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Grading of Well-differentiated Pancreatic Neuroendocrine Tumors Is Improved by the Inclusion of Both Ki67 Proliferative Index and Mitotic Rate

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

The American Journal of Surgical Pathology: November 2013 - Volume 37 - Issue 11 - p 1671–1677
doi: 10.1097/PAS.0000000000000089
Original Articles

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.

Departments of *Pathology

§Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD

Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN

Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY

Department of Surgery, University of Colorado Anschutz Medical Campus, Aurora, CO

Conflicts of Interest and Source of Funding: R.H.H. is supported by NIH grants P50-CA62924 and P30-CA006973. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

Correspondence: Ralph H. Hruban, MD, Department of Pathology, The Johns Hopkins University School of Medicine, 401 North Broadway, Baltimore, MD 21231 (e-mail:

© 2013 by Lippincott Williams & Wilkins.