Evaluating Cytokine and Molecular Biomarkers for Diagnosing Primary Vitreoretinal LymphomaBiomarkers Show Promise in Detecting Vitreoretinal Lymphoma

PURPOSE: To evaluate the individual and combined diagnostic performance of cytokine, molecular, and clonality biomarkers for primary vitreoretinal lymphoma (PVRL). DESIGN: Systematic review and meta-analysis. PARTICIPANTS: A total of 2411 patients from 41 studies with confirmed PVRL or benign ocular inflammatory diseases. METHODS: Prospectively registered (CRD420251265910). Four databases were searched through November 25, 2025. Methodologic quality was assessed using QUADAS-2 and Comparative tools. Diagnostic accuracy was pooled using hierarchical summary receiver operating characteristic (HSROC) models with GRADE certainty assessment. MAIN OUTCOME MEASURES: Pooled sensitivity, specificity, and AUSROC for each biomarker with GRADE certainty ratings. RESULTS: Of 41 included studies, most were rated at high or unclear risk of bias across Quality Assessment of Diagnostic Accuracy Studies 2 domains, predominantly in patient selection because of retrospective designs and nonconsecutive sampling, and in the index test domain because of post hoc threshold selection. The interleukin (IL)-10 to IL-6 ratio (27 studies; 1370 patients; AUSROC, 0.98; sensitivity, 0.89; specificity, 0.98; I = 61% and 69%, respectively; low certainty) showed no publication bias. MYD88 (12 studies; 382 patients; AUSROC, 0.89; sensitivity, 0.73, specificity, 0.99; I = 37% and 68%, respectively; very low certainty), IGH (12 studies; 649 patients; AUSROC, 0.97; sensitivity, 0.85, specificity, 0.97; I = 80% and 87%, respectively; very low certainty), and IL-10 alone (11 studies; 549 patients; AUSROC, 0.94; sensitivity, 0.87, specificity, 0.95; I = 58% and 84%, respectively; low certainty) did not outperform IL-10 and IL-6 statistically. CD79B (4 studies; 123 patients; AUSROC, 1.00; sensitivity, 0.40; specificity, 1.00; I = 35% and 0%, respectively; low certainty) showed numerically higher accuracy (P = 0.055). Parallel testing of IL-10 to IL-6 ratio and MYD88 achieved 97.1% sensitivity and 97.0% specificity, reducing false-negative rates from 11% to 2.9%. CONCLUSIONS: Parallel testing of IL-10 to IL-6 ratio and MYD88 seemed to offer the highest diagnostic performance among evaluated strategies for PVRL, although this finding requires prospective validation given the low to very low certainty of the underlying evidence. Aqueous humor cytokine testing yielded higher diagnostic odds ratios than vitreous fluid, suggesting anterior paracentesis for IL-10 to IL-6 ratio before vitreous biopsy for molecular confirmation. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.