The Siewert’s classification is widely used for surgical procedure of AEGs, while the Nishi’s classification from Japan is almost the same as the Siewert II. Previous studies have been more focused on comparing the differences among Siewert I to Siewert III , or comparing the clinicopathological features between GEJ tumors with GCs. In the fifth WHO classification of tumors of the digestive system, Nishi’s classification is used in the definition of AEGs. The change in the definition of GEJ tumors is significantly important for clinicopathological assessment and clinical management, such as the surgical choice and lymph node dissection.
In this study, we compared the clinicopathological features between AEGs and GCs with fourth and fifth edition respectively according to the fifth WHO classification. The difference between the AEGs and the GCs was mainly focused on the AEGs and distal gastric adenocarcinoma with the criteria of the fourth edition. The AEGs had higher T-classification than distal gastric with the criteria of both the fourth and fifth edition. This was in accord with previous studies, that proximal (GEJ and cardia) tumors were associated with poor outcomes . However, when analyzed the N-classification and the rate of lymph node metastasis, the difference between AEGs and distal gastric with the fourth edition criteria turned into the difference between the proximal and the distal gastric adenocarcinoma with the fifth edition criteria. This was perhaps due to the tumors of 2cm-5cm from the GEJ classified to the proximal gastric tumors in the fifth edition. Moreover, the tumors of 2cm-5cm was same as the Siewert III.A multivariate analysis showed only lymph node metastases predicted the gastric carcinoma survival . The majority of patients were found to have more lymph node involvement in the Siewert III , which was consistent with our results. From the results of this part, the Siewert III tumors were no longer included in GEJ adenocarcinoma, the treatment for GEJ tumors need update as well. Total gastrectomy or more extensive distal gastric lymph node dissection may not be required. On the other hand, the scope of proximal gastric tumors (excluding GEJ) was also changed with the update of the definition of GEJ. The proximal gastric adenocarcinoma statistically exhibited longer tumor diameter, higher T-classification and higher N-classification than distal gastric adenocarcinoma, that didn’t appear in the fourth edition. What should be noted is that proximal gastric tumors rather than GEJ may have the worse survival and need to be treated especially and comprehensively. Besides, there was no significant difference in histologic types between AEGs and GCs, indicating that the tumor morphology could not help to distinguish AEGs from GCs.
Furthermore, we also compared the clinicopathological features between the AEGs (2cm from GEJ) and non-AEGs (2cm-5cm from GEJ) according to the fifth edition. The data showed AEGs of 2cm from GEJ had shorter tumor diameter, lower T-classification and lower N-classification than non-AEGs of 2cm to 5cm from GEJ. It seemed the AEGs were less invasive than non-AEGs. Notably, the extent of lymph node dissection in the mediastinum and the choice of distal esophagectomy made great important in GEJ tumors treatment. A multicenter retrospective study considered only the distance from the GEJ was significantly related to metastasis, and the longer the distance, the higher rate of lymph node metastasis . In this study, AEGs were shorter in diameter than non-AEGs, which stood that AEGs were less likely to be lymph node involvement. Besides, some studies suggested lower mediastinal lymphadenectomy was recommended for oesophageal invasion of 3 cm or less; the extent of upper or middle mediastinal lymphadenectomy for oesophageal invasion of ≥ 3 cm . Although shorter in diameter, the AEGs in our cohort had a higher rate than non-AEGs in terms of the length of oesophageal invasion more than 3cm, which showed AEGs need upper or middle mediastinal lymphadenectomy. Therefore, mediastinal lymph node dissection and surgical resection were not completely unified in AEGs, even though the scope of AEGs became narrowed under the fifth edition. The tumor’s diameter and the length of oesophageal invasion both required special attention. What’s more, we also compared the difference of mediastinal lymph node involvement between the two groups. The proportion of AEGs (57%) were slightly higher than non-AEGs, but with no statistical difference. This may be due to the lack of an accurate assessment of the length of oesophageal invasion before operation and the incomplete extent of lymph node dissection.
HER2 test is another significant point which was formally required in the fifth edition. This marker’s expression and its relevant clinicopathological features were studied in previous researches with Siewert’s classification . On the basis of the fifth edition, we re-evaluated the clinicopathological features of total 566 cases and their HER2 status. The HER2-expression in GEJ and proximal tumors were statistically higher than that in body and distal tumors, which was consistent with other studies . On the contrary, a study of 612 cases in Japan reported that the HER2-overexpression was not influenced by tumor location with Siewert’s classification . We assessed the HER2 status with both IHC and FISH and classified the tumor locations with Nishi’s classification (fifth edition). Our results demonstrated GEJ tumors had a higher expression of HER2 than body and distal tumors even if the number of GEJ tumors was decreased at the new criteria. This should be a crucial factor to emphasize the need for HER2 test in GEJ tumors. In addition, our analyses showed a statistically significant association between HER2-expression and pathological grade, tumor diameter and M-classification of gastric tumors. HER2-expression tumors had poor differentiation, longer diameter and more metastasis than HER2-negative ones, that meant HER2-expression tumors presented more invasive than HER2-negative ones. These results were agreed with other studies . Therefore, the relevant clinicopathological features of HER2-expressing GEJ tumors were almost not changed in the fifth edition. Microsatellite instability was another significant molecular detection in gastric carcinoma, that 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 . Patients with MSI-H were more than 30 percent likely to develop Lynch syndrome. Even though no statistically significant difference between MSI 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 more data were needed for further verification.
In conclusion, our study comprehensively compared the clinicopathological features among AEGs and non-AEGs tumors, GEJ and proximal and distal gastric tumors. The analyses showed that the difference was mainly between GEJ and distal adenocarcinoma in the fourth edition, but some of these differences were between proximal and distal adenocarcinoma in the fifth edition. And the invasiveness of proximal gastric tumors appeared to be relatively more invasive than GEJ and distal gastric tumors. The clinical management of proximal gastric tumors may need more attention and further research. In addition, the criteria of GEJ adenocarcinoma (fifth edition) are equivalent to the tumors of Siewert II (fourth edition). The Siewert III, with the worst prognosis, is no longer included in the category of the GEJ tumors. The treatment of the GEJ tumors does not have to be too aggressive. However, our data showed that tumors with longer invasion of the oesophagus were still mainly concentrated in GEJ tumors of fifth edition. 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 GEJ carcinoma became narrowed after the revision, the expression of HER2 in GEJ and proximal gastric adenocarcinoma was still higher than that in gastric body and distal site, which was basically consistent with the conclusion of the fourth edition classification.