Liquid Biopsy Could Replace Surgical Biopsy for Diagnosing Primary Central Nervous Lymphoma

Primary central nervous system lymphoma (PCNSL) is typically diagnosed through surgical biopsy, which remains the gold standard but carries substantial risk. Operability depends heavily on tumor location, size, and the patient’s overall condition, making biopsy unsafe or impossible in some cases. Lesions near the brainstem and frail or elderly patients pose particular challenges. To overcome these limitations, researchers evaluated whether a minimally invasive approach could reliably diagnose PCNSL and allow treatment to begin without surgery.

The study was led by Niigata University (Niigata, Japan) and conducted as a multi-institutional investigation across five medical centers. The approach builds on earlier work demonstrating that MYD88 L265P mutations can be reliably detected in cerebrospinal fluid cell-free DNA. In this study, cerebrospinal fluid was collected via lumbar puncture, followed by the extraction of cell-free DNA. Droplet digital PCR was used to detect MYD88 L265P–mutant droplets, enabling molecular diagnosis directly from circulating tumor DNA without the need for tissue biopsy.

In the latest study, 10 PCNSL patients considered unsuitable for surgical biopsy were included. Eight patients had tumors located in deep or high-risk areas such as the brainstem, while two were excluded from surgery due to advanced age or poor performance status. MYD88 L265P mutations were detected in cerebrospinal fluid samples from all patients. Based solely on liquid biopsy results, all patients were diagnosed and treated without a surgical biopsy. Treatment response was observed in every case, and in one patient with chronic renal failure, liquid biopsy also proved useful in ruling out disease relapse.

The findings, published in Neuro-Oncology Advances, demonstrate that cerebrospinal fluid liquid biopsy can serve as a reliable, less invasive alternative for diagnosing PCNSL in patients who cannot safely undergo surgery. Early diagnosis through this method may allow faster initiation of therapy and reduce procedure-related risks. While promising, the researchers emphasize that larger, prospective studies are needed to confirm diagnostic reliability and define how liquid biopsy could be integrated into standard clinical workflows for PCNSL.

“At present, surgical biopsy is the gold standard for diagnosis of PCNSL,” said Dr. Manabu Natsumeda, who led the research team. “However, this method is a potential game changer for the diagnosis of PCNSL in patients with difficult-to-access lesions or who are too frail to receive surgical biopsies, as we found the method to be very reliable.”

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Niigata University