Intra- and intertumoral discordance of Claudin-18.2: a systematic review and meta-analysis.

Background: Claudin-18.2 status is increasingly used to guide targeted therapy based on immunohistochemistry of limited tumor tissue. Spatial heterogeneity may produce discordant expression patterns within a primary tumor or discordant positivity classification between primary and metastatic sites, limiting the representativeness of a single specimen. No prior meta-analysis has quantified the magnitude of this discordance, either in gastric/gastroesophageal junction (GEJ) cancer or in other tumor types. Materials and methods: We carried out a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant systematic review and meta-analysis. MEDLINE, Embase, and Scopus were searched for studies reporting Claudin-18.2 intratumoral discordance within primary tumors and/or intertumoral discordance between primary tumors and matched metastases. Intratumoral discordance was operationalized according to each study's reported evidence of spatial variation in expression, whereas intertumoral discordance was defined as disagreement in positivity classification between matched primary and metastatic samples using study-specific cut-offs. Random-effects models pooled logit-transformed discordance proportions. Robustness was evaluated using leave-one-out sensitivity analyses and subgroup analyses explored potential sources of heterogeneity. Between-study heterogeneity and small-study effects were assessed using Cochran's Results: Thirteen studies ( Conclusion: Claudin-18.2 expression shows substantial intratumoral and clinically meaningful discordance between primary and metastatic tumors in gastric/GEJ cancer. Single-specimen testing may misclassify eligibility and multisite testing should be considered.