Grading of neuroendocrine neoplasms: Mitoses and Ki-67 are both essential

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.