Carcinomatous meningitis

Associated meningeal carcinomatosis develops in 5-8% of patients with solid tumors.

Leptomeningeal metastasis occurs due to the seeding of malignant cells the leptomeninges, pia mater, arachnoid mater, subarachnoid space, and other CSF compartments.

Tumor cells can disseminate hematogenously,, endoneural, and perineural routes, or continuously from the brain or bone metastases.
Neoplastic meningitis can result from hematologic cancers, metastatic solid tumors, or in rare cases, primary brain cancers.
Metastases to the CSF can be due to hematogenous spread or contiguous extension from brain parenchymal tumors or bony disease.

A devastating complication associated with poor prognosis, and usually occurs late on the natural history of disease with patients often heavily pre-treated with several systemic agents.

Patient is generally present with acute to subacute neurological deficits that can be debilitating.
Median survival from time of diagnosis is 3-4 months for patients with solid tumors.

Incidence has been increasing steadily due to higher success rates of systemic disease with prolonged survival of patients with extra neural disease, and by poor access of chemotherapeutic agents to the CNS.

Estimated 7-9000 cases per year by SEER.

Leptomeningeal cancer is associated with later stages of cancer, and is unusual at the time of diagnosis.

CSF malignancy referred to as leptomeningeal cancer and neoplastic meningitis.

Overlooked, underdiagnosed and under treated process.

The incidence of neoplastic meningitis is highest in patients with lymphoma.

Autopsy studies demonstrate that 19% of patients with cancer have evidence of neoplastic meningitis, suggesting the diagnosis is often not recognized premortem.

Diagnosis is difficult since the disease most frequently occurs with uncontrolled or relapse this that make disease, symptoms may be masked or minimized by supportive treatments and confounded by extra neural metastases or misdiagnosed with subtle presentation.

Malignant cells can reach the subarachnoid space through the blood by venous or arterial channels, by growing along nerve and vascular sheaths, by migration from a tumor adjacent to the CSF, or by iatrogenic spread of tumor cells following resection of brain metastases.

Malignant cells migrate to the CSF from direct extension from a tumor embedded in the brain, or from tumor in the vertebra, subdural or epidural spaces.

Cancer cells may migrate through perineural spaces, and perivascular spaces and from the choroid plexus and shed cells into the CSF.

Malignant cells may spread via retrograde invasion of the peripheral or cranial nerves or hematogenously.

An uncommon cause of CSF pleocytosis.

Hallmark is spread of malignant cells to the CSF and leptomeninges (arachnoid, pia, and subarachnoid space).

The CSF space and surrounding pia and arachnoid is a distinct CNS compartment and is treated differently from metastases to the overlying dura or underlying brain or spine.

Patients often present with subtle or limited disease, but generally the disease progresses rapidly with involvement of all neurologic compartments of the CNS, brain, cranial nerves and spinal cord, with the found neurologic dysfunction and death.

Diagnostic methods used include neurologic examination and history, signs and symptoms, contrast enhanced MRI, an examination of the CSF.

May affect any leptomeningeal compartment including brain, cranial nerves, CSF, spinal cord and spinal nerve roots.

Typical findings on lumbar puncture include elevated opening pressure, low CSF glucose, and elevated CSF protein.

Contrast enhanced MRI sensitive for diagnosis for leptomeningitis in 70% of cases(Pavlidis N).

Gold standard for diagnosis is CSF cytology which is positive in 50-70% of cases on the initial CSF analysis.

Diagnosis on CSF fluid for cytology increases to almost 100% with 3 attempts at analysis of CSF (Glantz MJ et al).

Cytologic diagnosis on CSF increased with obtaining at least 10.5 mL of CSF for analysis.

CSF cytology remaining falsely elevated in 14% of patients, even after 3 samples have been taken.

CSF analysis should be performed as closely as possible to the site of clinical evident disease.

Ventricular and lumbar puncture analysis are discordant in 30% of cases and in the presence of spinal signs or symptoms lumbar CSF cytology analysis is more likely to be positive then ventricular studies.

Conversely, when cranial signs or symptoms are present ventricular CSF cytology studies are more likely to be positive then lumbar puncture analysis.

CSF cytology and MRI in patients with carcinomatous meningitis or complementary tests and the diagnosis.

In a comparison study of CSF cytology and MRI in patients with neoplastic meningitis from solid tumors, neuroimaging was positive in 80% of cases and CSF positive in 85% of those tested (Clarke JL et al).

Opening CSF pressure of greater than 15 cm of H2O, elevated CSF WBC count, glucose of less than 60 mg/dL, or protein of greater than 50 mg/dL are suggestive of carcinomatous meningitis.

Most common associated malignancies are breast cancer, small cell lung cancer and melanoma, gastrointestinal tract and adenocarcinoma of unknown origin.

Leptomeningeal metastases probability is greatest for patients with melanoma, 22-46% risk, small cell lung cancer, 10-25% risk, and breast cancer about 5% risk(Taillibert S et al).

The incidence of carcinomatous meningitis in metastatic breast cancer is about 5%, but is probably an underestimate due the nonspecific symptoms and signs and to the poor sensitivity of diagnostic methods.

Risk for development of neoplastic meningitis includes the presence of an aggressive lymphoma subtype, such as Burkitt’s, lymphoblastic, or diffuse large B cell lymphoma, uncontrolled systemic disease, the presence of 2 or more extra nodal sites of metastases, especially uveoretinal, testicular, retroperitoneal and parasinal disease, and age younger than 60 years.

Lobular type of breast cancer more prone to develop leptomeningeal metastases than other types of breast cancer.

Other cancers less frequently associated with CM include: head and neck cancer, cervical cancer, ovarian, renal and bladder cancer.

About 30-40% of patients with neoplastic meningitis or have coexistent parenchymal brain metastasis.

Can involve the entire neuraaxis and presentation may include multifocal neurologic signs and symptoms according to the site involved with 15% cerebral, 35% cranial nerve and 60% spine manifestations (Lombardi G et al).

Colorectal cancer is rarely associated with CM, occurring in 0.019% of cases, and accounts for 0.56% of cases of meningeal carcinomatosis (Oh SY et al).

Secondary to melanoma has a mean survival of 2-6 months after diagnosis.

The incidence of carcinomatous meningitis in small cell lung cancer is 0.5% at diagnosis and 25% after 3 years of survival.

Increasingly common because of prolonged survival of patients with metastatic disease and because of better diagnostic methods.

Median survival for untreated patients is 4-6 weeks, with treatment survival may be extended to 4-6 months (Shapiro WR et al).

Incidence increasing in tumors that were previously rarely associated, and include prostate cancer, ovarian cancer, gastric cancer, cervical cancer, and endometrial cancer.

Typically, only 50% of patients have malignant cells identified in the first lumbar puncture, and even after three lumbar punctures will demonstrate tumor cells in only 90% of patients.

The most common clinical manifestations include: headache, mental changes nausea,vomiting, impaired coordination, diplopia, visual loss, and hearing loss.

Patients may manifest lower motor neuron weakness, sensory loss, radicular back and neck pain.

Patients can present with diverse and multifocal neurologic symptoms.

Symptoms and signs of involvement of three compartments of the nervous system: cerebral hemispheres with headache altered mentation, loss of consciousness, seizures; cranial nerves with diplopia visual loss, hearing loss and facial palsy; and the spinal cord with emanating nerve roots with back pain, cauda equine syndrome, and radiculopathies.

Up to 25% of patients can be diagnosed by clinical examination alone, but all such cases need further confirmation.

Diagnostic imaging is best performed with MRI with and without gadolinium enhancement of the entire central nervous system, as it has a high sensitive and specificity.

MRI as higher sensitivity and specificity then contrast enhanced CT scan of the nervous system.

MRI findings include focal or diffuse leptomeningeal enhancement, enhancement of tumor nodules and intradural spinal nerves: these changes are not pathognomonic, however.

Gadolinium MRI sensitivity for neoplastic as a sensitivity and specificity of about 75% or greater.

Gadolinium MRI has about a 30% incidence of false-negative results, therefore a negative image does not exclude the diagnosis of carcinomatoud meningitis in a patient with typical signs and symptoms.

A positive gadolinium MRI alone may be sufficient to establish a diagnosis, in particular in cases where there is CSF is negative, a lumbar puncture can not be performed, and a clinical suspicion is high.

Differential diagnosis for MRI meningeal enhancement includes: granulomatous disease inflammatory diseases such as rheumatoid arthritis, central nervous system infections, subarachnoid hemorrhage and chemical meningitis.

Treatment is not standardized and includes surgery, radiation, intrathecal chemotherapy, systemic chemotherapy and supportive care.

Use of intrathecal chemotherapy has not made a major impact on survival and has substantial neurologic toxicity.

Conventional interventions, including craniospinal radiotherapy, systemic chemotherapy, intrathecal treatment increases survival time by and average of three months after diagnosis.

Intrathecal treatment is not effective for bulk disease involving bone meninges since agents can only penetrate 2-3 mm into such tumors.

Intrathecal chemotherapy can be administered via a lumbar puncture for through an intraventricular device into the lateral ventricle using a Ommaya reservoir.

Median survival in the range of 2-6 months.

Most untreated patients with solid tumor meningeal metastases died within 3-6 weeks, and at progressive neurologic dysfunction as the most frequent cause of death.

In patients considered for intra-CSF therapy, a cisternogram or CSF radionuclide flow study is recommended.

Treatment, median survival time can increase for height in 6 months, and occasional long-term survival can occur.

Focal radiation can be utilized to treat bulky disease and in patients with CSF flow blockage.

In patients CSF flow blockage radiation to this site before intrathecal chemotherapy improves survival and outcomes.

Focal radiation can relieve CSF blockage in approximately 50% of cases.

Intrathecal chemotherapy is the primary therapy for patients with carcinomatous meningitis.

Most controlled trials of intrathecal management have used methotrexate, cytosine arabinoside, liposomal cytosine arabinoside or thiotepa.

Intrathecal methotrexate and thiotepa are comparable, and a combination of intrathecal methotrexate and cytosine arabinoside is not better than methotrexate alone(Grossman SA et al, Hitchins RN et al.

A comparison of intrathecal liposomal cytosine showed improvement in meningitis free survival for the liposomal arm (Glantz MJ et al).

Intrathecal treatment offers local therapy with minimal systemic toxicity, avoids blood-brain barrier, and medication is distributed throughout the subarachnoid space, high doses of the intrathecal agent can be achieved in the spinal fluid.

Primary agents for intrathecal use are methotrexate, free and liposomal cytarabine.

High dose methotrexare has some efficacy in leptomeningeal cancer with a loading dose of 700 mg/m2 and a 23 hour infusion of 2800 mg/m2 and leucovorin starting 6 hours after the end of the mtx infusion (Tetef ML et al).

Liposomal cytarabine (DepoCyte) maintains continuous cytotoxic drug concentrations in the subarachnoid space or 2 weeks following a 50 mg intrathecal dose.

In a study of intrathecal methotrexate versus liposomal cytarabine induction phase responses occurred in 20% of methotrexate treated patients and 26% of liposomal cytarabine treated patients, with median survivals of 78 days and 105 days respectively (Glantz MJ et al).

Intrathecal immunotherapy has been demonstrated to be effective in leptomeningeal melanoma.

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