J Pathol Transl Med.  2017 Jul;51(4):396-402. 10.4132/jptm.2017.04.24.

HER2 Status and Its Heterogeneity in Gastric Carcinoma of Vietnamese Patient

• Phan DA
• Nguyen VT
• Hua TN
• Ngo QD
• Doan TP
• Nguyen ST
• Thai AT
• Nguyen VT

• KMID: 2392580
• DOI: http://doi.org/10.4132/jptm.2017.04.24

Abstract

BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is related to the pathogenesis and poor outcome of numerous types of carcinomas, including gastric carcinoma. Gastric cancer patients with HER2 positivity have become potential candidates for targeted therapy with trastuzumab.
METHODS
We investigated 208 gastric cancer specimens using immunohistochemistry (IHC), fluorescence in situ hybridization and dual in situ hybridization (ISH). We also investigated the concordance between IHC and ISH. The correlation between HER2 status and various clinicopathological findings was also investigated.
RESULTS
In total, 15.9% (33/208) and 24.5% (51/208) of gastric cancers showed HER2 gene amplification and protein overexpression, respectively. A high level of concordance between ISH and IHC analyses (91.3%, κ = 0.76) was found. A significant correlation between HER2 status and intestinal-type (p < .05) and differentiated carcinomas (p < .05) was also noted. The HER2 heterogeneity was high in gastric cancers; we found 68.8% phenotypic heterogeneity and 57.6% genotypic heterogeneity. Heterogeneity in HER2 protein expression and gene amplification showed a close association with diffuse histologic type and IHC 2+.
CONCLUSIONS
HER2 protein overexpression and gene amplification were detected in 24.5% and 15.9% of gastric cancer specimens, respectively. Intestinal-type showed a higher level of HER2 protein overexpression and gene amplification than diffuse type. HER2 status also showed a significant relationship with well- and moderately-differentiated carcinomas. The ratio of phenotypic and genotypic heterogeneity of HER2 was high in gastric carcinomas and was associated with HER2 IHC 2+ and diffuse histologic type.

Keyword

Protein HER2; Stomach neoplasms; Protein overexpression; Immunohistochemistry; Gene amplification; Fluorescence in situ hybridization; Dual-color silver in situ hybridization

MeSH Terms

Asian Continental Ancestry Group*
Fluorescence
Gene Amplification
Genes, erbB-2
Humans
Immunohistochemistry
In Situ Hybridization
Population Characteristics*
Receptor, Epidermal Growth Factor
Stomach Neoplasms
Trastuzumab
Receptor, Epidermal Growth Factor
Trastuzumab

Figure

• 

  Fig. 1. The human epidermal growth factor receptor 2 (HER2) protein expression detected by immunohistochemistry (IHC). HER2 IHC scores of 1+ (A), 2+ (B), and 3+ (C).

• 

  Fig. 2. The human epidermal growth factor receptor 2 (HER2) gene status detected by fluorescence in situ hybridization (FISH) and dual-color silver in situ hybridization (SISH). Representative photomicrographs of FISH (A, C) and dual-color SISH (B, D). Non-amplified cases detected by FISH (A) and dual-color SISH (B). Amplified cases detected by FISH (C) and dual-color SISH (D).

• 

  Fig. 3. Intratumoral heterogeneity of human epidermal growth factor receptor 2 (HER2). Heterogeneity of HER2 protein expression (A) and heterogeneity of HER2 gene amplification (B).

Reference

1. Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015; 136:E359–86.

2. Kuo CY, Chao Y, Li CP. Update on treatment of gastric cancer. J Chin Med Assoc. 2014; 77:345–53.

3. Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone fortreatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010; 376:687–97.

4. Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol Histopathol. 2005; 20:1005–15.

5. Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013; 31:3997–4013.

6. Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008; 52:797–805.

7. Takehana T, Kunitomo K, Kono K, et al. Status of c-erbB-2 in gastric adenocarcinoma: a comparative study of immunohistochemistry, fluorescence in situ hybridization and enzyme-linked immuno-sorbent assay. Int J Cancer. 2002; 98:833–7.

8. Yan SY, Hu Y, Fan JG, et al. Clinicopathologic significance of HER-2/neu protein expression and gene amplification in gastric carcinoma. World J Gastroenterol. 2011; 17:1501–6.

9. Park YS, Hwang HS, Park HJ, et al. Comprehensive analysis of HER2 expression and gene amplification in gastric cancers using immunohistochemistry and in situ hybridization: which scoring system should we use? Hum Pathol. 2012; 43:413–22.

10. 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; 15:65–71.

11. 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; 18:2833–40.

12. Park DI, Yun JW, Park JH, et al. HER-2/neu amplification is an independent prognostic factor in gastric cancer. Dig Dis Sci. 2006; 51:1371–9.

13. Shan L, Ying J, Lu N. HER2 expression and relevant clinicopathological features in gastric and gastroesophageal junction adenocarcinoma in a Chinese population. Diagn Pathol. 2013; 8:76.

14. Barros-Silva JD, Leitao D, Afonso L, et al. Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients. BrJ Cancer. 2009; 100:487–93.

15. Cho J, Jeong J, Sung J, et al. A large cohort of consecutive patients confirmed frequent HER2 positivity in gastric carcinomas with advanced stages. Ann Surg Oncol. 2013; 20 Suppl 3:S477–84.

16. 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; 62:221–8.

17. Grabsch H, Sivakumar S, Gray S, Gabbert HE, Müller W. HER2 expression in gastric cancer: rare, heterogeneous and of no prognostic value: conclusions from 924 cases of two independent series. Cell Oncol. 2010; 32:57–65.

18. 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; 19:2171–8.

19. Moelans CB, Milne AN, Morsink FH, Offerhaus GJ, van Diest PJ. Low frequency of HER2 amplification and overexpression in early onset gastric cancer. Cell Oncol (Dordr). 2011; 34:89–95.

20. Zhang XL, Yang YS, Xu DP, et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009; 33:2112–8.

21. Yonemura Y, Ninomiya I, Yamaguchi A, et al. Evaluation of immunoreactivity for erbB-2 protein as a marker of poor short term prognosis in gastric cancer. Cancer Res. 1991; 51:1034–8.

22. Vance GH, Barry TS, Bloom KJ, et al. Genetic heterogeneity in HER2 testing in breast cancer: panel summary and guidelines. Arch Pathol Lab Med. 2009; 133:611–2.

23. Nishida Y, Kuwata T, Nitta H, et al. A novel gene-protein assay for evaluating HER2 status in gastric cancer: simultaneous analyses of HER2 protein overexpression and gene amplification reveal intratumoral heterogeneity. Gastric Cancer. 2015; 18:458–66.

24. Lee S, de BoerWB, Fermoyle S, Platten M, Kumarasinghe MP. Human epidermal growth factorreceptor 2 testing in gastric carcinoma: issues related to heterogeneity in biopsies and resections. Histopathology. 2011; 59:832–40.