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

Abstract

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.