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Risk Factors and Tumor Recurrence in pT1N0M0 Gastric Cancer after Surgical Treatment

Purpose This study aimed to evaluate the rate, patterns, and risk factors associated with tumor recurrence in patients with T1N0 gastric cancer. Materials and Methods The medical records of 8,753 patients with pathological T1N0M0 gastric cancer who underwent gastrectomy between 1994 and 2014 at Sungkyunkwan University School of Medicine were examined. Results Among the 8,753 patients, 95 patients (1.1%) experienced tumor recurrence; this included 31 remnant, 27 hematogenous, 9 lymph nodal, 5 peritoneal, and 23 multiple-site recurrences. When patients were divided into two groups according to the presence of tumor recurrence, the following characteristics were higher in the recurrence group than in the non-recurrence group: older age (≥65 years), male gender, undifferentiated histology, submucosal invasion, and venous invasion. In multivariate analysis, older age, male gender, tumor depth (sm2 and sm3 invasion), and venous invasion were independent risk factors for tumor recurrence. The recurrence rates were 0.7% in patients with less than two risk factors, 1.7% in those with two risk factors, 3.0% in those with three risk factors, and 6.3% in those with four risk factors (P<0.001). Conclusions Although tumor recurrence is rare in pT1N0M0 gastric cancer, some patients with certain risk factors demonstrate an increased rate of tumor recurrence. Careful follow-up is required for patients with three or four risk factors.

Clinicopathological characteristics included patient age and gender; tumor size, location, histological type, and Lauren classification; the presence of lymphatic, perineural, or venous invasion; and the depth of invasion. Histological type was divided into differentiated-type (including papillary adenocarcinoma and well-to-moderately differentiated tubular adenocarcinoma) and undifferentiated-type (including poorly differentiated tubular adenocarcinoma, mucinous adenocarcinoma, and signet ring cell adenocarcinoma). Tumor recurrence was identified according to standard clinical practices, which consisted of patient evaluation every 6 months for 2 years after surgery, followed by every 12 months thereafter for up to 5 years after surgery, with physical examinations, laboratory tests, imaging (abdomen-pelvis computed tomography and chest x-ray), and endoscopy. Tumor recurrence patterns were classified as remnant stomach, peritoneal, hematogenous, distant lymph node, or multiple type.
Statistical analysis was performed using IBM SPSS Statistics ver. 22.0 (IBM Co., Armonk, NY, USA), and statistically significant differences were defined as those with P<0.05. Continuous variables were presented as means±standard deviation, and categorical variables were compared using chi-square or Fisher's exact test. Kaplan-Meier curves and a Cox regression hazard model were adopted for the analysis of tumor recurrence. The hazard ratio and 95% confidence interval were calculated using Cox regression models.

Results
The clinicopathological features of 8,753 EGC patients with pT1N0M0 are shown in Table 1. Compared with the nonrecurrence group, the recurrence group was older, had a larger percentage of male patients, and demonstrated higher incidence rates of venous invasion, differentiated histology, intestinal-type Lauren classification, and deeper penetration into the submucosal area. There were no significant differences in tumor location, type of surgery, resection margin length, or lymphatic and perineural invasion between the recurrence and non-recurrence groups.  Values are presented as number only or mean±standard deviation.

Discussion
Recent studies using large groups of Korean patients have re-ported that the frequency of EGC recurrence was approximately 3.0% after curative resection. 5,7 Many studies have confirmed that the presence of lymph node metastasis indicates a higher probability of tumor recurrence. There has been minimal evaluation of tumor recurrence in EGC without lymph node metastasis, because it demonstrates a very low incidence of recurrence after surgery. As expected, this study found tumor recurrence in only 1.1% of patients with pT1N0M0 gastric cancer after gastrectomy.
Older age (≥65 years), male gender, deeper submucosal invasion, and venous invasion were identified as significant risk factors for tumor recurrence.
Previous investigations have reported that recurrence in node-negative gastric cancer is most commonly classified as locoregional recurrence with peritoneal seeding. 13,14 However, our study showed that the most common recurrence patterns for lymph node-negative EGC were remnant (32.6%) and hematogenous (28.4%) recurrences. Interestingly, in nine cases of local lymphatic recurrence, no lymph node metastases were detected at the time of the initial surgery. One possible explanation for this finding is micrometastasis. 12 Maehara et al. 15 reported that among 34 patients with pT1N0M0 EGC who died due to tumor recurrence, micrometastasis was eventually confirmed by cytokeratin staining in eight cases.
Hematogenous EGC recurrence could theoretically arise indirectly due to the seeding of lymphovascular tissue during submucosal invasion of cancer cells. 14,16 However, in the case of mucosal EGC invasion, the mechanism for hematogenous re- currence has yet to be adequately described. In our study, 11 of the 27 hematogenous recurrences showed mucosal invasion and 16 had submucosal invasion (Sm1, n=1; Sm2, n=7; Sm3, n=8).
A multicenter longitudinal study of the recurrence patterns of the two main gastric cancer histological types after radical surgery revealed that 41% of cases were intestinal-type tumors, while 65% were diffuse-type tumors (P<0.001). 17 Our study reported that the incidence of intestinal-type tumors was higher in the recurrence group (68.4%) than in the non-recurrence group (53.2%). Lauren classification was a significant factor for EGC recurrence, but it was not an independent risk factor (P=0.381).
Risk factors related to EGC recurrence have been discussed in several reports. Shiozawa et al. 18  rence. 5 Our study revealed that older age, male gender, tumor depth (sm2 and sm3 invasion), and venous invasion were all independent risk factors for pT1N0M0 EGC recurrence.
Node-negative EGC has a better prognosis than node-positive EGC, which may be explained by the less aggressive biological behavior of node-negative tumors. 14 Thus, lymph node metastasis remains a risk factor for EGC recurrence. 10 This study has several limitations. First, the inherent features of a nonrandomized retrospective cohort study were inevitable.
Secondly, this study is limited by its use of a single center and a Korean population; therefore, the results may not be applicable to other races or populations.
However, this study has several strengths. First, to the best our knowledge, this is the largest single-center study to present long-term follow-up data characterizing EGC recurrence.
Furthermore, we utilized multivariate analyses of many clinicopathological factors to adjust for confounding factors.
In conclusion, although recurrence is rare in pT1N0M0 gastric cancer, some patients with select risk factors showed a high recurrence rate. Follow-up with close monitoring is required for patients with three or four risk factors.

Conflicts of Interest
No potential conflict of interest relevant to this article was reported.