CSF Cell-Free DNA Superior to Cytology in Detecting Leptomeningeal Disease

cerebral spinal fluid
cerebral spinal fluid
Researchers sought to determine whether cell-free DNA analysis of cerebrospinal fluid can be used to accurately diagnose leptomeningeal disease compared with cytologic analysis, the current diagnostic standard.

Cerebrospinal fluid (CSF) cell-free DNA (cfDNA) analysis was more sensitive and accurate than cytologic analysis for the purpose of diagnosing leptomeningeal disease (LMD), a serious complication of cancer, according to study findings published in JAMA Network Open.

Cytologic analysis is currently the standard method for diagnosing LMD, but it’s an invasive diagnostic test that has low sensitivity. This has led to frequent underdiagnoses of LMD in patients with cancer. In an effort to improve sensitivity for LMD disease detection and clinical care, the study authors sought to compare the accuracy of CSF cfDNA with cytologic analysis in the detection of LMD.

A large team of US-based researchers conducted the diagnostic study in a neuro-oncology clinic at 2 separate tertiary medical centers. Researchers performed genomic sequencing of CSF samples from 30 patients (77% women; median age, 51 years) with either suspected or confirmed LMD. The analyses were performed to identify tumor-derived cfDNA. Additionally, the researchers performed cytologic analyses on the same CSF samples and compared the findings from the 2 tests.

In the study, a total of 22 patients had cytologically confirmed LMD without parenchymal tumors abutting their CSF, while 8 patients had parenchymal brain metastases with no symptomatic or cytologic evidence of LMD. The study examined the diagnostic accuracy of cfDNA analysis, which was defined as the number of tests that produced correct diagnoses out of the total number of assayed tests.

A total of 51 samples were obtained from the 30 patients. In 48 follow-up samples from patients who were previously diagnosed using cytologic analysis with LMD with no parenchymal tumor abutting CSF, the accuracy of the cfDNA findings was 94% (95% CI, 83%-99%). In contrast, cytologic analysis in these samples featured an accuracy of 75% (95% CI, 60%-86%). Overall, the accuracy of cfDNA was significantly greater than cytologic analysis in these follow-up samples (P =.02).

In the 43 LMD-positive samples, CSF cfDNA analysis was also superior to cytologic analysis in terms of sensitivity to LMD (93% [95% CI, 81%-99%] vs 72% [95% CI, 56%-85%], respectively; P =.02).

The researchers note that future studies should examine the clinical- and tumor-specific attributes possibly associated with sensitivity of the CSF cfDNA modality in an effort to provide greater understanding of this analysis in the detection of LMD.

In their conclusion, the researchers wrote that “improved diagnosis of LMD has the potential to lead to improved treatment decisions and patient outcomes and suggests that consideration of incorporating CSF cfDNA analysis into LMD diagnostic workflows is warranted.”

Disclosure: Multiple authors declared affiliations with the pharmaceutical industry. Please refer to the original article for a full list of disclosures.


White MD, Klein RH, Shaw B, et al. Detection of leptomeningeal disease using cell-free DNA from cerebrospinal fluid. JAMA Netw Open. Published online August 9, 2021. doi:10.1001/jamanetworkopen.2021.20040