Ki-67 in Pulmonary Neuroendocrine Tumors: Where Do We Stand?

Ki-67 in Pulmonary Neuroendocrine Tumors: Where Do We Stand?

Diagnostic Oncology
May 27, 2019

By Anja C. Roden, MD, and Natasha Rekhtman, MD, PhD
Posted: May 27, 2019

Dr. Anja C. Roden

Pulmonary neuroendocrine tumors are classified according to the World Health Organization into typical and atypical carcinoid tumors, small cell lung cancer (SCLC), and large cell neuroendocrine carcinomas (LCNEC).1 Whereas typical and atypical carcinoid tumors are considered to be of low and intermediate grade, respectively, SCLC and LCNEC are high-grade carcinomas with poorer prognosis. This classifi cation is solely based on morphologic features including cytologic characteristics, mitotic activity, and necrosis. The classification correlates well with outcome, with typical carcinoids having the highest 5-year survival rates, and LCNEC and SCLC having the lowest, with significant differences in survival between typical and atypical carcinoids and atypical carcinoids and LCNEC or SCLC independent of stage.2 Reproducibility of this classification is substantial among experienced lung pathologists.3







Dr. Natasha Rekhtman

Ki-67 labeling index (LI) does not play a role in the classification of resected lung neuroendocrine tumors, which contrasts with its status as a key parameter in the classification of gastrointestinal and pancreatic neuroendocrine tumors. In nonresection samples, expression of Ki-67 may be useful in the distinction of carcinoids from SCLC or LCNEC, specifically in small and/or crushed biopsies or cytology specimens. This application is supported by the experience of thoracic pathologists, as well as by current literature summarized in the “Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer,” which were recently published by members of the Pathology Committee of the IASLC.4 In these recommendations, we emphasized that, at this time, there is no role for this marker to distinguish typical from atypical carcinoid tumors. Many studies have shown that Ki-67 LI is higher in atypical carcinoids than in typical carcinoids, but there is some overlap between these two groups.5 Furthermore, several studies show that Ki-67 LI is associated with the risk for postsurgical recurrence of typical and atypical carcinoids; however, more data are needed to establish the added value of Ki-67 and to determine a possible cutoff.6,7

There is no standardized Ki-67 scoring method for pulmonary neuroendocrine tumors.8 Scoring of Ki-67 LI ranges from “eyeballing” the entire specimen to evaluating LI in hot spots either by manual count or digital analysis. Furthermore, reproducibility studies for the evaluation of Ki-67 LI are lacking. In metastatic gastrointestinal and pancreatic neuroendocrine tumors, Ki-67 is considered a key parameter in guiding systemic therapy. As a result, some clinical guidelines and recommendations9,10 have incorporated Ki-67 for clinical management of pulmonary neuroendocrine tumors, analogous to the approach used for gastroenteropancreatic tumors. However, the validity of Ki-67 LI for assessing prognosis and guiding therapy in metastatic pulmonary carcinoids still requires clinical validation. There are recent data on escalation of Ki-67 (and mitotic rate) during metastatic progression of lung carcinoids.11 The clinical implications of this phenomenon also awaits further clinical investigation.

We recently formed a neuroendocrine working group within the Pathology Committee of the IASLC. The working group will explore practice patterns and new data in pulmonary neuroendocrine tumors that have recently emerged and how those could be incorporated into diagnosis, prognosis, and treatment of patients with these tumors. ✦

About the Authors: Dr. Roden is professor of Pathology and a thoracic and surgical pathologist in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Dr. Rekhtman is a thoracic pathologist and cytopathologist in the Department of Pathology at Memorial Sloan Kettering Cancer Center.

1. Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG, eds. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.

2. 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(8):934-944.

3. Travis WD, Gal AA, Colby TV, Klimstra DS, Falk R, Koss MN. Reproducibility of neuroendocrine lung tumor classification. Hum Pathol. 1998;29(3):272-279.

4. Yatabe Y, Dacic S, Borczuk AC, et al. Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer. J Thorac Oncol. 2019;14(3):377-407.

5. Sadowski SM, Christ E, Bedat B, et al. Nationwide multicenter study on the management of pulmonary neuroendocrine (carcinoid) tumors. Endocr Connect. 2018;7(1):8-15.

6. 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(8):947-951.

7. Marchio C, Gatti G, Massa F, et al. Distinctive pathological and clinical features of lung carcinoids with high proliferation index. Virchows Arch 2017;471(6):713-720.

8. 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(12):1770-1786.

9. NCCN Guidelines. Neuroendocrine tumors of the gastrointestinal tract, lung and thymus (carcinoid tumors). Neuroendocrine and Adrenal Tumors, Version 1.2019. Published March 5, 2019. Accessed April 6, 2019.

10. 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(8):1604-1620.

11. Rekhtman N, Desmeules P, Litvak AM, et al. Stage IV Lung Carcinoids: Spectrum and Evolution of Proliferation Rate, Focusing on Variants with Elevated Proliferation Indices. Mod Pathol. 2019 Mar 28. [Epub ahead of print].