Combination of lymphovascular invasion and the AJCC TNM staging system improves prediction of prognosis in N0 stage gastric cancer: results from a high-volume institution

Continuous clinical-pathological data from 3128 patients with gastric cancer who underwent surgical resection from January 2006 to December 2011 at Fujian Medical University Union Hospital (FMUUH) were retrospectively analyzed. The inclusion criteria were as follows: 1) gastric adenocarcinoma confirmed by histopathology, 2) gastrectomy with D2 or D1+ lymphadenectomy,3) complete clinicopathological and follow-up data. Patients with incomplete clinical data (n = 195), stage IV (n = 323) disease, those who underwent nonradical surgery (n = 327) and patients who were lost to follow-up (n = 113) were excluded. Patients who underwent neoadjuvant chemotherapy were also excluded from the study (n = 68). Thus, 2102 patients were included in the final analysis. Preoperative clinical staging was based on gastroscopy and abdominal computed tomography (CT). Postoperative pathological diagnosis and staging were performed in accordance with the 8th edition of the AJCC TNM staging system. Hematoxylin & eosin (HE) staining was performed to evaluate the presence of venous invasion, and IHC stain for D2–40 was performed using a mouse monoclonal antibody against human lymphatic endothelium antigen to evaluate lymphatic invasion [14]. Patients with N0 stage who were treated with surgery alone were categorized into the surgery alone group (SA-group), and patients with N0 stage who were treated with adjuvant chemotherapy after surgery were categorized into the adjuvant chemotherapy group (AC-group). The study protocol was approved by the ethical committee of the FMUUH.

It was suggested that patients with pathological stage II/III be hospitalized for chemotherapy within 4–6 weeks after surgery [12]. Those patients were recommended to receive fluorouracil-based monotherapy or combination chemotherapy with a regimen involving the equivalent of at least one course of treatment after surgery. Most patients with stage II or III gastric cancer in our center usually received fluoride-based adjuvant chemotherapy, including FOLFOX, XELOX, SOX regimen. Ultimately, the decision as to whether a patient receives chemotherapy depends on the patient’s willingness and economic income.

The endpoint of this study was December 2011 or the time of patient death. Patients were seen at either our outpatient clinic or a local hospital. To determine OS, we calculated the time from the date of surgery to death or the censor date (December 2011). Patients were seen regularly at 3-month intervals during the first 2 year, every 6 months from years 3 to 5, and on a yearly basis thereafter. Generally, physical examination and laboratory tests (such as tumour markers) were performed in each follow-up visit. Examinations including abdominal CT, and endoscopy were performed every 6 months during the first 3 years and annually thereafter. When relapse was suspected, further evaluation, such as PET, whole-body bone scanning and magnetic resonance imaging (MRI), was performed. Recurrence patterns were classified as local recurrence (anastomotic or gastric remnant),lymph node and distant metastasis (peritoneal,hepatic, pulmonary, or other sites of metastatic disease) [15].

Significance was tested using Student’s t-test for continuous variables and χ2 tests for categorical variables. Univariate and multivariate analyses of risk factors for OS after surgery were performed using Cox proportional hazards models, and the results were expressed in terms of HR values and corresponding 95% confidence intervals. OS rates were calculated using the Kaplan-Meier method, and the log-rank test was used to analyze between-group differences in survival rate. The significance threshold was 5%, and all statistical tests were 2-sided. Analyses were performed using Statistical Package for the Social Sciences (SPSS) 23.0 for Windows (SPSS, Chicago, IL, USA).

The clinico-pathological data of the 2102 included patients are shown in Table 1. Out of all patients, 1593 were male (75.8%) with an average age of 63.9 years (range 21–89 years) and 509 were female (24.2%)with an average age of 63.2 years (range 20–91 years). The median follow-up time was 58 months (range 2–111 months). The average tumor size was 4.9 cm, and the average BMI was 21.5 kg/m². Of the 736 N0 patients, 106 had lymphovascular invasion, which accounted for 14.4% of all N0 patients.

Additional file 1: Table S1 shows the incidence of lymphovascular invasion according to pT stage. The incidence of lymphovascular invasion in pT1, pT2, pT3, and pT4 disease was 8.3, 13.0, 29.1, and 22.0%, respectively. Univariate and multivariate analyses of lymphovascular invasion in N0 patients showed that only pT stage (HR 3.13, 95% CI (1.75–5.59), p < 0.001) was an independent risk factor for lymphovascular invasion (Additional file 2: Table S2).

As shown in Fig. 1a, the 3-year and 5-year overall survival rates (3-year OS and 5-year OS) of N0 patients with lymphovascular invasion were significantly lower than those of N0 patients without lymphovascular invasion (3-year OS: 78.3% vs 92.5%, 5-year OS: 70.0% vs 88.3%, p < 0.001). Additional file 3: Figure S2. shows the Recurrence-free survival (RFS) and Disease-specific survival (DSS) for N0 patients with or without lymphovascular invasion.(3-year RFS: 76.1% vs 92.0%, 5-year RFS: 64.2% vs 84.8%, p < 0.001;3-year DSS: 78.1% vs 93.1%, 5-year DSS: 70.2% vs 87.8%, p < 0.001). The recurrence rate of N0 patients with lymphovascular invasion was 18.5% while 7.8% of N0 patients without lymphovascular invasion occurred recurrence. Among all patients with recurrence, the incidence of distant metastasis was 14.3%, and that of local recurrence was 12.3%.

According to the univariate analyses, age, tumor location, lymphovascular invasion, and pT stage were significantly associated with OS (all p < 0.05) (Table 2). Moreover, age (HR 2.16, 95% CI (1.39–3.38), p < 0.001), lymphovascular invasion (HR 2.474, 95% CI (1.64–3.72), p < 0.001), and pT stage (HR 3.18, 95% CI (1.82–5.59), p < 0.001) were independently associated with OS in a multivariate analysis (Table 2).

The overall survival rate of N0 patients with lymphovascular invasion was similar to that of N1 patients (3-year OS: 78.3% vs 78.7%, 5-year OS: 70.0% vs 75.1%) (Fig. 1b). The difference between the 8th edition of the AJCC TNM staging system combined with lymphovascular invasion and the 8th edition of the AJCC TNM staging system alone is shown in the Additional file 4: Figure S1. N0 patients with lymphovascular invasion were upgraded to stage N1, while N0 patients without lymphovascular invasion remained in stage N0. Figure 2 shows the changes in the 8th edition of the AJCC TNM staging system combined with lymphovascular invasion compared with the 8th edition of the AJCC TNM staging system alone. In all, 32 patients with pT1N0M0 disease and lymphovascular invasion were upgraded to pT1N1M0, 16 patients with pT2N0M0 disease and lymphovascular invasion were upgraded to pT2N1M0, 34 patients with pT3N0M0 disease and lymphovascular invasion were upgraded to pT3N1M0, and 22 patients with pT4N0M0 disease and lymphovascular invasion were upgraded to pT4N1M0.

Figure 3 shows the survival curve of the 8th edition of the AJCC TNM staging system combined with lymphovascular invasion and the 8th edition of the AJCC TNM staging system alone. The 8th edition of the AJCC staging system combined with lymphovascular invasion demonstrated a better linear trend χ2, likelihood ratio χ2 statistics, and AIC value (68.99 vs 58.58, 70.18 vs 58.36, 1473.38 vs 1485.04) compared with the 8th edition of the AJCC staging system (Table 3).

As shown in Fig. 4, no significant difference was observed in the 3-year OS or the 5-year OS between the adjuvant chemotherapy group and the surgery alone group in pT1-2N0M0 patients without lymphovascular invasion (pT1N0M0, p = 0.178; pT2N0M0, p = 0.803) and in pT1-2N0M0 patients with lymphovascular invasion (pT1N0M0, p = 0.872; pT2N0M0, p = 0.172). Compared with the surgery alone group, pT3N0M0 patients without lymphovascular invasion who received adjuvant chemotherapy exhibited a similar survival (3-year OS: 83.3% vs 84.9%, 5-year OS: 80.0% vs 79.2%, p = 0.78). In pT3N0M0 patients with lymphovascular invasion, the 3-year and 5-year overall survival rates of the adjuvant chemotherapy group were higher than those of the surgery alone group (3-year OS: 83.3% vs 68.2%, 5-year OS: 72.3% vs 50.0%, p = 0.048).