Clinical implementation of rapid genotyping of cell-free DNA in CSF accelerates diagnosis of CNS lymphoma (CNSL). (A) Analysis of a historical cohort of 1007 patients with new CNS lesions of unknown cause for which CNSL was in the differential diagnosis showed that only 14.7% are ultimately diagnosed with CNSL. Securing a CNSL diagnosis required 95.6% of patients to undergo neurosurgical biopsy, resulting in a median time to diagnosis of 10 days (top pathway, adapted from Gupta et al²). Because 53% of CNS lymphoma cases in our institutional experience were positive for the MYD88 L265P variant (Figure 1), we estimated that 7.7% of the initial cohort would harbor this variant. Following clinical implementation of the Clinical Laboratory Improvement Amendments–certified cell-free DNA assay, a similar percentage of CNSL bearing the MYD88 L265P mutation was identified, with a median turnaround time of 2 days (bottom pathway). (B) The rate of accrual of CSF specimens was 1 sample/5.3 days in the prospective rapid genotyping cohort (middle panel) vs 1 sample/3.2 days following clinical implementation (right panel) (P = .002). The frequency of MYD88 L265P detection in these study populations was 8 of 70 patients (11.4%) and 5 of 66 patients (7.6%), respectively, similar to the 78 of 1007 patients (7.7%) found in the historical cohort (left panel).