Clinicopathological Implication of HER2/neu Expression in Carcinoma Stomach

Introduction

Gastric cancer is one of the most significant causes of cancer-related morbidity and mortality worldwide. It is the fifth most frequently diagnosed and third leading cause of cancer-related deaths.¹ Most of the patients present with gastric cancer at an advanced stage increasing the frequency of metastasis, making the existing therapeutic options unsatisfactory. The median survival associated with this neoplasm in advanced cases is only a year.² Hence, there is a need to identify molecular biology associated with the oncogenesis of gastric cancer and develop targeted therapies designed on a molecular level. However, there is increasing evidence that human epidermal growth factor receptor (HER2/neu) overexpression is a frequent molecular abnormality in gastric and gastroesophageal junction cancer. Taking clues from breast cancer treatment, trastuzumab (Herceptin) has been considered a potential treatment option in HER2/neu positive cases of gastric cancer. Immunohistochemistry (IHC) is one of the current standard methods for tissue HER2/neu status in gastric cancer. The frequency of HER2/neu overexpression in gastric and gastroesophageal junction cancer varies from 4.4 to 53.4% with a mean of 17.9%.³ There is a lack of Indian studies, hence a need to determine the frequency of HER2/neu in the Indian population for better patient management. Therefore, we aimed to evaluate HER2/neu expression status by IHC in gastric cancer. Furthermore, we also find the association of HER2/neu expression with different clinicopathologic parameters to identify the positive cases that may benefit from targeted therapy.

Materials and Methods

Results

Demographics and Clinicopathologic Characteristics

The basic demographic and clinicopathologic characteristics of the 30 patients having gastric cancer with metastasis in this descriptive study are summarized in Table 1. The mean age of the patients was 61.1 ± 10.4 years, with the most common age of presentation ranging from 61 to 70 years (36.66%), which accounted for the largest group, followed by those within the age range of 51 to 60 (30%). Most of the metastatic gastric cancer patients were males (70%) and were nonvegetarian (56.67%) by diet, who were both fish and other meat eaters. For patients with metastasis, palliative care is preferred. Therefore, endoscopic biopsies (90%) were taken in the majority of the study. Amidst gastrectomy cases, only three fulfilled our criteria of gastric cancer with metastasis (locoregional /distant) since their TNM staging was T4N1M1 with tumor deposits in the omentum. Lymph node metastasis was found to be the most common (53.33%), followed by both lymph node and liver metastasis (13.33%) and liver metastasis alone (10%). The proximal (60%) site of the tumor, with a highly intestinal (66.66%) histological type of distribution was the most common in the study subjects. However, the most common grade of gastric carcinoma was moderately differentiated (53.33%), followed by poorly differentiated (36.67%) tumors (Fig. 1). Furthermore, the chi-square test analysis showed that there was no statistically significant association of HER2/neu expression with age, gender, diet, tumor site, subtype, and grade.

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Fig. 1

Histopathological grading analysis showing well-differentiated (A), moderately differentiated (B), and poorly differentiated (C) adenocarcinoma of stomach (hematoxylin and eosin [H&E], 10 ×).

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Table 1 Demographic and clinicopathologic characteristics of subjects (n = 30)

Characteristic	N, %
Age(y)
< 50	05, 16.67
51–60	09, 30.00
61–70	11, 36.66
>70	05, 16.67
Gender
Male	21, 70.00
Female	09, 30.00
Diet type
Nonvegetarian	17, 56.67
Vegetarian	13, 43.33
Specimen type
Biopsy	27, 90.00
Resection	03, 10.00
Distribution of metastasis
Bone metastasis	02, 06.67
Liver metastasis	03, 10.00
Lymph node metastasis	16, 53.33
Lymph node and liver metastasis	04, 13.33
Peritoneal metastasis	02, 06.67
Omental metastasis	02, 06.67
Malignant diffusion	01, 03.33
Tumor site
Proximal	18, 60.00
Distal	12, 40.00
Histological type
Diffuse	08, 26.67
Intestinal	20, 66.66
Mixed	02, 06.67
Grade of carcinoma
Poorly differentiated	11, 36.67
Moderately differentiated	16, 53.33
Well-differentiated	03, 10.00

Discussion

The third most common cause of mortality worldwide due to cancer is carcinoma stomach.⁵ According to the National Cancer Registry, 32,713 patients with gastric cancer were identified in the year 2020, which is the sixth most common type of cancer in females, and the fifth most common type in Indian males.^6,7 Therefore, it is important to determine and identify the gastric cancer histological type, grade, and HER2/neu expression. This would help to find patients who can benefit from monoclonal antibody-based trastuzumab therapy. With this background, this study aimed to assess the HER2/neu expression in advanced gastric carcinoma by IHC. The mean age of the study population was 61.4 years with the range of the patient varying from 33 to 80 years with a predominance in males. This could be due to the higher exposure of males to certain risk factors such as tobacco, alcohol, inorganic dust, nitrosamines, etc.^8,9

This study observed that nonvegetarian diet-following patients had a majority succumbing to carcinoma stomach (56.7%), compared to the vegetarian diet-based study population. In addition, the most common pattern of metastasis noted in this study was lymph node metastasis (53.3%), followed by both lymph node and liver metastasis (13.33%), and our findings were in concordance with the study by Verstegen et al.¹⁰ Several studies including our study showed the presence of tumor in the proximal portion (predominantly fundus) of the stomach.^11–13 Microscopically, 67% of the carcinomas in this study were intestinal type, and similar findings were observed in other studies.^14–16 Moreover, moderately differentiated carcinoma was the predominant grade followed by poorly and well-differentiated carcinoma similar to the Gupta et al study.¹⁴ Furthermore, this study did not find any statistical significance in the association of HER2/neu expression with age, gender, diet, tumor site, subtype, and grade; it might be attributable to the relatively low sample size.

The immunohistochemical analysis of HER2/neu status was according to Hoffman's scoring criteria for determining the IHC score.⁴ This included strongly positive membranous staining as a 3+ score, while cytoplasmic and luminal staining were not included. This study showed 13.3% positivity of HER2/neu by IHC, which lies in the range (8.253.4%) reported by various international articles from Japan, Australia, etc.^16,18–20 Studies done before Hoffman's scoring criteria were developed, showed higher positivity. The broad variations in the HER-2/neu overexpression were due to different scoring criteria and interobserver variability. Another reason is the use of several methodologies to detect overexpression. The different populations (genetic differences) studied by the various groups could also be held accountable. The genetic differences among the various populations studied by different groups could be a factor for variation in the wide range of positivity for HER2 by IHC. This study found only four patients with HER2/neu positive status, which could be because of following the strict protocols including methodology and Hoffman's scoring criteria. Studies done recently, following standard protocols and scoring criteria, have reported HER2/neu overexpression close to 15%. A study done by Shan et al done on 1,463 patients showed 9.8% positivity.^17,21

Conclusion

Overall, this study indicates that HER2/neu expression is not associated with any of the clinicopathological parameters. Therefore, overexpression of HER2/neu can be taken as an independent prognostic factor in patients with carcinoma stomach. Moreover, HER2 positivity by IHC would help to decide the therapy to be implemented and it will further help in improving the overall quality of life and survival of patients with carcinoma stomach.