Gastric cancer (GC) is the fourth most common malignancy worldwide. Endoscopy and pathological biopsy are necessary for its diagnosis. Although the manifestations of this disease vary, the presentation of GC as submucosal tumours (SMTs) is extremely rare. The first case of GC with features of a submucosal tumour (GCSMT) in the English-language literature was reported by Ohara et al. in 1997 (1). Currently, the clinicopathological characteristics of GCSMT remain unclear since a limited number of cases have been reported to date. The diagnosis of GCSMT via endoscopic biopsy is also extremely difficult because the tumour cells often remain undetected, even if multiple biopsies are performed. In the present paper, we report four cases of GCSMT and perform a combined review of the data and the related literature to provide an overview of the clinicopathological characteristics and immune phenotypes of GCSMT. We hope that our results can serve as a reference to enhance the knowledge of clinicians and pathologists on this rare tumour type and avoid missed diagnosis and misdiagnosis in clinical practice in the future.

Gastric SMTs are usually caused by various neoplastic or non-neoplastic diseases in the submucosa or in deeper tissues of the stomach, including gastrointestinal stromal tumours, neurilemmomas, lipomas, and lymphomas. GCSMT refers to a GC that presents endoscopically as an SMT, with the surface mucosa appearing normal or manifesting as local foci accompanied by small umbilicus-like indentations. It is a rare disease that accounts for only 0.1%–0.63% of all GC cases (21, 25). The clinicopathological characteristics of GCSMT remain unclear since only a limited number of cases have been reported to date.

Among the cases of asymptomatic SMTs discovered during routine endoscopy, most were non-epithelial tumours, and only a small number of them were GCSMT. Certain differences in the endoscopic morphology of GCSMTs and submucosal non-epithelial tumours exist. For instance, the former manifest as low-height protrusions, a disordered base region, visible indentations on the surface, which occupy a large area of the entire lesion, and shallow depressions on the surface.

Mucinous adenocarcinoma is a histological subtype of adenocarcinoma. In GC, gastric mucinous adenocarcinoma is relatively rare and accounts for only 2.1%–8.1% of all GC cases (26). However, up to 29.0% of the 31 GCSMT cases reviewed in this study were mucinous adenocarcinoma cases (9/31). Early mucinous adenocarcinoma is even rarer, with most cases of early gastric mucinous adenocarcinoma manifesting as SMTs. Therefore, when SMTs are found endoscopically, the possibility of an early mucinous adenocarcinoma diagnosis should be considered. During endoscopy, attention should be paid to subtle changes, such as the presence or absence of erosion, depressions, and the state of the tumour margins. When necessary, endoscopic ultrasonography-guided fine needle aspiration biopsy or SMT resection may be performed to confirm the diagnosis at an early stage and avoid treatment delay as much as possible. Some researchers believe that mucinous adenocarcinoma arises initially as a typical adenocarcinoma, and then becomes mucinous with tumour progression. This is consistent with the decreased intraluminal mucoprotein excretion and increased intramural mucoprotein accumulation observed following the tumour infiltration of the gastric wall (27). We deduce that mucin accumulation within the gastric wall may be the main cause of the SMT-like appearance of GCSMTs. The biological behaviour of gastric mucinous adenocarcinoma is similar to that of non-mucinous GC, and its outcomes are related to the tumour differentiation, size and location, the depth of infiltration, lymph node metastasis and clinical staging, and not to the mucoprotein content. The multivariate analysis results indicated that the mucinous histological subtype is not an independent prognostic factor of patients with GC; however, patients with early gastric mucinous adenocarcinoma have good postoperative outcomes (4). Among the nine cases of mucinous adenocarcinoma reviewed in the present paper, eight were treated via radical gastrectomy for GC and one was treated via local gastric wall resection. The three patients whose follow-up data were available (one patient with pT1bN0M0 disease and two patients with T2N0M0 disease), were followed-up for 5–34 months, during which no recurrence or metastasis was observed.

Lymphoepithelioma-like carcinoma, also known as gastric carcinoma (adenocarcinoma) with lymphoid stroma (GCLS), accounts for 1.0%–7.0% of all GC cases (26) and approximately 22.6% of the 31 GCSMT cases reviewed in this paper (7/31). Kobayashi et al. analysed 11 cases of lymphoepithelioma-like carcinoma, among which three cases (27.3%, 3/11) endoscopically exhibited an SMT-like morphology. Results indicated that the disease was associated with the male sex, a proximal location, and an SMT-like appearance. Diagnosis was difficult since five cases (45.5%) were negative upon pathological examination via biopsy. The tumour invasion depth was more than 1,000 µm into the submucosa in all cases. In the five patients who underwent radical gastrectomy for GC, no lymph node metastasis was observed. Follow-up was performed for 12–48 months, and neither local recurrence nor distant metastasis was reported during the follow-up period. The researchers asserted that submucosa-invasive lymphoepithelioma-like carcinoma can be entirely excised endoscopically to avoid excessive and unnecessary gastrectomy (20). All seven cases of lymphoepithelioma-like carcinoma reviewed in this paper were treated using gastrectomy or ESD, among which six had stage T1b disease and one had stage T2 disease. Postoperative pathological examinations showed an absence of lymph node metastasis. The patients were followed-up for 8–66 months, during which recurrence or metastasis was not observed. More data are needed to further study the indications for ESD treatment and the prognosis of patients with lymphoepitheliomatoid carcinoma.

Several pathological mechanisms related to the occurrence of GCSMT have been described in the literature, including lymphocyte infiltration in lymphoepithelioma-like carcinoma, mucin aggregation in mucinous adenocarcinoma, adenocarcinoma arising from a heterotopic pancreas in the gastric wall, GC arising from gastritis cystica profunda (GCP) (6) and excessive fibrosis in the surrounding tissues of GC (28).

Differential diagnoses may be performed in the following cases: 1. GCP: clinical and endoscopic observations may be similar; however, a history of gastric surgery is usually present in GCP cases. In the absence of surgical history, multiple cysts may be observed in the hypertrophic submucosal layer via endoscopic ultrasonography. The presence of non-atypic, well-differentiated dilated glands of various sizes within and below the muscularis mucosae can be observed by histological examination; 2. Heterotopic pancreas: there is usually a lack of clinical manifestations of a heterotopic pancreas. The condition is usually accidentally discovered during surgery or examination. In approximately 90% of cases, the heterotopic pancreas is located in the upper gastrointestinal tract, mainly in the stomach (usually on the side of the greater curvature within 5 cm from the pylorus), duodenum and jejunum. It usually manifests endoscopically as submucosal protrusion lesions, accompanied by a central umbilicus-like indentation. The pancreatic ducts, acini and/or islets can be observed during pathological examination, along with non-atypic cells. 3. Metastasis of pancreatic cancer in the gastric wall induced by endoscopic ultrasound-guided fine needle aspiration (29): a differential diagnosis is mainly made based on the medical history and lesion site. 4. Metastatic cancer: a differential diagnosis can be made based on the medical history and the morphological and immunohistochemical indicators of the actual tumour.

Endoscopic biopsy of GCSMT usually produces a negative result, increasing the tendency of the occurrence of missed diagnosis or misdiagnosis as non-epithelial tumours, thereby resulting in delayed treatment. Upon the observation of high-risk characteristics, such as irregular boundaries, surface ulcerations, an obvious volume increase, intra-lesion heterogeneity or local lymphadenectasis, biopsy or endoscopic local resection should be performed in a timely manner to avoid treatment delay. A larger number of cases are required for further investigation to enhance our understanding of the disease and guide future clinical practice.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

Analysis of the results and the writing of the manuscript: CW. Collection of data: FY, HZ, JC and LM. Analysis of the results and pathological pictures: CW, FY and HZ. Design and implementation of the research and revision of the manuscript: XH. All authors contributed to the article and approved the submitted version.