Nuclear staining of claudin‐18 is a new immunohistochemical marker for diagnosing intramucosal well‐differentiated gastric adenocarcinoma

Diagnosis of gastric adenocarcinoma using small biopsy samples is occasionally difficult. Various markers have been employed for improving the diagnostic accuracy, but there remains room for improvement. A total of 129 endoscopically biopsied samples were studied, consisting of 104 intramucosal tubular adenocarcinomas, 24 non‐cancerous lesions and one cancer sample originally suspected of non‐cancer but revised as cancer after immunostaining. We evaluated the association between histopathology and immunohistochemical expression of MUC1, HER2, p53, CEA, E‐cadherin, β‐catenin and claudin‐18. Regarding β‐catenin and claudin‐18, not only membranous expression (β‐catenin(M) and claudin‐18(M)) but also nuclear expression (β‐catenin(N) and claudin‐18(N)) were analyzed. When subtyped with mucin core protein expression, the gastric‐type cancers dominantly expressed claudin‐18(M), while claudin‐18(N) was significantly encountered in intestinal‐ and mixed‐types. Expression of MUC1 ( P = 0.0010), HER2 ( P = 0.0173), p53 ( P = 0.0002), CEA ( P = 0.0019) and claudin‐18(N) ( P < 0.0001) revealed significant correlation with gastric cancers. Negative correlation of claudin‐18(M) ( P = 0.0125) was also noted. MUC1 and p53 were negative in non‐cancer lesions. The non‐cancer group exceptionally expressed HER2 and β‐catenin(N). Membranous expression of E‐cadherin was consistent in both groups. Logistic regression analysis showed that MUC1 ( P = 0.0086), p53 ( P = 0.0031), claudin‐18(M) ( P = 0.0158) and claudin‐18(N) ( P = 0.0190) were independently associated with gastric cancers. Nuclear expression of claudin‐18 should be the novel diagnostic marker for gastric cancer.