The metastasis status of different lymph node groups in patients with EGC
A total of 2,245 patients with GC who underwent radical gastrectomy with lymphadenectomy at the First Affiliated Hospital of Sun Yat-Sen University between January 1, 2010 and December 31, 2018 were reviewed retrospectively. Three hundred fifty-four cases histologically proven to be EGC following the inclusion and exclusion criteria were enrolled for the next analysis. Among these 354 cases, there were 27 cases of upper-third EGC, 136 of middle-third EGC, and 142 of low-third EGC.
In this study, the incidence of LNM in EGC was 18.36% (65/354). In order to elucidate the role of LNM in EGC further, we analyzed the positive rate (Table 2) and location distribution (Table 3) of LNM for each lymph node station. As shown in Table 2, the positive rates of No. 3, No. 4, and No. 6 lymph nodes were 4.80%, 3.67%, and 3.95%, respectively, regardless of the tumor location. For tumors located in the upper-third of the stomach with LNM (n = 6), the No. 2 and No. 3 lymph nodes had high positive rates of LNM (Table 3). For tumors in the middle-third of the stomach (n = 28), No. 3, No. 4, No. 5, and No. 6 LNs had the highest positive rates of LNM. For tumors in the lower third of the stomach, the No. 3 and No. 6 lymph node stations had the highest metastasis rates.
Clinicopathological characteristics of patients with EGC according to LNM
As shown in Table 4, the current study consisted of 224 male patients (63.27%) and 130 female patients (36.72%), with a median age of 57.50 ± 11.399 years (range, 24–85 years). Among these 354 patients, 35 (9.89%) had tumors located in the upper third of the stomach, 165 (46.61%) had tumors located in the middle third of the stomach, and 175 (49.43%) had tumors located in the lower third of the stomach. The mean length and short diameter of the tumor were 2.254 ± 1.344 cm and 1.808 ± 1.184 cm, respectively. Postoperative pathology indicated LVI in 16 cases (4.52%) and poorly differentiated tumors in 185 cases (52.26%). The average number of lymph node dissections was 37.64 ± 23.203.
There were 61.58% (218/354) patients with intra-mucosal invasion (including Tis and T1a) and 38.41% (136/354) patients with submucosa (T1b) invasion. The percentages of LNM positivity were 12.38% (27/218) in the Tis/T1a group and 27.94% (38/136) in the T1b group (P < 0.001) (Table 4). There was no significant difference in the mean age of patients between the two groups, but there was a significant difference between patients aged <40 years and those aged ≥40 years (P=0.006), suggesting that young patients have a higher risk of LNM (risk ratio [RR] = 2.297; 95% CI, 1.333–3.947). Tumor sizes were significantly larger for LNM+ than LNM− (P = 0.009). Compared with LNM−, tumor invasion was deeper (P < 0.001; RR = 2.256; 95% CI, 1.447–3.518) and showed poor differentiation (P < 0.001; RR = 3.328; 95% CI, 1.914–5.787) in LNM+. However, the distribution of other variables including sex, body mass index, tumor maker, and tumor location were similar between the LNM− and LNM+ groups.
Univariable and multivariable analysis of LNM in EGC
The univariable analysis showed that LNM was closely related to age (<40 years), tumor size (>3 cm), depth of invasion (T1b), poor differentiation, and LVI (all P < 0.05, Table 5). Multivariate analysis showed that tumor size (odds ratio [OR] = 2.948; 95% CI, 1.480–5.872; P = 0.002), poor differentiation (OR = 5.879; 95% CI, 2.536–13.628; P = 0.001), and LVI (OR = 14.569; 95% CI, 2.493–85.135; P = 0.001) were independent predictors for LNM (Table 5). However, age and depth of invasion were not independent predictors of LNM. The receiver operating characteristic (ROC) curve (Fig. 2) was used to validate this multivariable regression model. This model showed an area under the curve (AUC) of 0.782. Figure 3 presents a nomogram for the prediction of LNM that was constructed based on the selected variables.
Correlation factors analysis of the extent of LNM in EGC
The rates of D1 station metastasis and D2 station metastasis in patients with EGC were 12.1% (43/354) and 6.214% (22/354), respectively (Table 6). An analysis of the clinical pathological characteristics was performed on patients with D1 station or D2 station LNM. There was no significant difference between the occurrence of D2 station LNM and the age, sex, tumor size, differentiation, location, depth of tumor invasion, and LVI. The levels of CA 19-9 and CEA were significantly different between the two groups (10.113 vs. 30.125 U/mL, P = 0.001 and 3.189 vs. 6.861 U/mL, respectively; P = 0.003). However, the difference in CA 125 was not significant (Table 6).
Analysis of the clinicopathological characteristics of patients with EGC with skip metastasis
According to the Japanese classification of gastric carcinoma (3rd edition) [12] and the definition of skip metastasis, patients with LNM (n = 65) were classified into a no skip metastasis group (n = 52) or a skip metastasis group (n = 13). The possibility of skip metastasis was 3.67% (13/354) in all patients with EGC. There was no significant difference between the two groups with respect to clinicopathological characteristics (Table 7).
Univariate and multivariate analyses of prognostic factors in patients with EGC
The 5-year survival rates of EGC between the LNM− and LNM+ groups were 96.26% and 79.17%, respectively (P = 0.011) (Table 4). The prognostic outcome of patients who were LNM+ was worse than that of LNM- patients (P = 0.008) (Fig. 4). The results of the univariate and multivariate analyses for prognostic factors are listed in Table 8. Tumor size (HR, 3.473; 95% CI, 1.372–8.791; P = 0.009) and LNM (HR, 4.895; 95% CI, 1.588–15.095; P = 0.006) were independent predictive factors for poor survival outcome in patients with EGC.
LNM rate in patients with EGC selected by the indications of ESD/EMR
The 2018 Japanese GC treatment guidelines [3] revealed that the indication for ER depends on the depth of invasion, differentiation type, diameter, and ulcerative findings. The LNM rates of these factors are demonstrated in Table 4. All patients with EGC (n = 354) were analyzed according to the absolute and expanded indications of ESD/EMR (Table 1), and only 75 (21.18%) patients conformed to the absolute and expanded indications of ESD/EMR. The rates of LNM in absolute and expanded indications were 2/61 (3.27%) and 4/14 (28.55%), respectively. Subgroup analysis showed that the rates of LNM with respect to the absolute indication of EMR/ESD and absolute indication of ESD 2 group were 0%. The rate of LNM with respect to the absolute indication of the ESD 1 group was 20%. For the submucosal invasive (T1b) EGC, the LNM status was analyzed with two conditions (≤2 cm, differentiated type: 7.40%; ≤2 cm, undifferentiated type: 35.375%), which was consistent with the outcome of the multivariable logistic analysis (Table 5).