Two Updates on Oesophagogastric Junction Adenocarcinoma from the Fifth WHO Classification of Tumors of the Digestive System: Alteration of Definition and Emphasis on HER2 Test.

Abstract

Background: The incidence of oesophagogastric junction adenocarcinoma has increased rapidly but remains controversial over the last decades. There are two crucial updates of the fifth World Health Organization(WHO) classification, including the alteration of its definition and the emphasize on human epidermal growth factor receptor 2 (HER2) test.

Methods: A total of 566 clinicopathological samples from patients who were diagnosed with gastric adenocarcinoma were retrospectively analyzed. We comprehensively compared the clinicopathological features of oesophagogastric junction adenocarcinoma between fourth (V4.0) and fifth (V5.0) WHO version. The clinicalpathological features among oesophagogastric junction, proximal and distal gastric tumors with fourth and fifth edition were also compared, respectively. Besides, we discussed the correlation of the HER2-expression with clinicopathological features according to the V5.0.

Results: The results showed that the difference was mainly between oesophagogastric junction and distal adenocarcinoma in V4.0, while some were found between proximal and distal adenocarcinoma in V5.0. Tumors invading oesophagus more than 3cm were still mainly oesophagogastric junction tumors. The expression of HER2 in oesophagogastric junction and proximal gastric adenocarcinoma was still higher than that in gastric body and distal site.

Conclusions: The clinicopathological parameters of the oesophagogastric junction tumors changed to some extent in the updated WHO version. The proximal gastric tumors tended to be more invasive, rather than that located in oesophagogastric junction. But the latter with oesophageal invasion required additional management. The HER2-expression of oesophagogastric junction adenocarcinoma is the highest. The classification of the V5.0 is reasonable and worth a recommendation.

Background

Gastric cancer is the fifth most common cancer worldwide and adenocarcinoma of oesophagogastric junction has drawn considerable attention, because of its remarkable increasing incidence [1]. Compared with oesophageal and gastric carcinoma, oesophagogastric junction adenocarcinoma requires different surgical procedure, as well as lymph nodes dissection. However, it remains unclear whether the tumor is of gastric or oesophageal origin. In particular, the computed tomography (CT) has a low specificity (44%) when diagnosing Siewert type II oesophagogastric junction adenocarcinoma [2, 3]. The location of pathological anatomy was considered the most accurate after operation, but the definition of oesophagogastric junction adenocarcinoma remains controversial in the last decades. Siewert et al has classified oesophagogastric junction adenocarcinoma into three types, including type I with its epicentre 1-5cm above the oesophagogastric junction, type II with its epicenter between 1 cm above and 2 cm below the junction, and type III with its epicenter 2–5 cm distal from the junction [4]. Meanwhile, Nishi et al. proposed that oesophagogastric junction tumor is located 2 cm above and 2 cm below the oesophagogastric junction, regardless of its different histological subtype [5]. Except Japan, the Siewert’s classification has been widely used to distinguish the oesophagogastric junction adenocarcinoma and recommended in the fourth World Health Organization (WHO) classification (V4.0) of tumors of the digestive system.

In 2019, the fifth WHO classification (V5.0) of tumors of the digestive system redefined the oesophagogastric junction adenocarcinoma as having its epicenter from 5 cm to 2 cm, showing almost no difference with Nishi’s classification [6]. The new definition of oesophagogastric junction adenocarcinoma is similar with Siewert II. Efforts have been made to discuss the difference of clinicopathological features among the three Siewert subtypes. For example, a study conducted by Feith Met al demonstrated that patients with Siewert III tended to have advanced stage, with more extensive lymph node involvement and worse survival [7]. However, some data showed in Eastern, the outcome of Siewert II was similar to Siewert III [8]. Moreover, when compared with distal gastric tumors, oesophagogastric junction adenocarcinoma was associated with worse outcome [9]. As for the difference of clinicopathological features among oesophagogastric junction adenocarcinoma subtypes, there is no consistent conclusion. Therefore, a detailed and comprehensive analysis among the clinicopathological features is necessary, not only between the V4.0 and the V5.0 for oesophagogastric junction adenocarcinoma, but also between the gastric and oesophagogastric junction adenocarcinoma.

Besides, it is now increasingly clear that human epidermal growth factor receptor 2 (HER2) should be detected routinely to identify patients who may benefit from the target therapy of trastuzumb, which has been proposed in the V5.0 [6]. HER2 is a pro-oncogene encoded by erbB2 on chromosome 17 and its amplification may result in angiogenesis, tumorigenesis and excessive cell growth in several tissues such as colon, ovary, bladder, uterine and breast [10]. HER2 has been evaluated in many studies focusing gastric or oesophagogastric junction adenocarcinoma. With the change of scoring criteria and the definition of oesophagogastric junction adenocarcinoma, the HER2-amplication rate exhibits a great discrepancy, which varies with an extremely wide range, from 4–53% (median, 20.2%) [11, 12]. Previous studies showed that HER2-positivity rate was higher in oesophagogastric junction than gastric adenocarcinoma [13, 14], while some studies suggested that the presence of HER2-expression was not associated with tumor location [15, 16]. HER2-expression is heterogeneous in gastric or oesophagogastric junction adenocarcinoma, thus it’s important to review the HER2 status and its correlating clinicopathological features according to the V5.0.

In the V5.0, the diagnosis of oesophagogastric junction adenocarcinoma and the emphasis on HER2 test were updated. In this study, we compared the clinicopathological features between gastric and oesophagogastric junction adenocarcinoma with V4.0 and V5.0, respectively. With that, we sought to assess the relationship between clinicopathological features and HER2-expression with V5.0, aiming to make an in-depth and comprehensive understanding about the V5.0 for oesophagogastric junction adenocarcinoma.

Methods

Case Selection

A retrospective analysis was conducted. A total of 566 patients were included, among of which, 464 were gastric adenocarcinoma and the remains were oesophagogastric junction adenocarcinoma (V4.0). All patients received radical resection of the tumor at Sichuan Cancer Hospital & Institute between 2016 and 2019. Patients who received neoadjuvant therapies were excluded. The study was approved by the ethics committee of Sichuan Cancer Hospital. .

Histological evaluation

Using a multi-headed microscope, hematoxylin and eosin-stained (HE) sections from surgical excisions of specimen in all cases were reviewed by two pathologists. The histologic features were assessed as following: T classification (depth of tumor invasion), N classification (nodal involvement), degree of tumor differentiation, lymphovascular invasion, nerve invasion and histologic type (Lauren’s classification). The TNM classification was consistent with the AJCC eight edition [17]. Moreover, the sites of lymph nodes metastasis included four groups: lower mediastinal/periesophageal (No110-No.112), perigastric (No.1-No.6), suprapancreatic (No.7-No.11), para-aortic (No.16) [18]. The sites of lymph node metastasis were divided into three grades: none (0), periesophageal (1), more than periesophageal and perigastric (≥2).

Immunohistochemistry

The rabbit monoclonal antibodies included anti-CDX-2 (RMA-0631, Maxim, Fuzhou, China), anti-CK7 (Kit-0021, Maxim), anti-CK20 (Kit-0025, Maxim) anti-KI67 (MIB-1, Maxim), anti-C-erbB-2 (EP3, Maxim) and antibodies for mismatch repair protein (MMR:MLH1, PMS2, MSH2 and MSH6). All procedures were performed in the EnVision System by a Benchmark-ULTRA automatic immunohistochemical staining instrument (Asia-core, China). HER2 scoring system proposed by Hoffman et al. was set as the criteria [19]. HER2 status was considered negative (HER2-) with scores of 0 and 1(No membranous reactivity in <10% or faint or barely perceptible reactivity in ≥10% of tumor cells). HER2 with score of 3 (strong and complete basolateral membranous reactivity in ≥10 of tumor cells) was considered as HER2-amplification. HER2 status with score 2 was considered positive unless tested for gene amplification. The status of microsatellite was evaluated by four markers of mismatch repair protein (MMR), including microsatellite stability (MSS) with four positive markers and microsatellite instability of high frequency (MSI-H) with deficiency of more than two markers [20].

Fluorescence in situ hybridization (FISH)

The level of HER2 amplification were tested with the cases whose IHC score was two. FISH test of HER2-amplification was performed with PanthVysion kit (GSP, LBP, Guangzhou, China). The evaluation towards HER2-amplification was based on the ratio of HER2 to centromere 17 copy number, according to the guidelines of 2007 ASCO/CAP [21]. Cases were considered gene amplified for the HER2/CEP17 ratio of 2.2, equivocal with ratio less than 2.2 but more than 1.8 and negative with the ratio less than 1.8. The equivocal cases were not selected in our cohort.

Statistical analysis

Data was analyzed with SPSS software for Windows, Version 18. The clinicopathological parameters were collected according to a standardized protocol. The Mann-Whitney U test and Kruskal-Wallis test were performed to assess the difference of clinicopathological features among oesophagogastric junction adenocarcinoma, proximal and distal gastric tumors. The difference of clinicopathological features between oesophagogastric junction adenocarcinoma of V4.0 and V5.0, and the correlation between clinicopathological features and HER2-expression were evaluated with the Mann-Whitney U test and Fisher’s exact test. P-value <0.05 was considered significantly different.

Results

Discussion

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 [22], 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 [25]. The majority of patients were found to have more lymph node involvement in the Siewert III [26], 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 [27]. 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 [16]. 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 [33]. 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 [34]. 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.

Conclusions

The clinicopathological parameters of the oesophagogastric junction adenocarcinoma changed in the updated WHO classification. Although the treatment tends to be more unified and standardized, the oesophagogastric junction tumors with extent of oesophageal invasion more than 3 cm required additional management. The HER2-expression of oesophagogastric junction adenocarcinoma is still higher than that of other sites of gastric in the updated version. Therefore, the emphasis on the detection of HER2 in oesophagogastric junction tumors is of great significance in clinical practice. The overall analyses showed it’s reasonable to recommend the updated V5.0 in pathological diagnosis, as well as clinical practice.

Abbreviations

WHO: World Health Organization; HER2: human epidermal growth factor receptor 2; V4.0: fourth version; V4.0: fourth version; CT: computed tomography; HE: hematoxylin and eosin-stained; MMR: mismatch repair protein; MSS: microsatellite stability; MSI-H: microsatellite instability of high frequency; FISH: Fluorescence in situ hybridization

Declarations

Acknowledgements

The authors thank Sichuan Cancer Hospital & Institute for clinical data supported.

Authors' contributions

ML made the pathological diagnosis. JL provided the clinical information. YL drafted the manuscript. ML and JL participated in manuscript revision. All authors read and approved the final manuscript.

Funding

This work was supported by Foundation of Health Department of Sichuan Province (No.120044).

Availability of data and materials

The data used or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics approval and consent to participate

This article was approved by the Ethnic Committee of Sichuan Cancer Hospital & Institute. The data were used confidentially for research work.

Consent for publication

Not applicable

Competing interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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