Systematic Review and Meta-Analysis of TissueCypher and p53 Immunohistochemistry for Risk Stratification in Barrett's Esophagus

BACKGROUND AND AIMS: Barrett's esophagus surveillance relies on subjective biopsy grading that misses fast progressors. Although the Tissue Systems Pathology-9 (TSP-9) test and p53 immunohistochemistry (IHC) have each been evaluated separately, no prior study has directly compared the 2 within a single analytic framework. We compared both biomarkers for predicting progression to high-grade dysplasia or esophageal adenocarcinoma. METHODS: PubMed, Embase, Cochrane, and Web of Science were searched through December 2025. Studies were included if they evaluated TSP-9 or p53 IHC in patients with non-dysplastic Barrett's esophagus, indefinite for dysplasia, or low-grade dysplasia and reported prognostic outcomes. Pooled sensitivity, specificity, negative predictive value (NPV), odds ratios, and hazard ratios (HRs) were estimated using random-effects models. RESULTS: Twenty-three studies (7 TSP-9, 16 p53 IHC; 6655 patients) met inclusion criteria. TSP-9 yielded a higher pooled HR (HR: 7.65; 95% confidence interval: 5.86-9.99) compared with p53 IHC (HR: 5.05; 95% confidence interval: 4.27-5.97). Sensitivities were comparable (TSP-9: 57.1% vs p53 IHC: 60.1%), while p53 IHC demonstrated higher specificity (91.5% vs 83.5%). Both biomarkers exhibited robust NPVs exceeding 90% (p53 IHC: 94.7%; TSP-9: 91.1%). CONCLUSION: Both TSP-9 and p53 IHC substantially outperform standard histology for risk stratification in Barrett's esophagus. The higher HR with TSP-9 may reflect its multiplexed approach. The strong NPV of both assays supports safely extending surveillance intervals in low-risk patients.