Research ArticlesHER2 Genetic Heterogeneity in Gastric Cancer Evaluation According to the College of American Pathologists Breast Cancer CriteriaTreacy, Ann D. MB, MRCPI, FRCPath, FFPath; Karamchandani, Jason R. MD; Streutker, Catherine J. MSc, MD, FRCP(C); Grin, Andrea MD, FRCP(C)Author Information St. Michael’s Hospital, Department of Laboratory Medicine, Li Ka Shing Knowledge Institute and the University of Toronto, ON, Canada C.J.S. has received a speaking honorarium from Roche Canada. The remaining authors declare no conflict of interest. Reprints: Andrea Grin, MD, FRCP(C), St. Michael’s Hospital, Department of Laboratory Medicine, Li Ka Shing Knowledge Institute and the University of Toronto, 30 Bond Street, Toronto, ON, Canada M5B 1W8 (e-mail: [email protected]). Received June 23, 2014 Accepted August 4, 2014 Applied Immunohistochemistry & Molecular Morphology: October 2015 - Volume 23 - Issue 9 - p 628-632 doi: 10.1097/PAI.0000000000000136 Buy Metrics Abstract Gastric and gastroesophageal junction (GEJ) adenocarcinomas have been shown to display significant HER2 genetic heterogeneity (GH). This is typically seen as a cluster of HER2-positive cells but can also take the form of intermingled cells, referred to a “mosaic” pattern. GH is not well defined in gastric/GEJ tumors and the “mosaic” pattern has never been studied. We sought to evaluate the frequency and distribution of the “mosaic” pattern of GH in gastric/GEJ tumors using the College of American Pathologists-endorsed breast criteria of 5% to <50% amplified nuclei. We also postulated that the lower limit of this GH definition might be seen by chance in normal gastric epithelium. A total of 360 consecutive gastric/GEJ tumors were tested for HER2 by immunohistochemistry and in situ hybridization. Individual tumor cell HER2:CEP17 ratios were calculated for each case and the percentage of tumor cells with a ratio ≥2.0 determined. In addition, 300 normal gastric epithelial cells were scored for HER2 and CEP17 signals. Overall, 265 cases (73.4%) showed GH. The percentage of amplified cells in GH cases linearly correlated with the overall HER2:CEP17 ratio. In normal gastric epithelium, a cell with an “amplified” 2:1 ratio was seen in 9.7% (29/300) of cells, thus reaching GH. The chance of “GH” in scoring 20 normal epithelial cells was 87%. We conclude that GH is very common in gastric/GEJ tumors when College of American Pathologists breast criteria are applied and the lower threshold is likely of little clinical significance due to the finding “amplified” 2:1 nuclei in normal cells. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.