Intratumoral Genetic Heterogeneity: A Frequent Finding in Gastric Carcinoma
Ann D Treacy, Andrea Grin, Catherine J Streutker. St. Michael's Hospital, Toronto, Canada
Background: Gastric and gastroesophageal junction (GEJ) adenocarcinoma has been shown to display significant heterogeneity in HER2 protein expression by immunohistochemistry (IHC). Genetic heterogeneity may also be seen in HER2 gene amplification. This may have important clinical implications in identifying a subpopulation of tumor cells that are responsive to treatment. Genetic heterogeneity is not well defined or well studied in gastric/GEJ tumors. In breast carcinoma, intratumoral heterogeneity has been defined as a tumor showing at least 5% but <50% of tumor nuclei with a ratio of >2.2. Our study's aim was to evaluate the frequency and distribution of intratumoral genetic heterogeneity in gastric/GEJ tumors.
Design: We identified 360 consecutive gastric/GEJ tumors tested for HER2 by IHC and in situ hybridization (ISH) (Dual ISH, Ventana) from Nov. 2011-Sept. 2012. At least 20 nuclei were scored, with counts focused within IHC positive areas. In order to identify intratumoral heterogeneity, individual tumor cell HER2/CEP17 ratios were calculated for each case and the percentage of tumor cells with a ratio ≥2.0 (gastric/GEJ criteria) determined. Adapting the recommended breast criteria, a tumor was considered genetically heterogenous if at least 5% but <50% of tumor nuclei had a ratio of ≥2.0. The tumor was considered amplified if the overall HER2/CEP17 was ≥2.
Results: 57 cases (15.8%) were HER2 amplified (overall HER2/CEP17 ratio ³2.0). The percentage of amplified nuclei was compared between the two groups. Whilst the majority of amplified cases showed >50% amplified tumor cells, five (9%) were genetically heterogenous (4 of 5 were 3+ on IHC, ratios 2.0 – 2.5). Interestingly, 97% (293/303) of non-amplified cases showed genetic heterogeneity as per breast criteria. 10 non-amplified cases had >50% amplified cells (5 cases were 0+, 2 cases were 1+ and 3 cases were 2+ on IHC, ratios 1.36 – 1.81). Furthermore, 21 non-amplified cases (overall ratios 1.21 – 1.75) contained 40-49% amplified cells.
Conclusions: Gastric/GEJ tumors show considerable intratumoral genetic heterogeneity when breast criteria are applied as a single amplified nucleus meets diagnostic threshold. Scattered amplified cells can be found in the majority of non-amplified cases. Many non-amplified tumors also contained ≥40% amplified cells, a finding that may reflect ambiguous classification and requires further study. Since breast criteria for genetic heterogeneity have not been robustly tested in gastric/GEJ tumors we would advocate further evaluation prior to adopting this definition.
Monday, March 4, 2013 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 118, Monday Morning