Tumor-Derived HAVCR1 As a Reliable Fluid Biomarker for the Diagnosis of CNS Lymphoma

BACKGROUND: The early diagnosis of primary CNS lymphoma (PCNSL) is challenging due to its rapid progression and the lack of reliable noninvasive biomarkers. We aimed to identify robust fluid-based biomarkers for PCNSL, with a focus on primary vitreoretinal lymphoma (PVRL), which is a diagnostically difficult subtype given the scarcity and fragility of lymphoma cells in the vitreous. METHODS: Using retrospective cohorts (PCNSL/PVRL = 199; controls = 179) and nested case-control cohorts within large hospital-based (n = 100 526) and population-based (n = 515 326) settings, we performed proteomic screening with the Olink Reveal 1034 and Explore 3072 platforms, followed by ELISA validation. RESULTS: Hepatitis A virus cellular receptor 1 (HAVCR1) emerged as the only consistent and significant biomarker distinguishing PVRL from both normal and uveitic controls, yielding AUCs of 0.916 in the aqueous humor and 0.997 in an independent validation cohort. In the population-based nested case-control analysis, HAVCR1 achieved an AUC of 0.948, thus supporting its robustness in real-world screening scenarios. In the cerebrospinal fluid, HAVCR1 demonstrated exceptional diagnostic accuracy for PCNSL (AUCs: 0.999 and 0.969 in 2 validation cohorts). In prospective follow-up cohorts, HAVCR1 levels significantly decreased after complete remission (P < 0.05), thereby suggesting utility for treatment monitoring. Single-nucleus RNA sequencing demonstrated HAVCR1 expression restricted to malignant B-cell clusters, which was consistent with immunohistochemistry results in tissues and lymphoma cell lines. CONCLUSIONS: These findings establish HAVCR1 as a tumor-derived, fluid-accessible biomarker with high diagnostic performance for PCNSL and PVRL, thus supporting a minimally invasive strategy for early diagnosis and longitudinal monitoring.