Background     Neoplastic meningitis (NM) – also known as leptomeningeal metastases, meningeal carcinomatosis, or leukemic meningitis, is a common oncologic complication representing spread of tumor cells to the subarachnoid space (SAS).  While it can be associated with a short prognosis in many patients, ultimately, treatment options and prognosis depend critically on the tumor type.  

Epidemiology     NM is found in 20% of cancer patients at autopsy.  Among solid tumors, NM is common in breast cancer, small cell lung cancer, and melanoma while rare in gastrointestinal and gynecologic cancers. Most patients with solid tumors and NM have widespread metastatic disease; however, NM can also occur in the setting of controlled systemic disease or rarely as the isolated site of cancer metastasis.  NM is found in 40-50% of patients with hematological malignancies, mostly commonly the acute leukemias, high-grade lymphomas (such as large cell and Burkitt lymphomas), and lymphomas in which the primary cancer site is the breast, testes, or vitreoretinal space.   

Signs/Symptoms     Tumor reaches the SAS by hematogenous spread via arachnoid vessels or direct invasion along nerve roots.  Cancer cells in the SAS have the potential to: a) settle in dependent portions of the neuraxis (base of brain/cranial nerves or lower spinal canal), b) grow into the surface of the brain and fill the sulci, and c) block normal paths of cerebral spinal fluid (CSF) flow.  Thus, the hallmark of diagnosis is neurological signs/symptoms at more than one level of the neuraxis: 

• Brain – headaches, nausea/vomiting, seizure, hydrocephalus. 
• Cranial Nerves – diplopia, hearing loss, facial numbness, dysphagia, dysphonia. 
• Spinal – radicular pain, weakness (usually legs), parenthesis, bladder, and bowel dysfunction. 

Diagnosis     Lumbar puncture (LP) typically reveals a CSF profile of high opening pressure, low glucose, high protein, and lymphocytic pleocytosis. Cytology sensitivity for finding malignant cells is 40-60% for one sample, but increases with staining of suspicious cells for known tumor surface markers (HER2, EGFR, etc.) or flow cytometry in the case of hematologic cancer.  MRI can identify nodular/bulky areas of disease, hydrocephalus, and/or enhancement of the cortex/tentorium if tumor growth along the sulci leads to neovascularization, but MRI can show false negative results. Requesting thin slices on MRI scanning in the anatomic area of focal neurologic symptoms or triple dose gadolinium can improve the sensitivity. NM commonly causes abnormal CSF flow; this can be demonstrated by a radionucleotide cisternogram, or typical patterns of ventricular and sulcal enlargement, but is often less responsive to ventriculoperitoneal shunting due to altered fluid dynamics. Importantly, tumor markers relevant to treatment can differ between systemic disease and NM in ~10% of cases. This is why direct testing of the CSF by lumbar puncture or biopsy is often recommended. 

Prognosis and treatment     If systemic disease is controlled or untreated, some patients with NM can experience significant response to cancer treatment, but this depends crucially on the cancer molecular type (hormone or HER2 receptor positive breast cancer, EGFR or ALK mutant lung cancers, BRAF or immunotherapy-responsive melanoma, some lymphomas, etc.). In contrast, in patients whose systemic disease is resistant to therapy or do not have an effective treatment option (e.g., treatment refractory triple negative breast cancer) prognosis is usually quite short (1-4 months) with accumulating neurologic deficits. The number of circulating tumor cells in the CSF is also prognostic of survival. Since cognitive changes are common in NM, advance care planning and directives are recommended. Focal surgeries or radiation therapy can be considered if a small number of lesions are causing significant symptoms (e.g., mono-focal cord compression).  

• Radiation: Either cranio-spinal irradiation (entire spinal column) or focused radiation therapy to sites of bulky or symptomatic areas (e.g., cauda equina for radicular leg pain). 
• Other cancer therapy: Options are based upon the input of their cancer team and the patient’s goals of care: 
  • Systemic cancer therapy (e.g., cytotoxic chemotherapy, immunotherapy, targeted cell therapy). Agent choice is usually determined by patient’s specific cancer profile and its efficacy in the CNS (e.g., tucatinib in HER2 mutant breast cancer).  
  • Intrathecal (IT) cancer treatment:  in general, IT cancer treatment is reserved for when there is not an effective systemic therapy option or there is no systemic disease. It can be associated with more burden than systemic cancer therapy since it is administered 1-2 times per week either by repeated LP or via repeated puncture of an Ommaya reservoir.  Commonly used IT drugs include methotrexate or cytarabine. 

Summary     For select patients, NM can be effectively controlled for months or even years; others with NM have intractable disease.  Establishing the precise diagnosis by molecular tumor type, understanding the patient’s clinical status, their functional status, and goals of care are crucial to delivering patient-centered care.  Multidisciplinary treatment options require engaged participation from medical oncology, radiation oncology, neurology or neuro-oncology, pathology, neuroradiology and sometimes neurosurgeons. For patients with NM who are treated with comfort care, prognosis is typically in the range of weeks to months and therefore, hospice care resources should be considered. 

References  

1. Wasserstrom WR, Glass JP, Posner JB.  Diagnosis and treatment of leptomeningeal metastases from solid tumors. Cancer. 1982; 49:759-772. 
2. Grossman SA, Trupm DL, Chen ECP, Thompson G, Cargo EE. Cerebrospinal fluid flow abnormalities in patients with neoplastic meningitis. Am J Med. 1982; 73:641-647. 
3. Wilcox JA, Li MJ. Leptomeningeal metastases: new opportunities in the modern era. Neurotherapeutics,2022;19(6):1782-1798. 
4. Barbour A, Blouw B, et al. Prognostic value of cerebrospinal fluid tumor cell count in leptomeningeal disease from solid tumors. J Neurooncol,2024 epub online ahead of print 
5. Yang JT, Wijetunga NA, et al. Randomized phase II trial of proton craniospinal irradiation versus photon involved-field radiotherapy for patients with solid tumor leptomeningeal metastases. J Clin Oncol,2022;40(33):3858-3867/ 

Version History:  This Fast Fact was originally edited by David E Weissman MD and published in April 2005. 2nd Edition in April 2009; 3rd Edition by Sean Marks MD July 2015; 4th Edition by Jerome J Graber MD in March 2024. Since significant content was added in the 4th Edition, Dr. Graber was added as a co-author.
Conflicts of Interest: None to report