Central Nervous System Lymphoma in HIV: Background, Etiology and Pathogenesis, Epidemiology (original) (raw)

Overview

Background

Human immunodeficiency virus (HIV)-associated primary central nervous system lymphoma (PCNSL) is a diffuse, large-cell non-Hodgkin lymphoma of B-cell origin that usually occurs in the brain (rarely in the spinal cord). It is a late complication of HIV infection. Epstein-Barr virus (EBV) is identified in almost all cases.

In the general population, PCNSL accounts for roughly 4% of primary brain tumors and 1% of all non-Hodgkin lymphoma. In HIV-infected individuals it is an important etiology of focal brain lesions (FBLs) with a reported incidence of 2–6%, at least 1000 times higher than that in the general population. [1]

Patients with PCNSL present with lethargy, headache, focal neurologic symptoms and signs, and mental status changes (see Clinical).

On CT scan or MRI, lesions are more often single than multiple and enhance with contrast. A biopsy often is required to differentiate toxoplasmosis and progressive multifocal leukoencephalopathy (PML) lesions from lymphoma (see Workup).

The prognosis is better if both chemotherapy and radiation therapy are administered. The likelihood of a diagnosis of PCNSL increases in _Toxoplasma_-seronegative patients with a mass effect on imaging studies if EBV DNA was detected in the CSF. Steroid therapy should be avoided whenever possible until a diagnosis has been established, as rapid necrosis of lesions may occur before biopsy. [2]

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Etiology and Pathogenesis

HIV-associated primary central nervous system lymphoma (PCNSL) is typically of B-cell origin. Almost 100% of affected patients have evidence of EBV in the lymphomatous lesions and the CSF, where it is accompanied by impaired specific T-cell responses against EBV antigens. EBV transformation of chronically activated B cells is probably responsible for lymphoma development. The T cells in HIV-infected patients suppress the EBV-infected B cells less effectively. In addition, development of this opportunistic neoplasm is associated with CD4+ lymphocyte counts below 100 cells/µL. [3]

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Epidemiology

United States statistics

Primary central nervous system lymphoma (PCNSL) is the second-most common mass lesion (after toxoplasmosis) in patients with acquired immunodeficiency syndrome (AIDS), occurring in up to 5% of these patients. In up to 0.6% of patients, it is the presenting feature of AIDS. A definite decline in the incidence of HIV-associated CNS lymphoma has occurred since the adoption of highly active antiretroviral therapy (HAART).

International statistics

In a retrospective analysis at a German center, the incidence of primary CNS lymphoma peaked at 5.33 per 1000 person-years from 1991-1994 (pre-HAART) and then declined to 0.32 per 1000 person-years after 1999 (post-HAART). [4]

A study of a Norwegian cancer registry (1989–2003) indicated that patients with AIDS in Norway had a 5.5% lifetime risk of developing primary CNS lymphoma. [5]

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Prognosis

The prognosis in patients with HIV-associated CNS lymphoma has improved with the advent of HAART. [6, 7] In the pre-HAART era, median survival was poor, with death occurring a few weeks after diagnosis.

Survival duration is as follows:

Methotrexate may be combined with rituximab for increased efficacy. Temozolomide may also be used in those patients who do well with the treatment.

Use of HAART leads to an increase in CD4+ T cells and increases survival to more than 18 months. Some previous reports suggested that EBV-DNA levels in CSF are inversely associated with survival in HIV-related primary CNS lymphoma. [8]

Use of HAART leads to an increase in CD4+ T cells and increases survival to more than 18 months.

In a retrospective analysis by Biggar et al, 29% of patients with HIV-associated CNS lymphoma survived more than 24 months. [9]

In another study, 6 of 7 HAART-treated patients were alive at a median follow-up of 667 days. [10]

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  1. Ekenel M, Deangelis LM. Treatment of primary central nervous system lymphoma. Curr Treat Options Neurol. 2007 Jul. 9 (4):271-82. [QxMD MEDLINE Link].
  2. Maher EA, Fine HA. Primary CNS lymphoma. Semin Oncol. 1999 Jun. 26(3):346-56. [QxMD MEDLINE Link].
  3. 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 Mar 27. 4(3):e96. [QxMD MEDLINE Link]. [Full Text].
  4. Wolf T, Brodt HR, Fichtlscherer S. Changing incidence and prognostic factors of survival in AIDS-related non-Hodgkin's lymphoma in the era of highly active antiretroviral therapy (HAART). Leuk Lymphoma. 2005 Feb. 46(2):207-15. [QxMD MEDLINE Link].
  5. Haldorsen IS, Krakenes J, Goplen AK, Dunlop O, Mella O, Espeland A. AIDS-related primary central nervous system lymphoma: a Norwegian national survey 1989-2003. BMC Cancer. 2008 Aug 6. 8:225. [QxMD MEDLINE Link]. [Full Text].
  6. Bayraktar S, Bayraktar UD, Ramos JC, Stefanovic A, Lossos IS. Primary CNS lymphoma in HIV positive and negative patients: comparison of clinical characteristics, outcome and prognostic factors. J Neurooncol. 2011 Jan. 101 (2):257-65. [QxMD MEDLINE Link].
  7. Matinella A, Lanzafame M, Bonometti MA, Gajofatto A, Concia E, Vento S, et al. Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study. J Neurol. 2015 May. 262 (5):1317-27. [QxMD MEDLINE Link].
  8. Bossolasco S, Falk KI, Ponzoni M, et al. Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2006 Feb 15. 42(4):e21-5. [QxMD MEDLINE Link].
  9. Biggar RJ, Engels EA, Ly S. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr. 2005 Jul 1. 39(3):293-9. [QxMD MEDLINE Link].
  10. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS. 2003 Aug 15. 17(12):1787-93. [QxMD MEDLINE Link].
  11. Ambinder RF, Bhatia K, Martinez-Maza O, Mitsuyasu R. Cancer biomarkers in HIV patients. Curr Opin HIV AIDS. 2010 Nov. 5(6):531-7. [QxMD MEDLINE Link]. [Full Text].
  12. Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR. 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 Aug. 42(4):433-6. [QxMD MEDLINE Link].
  13. Yang M, Sun J, Bai HX, Tao Y, Tang X, States LJ, et al. Diagnostic accuracy of SPECT, PET, and MRS for primary central nervous system lymphoma in HIV patients: A systematic review and meta-analysis. Medicine (Baltimore). 2017 May. 96 (19):e6676. [QxMD MEDLINE Link].
  14. Moulignier A, Lamirel C, Picard H, Lebrette MG, Amiel C, Hamidi M, et al. Long-term AIDS-related PCNSL outcomes with HD-MTX and combined antiretroviral therapy. Neurology. 2017 Aug 22. 89 (8):796-804. [QxMD MEDLINE Link].
  15. Nagai H, Odawara T, Ajisawa A, Tanuma J, Hagiwara S, Watanabe T, et al. Whole brain radiation alone produces favourable outcomes for AIDS-related primary central nervous system lymphoma in the HAART era. Eur J Haematol. 2010 Jun. 84(6):499-505. [QxMD MEDLINE Link].
  16. Bossolasco S, Falk KI, Ponzoni M. Ganciclovir is associated with low or undetectable Epstein-Barr virus DNA load in cerebrospinal fluid of patients with HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2006 Feb 15. 42(4):e21-5. [QxMD MEDLINE Link].
  17. Aboulafia DM, Ratner L, Miles SA. Antiviral and immunomodulatory treatment for AIDS-related primary central nervous system lymphoma: AIDS Malignancies Consortium pilot study 019. Clin Lymphoma Myeloma. 2006 Mar. 6(5):399-402. [QxMD MEDLINE Link].

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Author

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Hereditary Neuropathy Center, Co-Director, Center for Memory Loss and Brain Health, Co-Director, ALS Center, Hackensack University Medical Center; Associate Dean of Faculty, Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Coauthor(s)

Krupa Pandey, MD Associate Professor of Neurology, Department of Neurology, Hackensack Meridian School of Medicine; Neurologist in Multiple Sclerosis, Director of the Clinical Research Division, Director of MS Comprehensive Care Center, Neurosciences Institute at Hackensack University Medical Center; Adjunct Professor of Neurology, NYU Langone School of Medicine

Krupa Pandey, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Biogen; Sanofi-Genzyme
Serve(d) as a speaker or a member of a speakers bureau for: Biogen; Sanofi-Genzyme; Horizon Therapeutics; Bristol Meyers Squibb; Genentech; .

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.