The Role of Biopsy in the Diagnosis and Management of Primary Central Nervous System Lymphoma: An Umbrella Review of Systematic Reviews and Meta-analyses

Abstract Primary central nervous system lymphoma (PCNSL) is a rare, aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system (CNS). Despite advances in imaging, definitive diagnosis requires tissue confirmation, most often via stereotactic or open biopsy. However, diagnostic yield is frequently compromised by preoperative corticosteroid use, and the role of surgical resection remains debated. This umbrella review synthesizes systematic reviews and meta-analyses to clarify the diagnostic utility, safety, and clinical impact of biopsy procedures in PCNSL. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a protocol was registered in PROSPERO (CRD420251103759). Electronic databases (PubMed, EMBASE, Cochrane, SCOPUS, ScienceDirect) were searched for systematic reviews and meta-analyses addressing biopsy in PCNSL. Eligible studies reported outcomes including diagnostic accuracy, safety, treatment impact, or survival. Methodological quality was assessed using AMSTAR 2, and findings were narratively synthesized due to heterogeneity. Six systematic reviews/meta-analyses comprising 91 unique primary studies were included. Brain biopsy demonstrated markedly superior diagnostic yield compared to cerebrospinal fluid (CSF) analysis (92.3 vs. 7.4%). Stereotactic biopsy was safe, with low morbidity (5.1%) and mortality (0.7%). Preoperative corticosteroid use significantly increased nondiagnostic biopsy risk (RR 2.1 overall; RR 3.0 for stereotactic procedures). Evidence for the survival benefit of surgical resection was inconsistent: one meta-analysis reported improved overall and progression-free survival (HR ∼0.63–0.64), while another found no significant differences. Clinical impact data showed biopsy altered management in ∼60% of cases and improved outcomes in ∼34%. Evidence quality ranged from critically low to high, with common methodological limitations. Brain biopsy should be prioritized over CSF analysis for suspected PCNSL, given its superior diagnostic yield and acceptable safety profile. Corticosteroids should be avoided pre-biopsy when clinically feasible, with open biopsy considered if steroids are unavoidable. Surgical resection may benefit selected patients with superficial, solitary lesions, though evidence remains of low certainty. Prospective randomized trials and standardized outcome definitions are urgently needed to refine diagnostic and therapeutic strategies in this rare disease.