WHO Histologic Classification Is an Independent Predictor of Prognosis in Lung Neuroendocrine (NE) Tumors but Ki-67 Proliferation Rate Is Not
Hangjun Wang, Akira Iyoda, Mee Sook Roh, Gabriel Sica, Natasha Rekhtman, Maria C Pietanza, Inderpal Sarkaria, William D Travis. Memorial Sloan-Kettering Cancer Center, New York, NY; Kitasato University, Kanagawa, Japan; Dong-A University College of Medicine, Busan, Korea; Emory University, Atlanta, GA
Background: Proliferation rate (PR) by Ki-67 immunohistochemistry has been shown to be useful in predicting prognosis of extrapulmonary NE tumors and has been incorporated into some classification schemes. A small number of studies have shown PR to be of prognostic significance in lung NE tumors, but it has not been rigorously compared with other prognostic factors.
Design: We studied 190 NE lung tumors including 87 typical carcinoids (TC), 22 atypical carcinoids (AC), 41 large cell NE carcinomas (LCNEC) and 40 small cell lung carcinomas (SCLC) diagnosed according to 2004 WHO criteria (WHO-C). Immunohistochemistry for Ki-67 (Ventana clone 30-9, Rabbit monoclonal antibody) was performed on whole tissue sections from 190 resection specimens. Nuclear positive cells were counted in hot spots per 100 cells.
Results: The mean (range) of mitoses per 2mm2 vs PR was for TC: 0.6 (0-1) vs 4.15 (1-15); AC: 4.55 (1-9) vs 17.8 (8-35); LCNEC: 49 (18-121) vs 63.9 (40-90); and SCLC: 56.3 (25-137) vs 77.5 (50-100). In all NE tumors (NET), necrosis (p<0.001), mitoses (p<0.001), PR (p<0.001), tumor size (p<0.001), stage (p<0.001), WHO-C (p<0.001) and age (p=0.002) were significant for overall survival (OS). For all NET in multivariate analysis stratified for stage, including WHO-C, PR, size, and age, WHO-C was the only independent predictor of survival (p=0.026). For TC/AC alone, necrosis (p<0.001), WHO-C (p<0.001) Stage (p=0.024), PR (p=0.001), and mitoses (p=0.007) were significant for OS. However in TC/AC, multivariate analysis stratified for stage including PR and WHO-C, showed only WHO-C was an independent predictor of survival. Within TC/AC, a PR cutoff of 10% (p=0.014), but not 5% (p=0.079) was predictive of OS.
Conclusions: Classification of pulmonary NET according to WHO criteria by routine light microscopy based on mitosis counting and assessing necrosis is an independent predictor of prognosis in pulmonary NET but PR assessment by Ki-67 is not. This finding applies to classification of NET overall as well as for TC/AC alone. Ki-67 staining is particularly useful as an aid in determining histologic grade in NET where mitoses are difficult to appreciate due to poor fixation, sectioning, staining, necrosis or crush artifact. However, these data do not support incorporation of Ki-67 as a primary criteria in the classification scheme of pulmonary NET.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 295, Monday Morning