17. Heterogeneity of HER2 overexpression in gastric dysplasia and carcinoma in an Australian cohort

Abstract

Background Trastuzumab has been approved in Europe for the treatment of advanced gastric carcinoma. There is a need to accurately identify HER2 status in gastric cancer. The issues of morphologic and molecular heterogeneity and HER2 expression in dysplasia have not been addressed. Aims To assess HER2 status and heterogeneity in gastric dysplasia and carcinoma in paired biopsies and gastrectomies. Methods Gastric carcinoma with biopsies and gastrectomies between January 2000 and December 2009 were retrieved from the PathWest archives. Immunohistochemistry (IHC) for HER2 was performed on gastrectomy tumour blocks, and assessed for HER-2 overexpression and heterogeneity. SISH was performed in 11 cases showing at least 1+ reaction. HER-2 and SISH was performed in biopsies from 3 cases which showed HER2 over-expression on gastrectomy. Results There were 89 cases of gastric carcinoma with paired biopsy and gastrectomy specimens. Sixteen of 89 (18.0%) showed HER2 overexpression (2+ or 3+) on IHC, including 5 cases where reactivity was limited to dysplastic epithelium. Of 44 cases with dysplasia, HER2 overexpression was observed in dysplastic epithelium in 10 (22.7%), and not seen in benign mucosa in any case. Heterogeneity of HER2 overexpression in invasive carcinoma was noted in all cases. The proportion of IHC 2+/3+ clones varied from less than 25% (n = 3), 25–50% (n = 3), 50–75% (n = 2) to >75% (n = 3). SISH confirmed HER2 amplification in 7 of 8 IHC positive cases (6/6 3+, 1/2 2+), and no amplification in 3 tumours with 1+ staining. SISH amplification correlated with the areas of IHC overexpression in all. All biopsies from three HER2 positive tumours demonstrated HER2 overexpression/amplification, including two cases where HER2 + clones accounted for Conclusions 1. HER2 status is comparable to previous studies in gastric carcinoma with good concordance between HER2 3+ overexpression and HER2 amplification. 2. Heterogeneity of tumour HER2 overexpression/amplification may have important implications for HER2 testing in biopsies with the potential for false negative results. 3. HER2 positive dysplasia with negative invasive carcinoma raises issues regarding its role in pathogenesis, and the potential for false positive biopsies. 4. HER2 overexpression appears sufficiently specific to be considered a potential biomarker of dysplasia although the sensitivity is low.