Lyon: IARC Press, 2004.

16. Pelosi G., Hiroshima K., MinoKenudson M. Controversial issues and new discoveries in lung neuroendocrine tumors. Diagn Histopathol 2014;20:392–7.

17. Moran C.A., Suster S., Coppola D., Wick M.R. Neuroendocrine carcinomas of the lung: a critical analysis. Am J Clin Pathol 2009;131(2):206–21.

18. Klimstra D.S., Modlin I.R., Adsay N.V. et al. Pathology reporting of neuroendocrine tumors: application of the Delphic consensus process to the development of a minimum pathology data set. Am J Surg Pathol 2010;34(3):300–13.

19. Klimstra D.S., Modlin I.R., Coppola D. et al. The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems. Pancreas 2010;39(6):707–12.

20. Yang Z., Tang L.H., Klimstra D.S. Gastroenteropancreatic neuroendocrine neoplasms: historical context and current issues. Semin Diagn Pathol 2013;30(3):186–96.

21. Pelosi G., Rodriguez J., Viale G., Rosai J. Typical and atypical pulmonary carcinoid tumor overdiagnosed as smallcell carcinoma on biopsy specimens: a major pitfall in the management of lung cancer patients. Am J Surg Pathol 2005;29(2):179–87.

22. Aslan D.L., Gulbahce H.E., Pambuccian S.E. et al. Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact. Am J Clin Pathol 2005;123(6):874–8.

23. Swarts D.R., van Suylen R.J., den Bakker M.A. et al. Interobserver variability for the WHO classification of pulmonary carcinoids. Am J Surg Pathol 2014;38(10):1429–36.

24. Pelosi G., Rindi G., Travis W.D., Papotti M. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol 2014;9(3):273–84.

25. Grimaldi F., Muser D., Beltrami C.A. et al. Partitioning of bronchopulmonary carcinoids in two different prognostic categories by Ki-67 score. Front Endocrinol (Lausanne) 2011;2:20.

26. Walts A.E., Ines D., Marchevsky A.M. Limited role of Ki-67 proliferative index in predicting overall short-term survival in patients with typical and atypical pulmonary carcinoid tumors. Mod Pathol 2012;25(9):1258–64.

27. Zahel T., Krysa S., Herpel E. et al. Phenotyping of pulmonary carcinoids and a Ki-67-based grading approach. Virchows Arch 2012;460(3):299–308.

28. Pelosi G., Papotti M., Rindi G., Scarpa A. Unraveling tumor grading and genomic landscape in lung neuroendocrine tumors. Endocr Pathol 2014;25(2):151–64.

29. Rindi G., Klersy C., Inzani F. et al. Grading the neuroendocrine tumors of the lung: an evidence-based proposal. Endocr Relat Cancer 2014; 21(1):1–16.

30. Pelosi G., Pattini L., Morana G. et al. Grading lung neuroendocrine tumors: controversies in search of a solution. Histol Histopathol 2017;32(3):223–41.

31. Righi L., Volante M., Rapa I. et al. Therapeutic biomarkers in lung neuroendocrine neoplasia. Endocr Pathol 2014;25(4):371–7.

32. Pelosi G., Volante M., Papotti M. et al. Peptide receptors in neuroendocrine tumors of the lung as potential tools for radionuclide diagnosis and therapy. Q J Nucl Med Mol Imaging 2006;50(4):272–87.

33. Gridelli C., Rossi A., Airoma G. et al. Treatment of pulmonary neuroendocrine tumours: state of the art and future developments. Cancer Treat Rev 2013;39(5):466–72.

34. Kunz P.L. Carcinoid and neuroendocrine tumors: building on success. J Clin Oncol 2015;33(16):1855–63.

35. Rouquette Lassalle I. Pulmonary neuroendocrine tumors and preneoplasic lesions. Ann Pathol 2016;36(1):34–43.

36. Mete O., Asa S.L. Precursor lesions of endocrine system neoplasms. Pathology 2013;45(3):316–30.

37. Pelosi G., Fabbri A., Cossa M. et al. What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms? Semin Diagn Pathol 2015;32(6):469–79.

38. Filosso P.L., Guerrera F., Evangelista A. et al. Prognostic model of survival for typical bronchial carcinoid tumours: analysis of 1109 patients on behalf of the European Association of Thoracic Surgeons (ESTS) Neuroendocrine Tumours Working Groupdagger. Eur J Cardiothorac Surg 2015;48:441–7.

39. Zeng M. Classification and pathology of lung cancer. Surg Oncol Clin N Am 2016;25(3):447–68.

40. Travis W.D., Rush W., Flieder D.B. et al. Survival analysis of 200 pulmonary neuroendocrine tumors with clarification of criteria for atypical carcinoid and its separation from typical carcinoid. Am J Surg Pathol 1998;22(8):934–44.

41. Beasley M.B., Thunnissen F.B., Brambilla E. et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol 2000;31(10):1255–65.

42. Tsuta K., Liu D.C., Kalhor N. et al. Using the mitosis-specific marker antiphosphohistone H3 to assess mitosis in pulmonary neuroendocrine carcinomas. Am J Clin Pathol 2011;136(2):252–9.

43. Swarts D.R., Van Neste L., Henfling M.E. et al. An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 2013;34(12):2726–37.

44. George J., Lim J.S., Jang S.J. et al. Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524(7563):47–53.

45. Swarts D.R., Scarpa A., Corbo V. et al. MEN1 Gene mutation and reduced expression are associated with poor prognosis in pulmonary carcinoids. J Clin Endocrinol Metab 2014;99(2):374–8.

46. Fernandez-Cuesta L., Peifer M., Lu X. et al. Frequent mutations in chromatinremodelling genes in pulmonary carcinoids. Nat Commun 2014;5:3518.

47. Warth A., Fink L., Fisseler-Eckhoff A. et al. Interobserver agreement of proliferation index (Ki-67) outperforms mitotic count in pulmonary carcinoids. Virchows Arch 2013;462(5):507–13.

48. Ha S.Y., Han J., Kim W.S. et al. Interobserver variability in diagnosing high-grade neuroendocrine carcinoma of the lung and comparing it with the morphometric analysis. Korean J Pathol 2012;46(1):42–7.

49. den Bakker M.A., Willemsen S., Grunberg K. et al. Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability. Histopathology 2010; 56(3):356–63.

50. Marchevsky A.M., Gal A.A., Shah S., Koss M.N. 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.

51. Wang H., Iyoda A., Roh M.S. et al. WHO histologic classification is an independent predictor of prognosis in lung neuroendocrine(NE) tumors but Ki-67 proliferation rate is not(abstract 1952). Mod Pathol 2013;26:469A.

52. 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.

53. Fasano M., Della Corte C.M., Papaccio F. et al. Pulmonary large-cell neuroendocrine carcinoma: from epidemiology to therapy. J Thorac Oncol 2015;10(8):1133–41.

54. Pelosi G., Rossi G., Cavazza A. et al. DeltaNp63 (p40) distribution inside lung cancer: a driver biomarker approach to tumor characterization. Int J Surg Pathol 2013;21(3):229–39.

55. Sturm N., Lantuejoul S., Laverriere M.H. et al. Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34betaE12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung. Hum Pathol 2001;32(9):918–25.

56. Rekhtman N., Pietanza M.C., Hellmann M.D. et al. 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.

57. Iyoda A., Travis W.D., Sarkaria I.S. et al. Expression profiling and identification of potential molecular targets for therapy in pulmonary large-cell neuroendocrine carcinoma. Exp Ther Med 2011;2(6):1041–5.

58. Quinn A.M., Chaturvedi A., Nonaka D. High-grade neuroendocrine carcinoma of the lung with carcinoid morphology: a study of 12 cases. Am J Surg Pathol 2017;41(2):263–70.

59. Nicholson S.A., Beasley M.B., Brambilla E. et al. Small cell lung carcinoma (SCLC): a clinicopathologic study of 100 cases with surgical specimens. Am J Surg Pathol 2002;26(9):1184–97.

60. Thunnissen E., Borczuk A.C., Flieder D.B. et al. 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 Oncology 2017;12(2):334–46.

61. Saito T., Tsuta K., Fukumoto K.J. et al. Combined small cell lung carcinoma and giant cell carcinoma: a case report. Surg Case Rep 2017;3(1):52.

62. Eberhardt W.E., Mitchell A., Crowley J. et al. The IASLC lung cancer staging project: proposals for the revision of the m descriptors in the forthcoming eighth edition of the tnm classification of lung cancer. J Thorac Oncol 2015;10(11):1515–22.