Assessment of risk factors of lymph node metastasis and prognosis of Siewert II/III adenocarcinoma of esophagogastric junction: a retrospective study


 Background Adenocarcinoma of esophagogastric junction (AEG) has a high incidence, while the extent of lymph node dissection (LND) and prognosis are still controversial. The present study aimed to explore the risk factors of lymph node metastasis (LNM) and prognosis in Siewert II/III AEG patients. Methods A total of 134 patients who underwent surgical operation between July 2013 and December 2019 at the Beijing Friendship Hospital were retrospectively reviewed. The patients were followed up until January 2020. The data were analyzed using logistic regression. Survival analyses were performed using Cox regression. Results Multivariate analysis revealed that the parameters infiltration depth (OR=4.341, 95%CI: 2.498-7.545, P=0.000), gross type (OR=3.626, 95% CI: 1.425-9.228, P=0.007) and intravascular cancer embolus (OR=2.888, 95%CI: 1.106-7.544, P=0.030) correlated with LNM. For all patients, the lymph nodes No. 1, 2, 3, 4, 7, 11 indicated higher lymph node metastatic rate in the abdominal cavity. However, No.5 and No. 6 indicated different tendency, which was higher in Siewert III AEG and lower in Siewert II AEG patients. Mediastinal LNM of Siewert II AEG mainly occurred in No. 110 and No. 111 cases corresponding to 7.1 and 3%, respectively, compared with those noted in Siewert III AEG patients. The 3-year overall survival analysis revealed that LNM ( P= 0.046) and chemotherapy ( P= 0.007) exhibited significant differences. Conclusion The infiltration depth, gross type and intravascular cancer embolus were independent risk factors of LNM. For Siewert II AEG patients, it is reasonable to remove both celiac and mediastinal lymph nodes. This was noted notably for No.1, 2, 3, 4, 7, 11, 110 and No.111. For No.5 and No.6 lymph nodes dissection was not required. For Siewert III AEG patients, mediastinal LND was not required. However, it was necessary to perform pyloric lymphadenectomy, which was performed for No.5 and No.6 lymph nodes. In addition, patients with LNM exhibited worse long-term prognosis. The data indicated that perioperative chemotherapy could improve the prognosis of AEG patients.

Mediastinal LNM of Siewert II AEG mainly occurred in No. 110 and No. 111 cases corresponding to 7.1 and 3%, respectively, compared with those noted in Siewert III AEG patients. The 3-year overall survival analysis revealed that LNM ( P= 0.046) and chemotherapy ( P= 0.007) exhibited signi cant differences.

Conclusion
The in ltration depth, gross type and intravascular cancer embolus were independent risk factors of LNM. For Siewert II AEG patients, it is reasonable to remove both celiac and mediastinal lymph nodes. This was noted notably for No. 1,2,3,4,7,11,110 and No.111. For No.5 and No.6 lymph nodes dissection was not required. For Siewert III AEG patients, mediastinal LND was not required. However, it was necessary to perform pyloric lymphadenectomy, which was performed for No.5 and No.6 lymph nodes. In addition, patients with LNM exhibited worse long-term prognosis. The data indicated that perioperative chemotherapy could improve the prognosis of AEG patients.

Background
Adenocarcinoma of esophagogastric junction (AEG) is a type of adenocarcinoma lesion that originates from the glandular epithelium of the gastrointestinal tract and invades esophagogastric junction [1]. In recent years, the incidence and mortality of AEG have increased [2][3][4]. This region is a special anatomical location, involving complex operation and multiple lymphatic drainage approaches [5]. The drainage boundary and dissection extends from the lymph nodes around the stomach and it is localized around the cardia for multiple groups of lymph nodes [6]. As a result, AEG can be treated with diverse surgical methods and exhibits worse prognosis compared with common gastric cancer [7,8]. Previous studies have shown that mediastinal LNM accounts for 10-20% of all lymphatic metastasis in AEG [9][10][11].
However, other studies reported that the mediastinal LNM rate was low [12,13]. Therefore, it is urgent to con rm whether the mediastinal LND of the lymph node drainage areas is required in Siewert II/III AEG in order to improve the curative effect of radical operation and prognosis. The present study attempted to analyze the risk factors of LNM and the follow-up survival data in patients with Siewert II/III AEG in order to provide more accurate treatments for AEG patients with different clinicopathological features.

General information
The clinical data from 134 Siewert II/III AEG patients undergoing surgical treatment (open or laparoscopic surgery) were selected between July 2013 and Dec 2019 from the General Surgery Department, Beijing Friendship Hospital. The 134 cases were retrospectively studied. Prior to surgery, the Siewert II/III AEG patients were diagnosed by routine endoscopy, ultrasound gastroscopy, enhanced CT of abdominal and pelvic cavity as well as pathological biopsy. The pathological biopsy is the gold standard for diagnosing cancer. In addition, preoperative evaluation of the tumor in ltration depth and lymphatic and distant metastasis was performed by endoscopy, ultrasound gastroscopy and enhanced CT for the abdominal cavity and the chest. The early stage AEG patients (cT 1 N 0 − 3 M 0 ) received radical gastrectomy initially and no less than 15 lymph nodes were dissected [14,15]. Subsequently, certain patients (pT 1 N 1 − 3 M 0 ) would receive rst-line chemotherapy regimen (XELOX or S-1). In addition, the patients with advanced stage AEG (cT 2 − 4 N 0 − 3 M 0 ) were con rmed with postoperative pathological examination (pT 2 − 4 N 0 − 3 M 0 ) and received rst-line chemotherapy regimen (XELOX) following surgery. For advanced stage patients (cT 3 − 4 N + M 0 ) who could not achieve R0 resection, three-cycle preoperative neoadjuvant chemotherapy (ECF) was initially administered. Subsequently, the patients would receive surgery if complete tumor resection was scheduled. Following operation, they would also receive postoperative chemotherapy (XELOX). The present study gained approval from the Ethics committee of the Beijing Friendship Hospital. The requirement for individual consent was wavied due to the retrospective nature of the study.
Inclusion criteria (1) Patients who were diagnosed as Siewert type II/III AEG (epicenter of the tumor located between 1 cm above to 5 cm below the esophagogastric junction) by pathological biopsy and endoscopy were included in the study. (2) The patients were evaluated based on the clinical stage and the epicenter of the tumor prior to the surgery, including abdominal enhanced CT and/or ultrasound gastroscopy. (3) The clinical stage was T 1 − 4 N 0 − 3 M 0 . Tumor staging was assessed as follows: Invasion of the tumor into the esophagogastric junction and location of its center at least 2 cm below the esophagogastric junction or invasion of the tumor into the esophagogastric junction and location of its center within 2 cm below the esophagogastric junction. For any of the aforementioned cases, the 8th version AJCC/UICC TNM staging system for gastric cancer was adopted. If the tumor invaded the esophagogastric junction and its center was located within 2 cm below the esophagogastric junction, then the 8th version of the AJCC/UICC TNM staging system for esophageal cancer was adopted [16]. (4) The patients who had a physical tness score, ECOG ≤ 2 points and were tolerant to radical gastrectomy were also included in the selection process. (5) Patients who did not have previous history of gastrointestinal operation, chemotherapy or radiotherapy were included in the study.

Exclusion criteria
The exclusion criteria used in the present study were the following: (1) Patients who suffered from gastric remnant carcinoma, recurrent cancer of gastric remnant or multiple primary malignant neoplasm of pelvis or had malignancy history within 5 years. (2) Patients who were unwilling to receive operations. (3) Patients who were con rmed with metastatic gastric cancer or gastric cancer of other parts intraoperatively. (4) Patients who suffered from uncontrollable internal diseases (including unstable angina, myocardial infarction and cerebrovascular accident that occurred within 6 months). (5) Patients who were unable to receive general anesthesia or surgical treatment due to conditions of other organs.

Mediastinal lymphadenectomy
The patients were placed in the supine position and the operation was performed through the ventral esophageal hiatus. Initially, an opening of the esophageal hiatus and an incision of both sides on the diaphragmatic feet at 1-2 cm were made. Subsequently, the surrounding tissue was dissociated, which was anterior to the pericardium, posterior to the aorta, lateral to the left and right pleura and upward to the inferior pulmonary vein. Thirdly, at the low margin of the inferior pulmonary vein, the tissue was stripped down along to the esophageal wall to the pre-cut line and the lymphatic connective tissue around the esophageal area was removed completely. Finally, the inferior mediastinal lymph node dissection was completed.

Observatory indicators
The clinical characteristics and the histopathological data of the enrolled Siewert II/III AEG patients were recorded, including gender, age, tumor site, tumor size, gross type, histological classi cation, in ltration depth, surgical approach, intravascular cancer embolus and cancerous node nodules. According to the age group proposed by the WHO, the patients were divided into the age < 60 years group and the age ≥ 60 years group. Tumor size was referred to the maximum diameter of the tumors. The gross type was divided into protruded type, at type and depressed type according to the Japanese Gastric Cancer Guidelines (2014). Histological classi cation was divided into differentiated type (well-and-moderate differentiated adenocarcinoma, tubular adenocarcinoma) and undifferentiated type (poor differentiated adenocarcinoma, mucinous adenocarcinoma and signet-ring cell carcinoma).

Follow-up
The patients were followed up every 6 months after surgery. After discharge, the patients were followed up by means of outpatient visit, telephone or mail. During the follow-up period, the patients received physical examination, laboratory tests, chest and abdominal CT scan assessment and annual endoscopic examination. Every patient had a minimum follow-up period of three years. The survival time was estimated from the operation date to the death date or until January 2020. The survival rate was determined by dividing the number of patients who survived for three years by the total number of enrolled patients.

Statistical analysis
Statistical analysis was performed using the SPSS 21.0 software. The count data were expressed as frequency and percentages and were compared using the χ 2 test, corrective χ 2 test or Fisher's exact test. Ranked data were expressed as frequency and percentages and were compared using the rank sum test. Multivariate analyses were performed using the logistic regression method. Survival analyses were performed using the Cox regression. A P value less than 0.05 (P < 0.05) was considered for signi cant differences.

Results
Baseline data and clinicopathological characteristics A total of 134 Siewert type II/III AEG patients, including 112 men (83.6%) and 22 women (16.4%), with a male to female ratio of 5.1:1 were included in the study. The patient age ranged from 27 to 82 years and the mean age was 62.1 years. A total of 53 cases out of 134 patients were < 60 years old (39.6%), whereas 81 cases were ≥ 60 years old (60.4%). A total of 99 patients suffered from Siewert II AEG, whereas 35 patients suffered from Siewert III AEG. Among them, 71 patients were combined with lymphatic metastasis and the remaining 63 patients did not present with lymphatic metastasis. No patients suffered from distant metastasis (Table 1).  (Table 3).

Univariate analysis
Among the 134 Siewert II/III AEG patients included in the present study, 71 cases suffered from LNM with a metastatic rate of 53%. Of these, the metastatic rates were 5% and 61.4% in patients with a tumor size of < 2 cm and ≥ 2 cm, respectively. This suggested that patients with a tumor size of ≥ 2 cm were more prone to LNM (P = 0.000). In addition, the LNM rate in patients with differentiated tumors was 38.2%, which was lower than that of 68.2% in patients with undifferentiated tumors (P = 0.001), whereas the LNM rate was elevated following an increase in the tumor in ltration depth (P = 0.000). The LNM rates in patients with intravascular cancer embolus and without intravascular cancer embolus were 75% and 35.1%, respectively (P = 0.000). Moreover, the parameters gross type (P = 0.000), surgical approaches (P = 0.037) and cancerous nodule (P = 0.014) were all signi cantly different between these two groups (Table 1). However, the parameters age, gender, tumor site were not associated with LNM (Table 1).

Multivariate analysis
As shown in Table 4, the parameters in ltration depth, gross type and intravascular cancer embolus were independent risk factors of LNM in Siewert II/III AEG patients. The LNM rate of advanced tumors was 4.341 times higher than that of the early tumor (95%CI: 2.498-7.545). The risk of depressed gross type was associated with lymph node metastasis and was 3.626 times higher than that of the other two types (95% CI: 1.425-9.228). The risk of lymph node metastasis in patients with intravascular cancer embolus was 2.888 times higher than that of patients without intravascular cancer embolus (95%CI: 1.106-7.544) ( Table 4).

Follow-up and survival analysis
The follow-up time of the 134 AEG patients was 1-75 months, whereas the median interval follow-up time was 27.9 months. During the follow-up period, 10 patients were lost to follow-up. The loss to followup rate was 7.5%. Among the 134 patients, 32 cases did not survive due to postoperative complications (7 patients), recurrence or distant metastasis (25 patients). Of these patients, 71 cases were followed up for more than 3 years. The median interval follow-up time period was 41.6 months, of which, the 3-year overall survival (OS) rate of the AEG patients without LNM (5 cases) and with LNM (23 cases) were 82.1% and 46.5%, respectively (P = 0.046, Fig. 1). In addition, the 3-year OS rate of AEG patients who accepted chemotherapy was higher than that of those who did not accept chemotherapy (P = 0.007, Fig. 2). The differences were signi cant (P < 0.05).

Discussion
Lymph node metastasis is one of the most important prognostic factors for AEG [17]. In addition, AEG can cause LNM and hematogenous metastasis at an early stage. Hence, the long-term prognosis of AEG patients has been demonstrated to be poor [18]. Radical surgery has been proposed as the effective treatment for AEG, including complete resection of lesions and lymph node dissection [19,20]. However, Siewert II/III AEG is characterized by speci c anatomical location and complex lymphatic drainage direction. Therefore, the correct evaluation of the lymph node metastasis can determine the extent of optimal lymph node dissection. The development of a reasonable treatment protocol is of great signi cance for improving the long-term prognosis in lymphatic metastasis patients with II/III AEG.
Certain studies have reported that the rates of mediastinal LNM are estimated from 5-25% [11,13,21,22], whereas the recurrence rates of mediastinal LNM following surgery ranged from 0 to 11% [12,21,23,24]. In the present study, Siewert II AEG was associated with celiac and thoracic lymph node metastasis. Metastasis to the celiac lymph nodes was noted, such as in the cases of No.  [26]. Siewert III AEG patients did not present with mediastinal LNM and presented with tumor recurrence in the thoracic cavity. It should be noted that the mediastinal LND can increase surgical trauma and cardiopulmonary complication, notably in the elderly population [27]. Therefore, mediastinal LND is not necessary for Siewert III AEG patients. However, No.5 and No.6 LNM rates were estimated to 10% and 16.7%, respectively. A previous study reported that the dissection of pyloric lymph nodes could improve long-term prognosis for Siewert III AEG [25,28]. Therefore, this type of patients should be treated with dissection of the pyloric lymph nodes. Moreover, we should emphasize on the en-bloc resection and avoid fragmented resection [29].
The assessment of the risk of LNM can aid the selection of the appropriate extent of lymph node dissection and individualized treatment strategy. At present, there is no effective method to evaluate LNM prior to surgery. However, the clinicopathological data exert a favorable prediction effect. In the present study, the in ltration depth, gross type and intravascular cancer embolus were independent risk factors for lymph node metastasis in patients with Siewert II/III AEG. Previous studies have reported that the LNM rate was signi cantly increased following an increase in the tumor in ltration [30]. The present study indicated similar outcomes demonstrating that the LNM rate was increased from 0 to 88.1% when the tumor in ltrated deeper gradually. This outcome may be attributed to the abundance of lymphatic capillaries in the submucosa, resulting in lymph node metastasis [31,32]. In addition, whether the gross type is a risk factor for LNM remains a controversial issue. Several studies have demonstrated that the gross type was associated with LNM, while other reports have produced opposite results [31,33,34]. Moon et al reported that the gross type was not an independent risk factor for LNM [35]. However, in the present study, the LNM rates of the depressed type (62.4%) and protruded type (18.2%) metastases were higher than those of the at type (7.1%). The gross type was a risk factor for LNM, which was in accordance with the results of Choi et al [36]. The present study indicated that although the gross type was not associated with LNM in the multivariate analysis, the opposite ndings were noted in the univariate analysis [36]. A similar Chinese study reported that the gross type was associated with metastasis and recurrence in the upper gastric cancer [37,38]. Hence, the gross type may become a useful indicator for the prediction of LNM. However, we need to further verify these ndings using largesample data. In addition, among the 60 patients who were combined with intravascular cancer embolus, 45 patients exhibited LNM. The incidence was higher than those patients who did not present with intravascular cancer embolus. A previous study demonstrated that 54 gastric cancer patients with intravascular cancer embolus exhibited 51 cases with lymph node metastasis (94.4%) [32]. This may be due to the capillary wall that does not contain a basal membrane and is composed of endothelial cells.
The majority of these cells are irregularly arranged. Therefore, the capillary wall has greater permeability than the capillary and is more susceptible to cancer cell invasion [32]. Nevertheless, since it is di cult to determine whether patients present with intravascular cancer embolus preoperatively, tumor in ltration depth and gross type remain valuable indicators for the prognosis of the disease.
In the present study, survival analysis revealed that LNM exhibited signi cant differences in the 3-year overall survival rate. The data indicated that patients with LNM exhibited worse long-term prognosis. It was reported that proximal gastric cancer could develop LNM and exhibit early recurrence [39]. Kim et al revealed that the survival rate was decreased following an increase in the LNM rate [40]. The data indicated that LNM was an independent prognostic risk factor for 86 patients [41]. A study conducted in China revealed that the 3-year and 5-year survival rates of 231 gastric cancer patients without LNM were 69.7% and 63%, respectively, while the survival rates of 481 gastric cancer patients with LNM were 38.4% and 28.7%, respectively (P = 0.001) [38]. In addition, a multi-center study demonstrated that Siewert II AEG patients with mediastinal LNM exhibited a higher recurrence rate and a poor prognosis [12]. As a result, LNM should be considered a prognostic evaluation index for gastric cancer patients who have received radical operation.
However, perioperative chemotherapy can improve the long-term prognosis of AEG patients to some extent. The current result was consistent with previous studies [42]. The EORTC40954 clinical trial indicated that the preoperative chemotherapy combined with surgery could increase R0 resection but failed to show survival bene t in stage III and IV (cM0) of AEG or gastric cancer patients [43]. In addition, the FNCLCC and FFCD9703 clinical trials revealed that perioperative chemotherapy could improve the curative surgical rate, the overall survival (OS) and the disease-free survival (DFS) [44]. In 2011, the ACTS-GC trial reported that postoperative treatment with S-1 chemotherapy could prolong the 5-year OS and DFS [45]. The CLASSIC study for stage II to stage IIB gastric cancer revealed that patients who received chemotherapy following surgery exhibited optimal prognosis than those treated with surgery alone [46]. Recently, the POET trial compared chemotherapy and surgery with induction chemotherapy, chemoradiotherapy and surgery [47]. The data demonstrated that induction chemotherapy and chemoradiotherapy could prolong progression-free survival (PFS) [47]. Therefore, chemotherapy has become a necessary treatment modality in advanced AEG.
The present study exhibits certain limitations. It is a retrospective, single-center study, involving a small number of samples. Therefore, the results are unlikely to fully re ect the regulation of LNM and long-term prognosis. There may be certain bias in the analysis of the clinical data. Hence, we need to further con rm the current ndings by large-sample, randomized controlled studies. to be further veri ed using large-sample, multi-center, randomized controlled studies.

Declarations Ethics approval and consent to participate
This study gained approval from the Ethics committee of Beijing Friendship Hospital. The need for individual consent was waived due to the retrospective nature of the study.

Consent for publication
Not applicable Availability of data and material The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests.

Funding
This study was supported by grants from the Beijing Municipal Science and Technology Commission The 3-year OS rate of AEG patients without LNM and with LNM was 82.1% and 46.5%, respectively (P=0.046).