What test should be performed to assess for leptomeningeal metastasis in an adult cancer patient who develops new neurological symptoms such as headache, seizures, cranial nerve deficits, radiculopathy, or encephalopathy?

CSF Cytology for Malignant Cells in Suspected Leptomeningeal Metastasis

For adult cancer patients with new neurological symptoms suspicious for leptomeningeal metastasis, CSF cytology remains the gold standard diagnostic test and should be performed with optimized collection technique: obtain at least 10 mL of CSF (minimum 5 mL), process within 30 minutes, and repeat once if initial cytology is negative. 1

Diagnostic Approach

Primary Diagnostic Test

• CSF cytology is the definitive diagnostic test for leptomeningeal metastasis, with specificity approaching 100% when positive 1, 2
• Positive cytology (presence of malignant cells) establishes the diagnosis and is a reliable indicator of leptomeningeal disease 1, 2
• Sensitivity ranges from 66-90% in recent cohorts, but this can be optimized with proper technique 1

Critical Collection Parameters to Maximize Sensitivity

Volume Requirements:

• Collect at least 10 mL of CSF for cytologic analysis (ideally >10 mL, minimum 5 mL) 1, 3
• Small CSF volumes are a major cause of false-negative results 3
• In one study, 97% of CSF specimens were of inadequate volume, contributing to false-negatives 3

Processing Time:

• Process CSF within 30 minutes of collection to prevent cellular degradation 1, 4
• Delayed processing beyond 30 minutes significantly increases false-negative rates 3
• Alternative: Fix fresh CSF samples with ethanol/Carbowax (CSF/fixative ratio 1:1) if immediate processing is not feasible 1, 4

Sampling Site:

• Lumbar puncture is the preferred sampling site for most patients 5
• Obtain CSF from a site close to symptomatic or radiographically demonstrated disease when possible 3
• Ventricular or cisternal CSF may be considered in patients with intracranial-only enhancement and negative lumbar sampling 1
• Lumbar CSF is significantly more sensitive than ventricular shunt CSF for detecting leptomeningeal metastases 5

Repeat Sampling:

• If initial cytology is negative or equivocal, perform a second lumbar puncture under optimized conditions 1
• This increases sensitivity to approximately 80% 1
• The yield of more than two CSF assessments remains doubtful 1

Cytology Reporting Classification

CSF cytology should be reported using three categories 1:

1. Positive: Presence of malignant cells in CSF
2. Equivocal: Detection of "suspicious" or "atypical" cells in CSF
3. Negative: Absence of malignant or equivocal cells in CSF

Adjunctive Techniques for Equivocal Cases

• Immunocytochemical staining for tumor-specific markers (e.g., HER2 in breast cancer, BRAFV600E in melanoma) may help clarify equivocal cases 1, 6
• Thin-layer preparations (Thinprep) show higher sensitivity than cytospin-coupled Wright-Giemsa stains 1
• Routine staining includes Papanicolaou and Giemsa 1

Common Pitfalls and How to Avoid Them

Technical Errors Leading to False-Negatives

• Insufficient volume: Always collect ≥10 mL; inadequate volume is the most common preventable error 3
• Delayed processing: Process within 30 minutes or use fixative immediately 1, 3
• Hemorrhagic contamination: Avoid traumatic taps as blood interferes with interpretation 1, 4
• Single sampling: Always repeat if first sample is negative, as sensitivity increases substantially 1

Interpretation Challenges

• False-positive results are extremely rare but can occur with inflammatory cells in lymphoma patients being mistaken for malignant cells 2
• "Suspicious" or "atypical" cell designations create diagnostic uncertainty; use immunocytochemistry to clarify 1
• CSF cytology provides qualitative results only and does not quantify tumor burden 1

Complementary Diagnostic Studies

Routine CSF Analysis

While not diagnostic, abnormal findings support the diagnosis in >90% of leptomeningeal metastasis patients 1:

• Elevated protein (>50 mg/dL): 56-91% of cases
• Increased leukocyte count (>4/mm³): 48-77.5% of cases
• Decreased glucose (<60 mg/dL): 22-63% of cases
• Increased opening pressure (>200 mm H₂O): 21-42% of cases

Neuroimaging

• Cerebrospinal MRI with gadolinium contrast should be performed in conjunction with CSF analysis 1, 6
• Brain MRI sequences: axial T1-weighted, axial FLAIR, axial diffusion, post-gadolinium 3D T1-weighted, and post-gadolinium 3D FLAIR 1
• Spinal MRI: post-gadolinium sagittal T1-weighted sequences 1
• 68-97% of cytology-positive patients have radiological evidence of leptomeningeal disease 1

Emerging Technologies (Not Yet Standard of Care)

• Circulating tumor DNA (ctDNA) and circulating tumor cell (CTC) detection show promise for enhanced sensitivity but require prospective validation and CLIA certification 1
• These techniques are currently limited to specialized centers and are not yet integrated into routine clinical practice 1