AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Background

HIV-associated CNS lymphoma is a diffuse, large-cell non-Hodgkin lymphoma that usually occurs in the brain (rarely in the spinal cord) and causes focal neurologic signs and mental status changes. It is a late complication of HIV infection.

Pathophysiology

HIV-associated CNS lymphoma is typically of B-cell origin. Almost 100% of affected patients exhibit evidence of Epstein-Barr virus (EBV) in the lymphomatous lesions and the cerebrospinal fluid (CSF). EBV transformation of chronically activated B cells is probably responsible for lymphoma development. Development of this opportunistic neoplasm is associated with CD4⁺ lymphocyte counts less than 100 cells/mm³.

Frequency

United States

HIV-associated CNS lymphoma is the second most common mass lesion (after toxoplasmosis) in patients with AIDS and occurs 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 occurred in the post–highly active antiretroviral therapy (HAART) era.

International

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).¹

Mortality/Morbidity

The prognosis of HIV-associated CNS lymphoma has improved with the advent of HAART.

• In the pre-HAART era, median survival was poor with death occurring a few weeks after diagnosis.


• In the post-HAART era, the 2-year survival increased to 29%.²


• In another study, 6 of 7 HAART-treated patients were alive at a median follow-up of 667 days.³

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

History

• The onset of CNS lymphoma is often more insidious than that of toxoplasmosis.
• Presenting symptoms may include lethargy, confusion, impaired memory, headache, seizures, or focal weakness.
• Fever is usually absent.

Physical

• Lethargy, confusion, impaired memory, and focal neurologic signs may be noted on physical examination.
• Funduscopy may reveal ocular involvement.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Other Problems to be Considered

CNS toxoplasmosis is the most important differential. A solitary mass is usually primary CNS lymphoma.
Brainstem syndromes
Myelopathy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Lab Studies

• Serology - CD4⁺ cell count (usually <100)
• CSF - Pleocytosis, elevated protein, and cytologic results positive for monoclonal malignant-appearing lymphocytes
• PCR amplification of EBV DNA in CSF corroborates the diagnosis of primary CNS lymphoma.

Imaging Studies

• CT scan of the brain
• • A hypodense or hyperdense lesion that enhances in a nodular, homogeneous, or ringlike pattern may be observed.
  • Significant edema and mass effect may be present.
  • Multiple lesions can occur, although less frequently than with toxoplasmosis.

• MRI may reveal additional lesions.
• Thallium 201 single photon emission computed tomography (201Tl SPECT)
• • Increased 201Tl uptake co-localizing with the lesion on MRI is highly specific for primary CNS lymphoma.

  • Tumor size of at least 2 cm increases the diagnostic yield.
  • Positive results need to be confirmed by biopsy of the identified lesion.

• 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) has a predictive value similar to that of SPECT.
• Chest radiography and an abdominal ultrasonography may be indicated to rule out systemic lymphoma as the underlying cause.

Procedures

• Definitive diagnosis requires stereotactic brain biopsy, usually after a therapeutic trial for cerebral toxoplasmosis.

Histologic Findings

Histologic findings vary and comprise a small, noncleaved type and a large, immunoblastic type.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Medical Care

No consensus exists on treatment. Few studies have addressed the management of HIV-associated CNS lymphoma, and most algorithms were formulated based on protocols in immunocompetent individuals.

• HAART and cranial radiation increase survival.
  
  
  • Adult dose is fractionated 4000-5000 cGy. This results in clinical improvement and radiographic regression of the lesions.
  
  
  • Based on the consistent association of EBV with HIV-associated CNS lymphoma, antiviral and immunomodulatory treatment are being tried.
  
  
  • Treatment with ganciclovir was associated with increased survival and undetectable CSF EBV DNA load.⁴
  
  
  • In a prospective study using high-dose ganciclovir and IL-2, 1 of 4 patients had complete remission.⁵
  
  
  • The CNS is a sanctuary site for lymphoma and can be a barrier to cure. CNS prophylaxis is recommended for all patients with HIV-associated lymphoma, even those without current clinical CNS involvement.
  
  
  • Little data exist to support the use of steroids.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

HAART with radiation is the mainstay of treatment.

Based on the study by Bossolasco et al, ganciclovir is associated with increased survival and undetectable EBV DNA load in CSF.⁴

Anecdotal reports are known of responses to systemic and intrathecal methotrexate (3 g/m² q14d with leucovorin rescue), thiotepa, and procarbazine. No dosage recommendations can be given at this time.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Prognosis

• Survival duration
  
  
  • 1 month without treatment
  
  
  • 2-5 months with radiotherapy, which is of benefit in more than 75%
  
  
  • 16-28 months with radiotherapy and systemic and intrathecal chemotherapy comprising methotrexate, thiotepa, and procarbazine (anecdotal reports)
  
  
  • 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.²

MULTIMEDIA

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

Media file 1:  On CT, cerebral lymphoma appears as focal lesions with nodular ring enhancement, mass effect, and surrounding edema. Common sites include the periventricular white and gray matter and cerebellum.
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Media type:  CT

Media file 2:  Light microscopic examination of primary CNS lymphoma is characterized by dense infiltrates of large lymphocytes with irregular nuclei. The tumor cells can display a prominent vasocentric pattern and infiltrate blood vessel walls. Areas of necrosis may be present. Contributed by Dr Beth Levy, Saint Louis University School of Medicine, St Louis, Missouri.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Multimedia
• References

1. 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. Feb 2005;46(2):207-15. [Medline].
2. Biggar RJ, Engels EA, Ly S. Survival after cancer diagnosis in persons with AIDS. J Acquir Immune Defic Syndr. Jul 1 2005;39(3):293-9. [Medline].
3. Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS patients with primary central nervous system lymphoma. AIDS. Aug 15 2003;17(12):1787-93. [Medline].
4. 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. Feb 15 2006;42(4):e21-5. [Medline].
5. 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. Mar 2006;6(5):399-402. [Medline].
6. AAN Quality Standards Subcommittee. Evaluation and management of intracranial mass lesions in AIDS. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. Jan 1998;50(1):21-6. [Medline].
7. de Gans J, Portegies P. Neurological complications of infection with human immunodeficiency virus type 1. A review of literature and 241 cases. Clin Neurol Neurosurg. 1989;91(3):199-219. [Medline].
8. Forsyth PA, DeAngelis LM. Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am. Oct 1996;10(5):1125-34. [Medline].
9. Gendelman HE, Lipton SA, Epstein L. The Neurology of AIDS. New York: Chapman & Hall; 1998.
10. Hoffman C. Primary CNS lymphoma. In: HIV Medicine. 2005.
11. Noy A. Update in HIV lymphoma. Curr Opin Oncol. Sep 2006;18(5):449-55. [Medline].
12. Offiah CE, Turnbull IW. The imaging appearances of intracranial CNS infections in adult HIV and AIDS patients. Clin Radiol. May 2006;61(5):393-401. [Medline].
13. Said G, Saimont AG, Lacroix C. Neurological Complications of HIV and AIDS. Philadelphia: WB Saunders; 1998.
14. Singh A, Strobos RJ, Singh BM, et al. Steroid-induced remissions in CNS lymphoma. Neurology. Nov 1982;32(11):1267-71. [Medline].

Article Last Updated: May 8, 2007