Definition/General
Introduction:
Malignant CSF contains neoplastic cells in cerebrospinal fluid
Results from leptomeningeal metastases or primary CNS tumors
Also called neoplastic meningitis or carcinomatous meningitis
Poor prognostic indicator
Requires urgent oncological management.
Origin:
Results from hematogenous spread to leptomeninges
Direct extension from brain/spinal tumors
Perineural spread
Ventricular seeding
Common primaries: lung, breast, melanoma, leukemia, lymphoma.
Classification:
Based on cell type: Carcinomatous (epithelial tumors)
Lymphomatous (hematologic malignancies)
Melanomatous (melanoma)
Based on origin: Metastatic vs primary CNS
Solid tumor vs hematologic.
Epidemiology:
Occurs in 4-15% of cancer patients
Most common primaries: breast (12-35%), lung (10-26%), melanoma (5-25%)
Hematologic malignancies (leukemia 5-15%, lymphoma 7-15%)
Median survival 2-4 months.
Clinical Features
Presentation:
Multifocal neurological deficits
Headache (most common symptom)
Altered mental status
Cranial nerve palsies
Cauda equina syndrome
Hydrocephalus.
Symptoms:
Headache (80% cases)
Altered mental status (65% cases)
Nausea and vomiting (40% cases)
Gait difficulties (40% cases)
Back pain (35% cases)
Cranial nerve dysfunction (35% cases)
Seizures (15% cases).
Risk Factors:
History of malignancy
Primary tumor types: lung, breast, melanoma
Advanced stage disease
Previous CNS involvement
Hematologic malignancies.
Screening:
MRI brain and spine with gadolinium
Lumbar puncture for CSF analysis
CSF cytology (multiple samples may be needed)
Flow cytometry for hematologic malignancies
CSF tumor markers.
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Gross Description
Appearance:
CSF may be clear to turbid
Xanthochromic (yellow-tinged)
Bloody in some cases
Elevated opening pressure common
May appear normal despite malignant cells.
Characteristics:
Elevated opening pressure (>200 mmH2O)
High protein (>45 mg/dL)
Low glucose (<40 mg/dL)
Elevated cell count variable
Tumor markers may be elevated.
Size Location:
Leptomeningeal enhancement on MRI
Communicating hydrocephalus
Multiple sites of involvement
Cranial and spinal involvement
Ventricular seeding.
Multifocality:
Diffuse leptomeningeal involvement
Multiple cranial nerve roots
Spinal nerve roots
Brain surface involvement
Ventricular walls.
Microscopic Description
Histological Features:
Malignant cells present as single cells and clusters
Cytological atypia
High nuclear-cytoplasmic ratio
Prominent nucleoli
Mitotic activity
Variable cell count.
Cellular Characteristics:
Large atypical cells
Pleomorphic nuclei
Hyperchromatic chromatin
Irregular nuclear contours
Increased cell size
Abnormal cell clustering.
Architectural Patterns:
Malignant cells in three-dimensional clusters
Molding artifact
Single cell pattern
Loss of cohesion
Background necrosis may be present.
Grading Criteria:
Based on nuclear atypia
Cell size variation
Chromatin pattern
Nucleolar prominence
Mitotic activity
Background changes.
Immunohistochemistry
Positive Markers:
Primary site-specific markers: Lung: TTF-1, Napsin A
Breast: GATA3, ER, PR
Melanoma: S-100, Melan-A, SOX10
Prostate: PSA, NKX3.1
Renal: RCC, PAX8.
Negative Markers:
GFAP (excludes astrocytic tumors in some contexts)
Neurofilament (excludes neurons)
EMA negative in some carcinomas
Vimentin variable.
Diagnostic Utility:
Essential for primary site determination
Epithelial vs hematologic differentiation
Melanoma identification
Panel approach recommended
Cell block preparation optimal.
Molecular Subtypes:
Based on primary tumor: Adenocarcinoma (lung, breast, GI)
Squamous cell carcinoma
Small cell carcinoma
Melanoma
Hematologic malignancies.
Molecular/Genetic
Genetic Mutations:
Depends on primary tumor: EGFR mutations (lung adenocarcinoma)
BRAF mutations (melanoma)
HER2 amplification (breast)
TP53 mutations common
Chromosomal abnormalities in hematologic malignancies.
Molecular Markers:
Tumor-specific markers
CEA (adenocarcinomas)
AFP (hepatocellular, germ cell)
Beta-hCG (choriocarcinoma)
PSA (prostate)
Thyroglobulin (thyroid).
Prognostic Significance:
Very poor prognosis overall
Median survival 2-4 months
Primary tumor type affects survival
Performance status important
Response to treatment limited
Karnofsky performance score predictive.
Therapeutic Targets:
Intrathecal chemotherapy
Radiation therapy
Systemic targeted therapy (CNS-penetrant agents)
Supportive care
Ventriculoperitoneal shunt for hydrocephalus.
Differential Diagnosis
Similar Entities:
Reactive lymphocytes (viral meningitis)
Activated macrophages (inflammatory conditions)
Choroidal plexus cells
Ependymal cells
Contaminating cells (skin, blood).
Distinguishing Features:
Malignant: Cytological atypia
Malignant: Abnormal clustering
Reactive: Uniform population
Choroidal plexus: Benign cytology
Ependymal: Ciliated borders
Contaminants: Processing history.
Diagnostic Challenges:
Low sensitivity (50-60% first LP)
Processing artifacts
Rare malignant cells
Reactive changes mimicking malignancy
Primary site identification
Multiple samples often needed.
Rare Variants:
Primary CNS lymphoma
Gliomatosis cerebri
Medulloepithelioma
Choroid plexus carcinoma
Pineal tumors
Craniopharyngioma.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
CSF, volume [X] mL, [appearance - clear/turbid/xanthochromic]
Adequacy
Adequate for cytological evaluation
Cellularity
[Cell count] cells/μL
Malignant Cells
POSITIVE for malignant cells
Morphological Features
Malignant cells present as [single cells/clusters]. Features include [nuclear characteristics] and [cytoplasmic features].
Cell Type
Morphology consistent with [carcinoma/lymphoma/melanoma/other]
Immunohistochemistry
IHC panel performed: [List positive and negative markers]
Primary Site Assessment
IHC pattern suggests origin from [primary site/unknown primary]
Final Diagnosis
MALIGNANT CSF - [Tumor type] consistent with [primary site] (Neoplastic meningitis/Leptomeningeal carcinomatosis)
Comment
Findings indicate leptomeningeal involvement by malignancy. Clinical correlation with imaging and known primary tumor recommended. Urgent oncology and neurology consultation advised. Additional CSF samples may improve diagnostic yield.