Neoplastic meningitis
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2]
Synonyms and keywords: NM; Carcinomatous meningitis; Leptomeningeal carcinomatosis; LC; Neoplastic arachnoiditis; Malignant meningitis; Leptomeningeal neoplasia, Meningeal carcinomatosis; Meningeosis neoplastica; Meningitis carcinomatosa; Leptomeningeal metastasis; Leptomeningeal metastases; Carcinomatous meningitis; Subarachnoid space metastasis; Subarachnoid space metastases
Overview
- Neoplastic meningitis is a secondary cancer of the subarachnoid space, meninges and pia matter from a primary tumor source. It is one of the dreaded complications of terminal malignancy. It could be from a distant metastasis or from a primary brain tumor. Most commonly documented primary distant source is beast cancer.
- Signs and symptoms vary widely depending on the site of the brain or spinal cord involved and is not necessarily limited to signs of meningeal irritation.
- Neoplastic meningitis have a very poor prognosis with survival limited to 4 - 6 weeks if left untreated and 2 - 6 months with palliative management.
- Treatment is palliative and is aimed at preventing and reducing neurological deficits and extending survival with good quality of life. Treatment is composed of any or all of the three components: radiotherapy, intraventricular or intrathecal chemotherapy and systemic radiotherapy. [3]
Historical Perspective
- The first case of neoplastic meningitis was described by Eberth in the 1870s.
- The metastatic site was first identified in the same decade in a patient with lung cancer [1]
Classification
- There is no classification system established for neoplastic meningitis.
Pathophysiology
- The pathophysiology of neoplastic meningitis involves spread of cancer cells to the meninges and subarachnoid space. The location could be the brain or the spinal cord. It could be from a distant source or from a primary CNS tumor (drop metastasis).
- Cancer from a distant source enter the CSF by means of the following:[4]
- Hematogenous Spread from a distant primary tumor site - cancer cells produce enzymes that allows them to microscopically invade blood vessels to reach the subarachnoid space through the systemic arterial circulation or by the Batsons venous plexus.
- Invasion from a primary brain tumor to the meninges - when cancer cells lodge into small arteries causing local ischemia and blood vessel damage leading to spillage of neoplastic cells to the Virchow-Robin spaces thereby providing access to the subarachnoid space.
- Infiltration to the spinal cord - Cancer cells gain access to the subarachnoid space through this route via the perivascular tissues the surround the blood vessels at the brain entrance. Direct infiltration of the spinal nerve roots (dorsal and ventral) has also been documented.
- Cancer spread a neural pathways to reach the meninges - The CSF carries cancer cells through the brain tracts. This occurs mostly in tumors of the head and neck.[5]
- Iatrogenic - from surgical procedures involving removal of a primary brain tumor
- Primary neoplastic meningitis has also been documented particularly with melanoma.[6]
Causes
- Neoplastic meningitis is a secondary cancer caused by the spread of tumor cells into the meninges and subarachnoid space from a primary source. Most common solid tumor sources documented are breast, lung, melanoma and hematologic cancers mostly acute lymphocytic leukemia. Cancers not previously thought to be predisposed to neoplastic meningitis but now has documented cases are gastric, prostate, ovarian, cervical and endometrial. [7]
Differentiating Neoplastic Meningitis from other Diseases
- Differential Diagnosis for Neoplastic Meningitis:
- Meningitis from infectious causes - infectious meningitis may to some degree manifest like neoplastic meningitis due to meningeal irritation. This include viral, bacterial, fungal and HIV-associated causes of meningitis.
- Neurosarcoidosis
- Vasculitis - the generalized nature of vessel involvement in these diseases may, to some extent involve the meninges. Vasculitis documented to present like neoplastic meningitis include Kawasaki disease, Takayasu arteritis, Polyarteritis nodosa, microscopic polyarteritis nodosa and Wegener granulomatosis.
- Systemic Connective Tissue Diseases - particularly SLE and Sjogrens syndrome share some of the manifestation of neoplastic meningitis.
Epidemiology and Demographics
- Neoplastic meningitis occurs in 3-5% of patients diagnosed with cancer. Autopsy shows that neoplastic meningitis is present is about 19-25% of the cases of malignant disease.
- Observational studies show that neoplastic meningitis develop in 1-5% of solid tumors, 5-15% of leukemia and lymphoma and 1-2% of patients with primary brain neoplasm. Of the solid tumors, adenocarcinoma is the most frequently observed histology.
- Neoplastic meningitis typically develop in the setting of an advanced stage and widely disseminated cancer in 70% of the cases. It can also present during the patients disease-free interval or remission in 20% of the time, and even be the first manifestation of cancer (5-10%) occasionally.
Risk Factors
- Factors that have been known to increase the risk of neoplastic meningitis involves:[8]
- Brain metastasis is one of the more obvious risk factors for neoplastic meningitis. Coexisting brain metastasis are associated with neoplastic meningitis in breast cancer (33-54%), lung cancer (56-82%) and melanoma (87-96%).
- Primary brain cancer always poses a risk for the development of neoplastic meningitis. It is diagnosed in 1-2% of cases of ependymoma, medulloblastoma, germinoma and glioblastoma combined.
- Brain surgery increases the chance of developing neoplastic meningitis. It has been observed after resection of brain tumor (particularly piecemeal resection vs en-block resection) particularly tumors located in the cerebellum. Other cranial surgeries done with involvement of ventricular system manipulation in a patient with known brain metastasis increases the risk. Furthermore, the incidence of neoplastic meningitis seem higher in patient treated with surgery followed by stereotactic radiosurgery compared with radiosurgery alone.
- ER-, PR-positivity in beast cancer increases incidence of neoplastic meningitis. Triple negative breast cancer and the HER2/neu gene positivity displays tropism for CNS metastasis. Among the histologic subtypes of breast cancer, loblular carcinoma demonstrated the highest prevalence for neoplastic meningitis.
Screening
- There is insufficient evidence to recommend routine screening for neoplastic meningitis. [9]
Natural History, Complications and Prognosis
- Neoplastic meningitis is one of the dreaded complications of malignancy as it is terminal and treatment has been established to be palliative management. [10]
- The 3 affected neurologic domains of neoplastic meningitis in order of involvement is spinal cord and roots (60%) cranial nerve (35%) and cerebral hemisphere (15%)[11]
- Symptoms are often multifocal and neuraxal. The most common presenting symptom of neoplastic meningitis is pain or seizure. [12]
- The rates of survival for neoplastic meningitis varies depending on the source of primary tumor, but generally median survival rate without treatment is limited to 1 to 2 months. With treatment, this could extend to 2 to 5 months for breast cancer, 3 to 6 months for non-small cell lung cancer and 2 to 4 months for melanoma. Factors affecting the prognosis of patients with neoplastic meningitis includes gene involvement and use of immunotherapy and other targeted therapies. For breast cancer, ER-positivity, lesser extend of initial disease and better performance status has been demonstrated to have better prognosis. For lung cancer, the use of epidermal growth factor (EGFR) inhibitors confers durable responses without the need for intra-CSF chemotherapy administration. Lastly, for melanoma, primary tumors located in the trunk has been documented to have a poor prognosis, but intra-CSF administration of chemotherapy significantly improves this prognosis.[13]
- Not surprisingly, patients with poor performance status, multiple fixed neurological deficits, bulks CNS disease, co-existent carcinomatous encephalopathy and CSF flow abnormalities will do poorly with intensive treatment of disease. Death typically results from progression of neurological dysfunction.[14]
- Some retrospective studies have demonstrated favorable outcomes in neoplastic meningitis: age less than 60, long duration of symptoms, controlled systemic disease, Karnofsky performance status >/= 70, absence of encephalopathy or cranial nerve deficit, initially low CSF protein level, absence of CSF compartamentalization or bulky CNS disease manifested by impedance of CSF flow and history of primary breast tumor.
Diagnosis
Staging | History and Symptoms | Physical Examination | Laboratory Findings | CT | MRI | Other Imaging Findings | Other Diagnostic Studies
Treatment
Medical Therapy | Surgery | Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies