The Siewert’s classification is widely used for surgical procedure of oesophagogastric junction adenocarcinoma, while the Nishi’s classification from Japan is almost the same as the Siewert II. The comparation among Siewert subtypes has been well studied , as well as those between gastric and oesophagogastric junction adenocarcinoma. In V5.0, the definition of oesophagogastric junction adenocarcinoma was the same as Nishi’s classification in addition to emphasis on adenocarcinoma. The change in the definition of oesophagogastric junction tumors is significantly important for clinicopathological assessment and clinical management, such as the surgical dissection procedure.
In this study, we compared the clinicopathological features between gastric and oesophagogastric junction adenocarcinoma with V4.0 and V5.0, respectively. The oesophagogastric junction adenocarcinoma had more advanced T-classification than distal gastric adenocarcinoma with the criteria of both the V4.0 and V5.0. This was concurred by previous studies, that proximal (oesophagogastric junction and cardia) tumors were associated with poor outcomes [23, 24]. However, there were still some changes between the clinicopathological features of V4.0 and V 5.0.When compared with V4.0, the differences of N-classification and the sites of lymph node metastasis were mainly focused on oesophagogastric junction and distal gastric adenocarcinoma. But these differences were mainly found on proximal gastric and distal gastric adenocarcinoma with the V5.0. This was perhaps because the oesophagogastric junction tumors of 2 cm-5 cm from the oesophagogastric junction with V4.0were classified to the proximal gastric tumors in the V5.0. Moreover, the tumors of 2 cm-5 cm was same as the Siewert III. A multivariate analysis showed only lymph node metastases predicted the survival of gastric carcinoma . The majority of patients were found to have more lymph node involvement in the Siewert III , which was consistent with our results. Based on these findings, the Siewert III tumors were no longer included in oesophagogastric junction adenocarcinoma and the treatment for oesophagogastric junction tumors needs update. Total gastrectomy or more extensive distal gastric lymph node dissection may not be considered. On the other hand, the scope of proximal gastric tumors also changed, with the update of the definition of oesophagogastric junction adenocarcinoma. The proximal gastric adenocarcinoma statistically exhibited larger tumor, advanced T-classification and N-classification than distal gastric adenocarcinoma, which was not identified in the V4.0. Notably, proximal gastric tumors, rather than oesophagogastric junction adenocarcinoma, may have the worse survival and need aggressive treatment. Besides, there was no significant difference in histologic types between gastric and oesophagogastric junction adenocarcinoma a, indicating that the tumor morphology could not be regarded as the criteria to distinguish oesophagogastric junction from gastric adenocarcinoma.
Furthermore, we also compared the clinicopathological features between the V4.0 (group 1) and V5.0 (group 2) of oesophagogastric junction adenocarcinoma. The data showed the group 2 had smaller tumor, earlier T-classification and N-classification than group 1. It seemed the group 1was less invasive. Notably, the extent of lymph node dissection in the mediastinum and the choice of distal esophagectomy made great importance in the treatment for oesophagogastric junction adenocarcinoma. A multicenter retrospective study indicated only the distance from the oesophagogastric junction was significantly related to metastasis. The longer the distance is, the higher rate of lymph node metastasis is . In newer version, oesophagogastric junction adenocarcinoma was smaller, which supported that oesophagogastric junction adenocarcinoma was less likely to have lymph node involvement. Besides, some studies suggested lower mediastinal lymphadenectomy should be recommended for oesophageal invasion of 3 cm or less, while the extent of upper or middle mediastinal lymphadenectomy was for oesophageal invasion of ≥ 3 cm [28, 29]. Although shorter in diameter, the group 2 had a higher rate than older ones in terms of the extent of oesophageal invasion of ≥ 3 cm, which showed oesophagogastric junction adenocarcinoma need upper or middle mediastinal lymphadenectomy. Therefore, mediastinal lymph node dissection and surgical resection were not completely unified in oesophagogastric junction adenocarcinoma, even though the scope of oesophagogastric junction adenocarcinoma became narrowed under the newer version. With that, we compared the difference of mediastinal lymph node involvement between the two groups. The proportion of group2 (57%) were slightly higher than group 1, but with no statistical difference. This may be due to the lack of an accurate assessment of the extent of oesophageal invasion before operation and the incomplete extent of lymph node dissection.
HER2 test is another significant point which was formally recommended in the V5.0. Its expression and relevant clinicopathological features has beenwell studied in previous researches with Siewert’s classification [30, 31]. We re-evaluated the clinicopathological features of total 566 cases with their HER2 status, using V5.0. The HER2-expression in oesophagogastric junction and proximal tumors were statistically higher than that in body and distal tumors, which was consistent with other studies [30, 32]. On the contrary, a Japanese study indicated that the HER2-overexpression was not associated with tumor location with Siewert’s classification . We assessed the HER2 status with both immunohistochemistry and FISH, and classified the tumor’s location with V5.0. Our results demonstrated oesophagogastric junction tumors had a higher expression of HER2 than body and distal tumors even if the scope of oesophagogastric junction adenocarcinoma was narrowed with the new criterion. This should be critical to emphasize the HER2 test in oesophagogastric junction adenocarcinoma. In addition, our analyses showed a statistically significant association between HER2-expression and pathological grade, tumor diameter and M-classification for gastric tumors. HER2-expression tumors had poor differentiation, larger diameter and more metastasis than HER2-negative ones, that indicated HER2-expression tumors were more aggressive. These results were consistent with previous studies . Therefore, the relevant clinicopathological features of HER2-expressingoesophagogastric junction adenocarcinoma remained unchanged in the V5.0. MSI was another significant molecular in gastric carcinoma, which was related to the contraction or expansion or of microsatellite sequences owing to the replication errors caused by mutations in the mismatch repair (MMR) in most cases . More than 30% patients with MSI-H were likely to develop Lynch syndrome. Even though no statistically significant in difference between microsatellite status and HER2-expression, there was merely one of the 19 MSI-H cases showing positive for HER2, while other 18 cases were all negative for HER2. This demonstrated that the HER2-expression cases probably did not suffer from MSI-H, but further verification is required.
Our study comprehensively compared the clinicopathological features among oesophagogastric junction, proximal and distal gastric adenocarcinoma. The analyses showed that the difference was mainly between oesophagogastric junction and distal adenocarcinoma in the V4.0, while some were identified between proximal and distal adenocarcinoma in the V5.0. The proximal gastric tumors seems more invasive than oesophagogastric junction and distal gastric tumors in newer version. The clinical management of proximal gastric tumors may need more attention. In addition, the Siewert III tumors usually showed the worst prognosisinV4.0, which were no longer included in the category of oesophagogastric junction adenocarcinoma in the newer version. The treatment of the oesophagogastric junction tumors would not be too aggressive. However, our data showed that tumors with extent of oesophageal invasion of ≥ 3 cm were the majority in candidates with V5.0. It should be noted that these tumors require additional middle even upper mediastinal lymph node dissection and longer scope of esophagectomy. Besides, although the scope of oesophagogastric junction adenocarcinoma became narrowed after the revision, the expression of HER2 in oesophagogastric junction and proximal gastric adenocarcinoma was still higher than that in gastric body and distal site, which was basically consistent with the conclusion of the V4.0.