Grading of well-differentiated pancreatic neuroendocrine tumors is improved by the inclusion of both Ki67 proliferative index and mitotic rate. Am J Surg Pathol 2013 Nov;37(11):1671-7
Date
10/15/2013Pubmed ID
24121170Pubmed Central ID
PMC3891823DOI
10.1097/PAS.0000000000000089Scopus ID
2-s2.0-84886401222 (requires institutional sign-in at Scopus site) 134 CitationsAbstract
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.
Author List
McCall CM, Shi C, Cornish TC, Klimstra DS, Tang LH, Basturk O, Mun LJ, Ellison TA, Wolfgang CL, Choti MA, Schulick RD, Edil BH, Hruban RHAuthor
Toby Charles Cornish MD, PhD Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdolescentAdult
Aged
Aged, 80 and over
Biopsy
Cell Differentiation
Cell Proliferation
Female
Humans
Immunohistochemistry
Kaplan-Meier Estimate
Ki-67 Antigen
Male
Middle Aged
Mitotic Index
Neoplasm Grading
Neoplasm Invasiveness
Neuroendocrine Tumors
Pancreatic Neoplasms
Predictive Value of Tests
Prognosis
Proportional Hazards Models
Young Adult