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]
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]
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]
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:
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 utilizing methotrexate, thiotepa, and procarbazine (anecdotal reports)
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]
The onset of CNS lymphoma is often more insidious than that of CNS toxoplasmosis. Presenting symptoms may include lethargy, confusion, impaired memory, headache, seizures, or focal weakness.
Lethargy, confusion, impaired memory, and focal neurologic signs may be noted on physical examination. Fever is usually absent. Funduscopy may reveal ocular involvement. Ocular involvement is seen in up to 20% of the patients, and a slit-lamp examination should be performed in these patients.
Almost 100% of affected patients exhibit evidence of Epstein-Barr virus (EBV) in the CSF and lymphomatous lesions. The development of HIV-associated CNS lymphoma is typically associated with a CD4+ lymphocyte count below 100 cells/mL. Chest radiography and an abdominal ultrasound may be indicated to rule out systemic lymphoma as the underlying cause.
CSF analysis in patients with CNS lymphoma shows pleocytosis and elevated protein. Cytologic results are positive for monoclonal malignant-appearing lymphocytes.
Amplification of EBV deoxyribonucleic acid (DNA) in CSF using the polymerase chain reaction (PCR) corroborates the diagnosis of primary CNS lymphoma. However, the declining incidence of CNS lymphoma may be diminishing the specificity of this finding.[11] Quantitative PCR may increase specificity: Corcoran et al found that using a cut-off of 10,000 EBV DNA copies/mL improved the specificity and positive predictive value when compared with a qualitative result for the diagnosis of CNS lymphoma (96% vs 66%, and 50% vs 10%, respectively).[12] The EBV DNA in the CSF has a low positive predictive value (10-50%) when used in isolation as a positive marker because elevated EBV DNA is also seen in patients with HIV without primary CNS lymphoma.
On computed tomography scans, 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. (See the image below.)
View Image
On CT scan, cerebral lymphoma appears as focal lesions with nodular ring enhancement, mass effect, and surrounding edema. Common sites include the per....
Multiple lesions can occur, although less frequently than with toxoplasmosis. Magnetic resonance imaging (MRI) may reveal additional lesions.
A thallium-201 single-photon emission computed tomography (201 TI SPECT) scan may be useful in distinguishing between lymphoma and toxoplasmosis. Increased201 Tl 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.
An 18-fluorodeoxyglucose positron emission tomography (18FDG-PET) scan study has a predictive value similar to that of201 TI SPECT.
MR spectroscopy in primary central nervous system lymphoma (PCNSL) typically shows decreased N -acetylaspartate and creatine, increased choline (suggesting a tumoral cell proliferation), and at-baseline lipid-lactate peaks reflecting necrosis, which is a common feature of PCNSL.
A systematic review and meta-analysis evaluated the diagnostic accuracy of SPECT, PET, and MRS in differentiating PCNSL from other focal brain lesions (FBLs) in HIV patients.[13] SPECT had good diagnostic accuracy in differentiating PCNSL from other FBLs in HIV patients, but the actual sensitivity and specificity may be lower than expected when only pathology and/or serology is used as the gold standard. PET may be superior but has less supporting clinical data and is more expensive.
Definitive diagnosis requires stereotactic brain biopsy, usually after a therapeutic trial for cerebral toxoplasmosis. Histologic findings in CNS lymphoma vary and consist of a small, non-cleaved type and a large, immunoblastic type. (See the image below.)
View Image
Light microscopic examination of primary CNS lymphoma is characterized by dense infiltrates of large lymphocytes with irregular nuclei. The tumor cell....
No consensus exists on treatment due to the reduction in incidence. Consequently, there is no consensus and only anecdotal evidence on the best treatment. Few studies have addressed the management of HIV-associated CNS lymphoma, and most algorithms were formulated on the basis of protocols in immunocompetent individuals. Current options include high-dose methotrexate (HD-MTX), radiotherapy, or antivirals such as ganciclovir.
A retrospective, single-center analysis found that combined short-term HD-MTX monochemotherapy and optimal combination antiretroviral therapy (cART) simply and effectively treat AIDS-related primary central nervous system lymphoma (AR-PCNSL), achieving long-term survival with few relapses.[14]
Prior studies assessing the role of radiation illustrated an average survival of less than 6 months. However, a Japanese study analyzed the outcomes in patients receiving a curative intent radiation dose (30 Gy or higher) of whole-brain radiation therapy achieved prolonged survival while maintaining a good quality of life.[15] Performance status was a significant prognostic indicator: the estimated 3-year overall survival rates of patients with a good and poor performance status were 100% and 38%, respectively.
Survival can be prolonged greatly if a combination of radiation therapy and chemotherapy is used. Few data exist to support the use of steroids.
Based on the consistent association of HIV-associated PCNSL with Epstein-Barr virus (EBV), antiviral and immunomodulatory treatments are being tried. Treatment with ganciclovir has been associated with increased survival and undetectable CSF EBV DNA load.[16] In a prospective study using high-dose ganciclovir and interleukin-2 (IL-2), 3 patients died but 1 had complete remission.[17] There are anecdotal reports of responses to systemic and intrathecal methotrexate (3 g/m2 q14d with leucovorin rescue), thiotepa, and procarbazine.
The CNS is a sanctuary site for lymphoma and can be a barrier to cure. CNS prophylaxis with cHAART is recommended for all patients with HIV-associated lymphoma, even those without current clinical CNS involvement.
Palliative care can address typical symptoms such as fatigue, nausea, and headaches that have the potential to severely disable patients with brain tumors. Advance care planning should be introduced proactively and early in the disease trajectory to ensure a dignified death and improved caregiver bereavement.
Highly active antiretroviral therapy (HAART) with radiation therapy is the mainstay of treatment. Preliminary evidence supports the use of ganciclovir. No dosage recommendations can be given at this time.
Clinical Context:
Ganciclovir is an acyclic nucleoside analogue of 2'deoxyguanasine. It phosphorylates first to the monophosphate form by a cytomegalovirus (CMV)–encoded protein kinase homologue, then to diphosphate and triphosphate forms by cellular kinases, allowing for a 100-fold greater concentration of ganciclovir in CMV-infected cells, possibly due to preferential phosphorylation of ganciclovir in virus-infected cells. It is thought to inhibit CMV replication by competitive inhibition of viral DNA polymerases and by incorporating itself into viral DNA, causing termination of viral DNA elongation. Like acyclovir, ganciclovir is virostatic and only exerts its effect on replicating virus.
These agents inhibit the synthesis of viral DNA. This therapeutic approach is mostly used in the experimental setting.
It is generally believed that EBV-associated lymphomas express only latent proteins, thus rendering antiviral treatments ineffective. Several researchers have tried ganciclovir, the combination of ganciclovir/zidovudine and interleukin 2, and hydroxyurea with variable results, suggesting that EBV-targeted therapy may be beneficial; however, the evidence at this stage is still poor.
What is HIV-associated primary central nervous system lymphoma (PCNSL)?What is the pathogenesis of HIV-associated primary central nervous system lymphoma (PCNSL)?What is the prevalence of HIV-associated primary central nervous system lymphoma (PCNSL) in the US?What is the global prevalence of HIV-associated primary central nervous system lymphoma (PCNSL)?What is the prognosis of HIV-associated primary central nervous system lymphoma (PCNSL)?Which clinical history findings are characteristic of HIV-associated primary central nervous system lymphoma (PCNSL)?Which physical findings are characteristic of HIV-associated primary central nervous system lymphoma (PCNSL)?Which conditions are included in the differential diagnoses of HIV-associated primary central nervous system lymphoma (PCNSL)?What are the differential diagnoses for Central Nervous System Lymphoma in HIV?Which studies are performed in the workup of HIV-associated primary central nervous system lymphoma (PCNSL)?What is the role of CSF analysis in the workup of HIV-associated primary central nervous system lymphoma (PCNSL)?What is the role of brain imaging in the workup of HIV-associated primary central nervous system lymphoma (PCNSL)?What is the role of brain biopsy in the workup of HIV-associated primary central nervous system lymphoma (PCNSL)?How is HIV-associated primary central nervous system lymphoma (PCNSL) treated?What is included in palliative care for HIV-associated primary central nervous system lymphoma (PCNSL)?What is the role of medications in HIV-associated primary central nervous system lymphoma (PCNSL) treatment?Which medications in the drug class Antivirals are used in the treatment of Central Nervous System Lymphoma in HIV?
Florian P Thomas, MD, PhD, MA, MS, Chair, Neuroscience Institute and Department of Neurology, Director, National MS Society Multiple Sclerosis Center and Hereditary Neuropathy Foundation Center of Excellence, Hackensack University Medical Center; Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Professor Emeritus, Department of Neurology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Krupa Pandey, MD, Assistant Professor of Neurology, Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Neurologist in Multiple Sclerosis, Neuroscience Institute at Hackensack University Medical Center; Adjunct Professor of Neurology, Multiple Sclerosis Comprehensive Care Center, NYU Langone School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Biogen; Sanofi-Genzyme; Teva; Serono; Genentech<br/>Serve(d) as a speaker or a member of a speakers bureau for: Biogen; Sanofi-Genzyme; Teva; Genentech.
Specialty Editors
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.
Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital
Disclosure: Nothing to disclose.
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
On CT scan, 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.
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.
On CT scan, 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.
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.
){kind=link}
){kind=link}