American Journal of Cancer

, Volume 1, Issue 6, pp 423–434 | Cite as

Lymphomatous Meningitis

Incidence, Prognosis and Treatment
  • Marc C. Chamberlain
  • Craig P. Nolan
  • Lauren E. Abrey
Review Article


Lymphomatous meningitis (LM) is a common problem in neuro-oncology, occurring in approximately 5% of all patients with systemic lymphoma. Notwithstanding frequent focal signs and symptoms in LM, LM is a disease affecting the entire neuraxis and therefore staging and treatment need to encompass all cerebrospinal fluid (CSF) compartments. CNS staging of LM includes contrast enhanced cranial computerized tomography (CE-CT) or magnetic resonance imaging (MR-Gd), contrast enhanced spine magnetic resonance imaging (MRS) or computerized tomographic myelography (CT-M) and radionuclide CSF flow study. Treatment of LM includes involved-field radiotherapy of bulky or symptomatic disease sites and intrathecal chemotherapy (intra-CSF) drug therapy. The inclusion of concomitant systemic therapy (high dose methotrexate or cytarabine) may benefit patients with LM and may obviate the need for intra-CSF chemotherapy. At present, intra-CSF drug therapy is confined to three chemotherapy agents (i.e. methotrexate, cytarabine and thiotepa) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Although treatment of LM is palliative, with an expected median patient survival of 6–10 months, it often affords stabilization and protection from further neurologic deterioration.



The authors have provided no information on sources of funding or on conflicts of interest directly relevant to the content of this review.


  1. 1.
    DeAngelis LM. Current diagnosis and treatment of leptomeningeal metastasis. J Neurooncol 1998; 38: 245–52PubMedCrossRefGoogle Scholar
  2. 2.
    Kaplan JG, DeSouza TG, Farkash A, et al. Leptomeningeal metastases: comparison of clinical features and laboratory data of solid tumors, lymphomas and leukemias. J Neurooncol 1990; 9: 225–9PubMedCrossRefGoogle Scholar
  3. 3.
    van Oostenbrugge RJ, Twijnstra A. Presenting features and value of diagnostic procedures in leptomeningeal metastases. Neurology 1999; 53: 382–5PubMedCrossRefGoogle Scholar
  4. 4.
    Freedman A, Nadler LM. Non-Hodgkin’s lymphomas. In: Holland J, Bast Jr RC, Morton ML, ET AL., editors. Cancer medicine. 4th ed. Baltimore (MD): Williams & Wilkins, 1997: 2757–95Google Scholar
  5. 5.
    Bishop PC, Wilson WH, Pearson D, et al. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol 1999; 17: 2479–85PubMedGoogle Scholar
  6. 6.
    Recht L, Straus DJ, Cirrincione C, et al. Central nervous system metastases from non-Hodgkin’s lymphoma: treatment and prophylaxis. Am J Med 1988; 84: 425–35PubMedCrossRefGoogle Scholar
  7. 7.
    Bollen EL, Brouwer RE, Hamers S, et al. Central nervous system relapse in non-Hodgkin’s lymphoma: a single-center study of 532 patients. Arch Neurol 1997; 54: 854–9PubMedCrossRefGoogle Scholar
  8. 8.
    Ersboll J, Schultz HB, Thomsen BL, et al. Meningeal involvement in non-Hodgkin’s lymphoma: symptoms, incidence, risk factors and treatment. Scand J Haematol 1985; 35: 487–96PubMedCrossRefGoogle Scholar
  9. 9.
    Litam JP, Cabanillas F, Smith TL, et al. Central nervous system relapse in malignant lymphomas: risk factors and implications for prophylaxis. Blood 1979; 54: 1249–57PubMedGoogle Scholar
  10. 10.
    Liang R, Chiu E, Loke SL. Secondary central nervous system involvement by non-Hodgkin’s lymphoma: the risk factors. Hematol Oncol 1990; 8: 141–5PubMedCrossRefGoogle Scholar
  11. 11.
    van Besien K, Ha CS, Murphy S, et al. Risk factors, treatment, and outcome of central nervous system recurrence in adults with intermediate-grade and immunoblastic lymphoma. Blood 1998; 91: 1178–84PubMedGoogle Scholar
  12. 12.
    Chamberlain MC, Kormanik PA. Non-AIDS related lymphomatous meningitis: combined modality therapy. Neurology 1997; 49: 1728–31PubMedCrossRefGoogle Scholar
  13. 13.
    Chamberlain M. Leptomeningeal metastases. In: Levin V, editor. Cancer in the nervous system. New York: Churchill Livingstone, 1996: 282–90Google Scholar
  14. 14.
    Murray J, Greco F, Wolff S, et al. Neoplastic meningitis; marked variations of cerebrospinal fluid composition in the absence of extradural block. Am J Med 1983; 75: 289–94PubMedCrossRefGoogle Scholar
  15. 15.
    Wasserstrom W, Glass J, Posner J. Diagnosis and treatment of leptomeningeal metastases from solid tumors experience with 90 patients. Cancer 1982; 49: 759–72PubMedCrossRefGoogle Scholar
  16. 16.
    Jeffery GM, Frampton CM, Legge HM, et al. Cerebrospinal fluid B2-microglobulin levels in meningeal involvement by malignancy. Pathology 1990; 22: 20–3PubMedCrossRefGoogle Scholar
  17. 17.
    Rhodes CH, Glantz MJ, Glantz L, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996; 77: 543–8PubMedCrossRefGoogle Scholar
  18. 18.
    Grossman SA, Krabak MJ. Leptomeningeal carcinomatosis. Cancer Treat Rev 1999; 25(2): 103–19PubMedCrossRefGoogle Scholar
  19. 19.
    Wasserstrom WR, Schwartz MK, Fleisher M, et al. Cerebrospinal fluid biochemical markers in central nervous system tumors: a review. Ann Clin Lab Sci 1981; 11(3): 239–51PubMedGoogle Scholar
  20. 20.
    Van Zanten AP, Twijnstra A, Hart AA, et al. Cerebrospinal fluid lactate dehydrogenase activities in patients with central nervous system metastases. Clin Chim Ada 1986; 161(3): 259–68CrossRefGoogle Scholar
  21. 21.
    Klee GG, Tallman RD, Goellner JR, et al. Elevation of carcinoembryonic antigen in cerebrospinal fluid among patients with meningeal carcinomatosis. Mayo Clin Proc 1986; 61(1): 9–13PubMedCrossRefGoogle Scholar
  22. 22.
    Twijnstra A, van Zanten AP, Hart AA, et al. Serial lumbar and ventricle cerebrospinal fluid lactate dehydrogenase activities in patients with leptomeningeal metastases from solid and haematological tumours. J Neurol Neurosurg Psychiatry 1987; 50(3): 313–20PubMedCrossRefGoogle Scholar
  23. 23.
    Twijnstra A, Ongerboer de Visser BW, van Zanten AP, et al. Serial lumbar and ventricular cerebrospinal fluid biochemical marker measurements in patients with leptomeningeal metastases from solid and hematological tumors. J Neuro Oncol 1989; 7(1): 57–63CrossRefGoogle Scholar
  24. 24.
    Stockhammer G, Poewe W, Burgstaller S, et al. Vascular endothelial growth factor in CSF: a biological marker for carcinomatous meningitis. Neurology 2000; 54(8): 1670–6PubMedCrossRefGoogle Scholar
  25. 25.
    Chamberlain MC. Cytologically negative carcinomatous meningitis: usefulness of CSF biochemical markers. Neurology 1998; 50(4): 1173–5PubMedCrossRefGoogle Scholar
  26. 26.
    Garson JA, Coakham HB, Kemshead JT, et al. The role of monoclonal antibodies in brain tumour diagnosis and cerebrospinal fluid (CSF) cytology. J Neurooncol 1985; 3(2): 165–71PubMedCrossRefGoogle Scholar
  27. 27.
    Hovestadt A, Henzen-Logmans SC, Vecht CJ. Immunohistochemical analysis of the cerebrospinal fluid for carcinomatous and lymphomatous leptomeningitis. Br J Cancer 1990; 62(4): 653–4PubMedCrossRefGoogle Scholar
  28. 28.
    Boogerd W, Vroom TM, van Heerde P, et al. CSF cytology versus immunocytochemistry in meningeal carcinomatosis. J Neurol Neurosurg Psychiatry 1988; 51(1): 142–5PubMedCrossRefGoogle Scholar
  29. 29.
    van Oostenbrugge RJ, Hopman AH, Ramaekers FC, et al. In situ hybridization: a possible diagnostic aid in leptomeningeal metastasis. J Neurooncol 1998; 38(2-3): 127–33PubMedCrossRefGoogle Scholar
  30. 30.
    Cibas ES, Malkin MG, Posner JB, et al. Detection of DNA abnormalities by flow cytometry in cells from cerebrospinal fluid. Am J Clin Pathol 1987; 88(5): 570–7PubMedGoogle Scholar
  31. 31.
    Biesterfeld S, Bernhard B, Bamborschke S, et al. DNA single cell cytometry in lymphocytic pleocytosis of the cerebrospinal fluid. Acta Neuropathol (Berl) 1993; 86(5): 428–32CrossRefGoogle Scholar
  32. 32.
    Van Oostenbrugge RJ, Hopman AH, Arends JW, et al. The value of interphase cytogenetics in cytology for the diagnosis of leptomeningeal metastases. Neurology 1998; 51(3): 906–8PubMedCrossRefGoogle Scholar
  33. 33.
    Rhodes CH, Glantz MJ, Glantz L, et al. A comparison of polymerase chain reaction examination of cerebrospinal fluid and conventional cytology in the diagnosis of lymphomatous meningitis. Cancer 1996; 77(3): 543–8PubMedCrossRefGoogle Scholar
  34. 34.
    Cheng TM, O’Neill BP, Scheithauer BW, et al. Chronic meningitis: the role of meningeal or cortical biopsy. Neurosurgery 1994; 34(4): 590–5PubMedCrossRefGoogle Scholar
  35. 35.
    Glass J, Melamed M, Chernik N, et al. Malignant cells in cerebrospinal fluid (CSF) the meaning of a positive csf cytology. Neurology 1979; 29: 1369–75PubMedCrossRefGoogle Scholar
  36. 36.
    Chamberlain M, Sandy A, Press G. Leptomeningeal metastasis a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology 1990; 40: 435–8PubMedCrossRefGoogle Scholar
  37. 37.
    Gomori JM, Heching N, Siegal T. Leptomeningeal metastases: evaluation by gadolinium enhanced spinal magnetic resonance imaging. J Neurooncol 1998; 36: 55–60PubMedCrossRefGoogle Scholar
  38. 38.
    Sze G, Soletsky S, Bronen R, et al. MR Imaging of the cranial meninges with emphasis on contrast enhancements and meningeal carcinomatosis. AJNR Am J Neuroradiol 1989; 10: 965–75PubMedGoogle Scholar
  39. 39.
    Collie DA, Sellar RJ, Steyn JP, et al. The diagnostic yield of magnetic resonance imaging (MRI) of the brain and spine requested by general practitioners: comparison with hospital clinicians. Br J Gen Pract 1999; 49: 559–61PubMedGoogle Scholar
  40. 40.
    Chamberlain MC. Comparative spine imaging in leptomeningeal metastases. J Neurooncol 1995; 23: 233–8PubMedCrossRefGoogle Scholar
  41. 41.
    Kim K, Ho S, Weinberg P, et al. Spinal leptomeningeal infiltration by systemic cancer myelographic features. AJR Am J Roentgenol 1982; 139: 361–5PubMedGoogle Scholar
  42. 42.
    Kramer E, Rafto S, Packer R, et al. Comparison of myelography with CT follow-up versus gadolinium MRI for subarachnoid metastatic disease in children. Neurology 1991; 41: 46–50PubMedCrossRefGoogle Scholar
  43. 43.
    Chamberlain M, Corey-Bloom J. Leptomeningeal metastases indium-DTPA CSF flow studies. Neurology 1991; 41: 1765–9PubMedCrossRefGoogle Scholar
  44. 44.
    Chamberlain MC. Leptomeningeal metastases: a review of evaluation and treatment. J Neurooncol 1998; 37: 271–84PubMedCrossRefGoogle Scholar
  45. 45.
    Paulus JA, Bos GM, Lowenberg B, et al. Treatment results and the prognosis in patients with localization of non-Hodgkin’s-lymphoma in the central nervous system. Ned Tijdschr Geneeskd 1998 Oct 3; 142: 2196–200PubMedGoogle Scholar
  46. 46.
    Yoshida S, Morii K, Watanabe M, et al. Characteristic features of malignant lymphoma with central nervous system involvement. Surg Neurol 2000; 53: 163–7PubMedCrossRefGoogle Scholar
  47. 47.
    Chamberlain MC, Kormanik PA. Prognostic significance of coexistent bulky metastatic central nervous system disease in patients with leptomeningeal metastases. Arch Neurol 1997; 54: 1364–8PubMedCrossRefGoogle Scholar
  48. 48.
    Blasberg R, Patlak C, Fenstermacher J. Intrathecal chemotherapy brain tissue profiles after ventriculo-cisternal perfusion. J Pharmacol Exp Ther 1975; 195: 73–83PubMedGoogle Scholar
  49. 49.
    Magrath IT, Haddy TB, Adde MA. Treatment of patients with high-grade non-Hodgkin’s lymphomas and central nervous system involvement: is radiation an essential component of therapy? Leuk Lymphoma 1996; 21: 99–105PubMedCrossRefGoogle Scholar
  50. 50.
    Balis F, Poplack D. Central nervous system pharmacology of antileukemic drugs. Am J Pediatr Hematol Oncol 1989; 11: 74–86PubMedCrossRefGoogle Scholar
  51. 51.
    Collins J. Pharmacokinetics of intraventricular administration. J Neurooncol 1983; 1: 283–91PubMedCrossRefGoogle Scholar
  52. 52.
    Bokstein F, Lossos A, Lossos IS, et al. Central nervous system relapse of systemic non-Hodgkins lymphoma: results of treatment based on high-dose methotrexate combination chemotherapy. Leuk Lymphoma 2002; 43: 587–93PubMedCrossRefGoogle Scholar
  53. 53.
    Siegal T, Lassos A, Pfeffer MR. Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy. Neurology 1994; 44: 1463–9PubMedCrossRefGoogle Scholar
  54. 54.
    Boogerd W, Hart AAM, Van der Sande F, et al. Meningeal carcinomatosis breast cancer: prognostic factors and influence of treatment. Cancer 1991; 67: 1685–95PubMedCrossRefGoogle Scholar
  55. 55.
    Fizazi K, Asselain B, Vincent-Salomon A, et al. Meningeal carcinomatosis in patients with breast carcinoma. Cancer 1996; 77(7): 1315–23PubMedCrossRefGoogle Scholar
  56. 56.
    Chamberlain MC, Kormanik P, Glantz M. Recurrent primary central nervous system lymphoma complicated by lymphomatous meningitis. Oncol Rep 1998; 5: 521–3PubMedGoogle Scholar
  57. 57.
    Philip T, Guglielmi C, Hagenbeek A, et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 333: 1540–5PubMedCrossRefGoogle Scholar
  58. 58.
    Williams CD, Pearce R, Taghipour G, et al. Autologous bone marrow transplantation for patients with non-Hodgkin’s lymphoma and CNS involvement: those transplanted with active CNS disease have a poor outcome: a report by the European Bone Marrow Transplant Lymphoma Registry. J Clin Oncol 1994; 12: 2415–22PubMedGoogle Scholar
  59. 59.
    Alvarnas JC, Negrin RS, Horning SJ, et al. High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 2000; 6: 352–8PubMedCrossRefGoogle Scholar
  60. 60.
    Giannone L, Greco F, Hainsworth J. Combination intraventricular chemotherapy for meningeal neoplasia. J Clin Oncol 1986; 4: 68–73PubMedGoogle Scholar
  61. 61.
    Hitchens R, Bell D, Woods R, et al. A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis. J Clin Oncol 1987; 5: 1655–62Google Scholar
  62. 62.
    Grossman SA, Finkelstein DM, Ruckdeschel JC, et al. Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. J Clin Oncol 1993; 11: 561–9PubMedGoogle Scholar
  63. 63.
    Shapiro W, Young D, Mehta B. Methotrexate distribution in cerebrospinal fluid after intravenous, ventricular and lumbar injections. N Engl J Med 1975; 293: 161–6PubMedCrossRefGoogle Scholar
  64. 64.
    Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol 1999; 17: 3110–6PubMedGoogle Scholar
  65. 65.
    Chamberlain MC, Kormanik PA. Complications associated with intraventricular chemotherapy in patients with leptomeningeal metastases. J Neurosurg 1997; 87: 694–9PubMedCrossRefGoogle Scholar
  66. 66.
    Rabkin CS, Yellin F. Cancer incidence in a population with a high prevalence of infection with human immunodeficiency virus type 1. J Natl Cancer Inst 1994 Nov 16; 86: 1711–6PubMedCrossRefGoogle Scholar
  67. 67.
    Cingolani A, Gastaldi R, Fassone L, et al. Epstein-Barr virus infection is predictive of CNS involvement in systemic AIDS-related non-Hodgkin’s lymphomas. J Clin Oncol 2000; 18: 3325–30PubMedGoogle Scholar
  68. 68.
    Taiwo BO. AIDS-related primary CNS lymphoma: a brief review. AIDS Read 2000; 10: 486–91PubMedGoogle Scholar
  69. 69.
    DeAngelis LM, Wong E, Rosenblum M, et al. Epstein-Barr virus in acquired immune deficiency syndrome (AIDS) and non-AIDS primary central nervous system lymphoma. Cancer 1992; 70: 1607–11PubMedCrossRefGoogle Scholar
  70. 70.
    Desai J, Mitnick RJ, Henry DH, et al. Patterns of central nervous system recurrence in patients with systemic human immunodeficiency virus-associated non-Hodgkin lymphoma. Cancer 1999; 86: 1840–7PubMedCrossRefGoogle Scholar
  71. 71.
    Balmaceda C, Gaynor JJ, Sun M, et al. Leptomeningeal tumor in primary central nervous system lymphoma: recognition, significance, and implications. Ann Neurol 1995; 38: 202–9PubMedCrossRefGoogle Scholar
  72. 72.
    Goldstein JD, Dickson DW, Moser FG, et al. Primary central nervous system lymphoma in acquired immune deficiency syndrome: a clinical and pathologic study with results of treatment with radiation. Cancer 1991; 67: 2756–65PubMedCrossRefGoogle Scholar
  73. 73.
    Raez LE, Patel P, Feun L, et al. Natural history and prognostic factors for survival in patients with acquired immune deficiency syndrome (AIDS)-related primary central nervous system lymphoma (PCNSL). Crit Rev Oncog 1998; 9: 199–208PubMedGoogle Scholar
  74. 74.
    Chamberlain MC, Kormanik PA. AIDS-related central nervous system lymphomas. J Neurooncol 1999; 43: 269–76PubMedCrossRefGoogle Scholar
  75. 75.
    Chamberlain M, Dirr L. Involved field radiotherapy and intra-ommaya methotrex-ate/ara-C in patients with AIDS-related lymphomatous meningitis. J Clin Oncol 1993; 11: 1978–84PubMedGoogle Scholar
  76. 76.
    Chamberlain MC, Kormanik PA. Prognostic significance of co-existent bulky metastatic CNS disease in patients with leptomeningeal metastases. Arch Neurol 1997; 54: 1364–8PubMedCrossRefGoogle Scholar
  77. 77.
    Chamberlain MC, Kormanik P. Prognostic significance of indium-DTPA CSF flow studies. Neurology 1996; 46(6): 1674–7PubMedCrossRefGoogle Scholar
  78. 78.
    Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol 2000; 18: 3144–50PubMedGoogle Scholar
  79. 79.
    Herrilinger U, Schabet M, Brugger W, et al. German Cancer Society Neuro-On-cology Working Group NOA-03 multicenter trial of single-agent high-dose methotrexate for primary CNS lymphoma. Ann Neurol 2002; 51: 247–52CrossRefGoogle Scholar
  80. 80.
    Fisher BJ, Sieferheld W, Schultz C, et al. Secondary analysis of RTOG 9310: an intergroup phase II combined modality treatment of primary central nervous system lymphoma with chemotherapy and hyperfractionated radiotherapy. Int J Radiat Oncol Biol Phys 2001; 51(3) Suppl. 1: 166–77CrossRefGoogle Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Marc C. Chamberlain
    • 1
  • Craig P. Nolan
    • 2
  • Lauren E. Abrey
    • 2
  1. 1.Department of NeurologyUniversity of Southern California/Norris Comprehensive Cancer Center and HospitalLos AngelesUSA
  2. 2.Department of NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

Personalised recommendations