Grading of well-differentiated pancreatic Neuroendocrine tumors is improved by the inclusion of both ki67 Proliferative index and mitotic rate

Chad M. McCall, Chanjuan Shi, Toby C. Cornish, David S. Klimstra, Laura H. Tang, Olca Basturk, Liew Jun Mun, Trevor A. Ellison, Christopher L. Wolfgang, Michael A. Choti, Richard D. Schulick, Barish H. Edil, Ralph H. Hruban

Research output: Contribution to journalArticle

94 Scopus citations

Abstract

The grading system for pancreatic neuroendocrine tumors (PanNETs) adopted in 2010 by the World Health Organization (WHO) mandates the use of both mitotic rate and Ki67/MIB-1 index in defining the proliferative rate and assigning the grade. In cases when these measures are not concordant for grade, it is recommended to assign the higher grade, but specific data justifying this approach do not exist. Thus, we counted mitotic figures and immunolabeled, using the Ki67 antibody, 297 WHO mitotic grade 1 and 2 PanNETs surgically resected at a single institution. We quantified the Ki67 proliferative index by marking at least 500 cells in "hot spots" and by using digital image analysis software to count each marked positive/negative cell and then compared the results with histologic features and overall survival. Of 264 WHO mitotic grade 1 PanNETs, 33% were WHO grade 2 by Ki67 proliferative index. Compared with concordant grade 1 tumors, grade-discordant tumors were more likely to have metastases to lymph node (56% vs. 34%) (P<0.01) and to distant sites (46% vs. 12%) (P<0.01). Discordant mitotic grade 1 PanNETs also showed statistically significantly more infiltrative growth patterns, perineural invasion, and small vessel invasion. Overall survival was significantly different (P<0.01), with discordant mitotic grade 1 tumors showing a median survival of 12 years compared with 16.7 years for concordant grade 1 tumors. Conversely, mitotic grade 1/Ki67 grade 2 PanNETs showed few significant differences from tumors that were mitotic grade 2 and either Ki67 grade 1 or 2. Our data demonstrate that mitotic rate and Ki67-based grades of PanNETs are often discordant, and when the Ki67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse than concordant grade 1 tumors. Patients with discordant mitotic grade 1/Ki67 grade 2 tumors have shorter overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki67 labeling be performed on all PanNETs in addition to mitotic rate determination to define more accurately tumor grade and prognosis.

Original languageEnglish (US)
Pages (from-to)1671-1677
Number of pages7
JournalAmerican Journal of Surgical Pathology
Volume37
Issue number11
DOIs
StatePublished - Nov 1 2013

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Keywords

  • Ki67
  • endocrine neoplasm
  • gastroenteropancreatic neuroendocrine tumor
  • neuroendocrine tumor
  • pancreas
  • pancreatic cancer
  • pancreatic endocrine neoplasm islet cell tumor
  • pancreatic neuroendocrine tumor

ASJC Scopus subject areas

  • Anatomy
  • Surgery
  • Pathology and Forensic Medicine

Cite this

McCall, C. M., Shi, C., Cornish, T. C., Klimstra, D. S., Tang, L. H., Basturk, O., Mun, L. J., Ellison, T. A., Wolfgang, C. L., Choti, M. A., Schulick, R. D., Edil, B. H., & Hruban, R. H. (2013). Grading of well-differentiated pancreatic Neuroendocrine tumors is improved by the inclusion of both ki67 Proliferative index and mitotic rate. American Journal of Surgical Pathology, 37(11), 1671-1677. https://doi.org/10.1097/PAS.0000000000000089