Prognostic factors in atypical carcinoid tumors

Abstract

Objectives: Carcinoid tumors are rare neuroendocrine neoplasms of the lung. Although typical and atypical carcinoids have different clinical courses, most studies in the literature evaluate them together. Therefore, we aimed to investigate prognostic factors in patients with atypical carcinoids, excluding typical carcinoids.

Methods: We included 32 patients with atypical carcinoids according to WHO 2021 criteria admitted to Uludag University Hospital. We retrospectively extracted the clinicopathological characteristics from electronic medical records. The log-rank tests were used to determine the prognostic factors on survival.

Results: Median age was 57 (24-71) years. Pathological stages were as follows: stage I in 41%, II in 9%, III in 34%, and IV in 16%. Median Ki-67 index was 11% (1-50). Median follow-up time was 46.2 (0.7-184.2) months. 12-month and 48-month disease-free survival (DFS) rates were 92.3% and 79.2%, respectively. 12-month and 48-month overall survival (OS) rates were 93.8% and 86.2, respectively. Receiver operating characteristic curve analysis determined the Ki-67 cut-off as 12.5%. The log-rank test indicated that Ki-67 and stage were statistically significant prognostic factors for DFS and OS. The patients with a Ki-67 index lower than 12.5% had longer DFS and OS (p = 0.007 and p = 0.020, respectively).

Conclusions: The Ki-67 index and 8th TNM staging have prognostic value on DFS and OS in patients with atypical carcinoids. Large-scale studies are needed to define the optimal cut-off value of Ki-67.

Keywords

• Lung carcinoid
• atypical carcinoid
• ki-67 index
• stage
• survival

References

1. 1. Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging. UpToDate. Available at: https://www.uptodate.com/contents/lung-neuroendocrine-carcinoid-tumors-epidemiology-risk-factors-classification-histology-diagnosis-and-staging. Accessed August 03, 2023.
2. 2. Hauso O, Gustafsson BI, Kidd M, Waldum HL, Drozdov I, Chan AK, et al. Neuroendocrine tumor epidemiology: contrasting Norway and North America. Cancer 2008;113:2655-64.
3. 3. Petursdottir A, Sigurdardottir J, Fridriksson BM, Johnsen A, Isaksson HJ, Hardardottir H, et al. Pulmonary carcinoid tumours: incidence, histology, and surgical outcome. A population-based study. Gen Thorac Cardiovasc Surg 2020;68:523-9.
4. 4. WHO Classification of Tumours Editorial Board. Thoracic Tumours. 5th ed. Lyon; France: International Agency for Research on Cancer; 2021.
5. 5. Detterbeck FC. Management of carcinoid tumors. Ann Thorac Surg 2010;89:998-1005.
6. 6. Metovic J, Barella M, Harari S, Pattini L, Albini A, Sonzogni A, et al. Clinical implications of lung neuroendocrine neoplasm classification. Expert Rev Anticancer Ther 2021;21:377-87.
7. 7. Yi C, Dai J, Song N, Wu C, Zhang L, Zhu Y, et al. Improvement of pathological staging system for neuroendocrine tumors of the lung. Ann Transl Med 2021;9:447.
8. 8. He Y, Zhao F, Han Q, Zhou Y, Zhao S. Prognostic nomogram for predicting long-term cancer-specific survival in patients with lung carcinoid tumors. BMC Cancer 2021;21:141.

9. 9. Chiappetta M, Sperduti I, Ciavarella LP, Leuzzi G, Bria E, Mucilli F, et al. Prognostic score for survival with pulmonary carcinoids: the importance of associating clinical with pathological characteristics. Interact Cardiovasc Thorac Surg 2020;31:315-23.
10. 10. Boland JM, Kroneman TN, Jenkins SM, Terra SBSP, Xie H, Molina J, et al. Ki-67 Labeling index in pulmonary carcinoid tumors: comparison between small biopsy and resection using tumor tracing and hot spot methods. Arch Pathol Lab Med 2020;144: 982-90.
11. 11. Dermawan JKT, Farver CF. The role of histologic grading and Ki-67 index in predicting outcomes in pulmonary carcinoid tumors. Am J Surg Pathol 2020;44:224-31.
12. 12. Dong S, Liang J, Zhai W, Yu Z. Development and validation of an individualized nomogram for predicting overall survival in patients with typical lung carcinoid tumors. Am J Clin Oncol 2020;43:607-14.
13. 13. Baudin E, Hayes AR, Scoazec JY, Filosso PL, Lim E, Kaltsas G, et al. Unmet medical needs in pulmonary neuroendocrine (carcinoid) neoplasms. Neuroendocrinology 2019;108:7-17.
14. 14. Neuroendocrine and Adrenal Tumors. Version1.2023. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/neuroendocrine. pdf. Accessed August 08, 2023.
15. 15. Lung neuroendocrine (carcinoid) tumors: Treatment and prognosis. UpToDate. Available at: https://www.uptodate.com/contents/lung-neuroendocrine-carcinoid-tumors-treatment-and-prognosis. Accessed August 03, 2023.
16. 16. Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2021;32:439-51.
17. 17. Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, et al. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki-67. Am J Pathol 1991;138:867-73.
18. 18. Menon SS, Guruvayoorappan C, Sakthivel KM, Rasmi RR. Ki-67 protein as a tumour proliferation marker. Clin Chim Acta 2019;491:39-45.
19. 19. Jonat W, Arnold N. Is the Ki-67 labelling index ready for clinical use? Ann Oncol 2011;22:500-2.
20. 20. Sun X, Kaufman PD. Ki-67: more than a proliferation marker. Chromosoma 2018;127:175-86.
21. 21. Sakin A, Tambas M, Secmeler S, Can O, Arici S, Yasar N, et al. Factors affecting survival in neuroendocrine tumors: a 15-year single center experience. Asian Pac J Cancer Prev 2018;19:3597-603.
22. 22. Cubukcu E, Sahin AB, Oz Atalay F, Ocak B, Ozsen M, Demiroz Abakay C, et al. The Ki-67 index and neutrophile-lymphocyte ratio are prognostic factors in patients with low-risk endometrial cancer. Eur J Gynaecol Oncol 2021;42:775-81.
23. 23. Şahin AB, Cubukcu E, Ocak B, Deligonul A, Oyucu Orhan S, Tolunay S, et al. Low pan-immune-inflammation-value predicts better chemotherapy response and survival in breast cancer patients treated with neoadjuvant chemotherapy. Sci Rep 2021;11:14662.
24. 24. Seo SH, Kim KH, Oh SH, Choi Y, Ahn KJ, Lee JY, et al. Ki-67 labeling index as a prognostic marker in advanced stomach cancer. Ann Surg Treat Res 2019;96:27-33.
25. 25. Pavel M, Öberg K, Falconi M, Krenning EP, Sundin A, Perren A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:844-60.
26. 26. Kasajima A, Konukiewitz B, Oka N, Suzuki H, Sakurada A, Okada Y, et al. Clinicopathological profiling of lung carcinoids with a Ki67 index > 20. Neuroendocrinology 2019;108:109-20.
27. 27. Aslan DL, Gulbahce HE, Pambuccian SE, Manivel JC, Jessurun J. Ki-67 immunoreactivity in the differential diagnosis of pulmonary neuroendocrine neoplasms in specimens with extensive crush artifact. Am J Clin Pathol 2005;123:874-8.
28. 28. La Rosa S. Diagnostic, prognostic, and predictive role of Ki67 proliferative index in neuroendocrine and endocrine neoplasms: past, present, and future. Endocr Pathol 2023;34:79-97.
29. 29. Centonze G, Maisonneuve P, Simbolo M, Lagano V, Grillo F, Fabbri A, et al. Lung carcinoid tumours: histology and Ki-67, the eternal rivalry. Histopathology 2023;82:324-39.
30. 30. Swarts DR, van Suylen RJ, den Bakker MA, van Oosterhout MF, Thunnissen FB, Volante M, et al. Interobserver variability for the WHO classification of pulmonary carcinoids. Am J Surg Pathol 2014;38:1429-36.
31. 31. Cree IA. From counting mitoses to Ki67 assessment: technical pitfalls in the new WHO classification of endocrine and neuroendocrine tumors. Endocr Pathol 2022;33:3-5.
32. 32. Reccia I, Pai M, Kumar J, Spalding D, Frilling A. Tumour heterogeneity and the consequent practical challenges in the management of gastroenteropancreatic neuroendocrine neoplasms. Cancers (Basel) 2023;15:1861.
33. 33. Sahin AB, Melek H, Ocak B, Oyucu Orhan S, Erkan B, Caner B, et al. Platin based chemotherapy does not improve survival in patients with non metastatic resected typical carcinoid tumors. Mol Clin Oncol 2022;17:146.
34. 34. Georgakopoulou VE, Zygouris E, Nikokiris C, Damaskos C, Pierrakou A, Garmpis N, et al. Predictive indicators of survival in patients with surgically resected lung carcinoid tumors at a Greek Medical Center. Cureus 2020;12:e10300