Diagnosis, Prophylaxis and Treatment of Central Nervous System Involvement by Non-Hodgkin Lymphoma in HIV-Infected Patients

  • Michele SpinaEmail author


With the widespread use of highly active antiretroviral therapy (HAART), the incidence of systemic non-Hodgkin lymphoma (NHL) in patients infected with the human immunodeficiency virus (HIV) has declined. HAART has also modified the clinical manifestations of these tumours, with a lower frequency of involvement of the central nervous system (CNS). Before the introduction of HAART, up to 25 % of patients showed CNS involvement; currently, the frequency of meningeal involvement at the time of diagnosis of NHL in HIV-infected patients varies between 3 and 5 %, and its frequency is related to histological subtype, ranging from uncommon in indolent lymphomas to more frequent in aggressive lymphomas such as diffuse large B-cell lymphoma (DLBCL), lymphoblastic lymphoma, blastoid variant of mantle cell lymphoma and Burkitt’s lymphoma (BL). Clinical criteria, such as involvement of the paranasal sinus, testes, orbital cavities or bone marrow, advanced stage, high International Prognostic Index, elevated LDH levels and the involvement of multiple extranodal sites all help to better identify the risk factors in patients for whom the administration of prophylaxis is strongly recommended.


Mantle Cell Lymphoma Central Nervous System Involvement Cytosine Arabinoside Central Nervous System Relapse Central Nervous System Prophylaxis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Robbins HA, Pfeiffer RM, Shiels MS, et al. Excess cancers among HIV-infected people in the United States. J Natl Cancer Inst. 2015;107(4):1–8.CrossRefGoogle Scholar
  2. 2.
    Vaccher E, Spina M, Talamini R, et al. Improvement of systemic human immunodeficiency virus-related non-Hodgkin lymphoma outcome in the era of highly active antiretroviral therapy. Clin Infect Dis. 2003;37(11):1556–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Navarro JT, Vall-Llovera F, Mate JL, et al. Decrease in the frequency of meningeal involvement in AIDS-related systemic lymphoma in patients receiving HAART. Haematologica. 2008;93(1):149–50.CrossRefPubMedGoogle Scholar
  4. 4.
    Hollender A, Kvaloy S, Nome O, et al. Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. Ann Oncol. 2002;13:1099–107.CrossRefPubMedGoogle Scholar
  5. 5.
    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;9:225–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Chamberlain MC, Sandy A, Press GA, et al. Leptomeningeal metastasis: a comparison of gadolinium-enhanced MR and contrast-enhanced CT of the brain. Neurology. 1990;40:435–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Zeiser R, Burger JA, Bley TA, et al. Clinical follow-up indicates differential accuracy of magnetic resonance imaging and immunocytology of the cerebral spinal fluid for the diagnosis of neoplastic meningitis – a single centre experience. Br J Haematol. 2004;124:762–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Freilich RJ, Krol G, De Angelis LM. Neuroimaging and cerebrospinal fluid cytology in the diagnosis of leptomeningeal metastases. Ann Neurol. 1995;38:51–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Pauls S, Fischer AC, Brambs HJ, Fetscher S, Höche W, Bommer M. Use of magnetic resonance imaging to detect neoplastic meningitis: limited use in leukemia and lymphoma but convincing results in solid tumors. Eur J Radiol. 2012;81(5):974–8.CrossRefPubMedGoogle Scholar
  10. 10.
    De Angelis LM, Cairncross JG. A better way to find tumor in the CSF? Neurology. 2002;58:339–40.CrossRefGoogle Scholar
  11. 11.
    Perske C, Nagel I, Nagel H, Strik H. CSF cytology—the ongoing dilemma to distinguish neoplastic and inflammatory lymphocytes. Diagn Cytopathol. 2011;39:621–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Bromberg JE, Breems DA, Kraan J, et al. CSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies. Neurology. 2007;68(20):1674–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Quijano S, López A, Manuel Sancho J, et al. Identification of leptomeningeal disease in aggressive B-cell non-Hodgkin’s lymphoma: improved sensitivity of flow cytometry. J Clin Oncol. 2009;27(9):1462–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Hegde U, Filie A, Little RF, et al. High incidence of occult leptomeningeal 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(2):496–502.CrossRefPubMedGoogle Scholar
  15. 15.
    Sancho JM, Orfao A, Quijano S, et al. Clinical significance of occult cerebrospinal fluid involvement assessed by flow cytometry in non-Hodgkin’s lymphoma patients at high risk of central nervous system disease in the rituximab era. Eur J Haematol. 2010;85(4):321–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Benevolo G, Stacchini A, Spina M, et al. Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination. Blood. 2012;120(16):3222–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Wilson WH, Bromberg JE, Stetler-Stevenson M, et al. Detection and outcome of occult leptomeningeal disease in diffuse large B-cell lymphoma and Burkitt lymphoma. Haematologica. 2014;99(7):1228–35.PubMedCentralCrossRefPubMedGoogle Scholar
  18. 18.
    Moriarty AT, Wiersema L, Snyder W, et al. Immunophenotyping of cytologic specimens by flow cytometry. Diagn Cytopathol. 1993;9:252–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Craig FE, Ohori NP, Gorrill TS, et al. Flow cytometric immunophenotyping of cerebrospinal fluid specimens. Am J Clin Pathol. 2011;135(1):22–34.CrossRefPubMedGoogle Scholar
  20. 20.
    Sayed D, Badrawy H, Ali AM, et al. Immunophenotyping and immunoglobulin heavy chain gene rearrangement analysis in cerebrospinal fluid of pediatric patients with acute lymphoblastic leukemia. Leuk Res. 2009;33:655–61.CrossRefPubMedGoogle Scholar
  21. 21.
    de Haas V, Vet RJWM, Verhagen OJHM, et al. Early detection of central nervous system relapse by polymerase chain reaction in children with B-precursor acute lymphoblastic leukemia. Ann Hematol. 2002;81:59–61.CrossRefPubMedGoogle Scholar
  22. 22.
    Ekstein D, Ben-Yehuda D, Slyusarevsky E, et al. CSF analysis of IgH gene rearrangement in CNS lymphoma: relationship to the disease course. J Neurol Sci. 2006;247:39–46.CrossRefPubMedGoogle Scholar
  23. 23.
    Chamberlain MC. Neoplastic, meningitis. Neurologist. 2006;12(4):179–87.CrossRefPubMedGoogle Scholar
  24. 24.
    Ernerudh J, Olsson T, Berlin G, et al. Cell surface markers for diagnosis of central nervous system involvement in lymphoproliferative disease. Ann Neurol. 1986;20:610–5.CrossRefPubMedGoogle Scholar
  25. 25.
    Mavligit GM, Stuckey SE, Cabanillas FF, et al. Diagnosis of leukemia or lymphoma in the central nervous system by Beta-2-microglobulin determination. N Engl J Med. 1980;303:718–22.CrossRefGoogle Scholar
  26. 26.
    Rajantie J, Koskiniemia M, Siimes MA, et al. CSF fibronectin in Burkitt’s lymphoma: an early marker for CNS involvement. Eur J Haematol. 1989;42:313–4.CrossRefPubMedGoogle Scholar
  27. 27.
    Weller M, Stevens A, Sommer N, et al. Comparative analysis of cytokine patterns in immunological, infectious and oncological neurological disorders. J Neurol Sci. 1991;104:215–21.CrossRefPubMedGoogle Scholar
  28. 28.
    Ernerudh J, Olsson T, Berlin G, et al. Cerebrospinal fluid immunoglobulins and Beta-2-microglobulin in lymphoproliferative and other neoplastic disease of the central nervous system. Arch Neurol. 1987;44:915–20.CrossRefPubMedGoogle Scholar
  29. 29.
    Weller M, Stevens A, Sommer N, Schabet M, Wiethölter H, Humoral CSF. Parameters in the differential diagnosis of hematologic CNS neoplasia. Acta Neurol Scand. 1992;86:129–33.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(1):129–33.CrossRefPubMedGoogle Scholar
  31. 31.
    Villa D, Connors JM, Shenkier TN, et al. Incidence and risk factors for central nervous system relapse in patients with diffuse large B-cell lymphoma: the impact of the addition of rituximab to CHOP chemotherapy. Ann Oncol. 2010;21(5):1046–52.CrossRefPubMedGoogle Scholar
  32. 32.
    Boehme V, Schmitz N, Zeynalova S, et al. CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Blood. 2009;113(17):3896–902.CrossRefPubMedGoogle Scholar
  33. 33.
    Schmitz N, Zeynalova S, Glass B, et al. CNS disease in younger patients with aggressive B-cell lymphoma: an analysis of patients treated on the Mabthera International Trial and trials of the German High-Grade Non-Hodgkin Lymphoma Study Group. Ann Oncol. 2012;23:1267–73.CrossRefPubMedGoogle Scholar
  34. 34.
    Shimazu Y, Notohara K, Ueda Y. Diffuse large B-cell lymphoma with central nervous system relapse: prognosis and risk factors according to retrospective analysis from a single-center experience. Int J Hematol. 2009;89(5):577–83.CrossRefPubMedGoogle Scholar
  35. 35.
    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;14:925–34.PubMedGoogle Scholar
  36. 36.
    Bernstein JI, Coleman CN, Strickler JG, et al. Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt’s and non-Burkitt’s types). J Clin Oncol. 1986;4:847–58.PubMedGoogle Scholar
  37. 37.
    Kaplan LD, Straus DJ, Testa MA, et al. Low-dose compared with standard-dose m-BACOD chemotherapy for non-Hodgkin’s lymphoma associated with human immunodeficiency virus infection. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997;336:1641–8.CrossRefPubMedGoogle Scholar
  38. 38.
    Sparano JA, Wiernik PH, Strack M, et al. Infusional cyclophosphamide, doxorubicin, and etoposide in human immunodeficiency virus- and human T-cell leukemia virus type I-related non-Hodgkin’s lymphoma: a highly active regimen. Blood. 1993;81(10):2810–5.PubMedGoogle Scholar
  39. 39.
    Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy suspension and tumor biology. Blood. 2003;101:4653–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Spina M, Jaeger U, Sparano JA, et al. Rituximab plus infusional cyclophosphamide, doxorubicin, and etoposide (RCDE) in HIV-associated non-Hodgkin’s lymphoma: pooled results from 3 phase II trials. Blood. 2005;105:1891–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Kaplan LD, Lee JY, Ambider RF, et al. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010. Blood. 2005;106(5):1538–43.PubMedCentralCrossRefPubMedGoogle Scholar
  42. 42.
    Mounier N, Spina M, Gabarre J, et al. AIDS-related non-Hodgkin lymphoma: final analysis of 485 patients treated with risk-adapted intensive chemotherapy. Blood. 2006;107:3832–40.CrossRefPubMedGoogle Scholar
  43. 43.
    Dunleavy K, Little RF, Pittaluga S, et al. The role of tumor histogenesis, FDG-PET, and short-course EPOCH with dose-dense rituximab (SC-EPOCH-RR) in HIV-associated diffuse large B-cell lymphoma. Blood. 2010;115(15):3017–24.PubMedCentralCrossRefPubMedGoogle Scholar
  44. 44.
    Spina M, Chimienti E, Martellotta F, et al. Phase 2 study of intrathecal, long-acting liposomal cytarabine in the prophylaxis of lymphomatous meningitis in human immunodeficiency virus-related non-Hodgkin lymphoma. Cancer. 2010;116:1495–501.CrossRefPubMedGoogle Scholar
  45. 45.
    Mazhar D, Stebbing J, Lewis R, et al. The management of meningeal lymphoma in patients with HIV in the era of HAART: intrathecal depot cytarabine is effective and safe. Blood. 2006;107:3412–4.CrossRefPubMedGoogle Scholar
  46. 46.
    Garcia-Marco JA, Panizo C, Garcia ES, et al. Efficacy and safety of liposomal cytarabine in lymphoma patients with central nervous system involvement from lymphoma. Cancer. 2009;115(9):1892–8.CrossRefPubMedGoogle Scholar
  47. 47.
    Tilly H, Lepage E, Coiffier B, et al. Intensive conventional chemotherapy (ACVBP regimen) compared with standard CHOP for poor-prognosis aggressive non-Hodgkin lymphoma. Blood. 2003;102(13):4284–9.CrossRefPubMedGoogle Scholar
  48. 48.
    Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010;116:4283–90.CrossRefPubMedGoogle Scholar
  49. 49.
    Siegal T, Zylber-Katz E. Strategies for increasing drug delivery to the brain: focus on brain lymphoma. Clin Pharmacokinet. 2002;41:171–86.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Division of Medical Oncology ANational Cancer InstituteAvianoItaly

Personalised recommendations