Primary SCC of stomach is extremely rare, with an annual incidence rate of 0.04–0.07% of all gastric cancers [1,2,3]. It occurs mostly in men and the male/female ratio is 5:1 [3, 5, 6], and the primary lesions were mostly found in the upper-third of the stomach [3].
Primary SCC of stomach is defined according to the following diagnostic criteria proposed by the Japanese Classification of Gastric Carcinoma [7]: (1) all tumor cells are composed by SCC cells, with no adenocarcinomatous components in any sections. (2) Distinct evidence that SCC originates in the gastric mucosa. There are also histopathologic criteria for diagnosis of SCC described by Boswell and Helwig as follows [8]: (1) keratinized cell masses forming keratin pearls. (2) Mosaic cell arrangement. (3) Intercellular bridges. (4) High concentration of sulfhydryl and/or disulfide groups, indicating the presence of keratin and prekeratin. At least one of these criteria should be satisfied for the confirmation of diagnosis.
The immunohistochemistry of CK5/6 and p40 [9] is also effective in the diagnosis of SCC.
Primary SCC has an aggressive behavior, such as metastasizes to lymph node, liver and other organs, they are usually diagnosed at advanced stage, which leads to poor prognosis [10,11,12,13]. The standard treatment for the primary SCC of stomach is radical resection [14]. Surgery alone might be insufficient for in advanced cases, therefore various adjuvant chemotherapy regimens were administered. However, most results were not promising and optimal regimen for the primary SCC of stomach has not yet been established [2, 3, 6, 14].
Although the pathogenesis of the primary SCC of stomach is still unknown, several hypotheses concerning the origin of the SCC have been reported as follows [1, 3, 4, 6, 15, 16]: (1) squamous differentiation in a preexisting adenocarcinoma; (2) squamous metaplasia of the gastric mucosa; (3) nests of ectopic squamous epithelium in the gastric mucosa; (4) multipotent stem cells in the gastric mucosa which has a potential to differentiate any type of cell. Takita et al. reported that EBV infection may be related to the pathogenesis of at least some primary SCC of stomach [17]. In this study, a liquid hybridization assay for HPV infection and a polymerase chain reaction for EBV infection was performed and revealed the presence of EBV infection in surgical specimens of the tumor.
EBV infection is known to cause gastric cancer, and EBV infection-associated gastric cancer accounts for approximately 10% of all gastric cancer [18]. EBV infection-associated gastric cancer is defined by monoclonal proliferation of cancer cells with latent EBV infection, as demonstrated by EBV-encoded small RNA (EBER) in situ hybridization [19].
A histological feature of EBV infection-associated gastric cancer is a mainly diffuse-type carcinoma accompanied by abundant lymphocyte infiltration. In case of the tumor invading submucosa, undifferentiated cancer cells and infiltrated lymphocytes compose a mass, causing submucosal nodules [20].
Recent cancer genome atlas research has divided gastric cancer into four molecular subtypes as follows [21]: (1) tumors positive for EBV; (2) microsatellite instability; (3) chromosome instability; (4) genomically stable tumors. The detailed mechanisms of how EBV causes gastric cancer are still unknown. It has been reported that EBV nuclear antigen 1 (EBNA1) destabilizes the p53 gene to suppress p-53-mediated apoptosis [22, 23], and also EBER-1 induces the expression of insulin-like growth factor-1 (IGF1), which causes the autocrine action, promoting proliferation of the EBV-infected cancer cells [18, 24].
In our case, histopathological findings revealed the partially keratinization in the tumor cells without gland formation or mucus production, indicating poorly differentiated SCC. Also immunohistochemistry staining of p40 and CK5/6 was positive. There was no squamous metaplasia or ectopic squamous epithelium around the tumor. Tumor cells invaded into subserosa and infiltration of lymphocytes and plasma cells into the stroma was found. All tumor cells were positive for EBER by in situ hybridization. Therefore, we diagnosed this case as EBV infection-associated primary squamous cell carcinoma of stomach. EBV infection-associated primary SCC of the stomach is very rare, and to our knowledge, there have been no other reports ever before which revealed the EBV infection using in situ hybridization. We performed radical resection, but considering lymph node metastasis in resected specimen, adjuvant chemotherapy was required. A standard chemotherapy regimen for this disease has not been established; the choice of its treatment tends to follow the principle of the treatment against gastric adenocarcinoma. On the basis of adjuvant regimen of gastric adenocarcinoma and the regimen against SCC of esophagus, we selected CapeOX. EBV infection-associated gastric cancer has molecular biological characteristics such as DNA methylation and PD-L1/2 overexpression, demethylating agents or anti-PD-L1 antibody may be one of the treatment options in the future. We need further research in this tumor and further studies would benefit the patients affected by this rare disease.