Anatomic Pathology / Proliferative Index in Pancreatic Neuroendocrine Tumors

Assessment of proliferative activity is required for grading well-differentiated pancreatic neuroendocrine tumors. However, a standardized method for obtaining the Ki-67 proliferative index is lacking. This study compared proliferative activity obtained by 3 methods: single-field hot spot (Ki-67 HS) and 10 consecutive field average (Ki-67 CFA) using the Ventana image analysis system (Ventana Medical Systems, Tucson, AZ) and mitotic index (MI). These methods resulted in discrepant grades in 30 (67%) of our 45 cases. With the current Ki-67 cutoff of more than 2% for intermediategrade tumors, MI, CFA, and HS resulted in specificities of 91%, 94%, and 31%, respectively, for detecting metastasis, with positive predictive values (PPVs) of 25%, 67%, and 31%, respectively. At a higher Ki-67 cutoff of 7.5%, HS analysis resulted in a specificity of 94% and PPV of 71% for predicting metastasis. While single-field HS analysis may be practical and reliable at a higher cutoff, this study emphasizes the variability that can exist when different methods of assessment are used. Well-differentiated pancreatic neuroendocrine tumors (PanNETs) are uncommon tumors, representing 1% to 2% of all pancreatic neoplasms with a prevalence of about 0.2 to 2 per million persons per year.1 The behavior of these tumors is difficult to predict and has been the subject of many studies. In addition to tumor size, histologic features such as necrosis, lymphovascular invasion, mitotic count, Ki-67 index, and immunohistochemical expression of cytokeratin 19 have been used as prognostic indicators.1-7 However, stage and grade seem to be the most predictive of prognosis in most studies.4,8,9 Recently, the World Health Organization (WHO) 2010 classification of neuroendocrine neoplasms of the digestive system,2 along with the AJCC Cancer Staging Manual, 7th edition,10 have adopted the use of mitotic count and Ki-67 index to determine tumor grade. The WHO 2010 classification of neuroendocrine neoplasms of the digestive system ❚Table 1❚ incorporates recent recommendations made by the European Neuroendocrine Tumor Society (ENETS) to use 2 classification systems. Instead of using a single hybrid gradeand stage-based system, the new WHO classification recommends a purely grade-based classification system and a separate sitespecific (TNM) staging system.7 All neuroendocrine tumors, including PanNETs (with the exception of neuroendocrine microadenomas <0.5 cm), are regarded as malignant tumors and the clinical behavior is largely determined by site-specific tumor biologic characteristics and stage at diagnosis. The proliferative index has emerged as a significant prognostic indicator and directly determines the tumor grade for PanNETs, especially in patients with same-stage Upon completion of this activity you will be able to: • describe the recommended guidelines for grading well-differentiated pancreatic neuroendocrine tumors. • recognize and discuss the pitfalls of Ki-67 grading. • apply a practical approach to interpreting Ki-67 index for determining grade of well-differentiated pancreatic neuroendocrine tumors. The ASCP is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The ASCP designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit TM per article. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity qualifies as an American Board of Pathology Maintenance of Certification Part II Self-Assessment Module. The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Questions appear on p 672. Exam is located at www.ascp.org/ajcpcme.