Early warning value of serum TFF3 combined with pepsinogen ratio for monitoring the progression of gastric precancerous lesions: a retrospective study

OBJECTIVE: Gastric cancer (GC) has high mortality due to late diagnosis. Identifying which patients with gastric low-grade intraepithelial neoplasia (LGIN) will progress to high-grade intraepithelial neoplasia (HGIN) or early gastric cancer (EGC) remains challenging. This study aimed to develop a non-invasive method combining serum TFF3 (reflecting malignant transformation) and pepsinogen ratio (PGR, indicating gastric atrophy) to predict progression. METHODS: A retrospective multicenter study included patients with confirmed LGIN, available serum, and full follow-up. Progression to HGIN/EGC within 24 months was the primary outcome. TFF3 and PGR were measured using ELISA and chemiluminescence immunoassay, respectively. Propensity score matching (1:4) balanced baseline variables. Predictive performance was assessed via ROC analysis, logistic regression, and Cox models. RESULTS: After matching, 85 patients (17 progressors) were analyzed. Progressors had higher TFF3 (11.28 vs. 7.15 ng/mL) and lower PGR (2.78 vs. 3.62; both p < 0.001). The combined model showed superior accuracy (AUC = 0.823) versus TFF3 or PGR alone, with sensitivity of 88.2%, specificity of 89.7%, and NPV of 98.3. Progressors exhibited yearly TFF3 increase (+ 1.82 ng/mL) and PGR decrease (-0.41). TFF3 correlated with Ki-67 (ρ = 0.437, p < 0.001). CONCLUSION: The TFF3 and PGR combination is a non-invasive tool for stratifying LGIN progression risk. Its high NPV safely excludes short-term progression, enabling extended follow-up for low-risk patients and better allocation of endoscopic resources. This approach supports personalized monitoring and may help reduce gastric cancer mortality.