Article | Published:

Stage IV lung carcinoids: spectrum and evolution of proliferation rate, focusing on variants with elevated proliferation indices

Abstract

The spectrum and evolution of proliferation rates in stage IV lung carcinoids is poorly defined. In particular, there are limited data on the prevalence and characteristics of tumors exceeding the standard upper proliferative criteria—as defined largely based on early-stage carcinoids—in metastatic setting. Sixty-six patients with stage IV lung carcinoids were identified, and all evaluable samples (n = 132; mean 2 samples per patient) were analyzed for mitotic counts and Ki-67 rate. Clinicopathologic and genomic features associated with elevated proliferation rates (>10 mitoses per 2 mm2 and/or >20% hot-spot Ki-67), and evolution of proliferation rates in serial specimens were analyzed. We found that mitoses and/or Ki-67 exceeded the standard criteria in 35 of 132 (27%) samples, primarily (31/35 cases) at  metastatic sites. Although neuroendocrine neoplasms with >10 mitoses per 2 mm2 are currently regarded as de facto neuroendocrine carcinomas, the notion that these cases are part of the spectrum of carcinoids was supported by (1) well-differentiated morphology, (2) conventional proliferation rates in other samples from same patient, (3) genetic characteristics, including the lack of RB1/TP53 alterations in all tested samples (n = 19), and (4) median overall survival of 2.7 years, compared to <1 year survival of stage IV neuroendocrine carcinomas in the historic cohorts. In patients with matched primary/metastatic specimens (48 pairs), escalation of mitoses or Ki-67 by ≥10 points was observed in 35% of metastatic samples; clonal relationship in one pair with marked proliferative progression was confirmed by next-generation sequencing. Notably, escalation of proliferation rate was documented in a subset of metastases arising from resected typical carcinoids, emphasizing that the diagnosis of typical carcinoid in primary tumor does not assure low proliferation rate at metastatic sites. In conclusion, stage IV lung carcinoids frequently exceed the standard proliferative criteria established for primary tumors, and commonly exhibit proliferative escalation at metastatic sites. Despite the overlap of proliferation rates, these tumors show fundamental morphologic, genomic and clinical differences from neuroendocrine carcinomas, and should be classified separately from those tumors. Awareness of the increased proliferative spectrum in metastatic carcinoids is critical for their accurate diagnosis. Further studies are warranted to explore the impact of proliferation indices on prognosis and therapeutic responses of patients with metastatic carcinoids.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

These authors contributed equally as co-first authors: Natasha Rekhtman, Patrice Desmeules

References

  1. 1.

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

  2. 2.

    Beasley MB, Brambilla E, Chirieac LR, et al. Carcinoid tumour. In: Travis WD, Brambilla E, Burke AP, et al. (editors). WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: IARC Press; 2015. p. 73–77.

  3. 3.

    Frilling A, Modlin IM, Kidd M, et al. Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol. 2014;15:e8–21.

  4. 4.

    Abdel-Rahman O. Modified staging system for pulmonary carcinoids on the basis of lung cancer TNM system. Clin Transl Oncol. 2018;20:670–77.

  5. 5.

    Travis WD, Rush W, Flieder DB, 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;22:934–44.

  6. 6.

    Klimstra DS. Pathologic classification of neuroendocrine neoplasms. Hematol Oncol Clin North Am. 2016;30:1–19.

  7. 7.

    Pelosi G, Rindi G, Travis WD, et al. Ki-67 antigen in lung neuroendocrine tumors: unraveling a role in clinical practice. J Thorac Oncol. 2014;9:273–84.

  8. 8.

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

  9. 9.

    Fabbri A, Cossa M, Sonzogni A, et al. 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;470:153–64.

  10. 10.

    Lin O, Olgac S, Green I, et al. Immunohistochemical staining of cytologic smears with MIB-1 helps distinguish low-grade from high-grade neuroendocrine neoplasms. Am J Clin Pathol. 2003;120:209–16.

  11. 11.

    Pelosi G, Rodriguez J, Viale G, et al. 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;29:179–87.

  12. 12.

    Velayoudom-Cephise FL, Duvillard P, Foucan L, et al. Are G3 ENETS neuroendocrine neoplasms heterogeneous? Endocr Relat Cancer. 2013;20:649–57.

  13. 13.

    Basturk O, Yang Z, Tang LH, et al. The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. Am J Surg Pathol. 2015;39:683–90.

  14. 14.

    Heetfeld M, Chougnet CN, Olsen IH, et al. Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2015;22:657–64.

  15. 15.

    Tang LH, Untch BR, Reidy DL, et al. Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clin Cancer Res. 2016;22:1011–7.

  16. 16.

    Milione M, Maisonneuve P, Spada F, et al. The clinicopathologic heterogeneity of grade 3 gastroenteropancreatic neuroendocrine neoplasms: morphological differentiation and proliferation identify different prognostic categories. Neuroendocrinology. 2017;104:85–93.

  17. 17.

    Raj N, Valentino E, Capanu M, et al. Treatment response and outcomes of grade 3 pancreatic neuroendocrine neoplasms based on morphology: well differentiated versus poorly differentiated. Pancreas. 2017;46:296–301.

  18. 18.

    Hijioka S, Hosoda W, Matsuo K, et al. Rb loss and KRAS mutation are predictors of the response to platinum-based chemotherapy in pancreatic neuroendocrine neoplasm with grade 3: a Japanese Multicenter Pancreatic NEN-G3 Study. Clin Cancer Res. 2017;23:4625–32.

  19. 19.

    Klöppel GCA, Hruban RH, et al. Neoplasms of the neuroendocrine pancreas, introduction. In: Lloyd RV, Osamura RY, Klöppel G, Rosai J (editors). WHO Classification of Tumours of Endocrine Organs. Lyon: IARC; 2017.

  20. 20.

    Hann CL, Weu MA, Rekhtman N, et al. Small-cell and neuroendocrine tumors of the lung. In: DeVita VT, Rosenberg SA, Lawrence TS (editors). DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th Edition. Philadelphia: Wolters Kluwer, 2018, p. 671–99.

  21. 21.

    Rekhtman N, Pietanza MC, Hellmann MD, 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;22:3618–29.

  22. 22.

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

  23. 23.

    Megyesi M, Berta M, Khoor A. Endobronchial large cell neuroendocrine carcinoma. Pathol Oncol Res. 2003;9:198–200.

  24. 24.

    Konno F, Jungbluth A, Frosina D, et al. Drastic loss of MIB1/Ki67 immunoreactivity in CytoLyt-fixed cell blocks. Lab Invest. 2015;95(Suppl. 1):95A.

  25. 25.

    Caplin ME, 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;26:1604–20.

  26. 26.

    Cheng DT, Mitchell TN, Zehir A, et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J Mol Diagn. 2015;17:251–64.

  27. 27.

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

  28. 28.

    George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nature. 2015;524:47–53.

  29. 29.

    George J, Walter V, Peifer M, et al. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018;9:1048.

  30. 30.

    Vivero M, Scholl LM. “Borderline” neuroendocrine carcinomas of the lung are clinically and genomically distinct from large cell neuroendocrine carcinoma. Mod Pathol. 2016;29(suppl 2):485A.

  31. 31.

    Naidoo J, Santos-Zabala ML, Iyriboz T, et al. Large cell neuroendocrine carcinoma of the lung: clinico-pathologic features, treatment, and outcomes. Clin Lung Cancer. 2016;17:e121–9.

  32. 32.

    Govindan R, Page N, Morgensztern D, et al. Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and end results database. J Clin Oncol. 2006;24:4539–44.

  33. 33.

    Nicholson AG, Chansky K, Crowley J, et al. The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the Clinical and Pathologic Staging of Small Cell Lung Cancer in the ForthcomingEighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11:300–11.

  34. 34.

    Wolin EM. Advances in the diagnosis and management of well-differentiated and intermediate-differentiated neuroendocrine tumors of the lung. Chest. 2017;151:1141–46.

  35. 35.

    Singh S, Hallet J, Rowsell C, et al. Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease. Eur J Surg Oncol. 2014;40:1517–22.

  36. 36.

    Shi C, Gonzalez RS, Zhao Z, et al. Liver metastases of small intestine neuroendocrine tumors: Ki-67 heterogeneity and World Health Organization grade discordance with primary tumors. Am J Clin Pathol. 2015;143:398–404.

  37. 37.

    Grillo F, Albertelli M, Brisigotti MP, et al. Grade increases in gastroenteropancreatic neuroendocrine tumor metastases compared to the primary tumor. Neuroendocrinology. 2016;103:452–9.

  38. 38.

    Panzuto F, Cicchese N, Partelli S, et al. Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms. PLoS One. 2017;12:e0179445.

  39. 39.

    Derks JL, Speel EJ, Thunnissen E, et al. Neuroendocrine cancer of the lung: a diagnostic puzzle. J Thorac Oncol. 2016;11:e35–8.

  40. 40.

    Lou F, Sarkaria I, Pietanza C, et al. Recurrence of pulmonary carcinoid tumors after resection: implications for postoperative surveillance. Ann Thorac Surg. 2013;96:1156–62.

  41. 41.

    Garcia-Yuste M, Matilla JM, Canizares MA, et al. Surgical treatment of low and intermediate grade lung net. J Thorac Dis. 2017;9:S1435–41.

  42. 42.

    National Comprehensive Cancer Network (NCCN) Guidelines Version 2.2018: Neuroendocrine and Adrenal Tumors.

  43. 43.

    Pavel M, O’Toole D, Costa F, et al. ENETS Consensus Guidelines Update for the Management of Distant Metastatic Disease of Intestinal, Pancreatic, Bronchial Neuroendocrine Neoplasms (NEN) and NEN of Unknown Primary Site. Neuroendocrinology. 2016;103:172–85.

  44. 44.

    Marchio C, Gatti G, Massa F, et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch. 2017;471:713–20.

  45. 45.

    Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol. 2011;35:853–60.

  46. 46.

    Yachida S, Vakiani E, White CM, et al. Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. Am J Surg Pathol. 2012;36:173–84.

  47. 47.

    Tang LH, Basturk O, Sue JJ, et al. A Practical Approach to the Classification of WHO Grade 3 (G3) Well-differentiated Neuroendocrine Tumor (WD-NET) and Poorly Differentiated Neuroendocrine Carcinoma (PD-NEC) of the pancreas. Am J Surg Pathol. 2016;40:1192–202.

  48. 48.

    Tsuta K, Raso MG, Kalhor N, et al. Histologic features of low- and intermediate-grade neuroendocrine carcinoma (typical and atypical carcinoid tumors) of the lung. Lung Cancer. 2011;71:34–41.

  49. 49.

    Beasley MB, Thunnissen FB, Brambilla E, et al. Pulmonary atypical carcinoid: predictors of survival in 106 cases. Hum Pathol. 2000;31:1255–65.

  50. 50.

    Wu JM, Fackler MJ, Halushka MK, et al. Heterogeneity of breast cancer metastases: comparison of therapeutic target expression and promoter methylation between primary tumors and their multifocal metastases. Clin Cancer Res. 2008;14:1938–46.

  51. 51.

    Cserni G. Tumour histological grade may progress between primary and recurrent invasive mammary carcinoma. J Clin Pathol. 2002;55:293–7.

  52. 52.

    Wick MR, Scheithauer BW. Oat-cell carcinoma of the thymus. Cancer. 1982;49:1652–7.

  53. 53.

    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;113:345–50.

  54. 54.

    Fabbri A, Cossa M, Sonzogni A, et al. 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;471:31–47.

  55. 55.

    Yi ES, Lee GK. Updates on selected topics in lung cancers: air space invasion in adenocarcinoma and Ki-67 staining in carcinoid tumors. Arch Pathol Lab Med. 2018;142:947–51.

  56. 56.

    Klimstra DS, Modlin IR, Adsay NV, 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;34:300–13.

  57. 57.

    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;31:1523–31.

  58. 58.

    Rindi G, Klimstra DS, Abedi-Ardekani B, et al. 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;31:1770–86.

  59. 59.

    Hlatky R, Suki D, Sawaya R. Carcinoid metastasis to the brain. Cancer. 2004;101:2605–13.

  60. 60.

    Chong CR, Wirth LJ, Nishino M, et al. Chemotherapy for locally advanced and metastatic pulmonary carcinoid tumors. Lung Cancer. 2014;86:241–6.

  61. 61.

    Riihimaki M, Hemminki A, Sundquist K, et al. The epidemiology of metastases in neuroendocrine tumors. Int J Cancer. 2016;139:2679–86.

Download references

Acknowledgements

This study was supported in part by the grant from the Fiona and Stanley Druckenmiller Center for Lung Cancer Research (to NR). This research was made possible by infrastructure support by the NIH/NCI Cancer Center Support Grant P30 CA008748.

Author information

Conflict of interest

The authors declare that they have no relevant conflicts of interest.

Correspondence to Natasha Rekhtman.

Supplementary information

Supplemental Figures

Supplemental Table 1

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7