HER2 as a potential biomarker of lymph node metastasis in undifferentiated early gastric cancer

Abstract

Human epidermal growth factor receptor 2 (HER2) is implicated in several cancers, including gastric cancer. However, limited data are available regarding its clinical significance in early gastric cancer (EGC). We evaluated the clinical significance of HER2 overexpression in patients with EGC. We retrospectively reviewed 727 patients who underwent surgical treatment for EGC between October 2010 and August 2017. HER2 expression was analysed in 680 EGC cases by immunohistochemistry and classified as negative (0 and 1+), equivocal (2+), or positive [overexpression (3+)]. Among patients with differentiated EGC, the number of patients with HER2 overexpression was not significantly different from that of HER2-negative patients in terms of age, sex, tumour size, location, gross type, depth of invasion, presence of lymphovascular invasion (LVI), and presence of lymph node metastasis (LNM). However, in patients with undifferentiated EGC, HER2 overexpression was significantly correlated with LVI and presence of LNM compared with HER2-negative patients. Multivariate analysis indicated HER2 overexpression as a good predictive marker of LNM in patients with undifferentiated EGC. HER2 expression is associated with LNM in undifferentiated EGC. Therefore, the importance of HER2 overexpression in EGC should not be overlooked, and further studies are needed to identify its clinical significance.

Figure 1

Representative cases showing an example of scoring in HER2 immunohistochemistry staining. (A) 0 Negative: No response to staining, no tumour cell membrane responds to staining at all. Cytoplasmic staining was not included in the scoring. (B) 1+ Negative: Tumour cells with very faint staining or barely recognisable staining. (C) 2+ Equivocal: refers to the case of weak or moderate complete staining on the basolateral and lateral sides of tumour cells. Tangentially cut cells in columnar cells tended to show a complete membrane staining pattern. (D) 3+ Positive: Tumour cells show a strong complete staining reaction in the basolateral and lateral membranes. It should be taken into account that some of the cells that appeared to show a complete membrane staining pattern were often tangentially cut columnar cells. Original magnification x 400 (A–D). HER2, Human epidermal growth factor receptor 2.

Figure 2

Patients with stage 1 in TNM staging system in the TCGA STAD dataset. We arranged The Cancer Genome Atlas Stomach Adenocarcinoma (TCGA STAD) patient samples that were stage I by T1 tumour stage in the TNM staging system and with available ERBB2 expression levels. Eleven samples were available and their differentiated statuses were accessed from pathology reports. The ERBB2 expression level of the poorly differentiated sample, TCGA-HU-A4G6-01, was only slightly higher than the ERBB2 mean value of whole tumour samples (coloured as red in the ERBB2 column), and its lymph nodes stage was N0. The ERBB2 expression of the TCGA-KB-A6F7-01 sample, which was poorly differentiated, was lower than the mean value (coloured as blue in the ERBB2 column), and its lymph nodes stage was N1 (coloured as red in the N column). #N/A indicates not available. D, differentiated adenocarcinoma; H, high; HER2, Human epidermal growth factor receptor 2; L, low; MD, moderately differentiated cancer; PA, papillary adenocarcinoma; PD, poorly differentiated cancer; UD, undifferentiated adenocarcinoma.

Figure 3

Flow chart of patient selection in this study. HER2, Human epidermal growth factor receptor 2.