International Journal of Hematology

, Volume 84, Issue 2, pp 128–135 | Cite as

Secondary Central Nervous System Lymphoma

  • Naoto Tomita
  • Fumio Kodama
  • Heiwa Kanamori
  • Shigeki Motomura
  • Yoshiaki Ishigatsubo
Review Article


This review summarizes current knowledge of secondary central nervous system lymphoma (SCNSL) in adults. We define SCNSL as CNS involvement not obvious at the initiation of treatment for systemic lymphoma. Recently, polymerase chain reaction and flow cytometry assays of cerebrospinal fluid have become available for the correct diagnosis of SCNSL. We reviewed reports of patients treated without CNS prophylaxis to evaluate the incidence of SCNSL. Elevated serum lactate dehydrogenase levels, the involvement of more than one extranodal site, an advanced stage, a high age-adjusted International Prognostic Index score at presentation, and special anatomic sites of involvement such as the testis are important risk factors for SCNSL. Histologic evidence of aggressiveness is generally an indicator of risk for SCNSL. In addition to conventional treatment, stem cell transplantation, intrathecal administration of rituximab, and liposomal cytarabine have come into clinical use for the treatment of established SCNSL. Prevention of isolated CNS recurrence is thought to be the main target of CNS prophylaxis. The value of CNS prophylaxis according to histologic subtype, status of systemic lymphoma, and other risk factors is summarized.Although prophylaxis is fundamental for treating highly aggressive non-Hodgkin’s lymphoma (NHL), it is beginning to be appreciated for the treatment of aggressive NHL. CNS involvement is almost always fatal; however, a CNS-active strategy could complement other approaches that have led to recent improvements in the prognosis for lymphoma.

Key words

Lymphoma Central nervous system Prophylaxis Prognosis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lister A. Secondary central nervous system lymphoma: the case for prophylaxis. Hematology (Am Soc Hematol Educ Program). 2002:290–293.Google Scholar
  2. 2.
    Bashir RM, Bierman PJ,Vose JM,Weisenburger DD,Armitage JO. Central nervous system involvement in patients with diffuse aggressive non-Hodgkin’s lymphoma. Am J Clin Oncol. 1991;14:478–482.CrossRefPubMedGoogle Scholar
  3. 3.
    Tomita N, Kodama F, Sakai R, et al. Predictive factors for central nervous system involvement in non-Hodgkin’s lymphoma: significance of very high serum LDH concentrations. Leuk Lymphoma. 2000;38:335–343.CrossRefPubMedGoogle Scholar
  4. 4.
    Bunn PA Jr, Schein PS, Banks PM, DeVita VT Jr. Central nervous system complications in patients with diffuse histiocytic and undif-ferentiated lymphoma: leukemia revisited. Blood. 1976;47:3–10.PubMedGoogle Scholar
  5. 5.
    Law IP, Dick FR, Blom J, Bergevin PR. Involvement of the central nervous system in non-Hodgkin’s lymphoma. Cancer. 1975;36:225–231.CrossRefPubMedGoogle Scholar
  6. 6.
    Litam JP, Cabanillas F, Smith TL, Bodey GP, Freireich EJ. Central nervous system relapse in malignant lymphomas: risk factors and implications for prophylaxis. Blood. 1979;54:1249–1257.PubMedGoogle Scholar
  7. 7.
    Wolf MM, Olver IN, Ding JC, Cooper IA, Liew KH, Madigan JP. Non-Hodgkin’s lymphoma involving the central nervous system. Aust N Z J Med. 1985;15:16–21.CrossRefPubMedGoogle Scholar
  8. 8.
    Liang R, Chiu E, Loke SL. Secondary central nervous system involvement by non-Hodgkin’s lymphoma: the risk factors. Hematol Oncol. 1990;8:141–145.CrossRefPubMedGoogle Scholar
  9. 9.
    Keldsen N, Michalski W, Bentzen SM, Hansen KB,Thorling K. Risk factors for central nervous system involvement in non-Hodgkins-lymphoma: a multivariate analysis. Acta Oncol. 1996;35:703–708.CrossRefPubMedGoogle Scholar
  10. 10.
    Herman TS, Hammond N, Jones SE, Butler JJ, Byrne GE Jr, McKelvey EM. Involvement of the central nervous system by non-Hodgkin’s lymphoma: the Southwest Oncology Group experience. Cancer. 1979;43:390–397.CrossRefPubMedGoogle Scholar
  11. 11.
    Levitt LJ, Dawson DM, Rosenthal DS, Moloney WC. CNS involvement in the non-Hodgkin’s lymphomas. Cancer. 1980;45:545–552.CrossRefPubMedGoogle Scholar
  12. 12.
    Lokich J, Galbo C. Leptomeningeal lymphoma: perspectives on management. Cancer Treat Rev. 1981;8:103–110.CrossRefPubMedGoogle Scholar
  13. 13.
    Johnson GJ, Oken MM, Anderson JR, O’Connell MJ, Glick JH. Central nervous system relapse in unfavourable-histology non-Hodgkin’s lymphoma: is prophylaxis indicated? Lancet. 1984;2:685–687.CrossRefPubMedGoogle Scholar
  14. 14.
    Murchison C. Case of ‘lymphadenoma’ of the lymphatic system, liver, lungs, heart and dura mater. Trans Pathol Soc Lond. 1870;21:372–389.Google Scholar
  15. 15.
    Davison C, Michaels JJ. Lymphosarcoma with involvement of the central nervous system. Arch Intern Med. 1930;45:908–925.CrossRefGoogle Scholar
  16. 16.
    Sparling HJ Jr,Adams RD, Parker F Jr. Involvement of the central nervous system by malignant lymphoma. Medicine. 1947;26:285–332.CrossRefPubMedGoogle Scholar
  17. 17.
    Williams HM, Diamond DH, Craver LF, Parsons H. Neurological Complications of Lymphomas and Leukemias. Springfield, Ill: Charles C. Thomas; 1959.Google Scholar
  18. 18.
    Young RC, Howser DM,Anderson T, Fisher RI, Jaffe E, DeVita VT Jr. Central nervous system complications of non-Hodgkin’s lymphoma: the potential role for prophylactic therapy. Am J Med. 1979;66:435–443.CrossRefPubMedGoogle Scholar
  19. 19.
    Blay JY, Conroy T, Chevreau C, et al. High-dose methotrexate for the treatment of primary cerebral lymphomas: analysis of survival and late neurologic toxicity in a retrospective series. J Clin Oncol. 1998;16:864–871.CrossRefPubMedGoogle Scholar
  20. 20.
    Abrey LE, Yahalom J, DeAngelis LM. Treatment for primary CNS lymphoma: the next step. J Clin Oncol. 2000;18:3144–3150.CrossRefPubMedGoogle Scholar
  21. 21.
    Recht L, Straus DJ, Cirrincione C, Thaler HT, Posner JB. Central nervous system metastases from non-Hodgkin’s lymphoma: treat- ment and prophylaxis. Am J Med. 1988;84:425–435.CrossRefPubMedGoogle Scholar
  22. 22.
    Zinzani PL, Magagnoli M, Frezza G, et al. Isolated central nervous system relapse in aggressive non-Hodgkin’s lymphoma: the Bologna experience. Leuk Lymphoma. 1999;32:571–576.CrossRefPubMedGoogle Scholar
  23. 23.
    Haioun C, Besson C, Lepage E, et al. Incidence and risk factors of central nervous system relapse in histologically aggressive non-Hodgkin’s lymphoma uniformly treated and receiving intrathecal central nervous system prophylaxis: a GELA study on 974 patients. Groupe d’Etude des Lymphomes de l’Adulte. Ann Oncol. 2000;11:685–690.CrossRefPubMedGoogle Scholar
  24. 24.
    Jahnke K, Coupland SE, Na IK, et al. Expression of the chemokine receptors CXCR4, CXCR5, and CCR7 in primary central nervous system lymphoma. Blood. 2005;106:384–385.CrossRefPubMedGoogle Scholar
  25. 25.
    Hegde U, Filie A, Little RF, et al. High incidence of occult lep-tomeningeal disease detected by flow cytometry in newly diagnosed aggressive B-cell lymphomas at risk for central nervous system involvement: the role of flow cytometry versus cytology. Blood. 2005;105:496–502.CrossRefPubMedGoogle Scholar
  26. 26.
    Griffin JW,Thompson RW, Mitchinson MJ, Kiewiet JC,Welland FH. Lymphomatous leptomeningitis. Am J Med. 1971;51:200–208.CrossRefPubMedGoogle Scholar
  27. 27.
    MacKintosh FR, Colby TV, Podolsky WJ, et al. Central nervous system involvement in non-Hodgkin’s lymphoma: an analysis of 105 cases. Cancer. 1982;49:586–595.CrossRefPubMedGoogle Scholar
  28. 28.
    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;91:1178–1184.PubMedGoogle Scholar
  29. 29.
    Montoto S, Lister TA. Secondary central nervous system lym-phoma: risk factors and prophylaxis. Hematol Oncol Clin North Am. 2005;19:751–763.CrossRefPubMedGoogle Scholar
  30. 30.
    Feugier P, Virion JM, Tilly H, et al. Incidence and risk factors for central nervous system occurrence in elderly patients with diffuse large-B-cell lymphoma: influence of rituximab. Ann Oncol. 2004;15:129–133.CrossRefPubMedGoogle Scholar
  31. 31.
    Bierman P, Giglio P. Diagnosis and treatment of central nervous system involvement in non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am. 2005;19:597–609.CrossRefPubMedGoogle Scholar
  32. 32.
    DeAngelis LM, Cairncross JG. A better way to find tumor in CSF? Neurology. 2002;58:339–340.CrossRefPubMedGoogle Scholar
  33. 33.
    Gleissner B, Siehl J, Korfel A, Reinhardt R,Thiel E. CSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes. Neurology. 2002;58:390–396.CrossRefPubMedGoogle Scholar
  34. 34.
    Kersten MJ, Evers LM, Dellemijn PLI, et al. Elevation of cerebrospinal fluid soluble CD27 levels in patients with meningeal localization of lymphoid malignancies. Blood. 1996;87:1985–1989.Google Scholar
  35. 35.
    Murase S, Saio M, Takenaka K, et al. Increased levels of CSF soluble CD27 in patients with primary central nervous system lym-phoma. Cancer Lett. 1998;132:181–186.CrossRefGoogle Scholar
  36. 36.
    Gendelman S, Rizzo F, Mones RJ. Central nervous system complications of leukemic conversion of the lymphomas. Cancer. 1969;24:676–682.CrossRefGoogle Scholar
  37. 37.
    Aviles A, Delgado S, Nambo MJ, Neri N, Murillo E, Cleto S. Primary breast lymphoma: results of a controlled clinical trial. Oncology. 2005;69:256–260.CrossRefGoogle Scholar
  38. 38.
    Sapozink MD, Kaplan HS. Intracranial Hodgkin’s disease: a report of 12 cases and review of the literature. Cancer. 1983;52:1301–1307.CrossRefGoogle Scholar
  39. 39.
    Ersboll J, Schultz HB, Thomsen BLR, Keiding N, Nissen NI. Meningeal involvement in non-Hodgkin’s lymphoma: symptoms, incidence, risk factors and treatment. Scand J Haematol. 1985;35:487–496.CrossRefGoogle Scholar
  40. 40.
    Hoerni-Simon G, Suchaud JP, Eghbali H, Coindre JM, Hoerni B. Secondary involvement of the central nervous system in malignant non-Hodgkin’s lymphoma: a study of 30 cases in a series of 498 patients. Oncology. 1987;44:98–101.CrossRefPubMedGoogle Scholar
  41. 41.
    Bollen EL, Brouwer RE, Hamers S, et al. Central nervous system relapse in non-Hodgkin lymphoma: a single-center study of 532 patients. Arch Neurol. 1997;54:854–859.CrossRefPubMedGoogle Scholar
  42. 42.
    Hollender A, Kvaloy S, Nome O, Skovlund E, Lote K, Holte H. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13:1099–1107.CrossRefPubMedGoogle Scholar
  43. 43.
    Colocci N, Glantz M, Recht L. Prevention and treatment of central nervous system involvement by non-Hodgkin’s lymphoma: a review of the literature. Semin Neurol. 2004;24:395–404.CrossRefPubMedGoogle Scholar
  44. 44.
    Spectre G, Gural A, Amir G, Lossos A, Siegal T, Paltiel O. Central nervous system involvement in indolent lymphomas. Ann Oncol. 2005;16:450–454.CrossRefPubMedGoogle Scholar
  45. 45.
    Laurenti L, Sica S, Voso MT, Chiusolo P, Zini G, Leone G. Central nervous system involvement after follicular large cell lymphoma. Haematologica. 2001;86:99.PubMedGoogle Scholar
  46. 46.
    Montserrat E, Bosch F, Lopez-Guillermo A, et al. CNS involvement in mantle-cell lymphoma. J Clin Oncol. 1996;14:941–944.CrossRefPubMedGoogle Scholar
  47. 47.
    Bishop PC, Wilson WH, Pearson D, Janik J, Jaffe ES, Elwood PC. CNS involvement in primary mediastinal large B-cell lymphoma. J Clin Oncol. 1999;17:2479–2485.CrossRefPubMedGoogle Scholar
  48. 48.
    Lopez-Guillermo A, Cid J, Salar A, et al. Peripheral T-cell lym-phomas: initial features, natural history, and prognostic factors in a series of 174 patients diagnosed according to the R.E.A.L. Classification. Ann Oncol. 1998;9:849–855.CrossRefPubMedGoogle Scholar
  49. 49.
    Buckstein R, Lim W, Franssen E, Imrie KL. CNS prophylaxis and treatment in non-Hodgkin’s lymphoma: variation in practice and lessons from the literature. Leuk Lymphoma. 2003;44:955–962.CrossRefPubMedGoogle Scholar
  50. 50.
    Bokstein F, Lossos A, Lossos IS, Siegal T. Central nervous system relapse of systemic non-Hodgkin’s lymphoma: results of treatment based on high-dose methotrexate combination chemotherapy. Leuk Lymphoma. 2002;43:587–593.CrossRefPubMedGoogle Scholar
  51. 51.
    Kawamura T, Koga S, Okamoto M, Kanno T, Iwamura H. Results of combined-modality therapy for primary and secondary malignant lymphoma of the central nervous system (CNS). Radiat Med, 2001;19:145–149.PubMedGoogle Scholar
  52. 52.
    Tomita N, Kodama F, Kanamori H, Motomura S, Ishigatsubo Y. Prophylactic intrathecal methotrexate and hydrocortisone reduces central nervous system recurrence and improves survival in aggressive non-Hodgkin lymphoma. Cancer. 2002;95:576–580.CrossRefPubMedGoogle Scholar
  53. 53.
    Batchelor T, Leahy N, Kaufman D. High-dose methotrexate for isolated central nervous system relapse in patients with testicular non-Hodgkin’s lymphoma. Clin Lymphoma. 2001;2:116–119.CrossRefPubMedGoogle Scholar
  54. 54.
    Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? J Clin Oncol. 1998;16:1561–1567.CrossRefPubMedGoogle Scholar
  55. 55.
    Kasamon YL, Jones RJ, Piantadosi S, et al. High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement. Biol Blood Marrow Transplant. 2005;11:93–100.CrossRefPubMedGoogle Scholar
  56. 56.
    Lotze C, Schuler F, Kruger WH, et al. Combined immunoradio-therapy induces long-term remission of CNS relapse of peripheral, diffuse, large-cell lymphoma after allogeneic stem cell transplantation: case study. Neuro-oncol. 2005;7:508–510.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Varadi G, Or R, Kapelushnik J, et al. Graft-versus-lymphoma effect after allogeneic peripheral blood stem cell transplantation for primary central nervous system lymphoma. Leuk Lymphoma. 1999;34:185–190.CrossRefPubMedGoogle Scholar
  58. 58.
    Williams CD, Pearce R, Taghipour G, Green ES, Philip T, Gold-stone AH. 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;12:2415–2422.CrossRefPubMedGoogle Scholar
  59. 59.
    Rubenstein JL, Combs D, Rosenberg J, et al. Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment. Blood. 2003;101:466–468.CrossRefPubMedGoogle Scholar
  60. 60.
    Schulz H, Pels H, Schmidt-Wolf I, Zeelen U, Germing U, Engert A. Intraventricular treatment of relapsed central nervous system lym-phoma with the anti-CD20 antibody rituximab. Haematologica. 2004;89:753–754.PubMedGoogle Scholar
  61. 61.
    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;17:3110–3116.CrossRefPubMedGoogle Scholar
  62. 62.
    McMillan A. Central nervous system-directed preventative therapy in adults with lymphoma. Br J Haematol. 2005;131:13–21.CrossRefPubMedGoogle Scholar
  63. 63.
    Cheung CW, Burton C, Smith P, Linch DC, Hoskin PJ,Ardeshna KM. Central nervous system chemoprophylaxis in non-Hodgkin lym-phoma: current practice in the UK. Br J Haematol. 2005;131:193–200.CrossRefPubMedGoogle Scholar
  64. 64.
    Akutsu M, Furukawa Y, Tsunoda S, Izumi T, Ohmine K, Kano Y. Schedule-dependent synergism and antagonism between metho-trexate and cytarabine against human leukemia cell lines in vitro. Leukemia. 2002;16:1808–1817.CrossRefPubMedGoogle Scholar
  65. 65.
    Moreton P, Morgan GJ, Gilson D, et al. The development of targeted chemotherapy for CNS lymphoma: a pilot study of the IDARAM regimen. Cancer Chemother Pharmacol. 2004;53:324–328.CrossRefPubMedGoogle Scholar
  66. 66.
    Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14:925–934.CrossRefPubMedGoogle Scholar
  67. 67.
    Mead GM, Sydes MR, Walewski J, et al. An international evalua- tion of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002;13:1264–1274.CrossRefPubMedGoogle Scholar
  68. 68.
    Cortes J, O’Brien SM, Pierce S, Keating MJ, Freireich EJ, Kantarjian HM. The value of high-dose systemic chemotherapy and intrathecal therapy for central nervous system prophylaxis in different risk groups of adult acute lymphoblastic leukemia. Blood. 1995;86:2091–2097.PubMedGoogle Scholar
  69. 69.
    Hoelzer D, Gokbuget N. New approaches to acute lymphoblastic leukemia in adults: where do we go? Semin Oncol. 2000;27:540–559.PubMedGoogle Scholar
  70. 70.
    Skarin AT, Canellos GP, Rosenthal DS, et al. Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD). J Clin Oncol. 1983;1:91–98.CrossRefPubMedGoogle Scholar
  71. 71.
    Bos GM, van Putten WLJ, van der Holt B, van den Bent M, Verdonck LF, Hagenbeek A. For which patients with aggressive non-Hodgkin’s lymphoma is prophylaxis for central nervous system disease mandatory? Dutch HOVON Group. Ann Oncol. 1998;9:191–194.CrossRefPubMedGoogle Scholar
  72. 72.
    Perez-Soler R, Smith TL, Cabanillas F. Central nervous system prophylaxis with combined intravenous and intrathecal methotrexate in diffuse lymphoma of aggressive histologic type. Cancer. 1986;57:971–977.CrossRefPubMedGoogle Scholar
  73. 73.
    Chua SL, Seymour JF, Streater J, Wolf MM, Januszewicz EH, Prince HM. Intrathecal chemotherapy alone is inadequate central nervous system prophylaxis in patients with intermediate-grade non-Hodgkin’s lymphoma. Leuk Lymphoma. 2002;43:1783–1788.CrossRefPubMedGoogle Scholar
  74. 74.
    Tilly H, Lepage E, Coiffier B, et al, for the Groupe d’Etude des Lymphomes de l’Adulte. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poorprognosis aggressive non-Hodgkin lymphoma. Blood. 2003;102:4284–4289.CrossRefPubMedGoogle Scholar
  75. 75.
    National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology, v.2.2006: Non-Hodgkin’s Lymphoma. National Comprehensive Cancer Network Web site.Available at: http://www. Accessed June 21, 2006.Google Scholar

Copyright information

© The Japanese Society of Hematology 2006

Authors and Affiliations

  • Naoto Tomita
    • 1
  • Fumio Kodama
    • 2
  • Heiwa Kanamori
    • 3
  • Shigeki Motomura
    • 2
  • Yoshiaki Ishigatsubo
    • 3
  1. 1.Department of HematologyYokohama City University Medical CenterYokohamaJapan
  2. 2.Department of ChemotherapyKanagawa Cancer Center, Yokohama City University Graduate School of MedicineYokohamaJapan
  3. 3.Department of Internal Medicine and Clinical ImmunologyYokohama City University Graduate School of MedicineYokohamaJapan

Personalised recommendations