ASC is exceedingly rare in the EGJ. We identified three important clinical issues in the present case: (1) ASC was considered to be originated from the squamous epithelia; (2) ASC of the EGJ can present as a submucosal tumor-like mass in the EGJ, and (3) both SCC and adenocarcinoma were metastasized in regional nodes.

No data of frequency of ASC in the EGJ is available. ASC is less frequently found in the esophagus. Previous studies reported it to be 0.37–1% of esophageal carcinoma in Western countries [3,4,5,6], and 0.6–1.0% in Japan [7, 8]. In gastric cancer, previous studies reported it to be less than 1% in Western countries [9], and 0.14–1.3% in Japan [10, 11].

Various theories regarding the origin of ASC have been suggested in esophageal ASC. Pascal and Clearfield [12] reported that ASC in the esophagus arises from the esophageal gland cells or the ductal cells. As the epithelium and submucosal glands are derived from the foregut during embryogenesis, adenocarcinoma has the potential to transform into SCC. Other authors [6, 8, 13,14,15,16] considered that ASC arises from the mucosa, where it develops into SCC firstly and then the glandular cells differentiate into ASC. Furthermore, a collision concept was proposed, in which ASC may come from two individual stem cells that independently and simultaneously undergo malignant transformation [17, 18]. In esophageal ASC, most of the adenocarcinoma component is located at an invasive site. On the other hand, the SCC component is located in the superficial epithelial region adjacent to the adenocarcinoma component.

Five hypotheses have been proposed in gastric ASC: (1) squamous metaplastic transformation of adenocarcinoma [19,20,21,22]; (2) oncogenic transformation of the ectopic squamous epithelium [23]; (3) oncogenic transformation of the metaplastic non-neoplastic squamous cells [24], (4) collision of concurrent adenocarcinoma and SCC [25], and (5) differentiation of multipotential undifferentiated cancer cells toward both the glandular and squamous cells [26, 27]. In gastric ASC, most of the SCC component was located at an invasive site. In contrast, the adenocarcinoma component was located in the superficial mucosal region adjacent to the SCC component. Thus, many authors now believe that the SCC component results from metaplastic change of the adenocarcinoma component in gastric ASC. In the present case, the tumor was considered to be originated from the esophageal squamous epithelium, where it developed into SCC, and then SCC differentiated to adenocarcinoma sporadically. As the tumor continued into the squamous epithelium, it was mainly composed of the SCC component, and it was covered with the normal squamous epithelium and scattered SCC in the EGJ histopathologically.

It is interesting to note that the tumor was located in the stomach mainly with submucosal invasion, even though the origin of the tumor was considered to be the esophageal epithelium histopathologically. Kuwano et al. [28] proposed that there are four patterns of invasion of the stomach in esophageal SCC; however, these patterns did not include invasion of the gastric submucosa. Furthermore, Iriguchi et al. [29] reported a case of SCC located in the submucosa of the gastric cardia, developing from the esophageal mucosa of the EGJ. According to previous studies, SCC of the EGJ invading the gastric submucosa is rare. In contrast, special pathological types of esophageal carcinoma, such as ASC, may show a submucosal tumor-like form. Matsuda et al. [30] reported that three out of five cases of ASC in the esophagus showed subepithelial growth as a submucosal tumor-like form. Based on these findings, it is difficult for SCC to grow under the submucosa; however, it is easy for ASC to grow under the submucosa in the esophagus. The mechanism of invading the submucosa in the esophagus is that the cancer that occurs from the parabasal layer of the epithelium shows a downward growth, cancer arises from the esophageal gland cells or the ductal cells, and cancer arises from the esophageal cardiac glands [31]. The tumor may arise from the esophageal gland cell, the ductal cells, or the cardiac glands; however, we were unable to prove this histopathologically in the present case.

Node metastasis in ASC of the EGJ also remains poorly understood. Previous studies found that 33% of patients with esophageal ASC had node metastasis [32, 33]. Among them, SCC component accounted for 60.9–85.7%, both components accounted for 14.3–26.1%, and adenocarcinoma component accounted for 0–8.7%. In contrast, 70.2–83% of patients with gastric ASC had node metastasis [10, 11]. Among them, adenocarcinoma component, both, and SCC component accounted for 63%, 26%, and 11%, respectively. In the present case, seven of the eight nodes showed both metastases of SCC and adenocarcinoma, and a node in the right area of the gastric cardia showed metastasis of SCC only. We considered that many metastases had both components due to the volume of the tumor. Thus, esophageal ASC showed node metastasis from the SCC component, whereas gastric ASC showed metastasis from the adenocarcinoma component. In the present study, ASC was found in the EGJ; thus, metastasis and/or recurrence from both components should be considered in the future. In addition, HER2 was negative by fluorescence in situ hybridization; however, immunohistochemistry was 2+ in adenocarcinoma cells. When HER2 was positive, trastuzumab may be indicated for treatment of ASC of the EGJ.

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