Decreased expression of claudin-18.2 in alpha-fetoprotein-producing gastric cancer compared to conventional gastric cancer.

Background: Alpha-fetoprotein-producing gastric cancer (AFPGC) is a subtype of gastric cancer (GC) with more aggressive biological behavior. As a highly specific tight junction component exclusively present in gastric mucosa and gastric adenocarcinomas, claudin-18.2 (CLDN18.2) has become an emerging target in GC. In this study, we aimed to provide insight into AFPGC and investigate the expression and the clinical implications of CLDN18.2 in AFPGC. Methods: We retrospectively collected 98 cases of AFPGC and reviewed their clinical, morphological, and immunohistochemical features. Another 356 patients with stage-matched conventional GC (cGC) were enrolled as a control group. We further surveyed CLDN18.2 expression by immunohistochemistry (IHC) in 51 AFPGC tissues and explained its association with the clinicopathological parameters of AFPGC. Results: Our results showed that AFPGC was a unique GC type with elevated serum alpha-fetoprotein (AFP), which was a predictor of a worse prognosis. AFPGC showed typical morphological features and positive staining of at least 1 hepatocytic or enteroblastic marker. The expression rate of CLDN18.2 was low, with a positivity rate of 21.6%, which was much lower than that observed in cGC tissues (38.5%). A significant correlation was found between CLDN18.2 expression and the differentiation of AFPGC. CLDN18.2 expression was negatively correlated with the serum AFP level of AFPGC. We also found that AFPGC with a hepatoid type (HPT) component showed a significantly lower CLDN18.2 expression than those without. Conclusions: This study demonstrated that CLDN18.2 was significantly decreased in AFPGC and was negatively correlated with the patient's preoperative serum AFP level. The negative correlation between AFP and CLDN18.2 could be explained by retro-differentiation of AFPGC. Special treatment strategies might be needed for this unique tumor type.