Grading of Neuroendocrine Neoplasms: Mitoses and Ki-67 Are Both Essential

Abstract

Background: The current WHO classification for neuroendocrine neoplasms (NEN) of the gastrointestinal tract requires Ki-67 and mitotic index for grading. However, both indexes might be conflicting as far as grade is concerned. In this study, we investigate which of the two indexes is most informative to predict survival. Methods: We assessed 362 patients with NEN of gastrointestinal (n = 148), pancreatic (n = 29), lung (n = 77), unknown primary site (n = 102) and of miscellaneous (n = 6) origin. Follow-up and proliferative indexes were recorded. Results: Survival was clearly correlated with both proliferative indexes (p < 0.001). One hundred and nineteen samples (34%) showed discordance in grading between the Ki-67 and the mitotic index, of which 74 (62%) were biopsies and 45 (38%) resection specimens (p = 0.001). In 86% of these cases, survival matched with the highest proliferative index, which was the Ki-67 index in 87% of these cases. Seventeen cases had a mitotic index of 2 (threshold grade 2) and a Ki-67 index of <3% (grade 1). For these cases, survival curve matched that of patients with concordant indexes of grade 1. Conclusion: Grading NEN using two proliferative markers results in discordance between these indexes in one third of cases, more often in biopsy material than in resection specimens. If results are discordant, survival is for the most part associated with the grade of the highest index, for the most part Ki-67. Thus, grading with two proliferative indexes is useful as it highlights cases where one of these indexes may be incongruent.

Long-Term Survival with Long-Acting Somatostatin Analogues Plus Aggressive Cytoreductive Surgery in Patients with Metastatic Neuroendocrine Carcinoma

“…[23][24][25] In patients with discordant Ki-67 index and mitotic counts (up to 33% of cases), Ki-67, when elevated, is a better predictor for tumor biology. 26 Although tumor grade had no influence on a patient undergoing cytoreductive surgery in the SEER-Medicare cohort, patients with well-differentiated metastatic NET from GI primary were more likely to be treated with S-LAR than their counterparts. It has also been shown that patients with a robust T cell (CD3þ) tumor infiltrate have a superior outcome when compared with those with tumors containing high levels of infiltrating regulatory T cells.…”

Limited additive value of the Ki‐67 proliferative index on patient survival in World Health Organization‐classified pulmonary carcinoids

“…The Ki‐67 proliferation index, however, may be valuable for cases difficult to classify, including TC–AC and AC–HGNEC borderline cases . This is especially true for small biopsy specimens where it is difficult to screen 2 mm for mitotic cells, and some studies even indicate that Ki‐67 may outperform histopathological classification in biopsy material . This warrants an extensive study comparing performance of the WHO classification and Ki‐67 on a series of lung NETs for which both biopsy and resection material is available.…”

Comparative evaluation of three proliferation markers, Ki-67, TOP2A, and RacGAP1, in bronchopulmonary neuroendocrine neoplasms: Issues and prospects

“…The 2014 review by Pelosi et al describes the many different immunohistochemical evaluation systems used for Ki-67 measurement [8, 9, 12–14, 31, 32]. In the present study, we compared two widely used manual counting methods, the Ki-67-Average (magnification 400×, per 10 representative HPFs) and the Ki-67-Hotspot evaluation (magnification 400×, per 2000 cells), with each other and with a fully automated digital image analysis of Ki-67 IHC.…”