Leptomeningeal Carcinomatosis

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Practice Essentials

Leptomeningeal carcinomatosis (LC) is a rare complication of cancer in which the disease spreads to the membranes (meninges) surrounding the brain and spinal cord. LC occurs in approximately 5% of people with cancer and is usually terminal. If left untreated, median survival is 4-6 weeks; if treated, median survival is 2-3 months.[1]

Essential update: Impact of leptomeningeal carcinomatosis on survival in non-small-cell lung cancer patients

Due to improvements in treatment and survival, an increasing number of patients with metastatic non-small-cell lung cancer (NSCLC) are diagnosed with leptomeningeal carcinomatosis (LC). A retrospective review of 149 NSCLC patients with cytologically proven LC found that although prognosis of LC from NSCLC is poor, some patients do have improved median overall survival. According to researchers, intrathecal chemotherapy (ITC), whole-brain radiotherapy (WBRT), systemic therapy with epidermal growth factor receptor tyrosine kinase inhibitors, and ventriculoperitoneal (VP) shunt operations to treat LC might improve clinical outcomes in NSCLC patients.[1]

In this study, the median follow-up duration was 34 months, and median overall survival was 14 weeks following diagnosis of LC. Treatment numbers were as follows: ITC alone in 44 patients, ITC plus systemic therapy in 18 patients, ITC plus radiotherapy in 29 patients, all 3 treatments in 18 patients, other treatments without ITC in 20 patients, and only supportive care in 20 patients.[1]

Signs and symptoms

Meningeal symptoms are the first manifestations in some patients (pain and seizures are the most common presenting complaints) and can include the following:

CNS symptoms are divided into the following 3 anatomic groups:

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of LC is made with positive CSF cytologic results, subarachnoid metastases identified on radiologic studies, or a history and physical examination suggestive of LC along with abnormal CSF findings.

Lumbar puncture

Imaging studies

See Workup for more detail.

Management

Leptomeningeal carcinomatosis is incurable and difficult to treat. Treatment goals include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Most patients require a combination of surgery, radiation, and chemotherapy.

The standard therapies are (1) radiation therapy to symptomatic sites and regions where imaging has demonstrated bulk disease and (2) intrathecal chemotherapy.

Radiation palliates local symptoms, relieves CSF flow obstruction, and treats areas such as nerve-root sleeves, Virchow-Robin spaces, and the interior of bulky lesions that chemotherapy does not reach.

Intrathecal chemotherapy treats subclinical leptomeningeal deposits and tumor cells floating in the CSF, preventing further seeding.[2] Cytarabine (Ara-C), methotrexate (MTX), and thiotepa are 3 agents routinely administered.

Supportive care for patients includes analgesia with opioids, anticonvulsants for seizures, antidepressants, and anxiolytics. Attention problems and somnolence from whole-brain radiation can be treated with psychostimulants or modafinil.

See Treatment and Medication for more detail.

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:

Epidemiology

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.

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.[3]

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.[4]

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.

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.

History

Physical

Laboratory Studies

Imaging Studies

Other Tests

Procedures

Lumbar puncture is the most useful test.

Histologic Findings

Leptomeningeal biopsy may be necessary if the patient has no evidence of a primary tumor. The findings can be diagnostic if results of all other tests are negative, especially if taken from an enhancing region identified on MRI. Macroscopic pathology shows diffuse fibrotic thickening of the brain and spinal cord, as well as layering of the nerve roots with tumor tissue. Microscopic examination shows local fibrosis with tumor cells covering the blood vessels and nerves, either as a single layer or as aggregates.

Staging

Staging varies by primary cancer, but metastatic disease is stage IV by definition.

Medical Care

Treatment goals of leptomeningeal carcinomatosis (LC) include improvement or stabilization of the patient's neurologic status, prolongation of survival, and palliation. Some clinicians are hesitant to even treat LC, given the short duration of survival and risk of neurotoxicity, but a high index of suspicion and prompt treatment can prevent serious and irreversible neurologic damage. The lack of large randomized controlled trials has made the correct choice of treatment controversial. Most patients require a combination of surgery, radiation, and chemotherapy.

Surgical Care

Medication Summary

Chemotherapy is best administered intrathecally so that chemotherapeutic agents, which are usually hydrophilic, do not encounter the blood-brain barrier and easily reach tumor cells in the CSF or leptomeninges. The preferred route of administration is through an implanted subcutaneous reservoir (eg, Rickham or Ommaya reservoir) and ventricular catheter rather than LP, for 4 reasons. First, intraventricular injection through an Ommaya reservoir is easy and ensures entry into the CSF. Second, when injected into the ventricle, the drug follows normal CSF flow and thus reaches all parts of the CSF space. Third, repetitive LPs are arduous and painful for the patient. Fourth, about 10-15% of LPs do not deliver all of the drug intended to reach the subarachnoid space.

CSF flow abnormalities are common in patients with increased ICP and hydrocephalus, and 70% of patients with LC have ventricular outlet obstructions, abnormal spinal canal flow, or impaired flow over the cortical convexities, but these can be reversed with local radiation therapy. A CSF-flow study is recommended for all patients at the initiation of intrathecal chemotherapy, and such therapy should be deferred if an obstruction is noted. Systemic therapy can be useful if the blood-brain barrier already has been disrupted or if the chemotherapeutic agent is lipid soluble.

Methotrexate (Folex PFS, Rheumatrex)

Clinical Context:  Mainstay of treatment. Because meningeal infiltration interferes with drug clearance, CSF concentrations can be unpredictable. Monitor and maintain concentration near 10-6 M, and coadminister with folinic acid and hydrocortisone if necessary.

Cytarabine (Cytosar-U)

Clinical Context:  Second-line agent used if MTX not tolerated or ineffective. Not effective for solid tumors but useful in leukemic and lymphomatous meningitis. Half-life longer in CSF than serum. Sustained-release form available in United States; extends half-life to >140 h.

Thiotepa

Clinical Context:  Third-line agent, cleared from CSF within minutes and has survival curves similar to those of MTX with less neurologic toxicity (most common being transient limb paresthesias). Unlike MTX, no antidote for resulting myelosuppression is available. Causes cross-linking of DNA strands, inhibiting of RNA, DNA, and protein synthesis and thus cell proliferation.

Class Summary

These agents inhibit cell growth and proliferation.

Further Inpatient Care

Complications

Prognosis

Author

Michael J Schneck, MD, Vice Chair and Professor, Departments of Neurology and Neurosurgery, Loyola University, Chicago Stritch School of Medicine; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center

Disclosure: Boehringer-Ingelheim Honoraria Speaking and teaching; Sanofi/BMS Honoraria Speaking and teaching; Pfizer Honoraria Speaking and teaching; UCB Pharma Honoraria Speaking and teaching; Talecris Consulting fee Other; NMT Medical Grant/research funds Independent contractor; NIH Independent contractor; Sanofi Grant/research funds Independent contractor; Boehringer-Ingelheim Grant/research funds Independent contractor; Baxter Labs Consulting fee Consulting

Specialty Editors

Frederick M Vincent Sr, MD, Clinical Professor, Department of Neurology and Ophthalmology, Michigan State University Colleges of Human and Osteopathic Medicine

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Jorge C Kattah, MD, Head, Associate Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting; Sunovion Consulting fee None

Chief Editor

Stephen A Berman, MD, PhD, MBA, Professor of Neurology, University of Central Florida College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Lawrence D Recht, MD Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School

Lawrence D Recht, MD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Neurological Association, and Society for Neuroscience

Disclosure: Nothing to disclose.

R Andrew Sewell, MD Associate Research Scientist in Psychiatry and Mental Illness Research, Education,Veterans Affairs Connecticut Health Care System, Yale University School of Medicine

R Andrew Sewell, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, American Pain Society, and American Psychiatric Association

Disclosure: Nothing to disclose.

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