BackgroundGastric cancers with microsatellite instabilities (MSI) have been reported to be associated with favorable prognosis. However, the significance of the effect of MSI on the clinicopathological features, as well as its association with mucin phenotype, remains unclear.MethodsMSI status was assessed in 414 cases of gastric cancer using polymerase chain reaction analysis of five microsatellite loci, as recommended by National Cancer Institution criteria. The expression of mucins (MUC5AC, MUC6, MUC2, and CD10) was assessed.ResultsOut of 414 total cases of gastric cancer, 380 (91.7%), 11 (2.7%), and 23 (5.6%) were microsatellite stable (MSS), low-level MSI (MSI-L), and high-level MSI (MSI-H), respectively. Compared to MSS/MSI-L, MSI-H gastric cancers were associated with older age (p=0.010), tumor size (p=0.014), excavated gross (p=0.042), intestinal type (p=0.028), aggressive behaviors (increase of T stage [p=0.009]), perineural invasion [p=0.022], and lymphovascular emboli [p=0.027]). MSI-H gastric cancers were associated with tumor necrosis (p=0.041), tumor-infiltrating lymphocytes (≥2/high power field, p<0.001), expanding growth patterns (p=0.038), gastric predominant mucin phenotypes (p=0.028), and MUC6 expression (p=0.016). Tumor necrosis (≥10% of mass, p=0.031), tumor-infiltrating lymphocytes (p<0.001), intestinal type (p=0.014), and gastric mucin phenotypes (p=0.020) could represent independent features associated with MSI-H gastric cancers. MSI-H intestinal type gastric cancers had a tendency for poor prognosis in univariate analysis (p=0.054) but no association in Cox multivariate analysis (p=0.197).ConclusionsOur data suggest that MSI-H gastric cancers exhibit distinct aggressive biologic behaviors and a gastric mucin phenotype. This contradicts previous reports that describe MSI-H gastric cancer as being associated with favorable prognosis.

Despite wide acceptance of the chronic gastritis-intestinal metaplasia-dysplasia-carcinoma sequence, especially for intestinal-type gastric adenocarcinoma, the precise nature of the subtle precursor lesions of gastric cancer remains to be delineated. For example, pit dysplasia with surface foveolar maturation is not well defined, nor is its prevalence and biological characteristics well characterized. We have evaluated the surrounding gastric mucosa of 414 gastric cancers for the presence of gastric pit dysplasia. We investigated its relationship with various clinicopathological and immunophenotypic features of gastric adenocarcinoma, as well as the severity and extent of any surrounding gastritis and intestinal metaplasia. p53 expression and Ki-67 proliferation index were also evaluated. We have found that 21.0% (n=87) of gastric cancer cases showed pit dysplasia in adjacent gastric mucosa. Gastric cancers with pit dysplasia were significantly associated with older age, male sex, body/fundic location, and intestinal histologic type (P<0.05). Interestingly, gastric mucin-containing intestinal metaplasia (incomplete intestinal metaplasia) was highly associated with adenocarcinoma with pit dysplasia (P=0.000). In addition, MUC6 expression in gastric adenocarcinoma was associated with pit dysplasia (P=0.036). p53 overexpression and increased Ki-67 proliferation index were more evident in gastric pit dysplasia compared with adjacent gastric mucosa. We suggest that gastric pit dysplasia is an important candidate precursor of gastric adenocarcinoma and may represent another morphologic step in the pathogenesis of gastric adenocarcinoma, especially of intestinal type. More detailed prospective studies are needed to determine the precise significance of these findings.

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NTRK1 gene fusions, the targets of multikinase inhibitors, are promising therapeutic targets for colorectal cancer (CRC). However, screening methods for detecting NTRK1 gene fusions in CRC tissues have not been reported. In this study, we investigated the potential use of immunohistochemistry (IHC) for detecting NTRK1 gene fusions. We performed and compared IHC with fluorescence in situ hybridization (FISH) in 80 CRC patients. TrkA immunostaining was observed to be both membranous and cytoplasmic and was scored semiquantitatively using staining intensity and proportions. The tumors were observed to be NTRK1 gene fusion-positive when ≥20 out of 100 nuclei in FISH. A significant correlation between the IHC and FISH results for determination of the NTRK1 gene fusions was observed. We measured the cytoplasmic TrkA expression, which showed an area under the receiver operating characteristic (ROC) curve of 0.926 (range: 0.864-0.987, 95% CI, P = .001). By choosing 4.5 (sum of the intensity and proportion scores of cytoplasmic TrkA expression) as the cut-off value for the positive and negative NTRK1 gene fusion groups, the sensitivity and specificity for predicting lymph node metastasis were 100 and 83.8%, respectively (P = .001). Specifically, high cytoplasmic TrkA expression (sum of intensity and proportion scores >4) was associated with the presence of NTRK1 gene fusions (P < .0001, r = 0.528). Taken together, our data showed that IHC for TrkA can be used as an efficient screening method for detecting NTRK1 gene fusions in CRC.