The increasing frequency of adenocarcinoma of the esophagogastric junction (AEG) has raised concern worldwide (1). This trend may be due to the elimination of Helicobacter pylori and the increase in reflux gastroesophagitis. Based on the anatomic location of the tumor epicenter, AEG is classified into three subgroups (types I, II, and III) (2). Siewert type II and type III AEGs are more common in Eastern countries, which are mainly characterized by abdominal lymph node metastasis, but there are also differences in lymph node metastasis since they are different subtypes with different biological characteristics (3). Therefore, Siewert type III AEGs are often considered as gastric cancer with a transhiatal approach (4). Although the surgical approach for Siewert type II AEG remains controversial, clinicians usually recommend gastrectomy with resection of the lower esophagus for Siewert type II AEG (5). Radical gastrectomy with regional lymphadenectomy is the primary surgical strategy for AEG (6). The status of lymph node metastasis in AEG with a tumor diameter ≤4 cm was evaluated by the Japanese Gastric Cancer Association (JGCA), which also developed a flow diagram to identify the extent of the lymphadenectomy. The pyloric lymph nodes (PLNs, No. 5 and No. 6 lymph nodes) was not recommended to be dissected in the 5th edition of the Japanese gastric cancer treatment guidelines because the incidence of PLN metastasis in AEG with tumor diameter ≤4 cm was less than 1% (7, 8). However, the necessity of PLN lymphadenectomy was not mentioned for AEG with a tumor diameter >4 cm. Additionally, several studies from China demonstrated that the incidence of PLN metastasis exceeded 10% in AEG (9, 10). Recently, a prospective nationwide multicenter study revealed that the metastasis rate of PLNs was more than 10% in tumors >6 cm (11). Therefore, the incidence of PLN metastasis is controversial. In China, over 80% of the AEG patients are diagnosed at advanced stages and AEG cases in which the tumor diameter is >4 cm account for a large proportion (12, 13). To date, no consensus has been established on the extent of lymph node dissection for AEG with tumor >4 cm. This study aimed at evaluating the survival benefits of PLN dissection for Siewert type II/III AEG with tumor diameter ≤4 and >4 cm.

In the current study, the dissection of abdominal stations 1, 2, 3, 7, 8, 9, and 11 are supposed to be a routine procedure for Siewert type II/III AEG. Additionally, in Siewert type III AEG, the IEBLD of lymph node No. 10 showed a high therapeutic benefit of dissection. In contrast, dissection of the No. 4, 5, 6, and 12 lymph nodes is not recommended because of the relatively low IEBLDs in patients of Siewert type II/III AEG. Previous studies demonstrated the highest IEBLD of lymph nodes 1, 2, 3, and 7 as well as the lowest IEBLD of lymph nodes 5, 6, and 12 in Siewert type II/III AEG (4, 22). In this study, a subgroup analysis by tumor diameter showed that the IEBLDs of lymph nodes No. 5 and 6 revealed high therapeutic efficacy of dissection in Siewert type II AEG with a tumor diameter >4 cm and led to a recommendation for dissection of PLNs in Siewert type II AEG with a tumor diameter >4 cm. As far as we are concerned, no study has recommended PLN dissection based on IEBLDs for Siewert type II AEG with a tumor diameter >4 cm before. To date, several large randomized clinical trials have demonstrated that transabdominal gastrectomy with resection of the lower esophagus should be the standard treatment strategy for Siewert type II/III AEGs with esophageal invasion less than 3 cm, but the extent of optimal gastric resection remains unclear (20, 23, 24). One of the obvious advantages of total gastrectomy is to achieve a more thorough lymphadenectomy. Proximal gastrectomy is known as function-preserving and achieves a survival rate similar to that of total gastrectomy (25). Nevertheless, proximal gastrectomy for AEG has not been widely accepted because its nutritional benefits remain uncertain with a high risk of reflux symptoms. The No. 5 and No. 6 lymph nodes are not dissected in proximal gastrectomy.

The dissection of PLNs is controversial due to its uncertain potential benefit for Siewert type II/III AEGs. Several reports from Japan have shown that the metastatic rate of No. 5 or 6 lymph nodes in Siewert type II/III patients is very low (20, 22). Recently, one study has revealed that the incidence of PLN metastasis was less than 1% and concluded that PLN dissection offered marginal therapeutic benefits for patients with AEG despite their high dissection rates (8). However, in that study, most patients were in the early stages of the disease, and cases in the T1 and T2 stages accounted for 78.1% (1,861/2,384); moreover, patients with AEG were classified based on the Nishi classification. In accordance with the studies mentioned above, the JGCA states that it is not necessary to dissect PLNs for AEGs with a tumor diameter ≤4 cm (7). However, the guidelines do not mention relevant recommendations for AEG with a tumor diameter >4 cm. Therefore, in the present study, we have chosen diameter of 4 cm as the threshold to investigate the metastasis rate of PLNs. In Japan, patients diagnosed with AEG are mostly at an early stage, whereas approximately 80% of patients are diagnosed at advanced stages, and cases of AEG with a tumor diameter >4 cm account for a large proportion in China (12, 13). Chen et al. and Hu et al. revealed that the frequency of PLN metastasis exceeded 10% in AEG (9, 10). Similarly, in the current study, the incidence of PLN metastasis in the total cohort was 9%. One possible explanation for the discrepancy among these reports is that patients with pT4 account for 70% of those in studies that report a high incidence of PLN metastasis. Recently, a prospective nationwide multicenter study revealed that the metastasis rate of PLNs was more than 10% if the tumor size exceeded 6 cm (11). Therefore, whether diameter is a risk factor that increases the incidence of PLN metastasis in Siewert type II/III AEGs is worthy of further investigation. Similarly, our reports showed that the incidence of PLN metastasis exceeded 10% when the tumor diameter was >4 cm in Siewert type II/III AEGs. Surprisingly, our results showed that the IEBLDs of lymph nodes 5 and 6 yielded high therapeutic efficacy in Siewert type II AEG with a tumor diameter >4 cm. However, in Siewert type III AEG, the IEBLDs of lymph nodes 5 and 6 were still low regardless of tumor diameter.

The JGCA comes up with a flow diagram for the identification of the extent of the lymphadenectomy for AEG with a tumor diameter ≤4 cm. However, these reports do not present a detailed investigation of the IEBLDs based on tumor diameter. For all we know, we are the first to evaluate the IEBLDs of Siewert type II/III AEGs based on tumor diameter. Our results showed that the IEBLDs of lymph nodes 1, 2, 3, 7, 8, 9, and 11 were still high, which indicates that dissection of these nodes is inevitable regardless of tumor diameter in Siewert type II/III AEGs. We also found high IEBLDs in greater curvature and splenic hilar lymph nodes in Siewert type III AEG in which the tumor diameter was >4 cm, which was consistent with the study by Huang et al., who proposed that spleen-preserving No.10 lymphadenectomy is associated with better prognosis of Siewert type III AEG with a tumor diameter >4 cm (26). This suggests that No. 10 lymphadenectomy is recommended for Siewert type III AEG with a tumor diameter >4 cm (26).

Although Siewert type III cancers had more metastatic lymph nodes in this study, the metastasis rate of PLNs was comparable between Siewert type II and Siewert type III AEGs. This finding is consistent with that of Huang et al., who suggested that the reason might be the limited sample of PLN-positive patients (17). In the present study, tumor size, pN stage, and PLN status were independent risk factors for OS in Siewert type II/III AEGs. These results reflect those of Huang et al., who also found that age, tumor size, pT stage, pN stage, pM stage, PLN status, and the number of positive lymph nodes were related to poorer OS (17). These findings were also reported by Wu et al., who revealed that pT stage, lymph node ratio, and PLN status have something to do with OS (27). Then, we further investigated the prognosis of PLN-positive Siewert type II/III AEGs. Of those with Siewert type II/III AEG, PLN-positive patients with stage III AEG had a significantly worse prognosis than PLN-negative patients with stage III AEG. Of those with Siewert type II AEG, a subgroup analysis by Siewert type showed that PLN-positive patients with stage III AEG had a similar prognosis to PLN-negative patients with stage III AEG. However, in the Siewert type III AEG group, PLN-positive patients with stage III AEG had a significantly worse prognosis than PLN-negative patients with stage III AEG. However, the findings of the present study do not support the previous research. Huang et al. proposed that the survival of PLN-positive patients was poorer than that of stage III patients without PLN metastasis regardless of Siewert type (17). To investigate the reason why the prognosis of PLN-positive patients of Siewert type II AEG is better than that of patients with Siewert type III AEG, we assessed the metastatic rate of the lymph nodes in PLN-positive Siewert type II/III cancers at each station ( Figure 6 ). We found that PLN-positive Siewert type III AEGs had a higher probability of lymph node metastasis on the greater curvature of the stomach and a relatively wider range of metastatic lymph nodes than PLN-positive Siewert type II AEGs, which may lead to a worse prognosis and may partly explain such a discrepancy. Another explanation for this result may be that dissection of PLNs in Siewert type II AEG with a tumor diameter >4 cm yields a high therapeutic benefit based on previous IEBLD results and improves survival.

In Siewert type II AEG with a tumor diameter ≤4 cm, the IEBLDs of PLNs were low in the current study. A previous study demonstrated that lymph node metastasis is more likely to occur in Siewert type II AEGs with larger tumor diameters (20). Therefore, we suggest that dissection of PLNs may be unnecessary and that the distal stomach could be preserved in Siewert type II AEG with a tumor diameter ≤4 cm. Further researches are required to explore the underlying benefits of proximal gastrectomy over total gastrectomy, such as a better postoperative quality of life (28). However, based on the IEBLDs of PLNs (>3.0), we suggested the adoption of total gastrectomy with lymphadenectomy for Siewert type II AEG with a tumor diameter >4 cm. The current study showed that the IEBLDs of PLNs were low in Siewert type III AEG regardless of tumor diameter. A previous study revealed that lymphatic flow originates from the middle third of the stomach to the lower perigastric lymph nodes (29). Typically, Siewert type III AEG always has a large tumor diameter and therefore invades the middle third of the stomach. Hence, total gastrectomy with D2 lymphadenectomy is suitable for Siewert type III AEG regardless of tumor size.

There were several limitations of this study. First of all, it was retrospective research performed at a single institution, and not all of the patients received a uniform extent of lymphadenectomy. We excluded patients with retrieved lymph nodes <16 for the minimization of false-negative influence on the current results. Second, in this study, the value of mediastinal lymph node dissection was not assessed because mediastinal lymph node dissection was not a routine procedure, especially in the early study period. The 14th edition of the JGCA guidelines recommended lower mediastinal lymph node dissection for patients with AEG (18), which is not mentioned in the former JGCA guidelines during the early study period. Third, to accurately evaluate the histological status of each lymph node, we excluded cases who received neoadjuvant chemotherapy which may include a selection bias. The present results require more accurate evidence from a large multicenter randomized study.

We recommended that a total gastrectomy with lymphadenectomy should be adopted for Siewert type II AEG with a tumor diameter >4 cm and Siewert type III AEG. In contrast, omitting dissection of PLNs and preservation of the distal part of the stomach might be optional for patients of Siewert type II AEG with a tumor diameter ≤4 cm.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (Ethics Committee of the First Affiliated Hospital of Army Medical University, PLA, China, approval number: KY2020272) and with the Helsinki Declaration of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.

XL: contributed to study design, data collection, and writing. ZL: contributed to data collection. CT: contributed to data collection. XY: contributed to data collection. JX: contributed to data collection. JL: contributed to data collection. AM: contributed to data collection. YS: contributed to data analysis. FQ: contributed to data analysis. PY: contributed to data analysis. YZ: contributed to study design. All authors contributed to the article and approved the submitted version.

This research is funded by the National Natural Science Foundation of China (Grant Number: 81872016).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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