Risk evaluation of splenic hilar lymph node metastasis and survival analysis of advanced gastric cancer patients

DOI: https://doi.org/10.21203/rs.3.rs-1784471/v1

Abstract

Background: There is no consensus in the influence of NO.10 lymph node(LN) dissection for advanced gastric cancer(AGC) patients. We aimed to evaluate whether AGC patients could benefit from NO.10 LN dissection and the clinicalpathological indicators of NO.10 LN metastasis.

Methods: We analyzed data on 218 patients with AGC patients who had underwent standard D2 lymphadenectomy(n=108) or modified D2 lymphadenectomy(n=110) from January 2017 to January 2021. Additionally, we also examined the influencing factors of NO.10 lymph node metastasis in the SD2 group.

Results: The differentiation, tumor size and NO.4 positive LN were significantly correlated with the NO.10 LN metastasis(P<0.05). The Borrmann’s classification, differentiation, depth of invasion, lymph node metastasis (N), and tumor size were found to correlate with survival on univariate analyses. The age, gender, extent of gastrectomy, tumor location and lymphadenectomy extent were not related to survival(P>0.05). The median survival time was 72.23 months and 68.56 months for the SD2 and MD2 groups, respectively(P=0.635). Postoperative major morbidity and mortality rates were 37.96% and 3.70% in the SD2 group, and 23.64% and 1.82% in the MD2 group, respectively.

Conclusions: The prophylactic NO.10 lymphadenectomy may be recommended in AGC patients with positive NO.4 LN, poor differentiation and tumor located on the greater curvature.

Introduction

Gastric cancer is the 4th most common cause of death from cancer and the 5th most commonly diagnosed cancer type, accounting for 5.6% of all new cancers reported in the worldwide[1]. AGC is prone to lymph node metastasis: the deeper tumor invaded the higher tendency to lymph nodes involvement[2]. Lymph node metastasis often takes place from the primary site and is the most important way of tumor spread, which was confirmed by one study using carbon particles[3]. The surgical resection of the primary tumor with curative lymphadenectomy remains the gold standard for AGC patients. Advanced gastric cancer sometimes metastasizes to the splenic hilar lymph node(NO.10 LN), which was defined as N2 station according to the guidelines. Because of NO.10 LN special position located in the ligament of spleen, it is technically difficult to completely remove the NO.10 LN without some surgical complications, such as bleeding, infection, pancreatic fistula, damaged immune system and postoperative thrombosis[4-6]. Several studies have reported that patients who have undergone complete lymphadenectomy for NO.10 LN have shown no survival benefits[7, 8]. Due to relatively low rate of NO.10 LN metastasis and high complications, surgeons must weigh both risks of postoperative complications and benefits to make a decision on whether or not NO.10 LN dissection should be undertaken during operations. This study analyzed clinicalpathological factors to confirm indicators of NO.10 LN metastasis and survival in AGC patients.

Patients And Methods

A total of 218 patients who underwent D2 curative proximal or total gastrectomy for advanced gastric carcinoma from January 2017 to January 2021 were enrolled in this study. The gender, age, Borrmann’s classification, differentiation, depth of invasion(T), lymph node metastasis(N), extent of gastrectomy, tumor location and tumor size were retrospectively correlated survival. 

Standard D2 lymphadenectomy(SD2) included the removal of the following lymphatic fat tissue: NO.1/2/3/4/5/6/7/8a/9/10/11/12a for total gastrectomy;NO.1/2/3/4/7/8a/9/10/11 for proximal gastrectomy.

Modified D2 lymphadenectomy(MD2) included the removal of the following lymphatic fat tissue: NO.1/2/3/4/5/6/7/8a/9/11/12a for total gastrectomy; NO.1/2/3/4/7/8a/9/11 for proximal gastrectomy.

According to the computer randomly generated random indicator, the AGC patients were randomly assigned to the SD group and MD group. Patients in both groups were matched for the gender, age, Borrmann’s classification, differentiation, depth of invasion(T), lymph node metastasis(N), extent of gastrectomy, tumor location and tumor size. We also compared these clinicopathological parameters between positive NO.10 LN and negative NO.10 LN in the SD2 group. And the complications were also used to be analyzed between the SD2 and MD2 group.

Follow-up assessments

All patients above enrolled in our hospital had complete personal follow-up files and explicit pathological diagnosis. The patients with obvious NO.10 LN metastasis or those with direct invasion of the spleen or those with preoperative chemoradiation therapy were excluded. All patients underwent follow-up assessments every 3 months for the first 2 years postoperatively, then 6 months during the third year, and 12 months thereafter. The outpatient or inpatient reviews and telephone or E-mails were used to follow up.

Ethics

This study was performed in accordance with the Helsinki Declaration and was approved by the Institutional Review Board of the Xuzhou Central Hospital. All patients have the written informed consent.

Statistical analysis 

All statistical analyses were carried out using SPSS 13.0 software (SPSS Inc, Chicago, USA). Relevant patient clinical and pathological factors were compared by the chi-square test between the two groups. The relationship between clinicopathological factors and metastasis to NO. 10 LN was evaluated by chi-square test. The comparison of morbidity and mortality between the two groups was also compared by chi-square test. Overall survival was analyzed with Kaplan-Meier method and statistical significance was calculated by the log-rank test. Multivariate analysis was conducted using logistic regression analysis. Differences associated with P<0.05 were considered significant.

Results

1. The clinicopathologic factors of the AGC patients. 

All the patients underwent curative gastrectomy with D2 lymph node dissection. There were 132 males and 86 females with a median age of 54.5 years (range 33-82). Of the 218 cases, 192 were under 70 years old, and 26 were over 70 years old. In the Borrmann type, 74 were the type of I and II, 144 were the type of III and IV. There were 90 patients with well-differentiated and moderately degree, meanwhile, 128 were poorly differentiated. In depth of invasion, 115 patients were the stage of T2 and T3, and 103 were the T4 stage. 141 patients were N1 and N2 stage and 77 patients were N3 stage. All the patients underwent gastrectomy, 74 of subtotal and 144 of total. 108 patients were located at the lesser curvature, 110 were located at greater curvature. 128 patients’ lesion was <=5cm and 90 was >5cm. The SD2 group included 108 patients and MD2 group included 110 patients(Table 1). 

2. The influencing factors of NO.10 lymph node metastasis in the SD2 group.

Table 2 showed that the differentiation, tumor location and NO.4 positive LN were significantly correlated with the NO.10 LN metastasis(P<0.005). The incidence of metastasis to NO.10 LN metastasis differed significantly between the tumor location at lesser curvature and greater curvature(P=0.022). The poorer the tumor differentiation was the more was it prone to lymph node metastasis(P=0.018). Of the 108 AGC patients in SD2 group who had undergone standard D2 lymphadenectomy, 45 had positive NO.4 LN metastasis. Of the 63 patients with negative NO.4 LN, only two patients had positive NO.10 LN metastasis (Table 2).

3. The univariate and multivariate analysis results. 

The Borrmann’s classification, differentiation, depth of invasion, lymph node metastasis, and tumor size were found to correlate with survival on univariate analyses. The age, gender, extent of gastrectomy tumor location and lymphadenectomy extent were not related to survival(P>0.05). The median survival time was 72.23 months and 68.56 months for the SD2 and MD2 groups, respectively(P=0.635). Although patients in MD2 group had a worse survival than patients in SD2 group, there is no statistical significance(Fig.1). Moreover, the Cox proportional regression hazard model showed that differentiation, depth of invasion and lymph node metastasis were independent prognostic factors (Table 3) (Fig.2-4).

4. The complications between the two groups.

As seen in Table 4, the morbidity and mortality rates of patients in the SD2 group was higher than those in the MD2 group. Postoperative major morbidity and mortality rates were 37.96% and 3.70% in the SD2 group, and 23.64% and 1.82% in the MD2 group, respectively (Table 4).

Discussion

Nowadays surgical resection with lymph node dissection remains the only curative treatment for AGC patients. Some papers reported that there was approximately 10% of AGC patients who have developed NO.10 LN metastasis[9-11]. Some surgeons performed standard D2 lymphadenectomy in order to complete NO.10 LN dissection, but the complications have disadvantaged them to rethink this surgery type[12, 13]. Moreover patients with NO.10 LN metastasis had a worse survival than patients without them, but they could not gain survival benefits from NO.10 LN dissection[8, 14]. Thinking the safety of surgery and patients’ quality of life, however, there is no clear consensus as to whether AGC patients without metastasis to NO.10 LN preoperatively could avoid prophylactic NO.10 lymph node dissection. Thus, the aim of this study was to evaluate the impact of prophylactic NO.10 lymph node clearance on the prognosis and postoperative complications of AGC patients. 

As is known to us, location was a key factor correlated with NO.10 LN especially with those in upper and greater curvature of the stomach[15, 16]. There was a reasonable explanation to this. The lymphatic flow of greater curvature located along upper body, is drained to splenic hilar lymph nodes via the short gastric artery, left gastroepiploic artery and posterior gastric artery. Tammaro reported that NO.10 LN dissection should be considered for those which tumor localized in the upper two thirds of the stomach, which was in good accordance with the current study[17]. Kusano et al. revealed that the rate of positive NO.10 LN locating at the greater curvature was 17.0%, higher than that at the lesser curvature(10%)[18]. Meanwhile, our paper revealed that the NO.10 LN rate locating at the greater curvature was 11.1%, higher than that at the lesser curvature(1.1%). The results suggested that NO.10 LN easily occurred in the gastric cancer at the greater curvature. Obviously, tumor location is absolutely a predictor for AGC patients.

To date, some researchers believed there existed closely negative correlation between differentiation degree and NO.10 LN metastasis[19, 20] In general, the poorer differentiation degree was, the higher rate of NO.10 LN would be. Our study showed that the rate of NO.10 LN in the group with well/moderately differentiation(2.8%) was lower than that in the group with poor differentiation(10.2%). Wu et al. explained that the positive NO.10 LN was correlated with higher level of Matrix Metalloproteinase3(MMP-3) expression which was induced by poorer differentiation of AGC patients[21]. Consequently, the lower differentiation should be a criterion for AGC patients who could benefit from NO.10 LN resection.

It was well-known that depth of invasion and tumor size can predict tumor staging in a certain degree. Some studies reported that the above two were potential NO.10 LN influencing factors [22, 23]. In our study, the positive rate of NO.10 LN in tumor size equal or larger than 5 cm was 10.2% while the rate in tumor size less than 5 cm was 2.8%. In our study, the NO.10 rate of T4 stage was 10.2%, higher than that T2 and T3 stage(2.8%). Some reported that NO.10 LN metastasis was observed in 3.4% patients with tumors smaller than 5 cm and in 21.3% patients with tumors larger than 5cm[24]. However there was no statistic difference between depth of invasion and tumor size on the NO.10 LN metastasis in our paper. Aoyagi et al. also reported that T stage was not associated with splenic hilar lymph node metastasis[14]. 

In addition, in the present study it showed that NO.10 LN was not associated with Borrmann type. The NO.10 LN rate of AGC patients with the type I/II and III/IV were 3.7% and 7.4% respectively. Some other studies reported that NO.10 LN metastasis more easily occurred in the infiltrative AGC patients compared with the local AGC patients, maybe because of tumor growth pattern[25]. But in our paper we failed to confirm the correlation between NO.10 LN and Borrmann type.

In our study we also found that when NO.4 lymph nodes was positive, NO.10 lymph node positive detection rate was as high as 26.7%; when NO.4 lymph nodes was negative, NO.10 lymph node positive detection rate was only 3.2%. The difference between them was statistically significant (P<0.001). Therefore, we can take NO.4 positive lymph nodes as the sentinel lymph nodes. This can be explained as followed: The NO.10 lymph node locates near the greater curvature and it will occur through NO.4 lymph nodes located along the greater curvature via lymphatic drainage[26]. Bian et al. have reported that for the certain group of AGC patients avoiding unnecessary NO.10 lymphadenectomy can lead to less invasive trauma and tissue damage[27]. As for the cases of NO.4 LN negative, NO.10 LN was still positive. The cancer cells will have to pass through lesser curvature lymph nodes, then NO.7, 9, and 11 lymph nodes, finally reach the NO.10 LNs. This is one of the possible mechanisms of explaining the phenomenon of "skip metastasis", but the rate is too low to confirm. And the incidence of this kind of skip metastasis was only 3.2 % in our study and was also very low in other reports[28].

Moreover, in our paper multivariate analysis showed that differentiation, depth of invasion and lymph node metastasis were independent prognostic factors(P<0.05). The patients with those characteristics have poor survival time. The results were basically consistent with other statistical reports[29-31]. As for the lymphadenectomy extent, Sano et al. enrolled 505 patients in his research showed no survival difference between SD2 group and MD2 group in AGC patients[32]. In 2014 some scholars analysed 8 RCTs and found that there was not a significant difference in the overall 5-year survival rate between the two groups[33]. In our study, we also found no significant difference in the survival rates between the two groups; the median survival time was 72.23 months and 68.56 months for the SD2 and MD2 groups, respectively(P=0.635). Although patients in MD2 group had a worse survival than patients in SD2 group, there is no statistical significance. A recent study also showed there was no statistically significant difference in 5-year survival for the patients with and without splenic hilar lymph node metastasis in the greater curvature group[34]. Huang et al. retrospectively compared patients who underwent and did not undergo NO.10 lymph node dissection in the spleen-preserving surgery group and found the 3-year disease-free survival time was significantly better in the dissection group but the overall survival time has no statistical significance[35]. 

The mortality and morbidity rates in the two groups were summarized in Table 4. The results in our study were similar to those previously reported. The overall postoperative morbidity in the SD2 group was higher, and the difference was statistically significant(P=0.022). Postoperative major morbidity and mortality rates were 37.96% and 3.70% in the SD2 group, and 23.64% and 1.82% in the MD2 group, respectively. We speculated that the fragile texture of the spleen and special anatomical location might increase the risk of postoperative complications.

Several limitations inherent in this study should be addressed. First, as a retrospective study, our study with a relative small number of patients from a single center included possible selection bias. Therefore, further randomized studies are required to compare the outcomes of SD2 versus MD2. Second, there were two false-negative cases in our study, namely, patients with negative NO.4 LN but positive NO.10 LN. So, we should find the sensitivity and specificity of better indicators of NO.10 LN. And large well-designed studies would also be needed to explore the role of NO.10 lymph node clearance in the AGC patients. But the unique nature of this paper provides a new insight into the lymphadenectomy extent for AGC patients.

Conclusion

In conclusion, for AGC patients without high risk factors, NO.10 lymphadenectomy may not be recommended whereas those with positive NO. 4LN, poor differentiation and tumor involving the greater curvature we should undergo standard D2 lymphadenectomy.

Declarations

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