Ki-67 proliferative index in gastroenteropancreatic neuroendocrine neoplasms

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are potentially malignant neoplasms that differ significantly in their clinical behavior and metastatic potential according to several factors. Among these factors, Ki-67 proliferative index (PI) is a crucial element in determining the World Health Organization (WHO) grade of GEP-NENs, which is in itself a major cornerstone in determining patient prognosis and guiding treatment. In this article, we report a case of a pancreatic neuroendocrine tumor demonstrating a characteristic slowly progressive course and eventually resulting in patient death. We utilize immunohisto-chemical staining for Ki-67 to determine the tumor's PI and classify it according to the 2010 WHO grading system. We then review the prognostic value of Ki-67 and its role in the current WHO classification of GEP-NENs, discuss the best methods of determining a tumor's PI based on Ki-67 immunohistochemistry, and address a few problematic issues in the current WHO grading scheme. We stress that Ki-67 PI should be estimated based on the hotspot technique, utilizing either conventional manual count or digital imaging analysis, but eyeball estimates should be avoided. Although the current WHO grading scheme provides good prognostic stratification, we suggest that it may require some future refinement in order to provide more site-specific categorization and include certain categories that are not well addressed in the current scheme.