AIDS-related lymphomas: Primary central nervous system lymphoma
- Lawrence D Kaplan, MD
Lawrence D Kaplan, MD
- Clinical Professor of Medicine
- University of California, San Francisco
- James L Rubenstein, MD, PhD
James L Rubenstein, MD, PhD
- Professor of Medicine, Division of Hematology/Oncology
- University of California, San Francisco
Infection with human immunodeficiency virus (HIV) predisposes individuals to the development of neoplasms. There are currently four acquired immune deficiency syndrome (AIDS)-defining malignancies: Kaposi's sarcoma, non-Hodgkin lymphoma (NHL) of high-grade pathologic type and of B cell or unknown immunologic phenotype, primary central nervous system lymphoma (PCL), and invasive cervical carcinoma. AIDS-related NHL is generally divided into three types: systemic NHL, PCL, and the primary effusion ("body cavity") lymphomas [1,2]. More unusual types, such as plasmablastic lymphoma, also occur. These disorders are primarily encountered in patients with more advanced HIV infection, with a CD4 count that is usually below 100/microL . (See "AIDS-related lymphomas: Epidemiology, risk factors, and pathobiology" and "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Epidemiology'.)
The major issues relating to AIDS-related PCL will be reviewed here. Reviews of the diagnosis and treatment of PCL not associated with HIV infection are presented separately. Although central nervous system (CNS) involvement also occurs in AIDS-related systemic lymphoma in the form of secondary spread of the tumor to the meninges, the disease is limited to the CNS in PCL. Evaluation of the CNS in patients with AIDS-related systemic lymphoma is discussed separately. (See "Clinical presentation, pathologic features, and diagnosis of primary central nervous system lymphoma" and "Treatment and prognosis of primary central nervous system lymphoma" and "AIDS-related lymphomas: Clinical manifestations, diagnosis, and staging of systemic lymphoma".)
The pathogenesis of PCL is strongly related to Epstein-Barr virus infection. This is described in more detail separately. (See "AIDS-related lymphomas: Epidemiology, risk factors, and pathobiology", section on 'Pathobiology'.)
PCL accounts for up to 15 percent of non-Hodgkin lymphomas (NHLs) in human immunodeficiency virus (HIV)-infected patients compared with only 1 percent of NHLs in the general population . The most common histology is diffuse large B cell lymphoma (immunoblastic variant) .
The reported incidence of PCL in HIV-infected patients is 2 to 6 percent (at least 1000 times higher than in the general population)  and has been as high as 10 percent in autopsy series . Risk factors for NHL in HIV-infected patients include low CD4 count, high HIV viral load, and chronic co-infection with hepatitis B and hepatitis C virus in patients receiving antiretroviral therapy. (See "AIDS-related lymphomas: Epidemiology, risk factors, and pathobiology".)
- Sandler AS, Kaplan LD. Diagnosis and management of systemic non-Hodgkin's lymphoma in HIV disease. Hematol Oncol Clin North Am 1996; 10:1111.
- Coté TR, Biggar RJ, Rosenberg PS, et al. Non-Hodgkin's lymphoma among people with AIDS: incidence, presentation and public health burden. AIDS/Cancer Study Group. Int J Cancer 1997; 73:645.
- Pluda JM, Yarchoan R, Jaffe ES, et al. Development of non-Hodgkin lymphoma in a cohort of patients with severe human immunodeficiency virus (HIV) infection on long-term antiretroviral therapy. Ann Intern Med 1990; 113:276.
- 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.
- Flinn IW, Ambinder RF. AIDS primary central nervous system lymphoma. Curr Opin Oncol 1996; 8:373.
- MacMahon EM, Glass JD, Hayward SD, et al. Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 1991; 338:969.
- Forsyth PA, DeAngelis LM. Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am 1996; 10:1125.
- DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient. Semin Oncol 1998; 25:492.
- Fine HA, Mayer RJ. Primary central nervous system lymphoma. Ann Intern Med 1993; 119:1093.
- Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol 1999; 26:346.
- Baumgartner JE, Rachlin JR, Beckstead JH, et al. Primary central nervous system lymphomas: natural history and response to radiation therapy in 55 patients with acquired immunodeficiency syndrome. J Neurosurg 1990; 73:206.
- Beral V, Peterman T, Berkelman R, Jaffe H. AIDS-associated non-Hodgkin lymphoma. Lancet 1991; 337:805.
- Biggar RJ, Burnett W, Mikl J, Nasca P. Cancer among New York men at risk of acquired immunodeficiency syndrome. Int J Cancer 1989; 43:979.
- Coté TR, Manns A, Hardy CR, et al. Epidemiology of brain lymphoma among people with or without acquired immunodeficiency syndrome. AIDS/Cancer Study Group. J Natl Cancer Inst 1996; 88:675.
- Skolasky RL, Dal Pan GJ, Olivi A, et al. HIV-associated primary CNS lymorbidity and utility of brain biopsy. J Neurol Sci 1999; 163:32.
- Johnson BA, Fram EK, Johnson PC, Jacobowitz R. The variable MR appearance of primary lymphoma of the central nervous system: comparison with histopathologic features. AJNR Am J Neuroradiol 1997; 18:563.
- Antinori A, Ammassari A, De Luca A, et al. Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 1997; 48:687.
- Thurnher MM, Thurnher SA, Schindler E. CNS involvement in AIDS: spectrum of CT and MR findings. Eur Radiol 1997; 7:1091.
- Jenkins CN, Colquhoun IR. Characterization of primary intracranial lymphoma by computed tomography: an analysis of 36 cases and a review of the literature with particular reference to calcification haemorrhage and cyst formation. Clin Radiol 1998; 53:428.
- D'Amico A, Messa C, Castagna A, et al. Diagnostic accuracy and predictive value of 201T1 SPET for the differential diagnosis of cerebral lesions in AIDS patients. Nucl Med Commun 1997; 18:741.
- Naddaf SY, Akisik MF, Aziz M, et al. Comparison between 201Tl-chloride and 99Tc(m)-sestamibi SPET brain imaging for differentiating intracranial lymphoma from non-malignant lesions in AIDS patients. Nucl Med Commun 1998; 19:47.
- Lorberboym M, Wallach F, Estok L, et al. Thallium-201 retention in focal intracranial lesions for differential diagnosis of primary lymphoma and nonmalignant lesions in AIDS patients. J Nucl Med 1998; 39:1366.
- Kessler LS, Ruiz A, Donovan Post MJ, et al. Thallium-201 brain SPECT of lymphoma in AIDS patients: pitfalls and technique optimization. AJNR Am J Neuroradiol 1998; 19:1105.
- Antinori A, De Rossi G, Ammassari A, et al. Value of combined approach with thallium-201 single-photon emission computed tomography and Epstein-Barr virus DNA polymerase chain reaction in CSF for the diagnosis of AIDS-related primary CNS lymphoma. J Clin Oncol 1999; 17:554.
- 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.
- Mathews C, Barba D, Fullerton SC. Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis. AIDS 1995; 9:1243.
- Chappell ET, Guthrie BL, Orenstein J. The role of stereotactic biopsy in the management of HIV-related focal brain lesions. Neurosurgery 1992; 30:825.
- Blumenthal DT, Raizer JJ, Rosenblum MK, et al. Primary intracranial neoplasms in patients with HIV. Neurology 1999; 52:1648.
- Ammassari A, Scoppettuolo G, Murri R, et al. Changing disease patterns in focal brain lesion-causing disorders in AIDS. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 18:365.
- Gasser O, Bihl FK, Wolbers M, et al. HIV patients developing primary CNS lymphoma lack EBV-specific CD4+ T cell function irrespective of absolute CD4+ T cell counts. PLoS Med 2007; 4:e96.
- Cingolani A, De Luca A, Larocca LM, et al. Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 1998; 90:364.
- Cinque P, Brytting M, Vago L, et al. Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 1993; 342:398.
- Plebani A, Pinzani R, Vago L, et al. Epstein-Barr virus DNA in the cerebrospinal fluid of an HIV patient with primary cerebral lymphoma. Eur J Pediatr 1998; 157:291.
- Yarchoan R, Jaffe ES, Little R. Diagnosing central nervous system lymphoma in the setting of AIDS: a step forward. J Natl Cancer Inst 1998; 90:346.
- Ivers LC, Kim AY, Sax PE. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis 2004; 38:1629.
- Chaudhari VV, Yim CM, Hathout H, et al. Atypical imaging appearance of toxoplasmosis in an HIV patient as a butterfly lesion. J Magn Reson Imaging 2009; 30:873.
- Corcoran C, Rebe K, van der Plas H, et al. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol 2008; 42:433.
- Corn BW, Trock BJ, Curran WJ Jr. Management of primary central nervous system lymphoma for the patient with acquired immunodeficiency syndrome. Confronting a clinical catch-22. Cancer 1995; 76:163.
- McNeil C. Evidence mounts that Epstein-Barr test may help diagnose AIDS brain lymphoma. J Natl Cancer Inst 1998; 90:355.
- Antinori A, Cingolani A, De Luca A, et al. Epstein-Barr virus in monitoring the response to therapy of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. Ann Neurol 1999; 45:259.
- d'Arminio Monforte A, Cinque P, Vago L, et al. A comparison of brain biopsy and CSF-PCR in the diagnosis of CNS lesions in AIDS patients. J Neurol 1997; 244:35.
- Bossolasco S, Nilsson A, de Milito A, et al. Soluble CD23 in cerebrospinal fluid: a marker of AIDS-related non-Hodgkin's lymphoma in the brain. AIDS 2001; 15:1109.
- Pilozzi E, Talerico C, Uccini S, et al. B cell clonality in multiple localizations of primary central nervous system lymphomas in AIDS patients. Leuk Lymphoma 2003; 44:963.
- Jacomet C, Girard PM, Lebrette MG, et al. Intravenous methotrexate for primary central nervous system non-Hodgkin's lymphoma in AIDS. AIDS 1997; 11:1725.
- Newell ME, Hoy JF, Cooper SG, et al. Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 2004; 100:2627.
- Hoffmann C, Tabrizian S, Wolf E, et al. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 2001; 15:2119.
- Sparano JA, Lee JY, Kaplan LD, et al. Rituximab plus concurrent infusional EPOCH chemotherapy is highly effective in HIV-associated B-cell non-Hodgkin lymphoma. Blood 2010; 115:3008.
- Rubenstein JL, Hsi ED, Johnson JL, et al. Intensive chemotherapy and immunotherapy in patients with newly diagnosed primary CNS lymphoma: CALGB 50202 (Alliance 50202). J Clin Oncol 2013; 31:3061.
- Forsyth PA, Yahalom J, DeAngelis LM. Combined-modality therapy in the treatment of primary central nervous system lymphoma in AIDS. Neurology 1994; 44:1473.
- Gupta NK, Nolan A, Omuro A, et al. Long-term survival in AIDS-related primary central nervous system lymphoma. Neuro Oncol 2017; 19:99.
- Shah GD, Yahalom J, Correa DD, et al. Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma. J Clin Oncol 2007; 25:4730.
- Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS 2003; 17:1787.
- Bayraktar S, Bayraktar UD, Ramos JC, et al. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol 2011; 101:257.
- Pajonk F, McBride WH. Survival of AIDS patients with primary central nervous system lymphoma may be improved by the radiosensitizing effects of highly active antiretroviral therapy. AIDS 2002; 16:1195.
- Travi G, Ferreri AJ, Cinque P, et al. Long-term remission of HIV-associated primary CNS lymphoma achieved with highly active antiretroviral therapy alone. J Clin Oncol 2012; 30:e119.
- Maggiorella L, Wen B, Frascogna V, et al. Combined radiation sensitizing and anti-angiogenic effects of ionizing radiation and the protease inhibitor ritonavir in a head and neck carcinoma model. Anticancer Res 2005; 25:4357.
- Corn BW, Donahue BR, Rosenstock JG, et al. Palliation of AIDS-related primary lymphoma of the brain: observations from a multi-institutional database. Int J Radiat Oncol Biol Phys 1997; 38:601.