Editorial New guidelines for HER2 pathological diagnostics in gastric cancer

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1 bs_bs_banner Pathology International 2016; 66: doi: /pin Editorial New guidelines for HER2 pathological diagnostics in gastric cancer Ryo Wada, 1 Kenichi Hirabayashi, 2 Nobuyuki Ohike 3 and Eiichi Morii 4 1 Department of Pathology, Juntendo University Shizuoka Hospital, Shizuoka, 2 Department of Pathology, Tokai University School of Medicine, 3 Department of Pathology, Showa University Fujigaoka Hospital, Kanagawa and 4 Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan The aim of this editorial is to introduce new guidelines, including novel evidence and figures, on the human epidermal growth factor receptor 2 (HER2) pathological diagnosis of gastric cancer. In breast cancer, HER2 protein overexpression and HER2 gene amplification are significant prognostic factors and are targets for therapy. Therefore, technical methods and criteria for determining HER2 overexpression have been developed. Since these HER2 findings are also important in gastric cancer, the quality control committee of the Japanese Society of Pathology produced guidelines for the pathological diagnosis of HER2 expression in gastric cancer, including methods for pathological analysis. These guidelines were led by Dr. Kijima Hiroshi and were published in November 2011 ( patho2/seidokanri/igan_her2.pdf). The guidelines suggested in this paper were created based on new evidence and include inputs from Dr. Wada Ryo, Dr. Hirabayashi Kenichi, and Dr. Ohike Nobuyuki who were recommended by the guideline s author, Dr. Kijima. New figures are also presented. These guidelines should be referred to for the pathological diagnosis of HER2 in gastric cancer. CLINICAL QUESTION (CQ)-1 What is the major histological subtype for the gastric cancer with HER2 protein overexpression? The rate of HER2 protein over-expression is higher in differentiated gastric adenocarcinomas than in undifferentiated gastric adenocarcinomas. Figure 1 Resected stomach. Hematoxylin and eosin (H&E) staining: moderately differentiated tubular adenocarcinoma (tub2). Immunohistochemistry (IHC) method: strong cell membrane (mainly lateral) positive tumor cells are observed in 10% or more of one section, equivalent to a score of 3 +. An anti-her-2/neu (4B5) rabbit monoclonal primary antibody (Roche Diagnostics, Tokyo, Japan) was used. The same antibody was used for the IHC in Figures 2 6. Dual color in situ hybridization (DISH) method: high amplification is seen, with a HER2/CEP17 ratio of 10.4, which was determined to be positive. R. W., K. H, and N. O. equally contributed to this work. April 2015 edition Edited by the committee of the Japanese Society of Pathology on guidelines for HER2 pathological diagnostics in gastric cancer

2 58 Editorial Figure 2 Resected stomach. Hematoxylin and eosin (H&E) staining: welldifferentiated tubular adenocarcinoma (tub1), intestinal type. Immunohistochemistry (IHC) method: weak cell membrane positive tumor cells are observed in 10% or more of one section, equivalent to a score of 2 +. Dual color in situ hybridization (DISH) method: mild amplification is seen, with a HER2/CEP17 ratio of 2.9, which was determined to be positive. Figure 3 Stomach biopsy. Hematoxylin and eosin (H&E) staining: poorlydifferentiated adenocarcinoma (por1). Immunohistochemistry (IHC) method: weak to moderate cell membrane positive tumor cell clumps are observed, equivalent to a score of 2 +. Dual color in situ hybridization (DISH) method: no amplification is seen, with a HER2/CEP17 ratio of 1.4, which was determined to be negative. Figure 4 Stomach biopsy. Hematoxylin and eosin (H&E) staining: poorly differentiated adenocarcinoma (por2). Immunohistochemistry (IHC) method: weak to moderate cell membrane positive tumor cell clumps are observed, equivalent to a score of 2 +. Dual color in situ hybridization (DISH) method: mild amplification is seen, with a HER2/CEP17 ratio of 3.2, which was determined to be positive. Outline of the evidence: HER2 overexpression in gastric cancer varies with tumor type. Fifteen to 50% of intestinal type gastric cancers overexpress HER2, whereas approximately 2 25% of diffuse/mixed type gastric cancers express HER2 (Figs 1 4). 1 6 All tumor classifications were based on Lauren s criteria. HER2 overexpression in intestinal or well-differentiated gastric carcinomas was associated with a worse prognosis than that of HER2-negative tumors, although there have been no studies on the prognostic differences between HER2 expression in diffuse or mixed types. 3 When several histological types are intermingled in the same materials, there are no criteria outlining which histological type to select for HER2 evaluation. The material including intestinal type may be selected because the rate of HER2 positivity is high in this type.

3 Editorial 59 1 Dang HZ, Yu Y, Jiao SC. Prognosis of HER2 over-expressing gastric cancer patients with liver metastasis. World J Gastroenterol 2012; 18: Fan XS, Chen JY, Li CF et al. Differences in HER2 overexpression between proximal and distal gastric cancers in the Chinese population. World J Gastroenterol 2013; 19: He C, Bian XY, Ni XZ et al. Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer. World J Gastroenterol 2013; 19: Kim KC, Koh YW, Chang HM et al. Evaluation of HER2 protein expression in gastric carcinomas: Comparative analysis of 1,414 cases of whole-tissue sections and 595 cases of tissue microarrays. Ann Surg Oncol 2011; 18: Liang JW, Zhang JJ, Zhang T, Zheng ZC. Clinicopathological and prognostic significance of HER2 overexpression in gastric cancer: A meta-analysis of the literature. Tumour Biol 2014; 35: Oh HS, Eom DW, Kang GH et al. Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection. Gastric Cancer 2014; 17: (the date of investigation). CQ-2 To what degree is the rate of the HER2 expression heterogenicity in gastric cancer due to HER2 protein overexpression? The incidence of HER2 expression heterogenicity in gastric cancers examined for HER2 protein overexpression has been reported to be 20 80%. Outline of evidence: HER2 expression heterogenicity is higher in gastric cancer than in breast cancer. HER2 heterogenicity is observed in approximately 45 79% of gastric cancers by immunohistochemistry (IHC) and in approximately 23 54% by in situ hybridization (ISH; fluorescence ISH, FISH). Heterogeneity tends to be detected better in IHC than in FISH (Fig. 5). 1 4 In particular, HER2 heterogenicity has been well observed in diffuse/mixed type cancers, score 2 HER2 cases by IHC, and low-level amplification cases by FISH. 2 When HER2 overexpression is limited to the intramucosal carcinoma lesion within the surgically resected material, the pathological details of this staining finding may be recorded. The pathological diagnosis of intramucosal gastric neoplasia differs between Japan and Western countries, and the ToGA test was based on the diagnosis in Western countries. This is why the description of HER2 expression in intramucosal lesions is recommended Kim MA, Lee HJ, Yang HK, Bang YJ, Kim WH. Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma. Histopathology 2011; 59: Lee HE, Park KU, Yoo SB et al. Clinical significance of intratumoral HER2 heterogeneity in gastric cancer. Eur J Cancer 2013; 49: Lee S, de Boer WB, Fermoyle S, Platten M, Kumarasinghe MP. Human epidermal growth factor receptor 2 testing in gastric carcinoma: Issues related to heterogeneity in biopsies and resections. Histopathology 2011; 59: Yang J, Luo H, Li Y et al. Intratumoral heterogeneity determines discordant results of diagnostic tests for human epidermal growth factor receptor (HER) 2 in gastric cancer specimens. Cell Biochem Biophys 2012; 62: Wada R, Abe H, Taki K, Kuwabara N. Immunohistochemical expression of c-myc oncogene products, c-erbb-2 gene product, protein kinase c and lysozyme in gastric super minute tubular adenocarcinomas (measuring up to 1 mm in diameter). Acta Histochem Cytochem 1991; 24: Yoshida H, Yamamoto N, Taniguchi H et al. Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch 2014; 465: Fusco N, Rocco EG, Del Conte C et al. HER2 in gastric cancer: A digital image analysis in pre-neoplastic, primary and metastatic lesions. Mod Pathol 2013; 26: Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastrooesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet 2010; 376: Fassan M, Mastracci L, Grillo F et al. Early HER2 dysregulation in gastric and oesophageal carcinogenesis. Histopathology 2012; 61: Valente P, Garrido M, Gullo I et al. Epithelial dysplasia of the stomach with gastric immunophenotype shows features of biological aggresiveness. Gastric Cancer 2015; 18: Boku N. HER2-positive gastric cancer. Gastric Cancer 2014; 17: (the date of investigation), except reference no. 5. CQ-3 To what degree is HER2 protein overexpression concordant between primary and metastatic gastric cancer lesions? The rate of HER2 overexpression concordance between primary and metastatic carcinomatous lesions in gastric cancer is more than 80%. Outline of the evidence: The concordance of HER2 expression between primary and metastatic carcinomatous lesions in gastric cancer is approximately % when measured by ISH (FISH; dual color in situ hybridization, DISH) and approximately 80 95% when measured by IHC. 1 4 Heterogeneity of HER2 expres-

4 60 Editorial Figure 5 Resected stomach. Left upper: Immunohistochemistry (IHC) method: intratumoral heterogeneity of HER2 expression. Left lower: IHC method: strong near-circumferential cell membrane positive cells, equivalent to a score of 3 +. Dual color in situ hybridization (DISH) method: high amplification is seen, with a HER2/CEP17 ratio of 11.5, which was determined to be positive. Right upper: IHC method: no positive cells are seen in the tumor cells, equivalent to a score of 0. Dual color in situ hybridization (DISH) method: no amplification is seen, with a HER2/CEP17 ratio of <2.0, which was determined to be negative. sion in primary lesions is observed in cases of nonconcordance between HER2 expression in primary and metastatic tumors (Fig. 6). If HER2 expression heterogeneity exists in the primary lesion, then there is a possibility for non-concordance among metastatic lesions. Currently, there is no evidence on the effectiveness of anti-her2 therapy in cases where HER2 is differentially expressed in primary and metastatic lesions. 3 Kim MA, Lee HJ, Yang HK, Bang YJ, Kim WH. Heterogeneous amplification of ERBB2 in primary lesions is responsible for the discordant ERBB2 status of primary and metastatic lesions in gastric carcinoma. Histopathology 2011; 59: Kochi M, Fujii M, Masuda S et al. Differing deregulation of HER2 in primary gastric cancer and synchronous related metastatic lymph nodes. Diagn Pathol 2013; 8: 191. (the date of investigation). 1 Bozzetti C, Negri FV, Lagrasta CA et al. Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma. Br J Cancer 2011; 104: Fassan M, Ludwig K, Pizzi M et al. Human epithelial growth factor receptor 2 (HER2) status in primary and metastatic esophagogastric junction adenocarcinomas. Hum Pathol 2012; 43: CQ-4 To what degree is the rate of HER2 overexpression concordant between biopsy and surgically resected specimens in gastric cancer?

5 Editorial 61 Figure 6 Gastric cancer with bone metastasis. Upper (resected stomach) (8-year-old material): Hematoxylin and eosin (H&E) staining: poorly-differentiated adenocarcinoma (por2). Immunohistochemistry (IHC) method: no positive tumor cells are observed, equivalent to a score of 0. Dual color in situ hybridization (DISH) method: unable to evaluate due to inadequate CEP17 staining. Lower (bone biopsy): H&E staining: metastatic adenocarcinoma. IHC method: strong near-circumferential cell membrane positive tumor cells are observed in 10% or more of one section, equivalent to a score of 3 +. DISH method: high amplification is seen, with a HER2/CEP17 ratio of 15.6, which was determined to be positive. The concordance rate of HER2 protein overexpression between biopsy and surgically resected gastric cancer specimens in gastric cancer is over 60%. Outline of the evidence: The concordance rate of HER2 expression between biopsy specimens and surgically resected specimens is 57 89% by IHC and 62 96% by ISH (FISH/DISH), there are no significant differences between IHC and ISH. 1 4 Yoshida et al. 4 reported that the concordance rates of HER2 expression between biopsy and surgically resected material were K = by IHC and K = by FISH. Using both IHC and ISH, the concordance rate of HER2 expression between biopsy specimens and surgically resected specimens is approximately 92 96%. 1,5 Lee et al. 2 reported that the relatively high concordance of HER2 expression between biopsy and surgically resected specimens was observed in score 0 (70%, 28/40 cases) and score 3 samples (71%, 5/7 cases), whereas there was no concordance in score 1(3 cases) or score 2 (4 cases) samples. The rate of HER2 expression concordance between biopsy and surgically resected specimens showed lower heterogeneity in surgically resected materials (24% vs. 80%, P = 0.016). 5 Although there are no clear criteria regarding how many samples should be taken during biopsy, there are no significant differences between the number of samples taken by biopsy and concordance (5.6 vs. 5.8, P = 0.83). 5 1 Pirrelli M, Caruso ML, Di Maggio M, Armentano R, Valentini AM. Are biopsy specimens predictive of HER2 status in gastric cancer patients? Dig Dis Sci 2013; 58:

6 62 Editorial 2 Lee S, de Boer WB, Fermoyle S, Platten M, Kumarasinghe MP. Human epidermal growth factor receptor 2 testing in gastric carcinoma: Issues related to heterogeneity in biopsies and resections. Histopathology 2011; 59: Yano T, Doi T, Ohtsu A et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol Rep 2006; 15: Yoshida H, Yamamoto N, Taniguchi H et al. Comparison of HER2 status between surgically resected specimens and matched biopsy specimens of gastric intestinal-type adenocarcinoma. Virchows Arch 2014; 465: Wang T, Hsieh ET, Henry P, Hanna W, Streutker CJ, Grin A. Matched biopsy and resection specimens of gastric and gastroesophageal adenocarcinoma show high concordance in HER2 status. Hum Pathol 2014; 45: (The date of investigation). (NOTE) DISH METHOD DISH method: the overexpression of HER2 in tumor cells occurs in association with genetic amplification at the DNA level. To observe this amplification, the FISH method is normally used; however, the clinical application of the DISH method, which enables the analysis of DNA in a bright field, is also expected. HER2 genes are labeled with silver particles, and the centromere of chromosome 17 is visualized by a red color. This method of evaluation is the same as that of the FISH method, and a HER2/CEP17 ratio 2.0 is determined to be positive. None declared. DISCLOSURE STATEMENT