Elsevier

Seminars in Oncology

Volume 33, Issue 3, June 2006, Pages 312-323
Seminars in Oncology

Neoplastic Meningitis From Systemic Malignancies: Diagnosis, Prognosis and Treatment

https://doi.org/10.1053/j.seminoncol.2006.04.016Get rights and content

Long-term survival is occasionally observed in patients with neoplastic meningitis (NM) accompanying breast cancer (13% one-year and 6% 2-year survival), melanoma, and lymphoma, but in general the survival of most patients is short and averages only 3 to 4 months. The incidence of NM appears to be increasing, in part due to earlier detection by magnetic resonance imaging (MRI), and in part due to development of more effective therapies for systemic cancer, which has resulted in a larger subset at risk for late-stage development of this complication. Survival of NM patients is negatively affected by concomitant progression of systemic disease despite multiple prior therapies. However, there are certain prognostic factors that have been identified as “favorable” in retrospective series, including age less than 60 years, long symptom duration, controlled systemic disease, Karnofsky performance status (KPS) ≥70, lack of encephalopathy or cranial nerve deficits, low initial cerebrospinal fluid (CSF) protein level, history of breast primary tumor, and lack of evidence of CSF compartmentalization or bulky meningeal disease as determined by CSF flow studies. Standard treatment has traditionally involved radiotherapy (RT) to sites of symptomatic or bulky disease, as detected by neuroimaging, and in selected patients, the administration of intrathecal, intraventricular, or systemic chemotherapy. However, treatment remains palliative and many patients and physicians choose supportive care only. Future hope is provided by studies that have improved our understanding of the disease pathogenesis, have identified prognostic variables associated with outcome, and have provided new therapeutic approaches, such as administration of high-dose systemic chemotherapy and investigations of novel therapeutic agents.

Section snippets

Incidence

In retrospective series, NM has been observed in approximately 4% to 8% of patients with solid tumors, 5% to 15% of patients with hematologic malignancies, and less than 2% of patients with primary brain tumors.1 The frequency is also dependent on the histology and grade of the tumor, and on the duration of disease. For example, up to 30% of patients with Burkitt’s lymphoma may develop this complication,9 and in at least one series, an increasing incidence of NM in patients with non-small cell

Pathogenesis

The traditional mechanisms proposed for the pathogenesis of NM have been primarily based on post mortem observations, and known mechanisms of metastatic spread. Thus, it is generally accepted that most meningeal metastases occur following hematogenous dissemination to the meninges, or by direct extension from para-meningeal or bony contiguous structures (eg, bone of the skull or vertebrae, regional lymph nodes, or soft tissues), or by retrograde growth along the adventitia of blood vessels and

Clinical Features

The clinical features of NM are well described elsewhere.1, 2, 4, 7, 11, 12, 14 Most commonly, patients present with mental status changes, headache, recurrent vomiting, seizures, lower extremity weakness, gait ataxia, and sensory findings. The classical meningeal sign of nuchal rigidity is present in less than 20% of patients.11, 13 Initially, symptoms may be experienced by the patient for weeks (sometimes months) prior to the eventual diagnosis, and on occasion can appear relatively benign at

Examination of CSF

The clinical diagnosis of NM is typically supported by appropriate findings on neuroimaging or by examination of the CSF for the presence of malignant cells. Still, in approximately 5% to 10% of patients, the clinical diagnosis cannot be confirmed by these ancillary procedures.25

The direct confirmation of tumor cells within CSF, consistent with the systemic primary tumor (if known), represents the definitive diagnostic method. The relative sensitivity of this test is dependent on several

Prognosis

Most patients with NM from solid tumors survive only 3 to 4 months following diagnosis.13 Patients with NM from breast cancer appear to have a slightly longer median survival, varying from 11% to 25% at 1 year.48, 49 Although several factors mentioned earlier appear to correlate with improved prognosis (Table 2), no factors have been clearly established as predictive of response to specific therapies.

Many intrathecal chemotherapeutic agents currently in use are cell cycle–specific, which

“Standard” Treatments

There are several unresolved and controversial issues with respect to treatment of patients with NM (Table 3). These issues must eventually be properly addressed via the conduct of carefully designed, prospective clinical trials. To date there are no “standard” treatments for NM that have been shown to definitively prolong overall survival of these patients. However, by default, some chemotherapeutic agents with palliative benefit have become community standards of care for treatment of

Summary and Conclusions

NM is a devastating, late stage complication of cancer. Treatment to date has not had a significant effect on survival, although palliative clinical benefit, clearing of CSF cells, and improvement in time to neurologic progression have been observed following RT and after intrathecal and/or systemic chemotherapy. At this time, therapy should probably only be recommended for patients with more favorable prognostic factors, who are highly motivated to receive additional treatment, or those

References (108)

  • NCCN Adult Brain Tumor Practice Guidelines

    Oncology

    (1997)
  • M.A. Grassi et al.

    Lymphomatous meningitis of the Burkitt type presenting with multiple cranial neuropathies

    Am J Ophthalmol

    (1992)
  • J.L. Nugent et al.

    CNS metastases in small cell bronchogenic carcinomaIncreasing frequency and changing pattern with lengthening survival

    Cancer

    (1979)
  • W.R. Wasserstrom et al.

    Diagnosis and treatment of leptomeningeal metastases from solid tumorsExperience with 90 patients

    Cancer

    (1982)
  • J.G. Kaplan et al.

    Leptomeningeal metastasescomparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias

    J Neurooncol

    (1990)
  • W.R. Wasserstrom et al.

    Diagnosis and treatment of leptomeningeal metastases from solid tumorsExperience with 90 patients

    Cancer

    (1982)
  • J.R. Little et al.

    Meningeal carcinomatosis. Clinical manifestations

    Arch Neurol

    (1974)
  • W.R. Shapiro et al.

    Treatment of meningeal neoplasms

    Cancer Treat Rep

    (1977)
  • S.T. Rosen et al.

    Carcinomatous leptomeningitis in small cell lung cancerA clinicopathologic review of the National Cancer Institute experience

    Medicine

    (1982)
  • M.H. Amer et al.

    Malignant melanoma and central nervous system metastasesIncidence, diagnosis, treatment and survival

    Cancer

    (1978)
  • J.C. Gonzalez-Vitale et al.

    Meningeal carcinomatosis

    Cancer

    (1976)
  • M.C. Chamberlain

    Radioisotope CSF flow studies in leptomeningeal metastases

    J Neurooncol

    (1998)
  • S.T. Rosen et al.

    Carcinomatous leptomeningitis in small cell lung cancerA clinicopathologic review of the National Cancer Institute experience

    Medicine

    (1982)
  • H.Y. Yap et al.

    Meningeal carcinomatosis in breast cancer

    Cancer

    (1978)
  • M.H. Amer et al.

    Malignant melanoma and central nervous system metastasesIncidence, diagnosis, treatment and survival

    Cancer

    (1978)
  • J.G. Kaplan et al.

    Leptomeningeal metastasescomparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias

    J Neurooncol

    (1990)
  • H.J. Stemmler et al.

    Application of intrathecal trastuzumab (Herceptin) for treatment of meningeal carcinomatosis in HER2-overexpressing metastatic breast cancer

    Oncol Rep

    (2006)
  • M.C. Chamberlain et al.

    Leptomeningeal metastasisA comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain

    Neurology

    (1990)
  • J.P. Glass et al.

    Malignant cells in cerebrospinal fluid (CSF)The meaning of a positive CSF cytology

    Neurology

    (1979)
  • M.J. Glantz et al.

    Cerebrospinal fluid cytology in patients with cancerMinimizing false-negative results

    Cancer

    (1998)
  • W.R. Wasserstrom et al.

    Cerebrospinal fluid biochemical markers in central nervous system tumorsA review

    Ann Clin Lab Sci

    (1981)
  • A. Twijnstra et al.

    Serial lumbar and ventricular cerebrospinal fluid biochemical marker measurements in patients with leptomeningeal metastases from solid and hematological tumors

    J Neurooncol

    (1989)
  • G. Stockhammer et al.

    Vascular endothelial growth factor in CSFA biological marker for carcinomatous meningitis

    Neurology

    (2000)
  • M.C. Chamberlain

    Cytologically negative carcinomatous meningitisUsefulness of CSF biochemical markers

    Neurology

    (1998)
  • R.J. van Oostenbrugge et al.

    In situ hybridizationA possible diagnostic aid in leptomeningeal metastasis

    J Neurooncol

    (1998)
  • A. Hovestadt et al.

    Immunohistochemical analysis of the cerebrospinal fluid for carcinomatous and lymphomatous leptomeningitis

    Br J Cancer

    (1990)
  • C.H. Rhodes et al.

    A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis

    Cancer

    (1996)
  • L.R. Rogers et al.

    Comparison of cisternal and lumbar CSF examination in leptomeningeal metastasis

    Neurology

    (1992)
  • T.M. Cheng et al.

    Chronic meningitisThe role of meningeal or cortical biopsy

    Neurosurgery

    (1994)
  • M. Schumacher et al.

    Imaging techniques in neoplastic meningiosis

    J Neurooncol

    (1998)
  • M.C. Chamberlain et al.

    Leptomeningeal metastasisA comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain

    Neurology

    (1990)
  • R.J. Freilich et al.

    Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastasis

    Ann Neurol

    (1995)
  • M.C. Chamberlain

    Radioisotope CSF flow studies in leptomeningeal metastases

    J Neurooncol

    (1998)
  • M.J. Glantz et al.

    Diagnosis, management, and survival of patients with leptomeningeal cancer based on cerebrospinal fluid-flow status

    Cancer

    (1995)
  • M.C. Chamberlain et al.

    Prognostic significance of 111 indium-DTPA CSF flow studies in leptomeningeal metastases

    Neurology

    (1996)
  • W.P. Mason et al.

    111Indium-diethylenetriamine pentaacetic acid cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases

    Neurology

    (1998)
  • M.C. Chamberlain et al.

    Leptomeningeal metastases111Indium-DTPA CSF flow studies

    Neurology

    (1991)
  • M.C. Chamberlain et al.

    111Indium-diethylenetriamine pentaacetic acid CSF flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases

    Neurology

    (1999)
  • B.J. Iskandar et al.

    Age-related variations in peak cerebrospinal fluid velocities in the foramen magnum

    J Neurosurg

    (2005)
  • L.M. DeAngelis

    Current diagnosis and treatment of leptomeningeal metastasis

    J Neurooncol

    (1998)

    • Cited by (67)

    • Leptomeningeal metastasis

      2018, Handbook of Clinical Neurology
      Citation Excerpt :

      Considering all histologic types and an optimal combination of therapeutic modalities, overall survival is mostly less than 6 months, with a median of 2–3 months. There are occasional long survivors, with approximately 15% 1-year survivorship (Shapiro et al., 1977; Chamberlain and Kormanik, 1997a; Choong et al., 2006; Jaeckle, 2006; Rudnicka et al., 2007; Harstad et al., 2008; Raizer et al., 2008; Clatot et al., 2009; Katayama et al., 2009; Siddiqui et al., 2009; Waki et al., 2009; Yi et al., 2009; Clarke et al., 2010a; Gauthier et al., 2010; de Azevedo et al., 2011; Masuda et al., 2011; Hata et al., 2012; Morris et al., 2012; Park et al., 2012; Togashi et al., 2012b; Zairi et al., 2012; Nakamichi et al., 2013; Xing et al., 2014; Kawamura et al., 2015; Chaul-Barbosa et al., 2016). The goal of LM-directed therapy is to improve or stabilize the neurologic status, maintain neurologic quality of life, and prolong survival.

    • Astatine-211 labeled anti-HER2 5F7 single domain antibody fragment conjugates: radiolabeling and preliminary evaluation

      2018, Nuclear Medicine and Biology

    • Diagnostic Pathology: Neuropathology

      2017, Diagnostic Pathology: Neuropathology

    • Management of neuro-oncologic emergencies

      2017, Handbook of Clinical Neurology

    • Management of leptomeningeal metastases: Prognostic factors and associated outcomes

      2016, Journal of Clinical Neuroscience

    • Survival following Ommaya reservoir placement for neoplastic meningitis

      2015, Journal of Clinical Neuroscience
    View all citing articles on Scopus
    View full text
    Copyright © 2006 Elsevier Inc. All rights reserved.