Prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma

Abstract

Purpose: Gastric carcinoma (GC) is a highly aggressive cancer and one of the leading causes of cancer-related deaths worldwide. Histopathological evaluation pertaining to invasiveness is likely to provide additional information in relation to patient outcome. In this study, we aimed to evaluate the prognostic significance of tumor budding and single cell invasion in gastric adenocarcinoma.

Materials and methods: Hematoxylin and eosin-stained slides generated from 296 gastric adenocarcinoma patients with full clinical and pathological and follow-up information were systematically reviewed. The patients were grouped on the basis of tumor budding, single cell invasion, large cell invasion, mitotic count, and fibrosis. The association between histopathological parameters, different classification systems, and overall survival (OS) was statistically analyzed.

Results: Among the 296 cases that were analyzed, high-grade tumor budding was observed in 49.0% (145) of them. Single cell invasion and large cell invasion were observed in 62.8% (186) and 16.9% (50) of the cases, respectively. Following univariate analysis, patients with high-grade tumor budding had shorter OS than those with low-grade tumor budding (hazard ratio [HR]: 2.260, P<0.001). Similarly, the OS of patients with single cell invasion and large cell invasion was reduced (single cell invasion, HR: 3.553, P<0.001; large cell invasion, HR: 2.466, P<0.001). Following multivariate analysis, tumor budding and single cell invasion were observed to be independent risk factors for gastric adenocarcinoma (P<0.05). According to the Lauren classification, patients with intestinal-type adenocarcinoma had better outcomes than those with diffuse-type adenocarcinoma (HR: 2.563, P<0.001).

Conclusion: Tumor budding and single cell invasion in gastric adenocarcinoma are associated with an unfavorable prognosis.

Keywords: gastric carcinoma; invasion type; metastasis; pathology; prognosis.

Figure 1

Microscopic observations for gastric adenocarcinoma (HE stain). Notes: (A) Tumor budding (arrows) was defined as a cluster of tumor cells composed of fewer than five tumor cells and was evaluated at 100× magnification. (B) Tumor budding (arrows) evaluated at 400× magnification. (C) Single cell invasion indicated by arrows at 400× magnification. (D) Large cell invasion was defined as a tumor cell whose nucleus diameter was quadruple the size of a small nearby lymphocyte. Indicated by arrows at 400× magnification. (E) Mitosis indicated by arrows at 400× magnification. (F) Fibrosis was confirmed if the area of fibrosis was >60% of the microscopic field. Evaluated at 100× magnification. Abbreviation: HE, hematoxylin and eosin.

Figure 2

Overall survival (OS) figures pertaining to tumor budding (A), single cell invasion (B), large cell invasion (C), and mitotic count (D) in gastric adenocarcinoma. Notes: (A) Kaplan–Meier survival curve for tumor budding in patients with gastric adenocarcinoma. The OS of cases with high-grade tumor budding was shorter than for cases exhibiting low-grade budding (P<0.001). (B) Patients with single cell invasion had shorter OS compared to those without single cell invasion (P<0.001). (C) Patients with large cell invasion had shorter OS compared to those without large cell invasion (P<0.001). (D) Patients with high mitotic count had shorter OS compared to those without high mitotic count (P=0.035).

Figure 3

Survival curves according to different classification systems in gastric adenocarcinoma. Notes: (A) Kaplan–Meier survival curve of WHO classification in patients with gastric adenocarcinoma. Papillary carcinoma showed statistically significant differences with tubular carcinoma subtype (P=0.001) but not with other subtypes (mucinous carcinoma, P=0.628; signet ring cell carcinoma, P=0.353; low-differentiated carcinoma, P=0.550; and undifferentiated carcinoma, P=0.528). P, T, M, S, L, and U represent papillary carcinoma, tubular carcinoma, mucinous carcinoma, signet ring cell carcinoma, minimally differentiated carcinoma, and undifferentiated carcinoma, respectively. (B) According to the Lauren classification, diffuse-type patients have unfavorable prognosis (P<0.001). I and D represent intestinal-type and diffuse-type gastric adenocarcinoma, respectively. (C) According to the Gosrki classification, the well-differentiated grades I and II had higher survival rates than the poorly differentiated grades III and IV. Grade I showed statistically significant differences compared with grades II, III, and IV (P=0.023, P<0.001, and P=0.002). I: well-differentiated and mucin-poor areas of tumor. II: well-differentiated and mucin-rich parts of the tumor. III: poorly differentiated and mucin-poor parts of the tumor. IV: poorly differentiated and mucin-rich parts of the tumor. (D) According to the new pathological classification, grade I showed statistically significant difference from grades II, III, and IV (P=0.001, P<0.001, and P<0.001). I: patients without tumor budding, single cell invasion, and large cell invasion. II: patients with single cell invasion. III: patients with tumor budding and single cell invasion. IV: patients with tumor budding, single cell invasion, and large cell invasion. Abbreviation: WHO, World Health Organization.