Ki-67 Proliferation Index and Mitotic Rate Discordance in Pancreatic Neuroendocrine Tumors Correlates with Aggressive Histologic Features and Decreased Overall Survival
Chad M McCall, Chanjuan Shi, Trevor Ellison, Ralph H Hruban, Christopher Wolfgang, Richard Schulick, Michael Choti, David Klimstra, Olca Basturk, Barish H Edil. The Johns Hopkins University School of Medicine, Baltimore, MD; Vanderbilt University School of Medicine, Nashville, TN; Memorial Sloan-Kettering Cancer Center, New York, NY
Background: By World Health Organization (WHO) guidelines, pancreatic neuroendocrine tumors (PanNETs) may be graded by either mitotic rate or Ki-67/MIB-1 proliferation index, with grade 1 defined as a mitotic rate less than 2 per 10 high-power fields and/or a Ki-67 proliferation index of less than 3%. Grade 2 is defined as a 2-20 mitoses per 10 high-power fields and/or a Ki-67 index of 3-20%. In order determine whether these two grading parameters are comparable, we performed Ki-67 immunohistochemical labeling on all mitotic grade 1 PanNETs in our institutional database and examined histologic features and survival outcomes.
Design: 361 PanNETs surgically resected at our institution from 1980-2009 were reviewed for mitotic rate, clinical data, and histologic features. 264 mitotic grade 1 cases were immunolabeled with an antibody to Ki-67. The percentage of Ki-67 positive cells was quantified using image analysis. Survival outcome was determined using the Social Security Death Index.
Results: Of 264 mitotic grade 1 PanNETs, 33% were grade 2 by Ki-67 proliferation index. Grade-discordant tumors were more likely to have lymph node (56% vs. 34%) (P = 0.0014) and known distant (46% vs 12%) (P < 0.0001) metastases than grade 1 concordant tumors. Grade-discordant PanNETs also showed statistically significantly more infiltrative growth pattern, perineural invasion and small vascular invasion. Median size was also greater (3.5 cm vs. 2.4 cm (P = 0.0009)). Overall survival was statistically significantly different (P = 0.0017), with grade-discordant tumors showing a median survival of 12 years, and grade 1 concordant tumors having greater than 50% of patients still alive, up to 25 years after resection. Grade-discordant tumors and grade 1 concordant tumors had no significant difference in median age at resection, gender, presence of necrosis, or large vascular invasion.
Conclusions: Our data demonstrate that mitotic rate and Ki-67-based grading of PanNETs are often discordant, and where the Ki-67 grade is greater than the mitotic grade, clinical outcomes and histopathologic features are significantly worse. Patients with discordant tumors have shortened overall survival and larger tumors with more metastases and more aggressive histologic features. These data strongly suggest that Ki-67 labeling be performed on all PanNETs to more accurately determine tumor grade and prognosis.
Monday, March 19, 2012 9:00 AM
Platform Session: Section G1, Monday Morning