eMedicine Specialties > Neurology > Neuro-oncology

Leptomeningeal Carcinomatosis

Author: R Andrew Sewell, MD, Clinical Instructor in Psychiatry and Mental Illness Research, Education, and Clinical Center (MIRECC) Fellow, Veterans Affairs Connecticut Health Care System, Yale University School of Medicine
Coauthor(s): Lawrence D Recht, MD, Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School
Contributor Information and Disclosures

Updated: Nov 23, 2009

Introduction

Background

Leptomeningeal carcinomatosis (LC), also termed neoplastic meningitis, is a serious complication of cancer that carries substantial rates of morbidity and mortality. It may occur at any stage in the neoplastic disease, either as the presenting sign or as a late complication, though it is associated frequently with relapse of cancer elsewhere in the body.

LC occurs with invasion to and subsequent proliferation of neoplastic cells in the subarachnoid space. Intra-axial CNS tumors of diverse origins and hematologic cancers may spread to this space, which is bound by the leptomeninges.

The leptomeninges consist of the arachnoid and the pia mater; the space between the 2 contains the CSF. When tumor cells enter the CSF (either by direct extension, as in primary brain tumors, or by hematogenous dissemination, as in leukemia), they are transported throughout the nervous system by CSF flow, causing either multifocal or diffuse infiltration of the leptomeninges in a sheetlike fashion along the surface of the brain and spinal cord. This multifocal seeding of the leptomeninges by malignant cells is called leptomeningeal carcinomatosis if the primary is a solid tumor, and lymphomatous meningitis or leukemic meningitis if the primary is not a solid tumor.

Lymphomatous or leukemic meningitis is somewhat of a misnomer, as meningitis implies an inflammatory response that may or may not be present. First recognized by Eberth in 1870, LC remains underdiagnosed even today. Nevertheless, it has been recognized more frequently in the last 3 decades than before because of improved diagnostic tools, therapy, and awareness. It is not a single entity pathologically; it can occur concurrently with CNS invasion or wide dissemination in the intraventricular spaces, or in association with CNS metastases, with the clinical picture differing somewhat in each case.

Pathophysiology

Metastatic seeding of the leptomeninges may be explained by the following 6 postulated mechanisms: (1) hematogenous spread to choroid plexus and then to leptomeninges, (2) primary hematogenous metastases through the leptomeningeal vessels, (3) metastasis via the Batson venous plexus, (4) retrograde dissemination along perineural lymphatics and sheaths, (5) centripetal extension along perivascular and perineural lymphatics from axial lymphatic nodes and vessels through the intervertebral and possibly from the cranial foramina to the leptomeninges, and (6) direct extension from contiguous tumor deposits. CSF flow then seeds the tumor cells widely, with infiltration greatest at the basilar cisterns and dorsal surface of the spinal cord, particularly the cauda equina.

Signs and symptoms are usually attributable to obstruction of CSF flow by tumor adhesions that leads to one of the following:

• Increased intracranial pressure (ICP) or hydrocephalus
• Local tumor infiltration in the brain or spinal cord that causes cranial-nerve palsies or radiculopathies
• Alterations in the metabolism of nervous tissue that cause seizures, encephalopathy, or focal deficits
• Occlusion of blood vessels as they cross the subarachnoid, leading to infarcts

Frequency

United States

Approximately 1-8% of patients with cancer are diagnosed with LC, and it is present in 19% of those with cancer and neurologic signs and symptoms on autopsy, usually in those with disseminated systemic disease. LC is present in 1-5% of patients with solid tumors, 5-15% of patients with leukemia, and 1-2% of patients with primary brain tumors. LC can be the presenting symptom 5-10% of the time; however, the exact incidence is difficult to determine. Gross inspection at autopsy may miss LC, and microscopic pathologic examination findings may be normal if the seeding is multifocal or if an unaffected area of the CNS is examined. The most frequent origin of such neoplasms is the lungs (30-70%), followed by breast (10-30%), GI tract (2-20%), and malignant melanomas (2-15%).

Adenocarcinomas are the most common tumors to metastasize to the leptomeninges, although any systemic cancer can do so. Small-cell lung cancers spread to the leptomeninges in 9-25% of cases; melanomas, in 23%; and breast cancers, in 5%. However, because of the different relative frequencies of these cancers, most patients with LC have breast cancer.

Uncommon neoplasms, such as embryonal rhabdomyosarcoma and retinoblastoma, also tend to spread to leptomeninges, but sarcomas rarely do. Medulloblastomas are among those tumors that spread to the CSF, as do ependymomas and glioblastomas on occasion. Squamous cell carcinomas of head and neck can spread to the meninges along cranial-nerve paths. Although LC is uncommon in children, it can be seen in those with acute lymphocytic leukemia (ALL) and primary brain tumors, particularly ependymomas, medulloblastomas, and germ-cell tumors.

The incidence of LC increases the longer a patient has the primary cancer; LC is accompanied by other intracranial metastases in 98% of patients with a nonleukemic primary cancer.

Mortality/Morbidity

The median survival is 7 months for patients with LC from breast cancers, 4 months for patients with LC from small-cell lung carcinomas, and 3.6 months for patients with LC from melanomas.

• Without therapy, most patients survive 4-6 weeks, with death occurring because of progressive neurologic dysfunction.
• With therapy, most patients die from the systemic complications of their cancer rather than the neurologic complications of LC.
• Fixed focal neurologic deficits (eg, cranial-nerve palsies) generally do not improve, but encephalopathies can improve dramatically with treatment.

Race

There is no evidence that races are differentially affected.

Sex

Men and women are equally affected.

Age

The incidence of most forms of cancer that lead to LC increases with age.

Clinical

History

• Meningeal symptoms are the first manifestations in some patients; however, most patients already have widespread and progressive cancer with few therapeutic options left.
• A high index of suspicion is necessary, and involvement of multiple anatomic sites in the CNS should raise the suspicion for LC, although multiple metastases are more likely with that presentation.
• The symptoms are protean and can include the following:
  • Headaches (usually associated with nausea, vomiting, lightheadedness)
  • Gait difficulties from weakness or ataxia
  • Memory problems
  • Incontinence
  • Sensory abnormalities
• Pain and seizures are the most common presenting complaints.

Physical

• Signs generally exceed patient-reported symptoms.
• Involvement of the CNS is divided into the following 3 broad anatomical groups:
  • Cerebral involvement results in headache, lethargy, papilledema, behavior changes, and gait disturbance (the latter can be due to either cerebellar or cauda equina involvement). Major dysfunction, such as hemiparesis and hemisensory loss or visual field defects, is rare and more indicative of parenchymal metastasis.
  • Cranial-nerve involvement presents with impaired vision, diplopia (most common), hearing loss, and sensory deficits, including vertigo. Palsies of cranial nerves III, V, and VI are most common; palsy of nerve VII is less common. Solid tumor-derived LC has a higher affinity for the optic and extraocular nerves, while leukemic meningitis preferentially affects the facial nerve. Involvement of multiple cranial nerves is the rule rather than the exception.
  • Spinal-root involvement is caused by either meningeal irritation, presenting with nuchal rigidity (15%) and neck and back pain (rare), or invasion of the spinal roots. The latter can cause leg weakness, radiculopathy (usually lumbar, mimicking a herniated disk), reflex asymmetry or loss (most common, noted in 70% of patients), sphincter incontinence (less common), positive Babinski reflexes, paresthesias, and numbness. Asymptomatic bladder enlargement can occur from spinal cord compression. Spinal-root symptoms are usually followed by cranial-nerve symptoms. Nuchal rigidity, positive results on the straight-leg raising test, and decreased rectal tone are rare.
• Over the course of the disease, cranial-nerve deficits are the most frequent signs, occurring in 94% of patients. Although these are seldom the presenting complaint (30% of patients), mild cranial-nerve abnormalities are usually present on physical examination; the abnormalities typically include diplopia, dysphagia, dysarthria, and hearing loss. However, most patients do not have isolated cranial-nerve deficits; rather, they have a combination of cranial-nerve, cerebral, and spinal signs.

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