Variability of Ki67 labeling index in multiple neuroendocrine tumors specimens over the course of the disease

Background: The Ki67-LI is a valid surrogate for biologic behavior of neuroendocrine tumors (NETs), with higher levels associated with aggressive behavior. The World Health Organization (WHO) classifies NETs according to Ki67-LI (G1: <3%; G2 : 3-20%; G3: >20%). Little is known about the evolution of NETs histologic characteristics over the disease course. We sought to evaluate variations in Ki67-LI throughout NETs disease course. Methods: We retrospectively reviewed the Sunnybrook Odette Cancer Center NET database for patients with multiple pathology specimens. Primary outcome was the WHO NET class based on Ki67-LI for each specimen. We assessed change in WHO class between specimens. Results: Forty-three patients were retrieved, of which 39 had specimens from the primary tumor and a metastatic focus, and 4 had specimens from multiple metastatic foci. Sixteen (37.0%) were identified with Ki67-LI falling in different WHO classes on distinct biopsies. For 12 (75.0%) of those 16 patients, Ki67-LI showed enough variability for WHO class to be upstaged: 5 (31%) from G1 to G2, 2 (13%) from G2 to G3, and 5 (31%) from G1 to G3. Conclusion: When multiple pathology specimens were available, Ki67-LI varied throughout NETs disease course, with a majority of cases upgraded to a higher WHO class. If confirmed, this finding may have implications in how neuroendocrine tumors are monitored and treated. Further research is warranted to confirm these findings, understand better the underlying mechanisms of Ki67 variability, and define its relationship to prognosis. (C) 2014 Elsevier Ltd. All rights reserved.