Impact of Subclassification of Serosal Invasion on the Survival of Patients With T4a Gastric Cancer

Abstract

Background/Aim: In the Japanese Classification of Gastric Carcinoma, T4a gastric cancer is defined as tumor invasion contiguous to the serosa or penetrating the serosa with exposure to the peritoneal cavity. The aim of this study was to assess the impact of T4a subclassification of gastric cancer on survival.

Patients and Methods: A total of 326 patients with T4a cancer who had undergone gastrectomy were enrolled. The T4a tumors were classified into two groups: serosa-contiguous or serosa-exposed.

Results: The serosa-exposed group had a significantly worse prognosis, and multivariate analysis identified the T4a subclass as an independent prognostic factor. Analysis of the risk factors for recurrence identified the T4a subclass as a significant risk factor for peritoneal recurrence in patients undergoing curative gastrectomy.

Conclusion: The serosa-contiguous and serosa-exposed subgroups of T4a gastric cancer showed different biological behaviors. These groups may need to be treated as separate.

Although the prognosis of patients with gastric cancer, which is the fifth most commonly diagnosed malignant tumor in the world, continues to improve, gastric cancer remains the third leading cause of cancer-related death worldwide (1). It is widely accepted that the most important prognostic indicators in patients with gastric cancer are the depth of invasion of the gastric wall and the status of lymph node metastasis (2-4). Therefore, accurate/optimal categorization of the invasion depth and lymph node metastasis is critical for determining the disease extent, treatment planning, and prediction of the outcome (5). In Japan, treatment for gastric cancer is guided by the Japanese Classification of Gastric Carcinoma (JCGC) (6).

In the JCGC, the depth of invasion (T1) is divided into T1a (mucosa, M) and T1b (submucosa, SM). T2 and T3 are defined as invasion up to the muscularis propria (MP) and subserosa (SS), respectively. T4 is divided into T4a (invasion of the serosa, SE) and T4b (invasion of adjacent structures, SI). T4a is defined as tumor invasion contiguous to the serosa or penetrating the serosa with exposure to the peritoneal cavity (6). However, few studies have compared the clinicopathological characteristics of tumors contiguous to the serosa and tumors exposed beyond the serosa in patients with T4a gastric cancer (7). Many studies examining the status of serosal invasion of the tumor have focused on the changes in the macroscopic appearance of the serosa caused by tumor invasion, that is, changes in the color/morphology of the serosal surface (8-11) and/or the width of serosal invasion (12,13). The objectives of this study were to investigate the clinical significance of subclassification of T4a gastric cancer into two groups: the tumor-contiguous group, with tumor invasion contiguous to the serosa, and the tumor-exposed group, with the tumor invading beyond the serosa and exposed to the peritoneal cavity and to assess the impact of this subclassification on the survival of patients with T4a gastric cancer.

Patients and Methods

Patients. Between January 2006 and June 2020, 1,468 patients with gastric cancer underwent gastrectomy at the Department of Gastroenterological Surgery of Tokai University School of Medicine. Of these, 326 were classified as having T4a cancer based on the tumor invasion depth. In the present retrospective study, we analyzed the data of these 326 patients. The gross classification and histopathological classification were based on the JCGC published by the Japanese Gastric Cancer Association (6). Staging was performed according to the American Joint Committee on Cancer (AJCC) staging manual, eighth edition (14). Patients were mainly followed-up on an outpatient basis at our hospital; however, those who had moved to other institutions were asked relevant questions over the phone. Follow-up was continued until June 2021, with a median duration of follow-up of 1,167 days (range=64-4,901 days). Tumor recurrence was confirmed by relevant investigations in patients in whom it was suspected on clinical grounds. In some patients, the initial recurrence was diagnosed at two or more sites, and in such patients, all of the sites were counted as sites of initial recurrence.

This research was conducted in accordance with the ethical standards of the institutional research committee and the 1964 Declaration of Helsinki and its later amendments. The study design and the informed consent provided by all study subjects were both approved by the institutional review board of Tokai University Hospital (registration number 21R-122).

Definition of the T4a subclasses. The resected stomach was opened and placed on a flat board with the mucosal side up, and fixed in 10% formalin. After fixation, the neoplasm was sectioned along the maximum cross-sectional plane parallel to the lesser curvature, based on the general rules of the JCGC (6). Several additional sections parallel to the maximum cross-sectional plane and one section perpendicular to this plane were prepared to identify the area with the deepest invasion. T4a gastric cancers were subclassified into a group in which the tumor invasion was contiguous to the serosa (serosa-contiguous group) and a group in which the tumor invasion penetrated the serosa and was exposed to the peritoneal cavity (serosa-exposed group), according to the JCGC (6) (Figure 1). One patient in whom the tumor invasion was contiguous to the serosa in one area, but was exposed beyond the serosa in another area was classified into the serosa-exposed group.

Figure 1. Pathological features of T4a gastric cancer (hematoxylineosin staining, ×100). A) Tumor invasion was contiguous to the serosa (arrow). B) Tumor invasion penetrated the serosa with exposure to the peritoneal cavity (arrow).

Statistical analysis. The chi-squared test was used to compare categorical data, and the Mann-Whitney U-test to compare continuous variables. Overall survival (OS) was defined as the time period from operation to death from any cause. Survival curves were estimated using the Kaplan-Meier method, and survival times were compared using the log-rank test. Multivariate logistic regression analysis was applied to identify the clinicopathologic factors significantly correlated with recurrence, and a Cox proportional hazards model was used to identify factors significantly correlated with the prognosis. Factors that were identified as being significant on univariate analysis and essential and additional prognostic factors for survival as specified by the AJCC staging manual, eighth edition, were selected as the covariates (14). p<0.05 was considered as being indicative of statistical significance. All the statistical analyses were performed using SPSS, version 26.0J (IBM Corp., Armonk, NY, USA).

Results

Clinicopathologic characteristics according to the T4a subclass. Of the 326 patients with T4a gastric cancer, 93 were classified into the serosa-contiguous group and 233 into the serosa-exposed group. We compared the clinicopathological factors between the two groups (Table I). As compared with the serosa-contiguous group, the serosa-exposed group showed significantly higher frequency of the macroscopic infiltrative type of tumor (p=0.001), a larger tumor diameter (p=0.001), a higher frequency of patients with more advanced disease stage (p=0.001), and a higher frequency of patients with residual tumor (p=0.001).

Table I. Association between clinicopathological parameters and T4a subclass.

Correlation of the T4a subclass with prognosis. The 5-year OS rates in the serosa-contiguous and serosa-exposed groups were 51.1% and 23.8%, respectively, indicating a significantly worse prognosis in the serosa-exposed group as compared with that in the serosa-contiguous group (p=0.001) (Figure 2). The prognostic impact of the T4a subclass was evaluated by univariate and multivariate analyses (Table II). Univariate analysis identified the gross tumor type, tumor size, lymphatic invasion, lymph node metastasis, distant metastasis, residual tumor, and T4a subclass as significant prognostic factors. Multivariate analysis identified distant metastasis and the T4a subclass as independent prognostic factors.

Figure 2. Kaplan-Meier curves and log-rank test for overall survival (OS) of all patients according to the T4a subclass. The prognosis was significantly worse in the serosa-exposed group than that in the serosacontiguous group (p=0.001).

Table II. Univariate and multivariate analyses of prognostic factors for overall survival of all patients.

CI: Confidence interval; HR: hazard ratio; SG: subtotal gastrectomy; TG: total gastrectomy.

Relationship between the T4a subclass and the prognosis by disease stage. The prognostic impact of the T4a subclass for each disease stage was evaluated. There were 55 stage II patients, including 28 in the serosa-contiguous group and 27 in the serosa-exposed group. Univariate and multivariate analyses identified the T4a subclass as the only independent prognostic factor (Table III). Next, the prognosis of the stage II patients, including the serosa-contiguous and serosa-exposed groups, was compared with that of the 168 stage III patients. The 5-year survival was 74.7% in the stage II serosa-contiguous group, 33.4% in the stage II serosa-exposed group, and 30.9% in the stage III patients. Thus, in stage II patients, the prognosis was significantly worse in the serosa-exposed group than in the serosa-contiguous group (p=0.004), and the serosa-exposed group and stage III patients showed overlapping survival curves and no significant difference in the prognosis (p=0.325) (Figure 3). Of the 168 stage III patients, 52 were classified into the serosa-contiguous group and 116 into the serosa-exposed group. Univariate and multivariate analyses were performed to identify the prognostic factors. Univariate analysis identified the gross tumor type, lymph node metastasis, and T4a subclass as significant factors influencing prognosis. Multivariate analysis identified the resection type and lymph node metastasis as independent prognostic factors (Table IV). Only 12 stage IV patients underwent curative resection; therefore, they were not evaluated for prognostic factors.

Table III. Univariate and multivariate analyses of prognostic factors for overall survival of stage II patients.

CI: Confidence interval; HR: hazard ratio; SG: subtotal gastrectomy; TG: total gastrectomy.

Figure 3. Kaplan-Meier curves and log-rank test for overall survival (OS) in the stage II serosa-contiguous group, stage II serosa-exposed group, and stage III patients. The stage II serosa-exposed group had a significantly worse prognosis than the stage II serosa-contiguous group (p=0.004). The stage II serosa-exposed group and stage III patients showed no significant difference in prognosis (p=0.325).

Table IV. Univariate and multivariate analyses of prognostic factors for overall survival of stage III patients.

CI: Confidence interval; HR: hazard ratio; SG: subtotal gastrectomy; TG: total gastrectomy.

Relationship between the T4a subclass and recurrence pattern. The relationship between the T4a subclass and the recurrence pattern was examined in the stage II and III patients. Of all the patients, 80 were classified into the serosa-contiguous group and 143 into the serosa-exposed group. The recurrence rate was 33.8% (27/80) in the serosa-contiguous group and 62.9% (90/143) in the serosa-exposed group, indicating a significantly higher incidence of recurrence in the serosa-exposed group (p=0.001). Analysis according to the recurrence pattern revealed that the incidence of peritoneal recurrence was 21.3% (17/80) in the serosa-contiguous group and 36.4% (52/143) in the serosa-exposed group; the incidences of lymph node recurrence were 13.8% (11/80) and 20.3% (29/143), and those of hematogenous recurrence were 15.0% (12/80) and 18.9% (27/143) in the two groups, respectively. Thus, the peritoneal recurrence rate was significantly higher in the serosa-exposed group (p=0.019). The impact of the T4a subclass on the likelihood of peritoneal recurrence was evaluated by univariate and multivariate analyses. The T4a subclass and histologic type were identified as independent risk factors for peritoneal recurrence (Table V).

Table V. Univariate and multivariate analyses of risk factors for peritoneal recurrence of stage II-III patients.

CI: Confidence interval; OR: odds ratio; SG: subtotal gastrectomy; TG: total gastrectomy.

Conflicts of Interest

The Authors declare that they have no conflicts of interest in regard to this study.

Authors’ Contributions

Conception and study design were conducted by NK, NE, and KK. Data collection and literature search were done by NK, TK, OM, and HH. Data analysis and interpretation were performed by NK and NK. The article was drafted by NK and KK. Finally, the article was revised and approved by all investigators.