A 47-year-old man presented with epigastric discomfort and dyspepsia. Esophagogastroduodenoscopy revealed a diffusely infiltrative submucosal lesion involving the upper body of the stomach along the greater curvature (Fig. 1A). The overlying mucosa was intact and non-ulcerative, but it showed tiny scattered mucosal openings with extruding mucus (Fig. 1B). Abdominal computed tomography scan demonstrated diffuse wall thickening with suspicious perigastric infiltration, consistent with Borrmann type 4 gastric cancer. The patient underwent four consecutive gastrofiberscopic examinations, with biopsies consisting of more than 10 pieces, but all biopsies were negative for adenocarcinoma. Subsequently, the patient underwent a diagnostic laparotomy and total gastrectomy and was diagnosed with gastric-type EWDA (pT4aN3aM1, stage IV). Microscopic examination revealed numerous irregular-shaped mucinous glands that diffusely extended from the submucosal layer to the visceral peritoneum (Fig. 1C). The mucosal layer was spared for the most part, with only some carcinoma glands found in the deep portion of the mucosa. The tumor glands consisted of mucin-rich columnar cells with basally located, small, bland-looking nuclei mimicking hyperplastic foveolar epithelium or dilated pyloric glands (Fig. 1D), which deeply infiltrated the proper muscle with no desmoplastic stromal reaction (Fig. 1E). There were also areas showing distinctly lobular proliferation of small glands often surrounding a larger central duct (Fig. 1F); such areas were frequently observed in the submucosa, and the central dilated duct occasionally opened through the overlying mucosal surface (Fig. 1G). The tumor cells were diffusely positive for MUC5AC (Fig. 1H), human gastric mucin (HGM), and carcinoembryonic antigen (CEA); focally positive for MUC6; and negative for MUC2, CD10, and p53. The Ki-67 labeling index was low (5%). We retrospectively reviewed the preoperative biopsy specimens and found a few scattered carcinoma glands in the basal portion of the oxyntic-type corpus mucosa (Fig. 2A). Despite not being atypical enough to be considered definite carcinoma, the glands were indisputably noticeable, with large size, abundant clear cytoplasm, mild nuclear atypia, and unusual location compared to normal mucous glands (Fig. 2B, C). Those atypical glands were more distinguishable on immunostaining for HGM, CEA, and MUC5AC (Fig. 2D).

To date, only nine cases (including the present one) of gastric-type EWDA have been reported in the English literature. The clinical and pathological findings of these patients are summarized in Table 1. The patients were all male with ages ranging from 47 to 81 years. The tumors in all reported cases were located in the upper or middle third of the stomach. Grossly, they were polypoid masses or submucosal tumors mimicking Borrmann type 4 gastric cancer. Preoperative biopsy findings were available in seven cases, five of which were diagnosed as benign lesions, one as a suspicious carcinoma, and one as definite carcinoma on repeat biopsy. It is very difficult to diagnose gastric-type EWDA in a preoperative biopsy specimen, especially in patients with Borrmann type 4 lesions. Nevertheless, the most important aspect in diagnosing gastric-type EWDA in a biopsy specimen is observation of the subtle atypical changes of mucous glands: mucous glands with conspicuously abundant mucinous cytoplasm, mild nuclear atypia, and slightly larger size should raise suspicion of gastric-type EWDA, particularly when they are abnormally clustered or seen in the deep portion of the corpus mucosa that is usually devoid of well-formed mucous glands. Additional immunostaining for CEA and gastric phenotype mucin can help to confirm the diagnosis.

The histologic characteristics of gastric-type EWDA, including deep invasion of extremely well-formed mucinous glands, minimal cellular atypia, and no significant desmoplastic stromal reaction, resemble those of minimal deviation adenocarcinoma (MDA) of the uterine cervix. Therefore, gastric-type EWDA has been considered as the gastric counterpart of MDA [4,5]. According to the new World Health Organization classification published in 2014, MDA is classified as an extremely well-differentiated form of gastric-type endocervical mucinous adenocarcinoma [7]. Lobular endocervical glandular hyperplasia (LEGH) has been described as a distinctive hyperplastic lesion of the endocervix characterized by lobular proliferation of small, rounded, non-invasive glands often surrounding a central dilated gland. It has been postulated that LEGH is a precursor lesion of MDA [8,9]. In the present case, we found LEGH-like areas with distinct histological characteristics of LEGH that occurred concurrently with invasive mucinous carcinoma. In addition, they were predominantly observed in the submucosal layer, just as LEGH is usually confined to the inner half of the endocervical wall. LEGH-like lesions have never been described in the stomach before, which may provide evidence to support gastric-type EWDA being the gastric counterpart of MDA of the uterine cervix.