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Last updated:
November 18, 2019
Years published: 2019
NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Nimish A. Mohile, MD FAAN, Associate Professor of Neurology and Oncology, University of Rochester Medical Center, for assistance in the preparation of this report.
Summary
A primary central nervous system lymphoma (PCNSL) is a type of cancer originating from immune cells known as lymphocytes (lymphoma) that develops in the brain and/or spinal cord (central nervous system; CNS). Around 1,500 patients are diagnosed each year in the United States. Older individuals and those with an impaired immune system (immunocompromised), especially those living with HIV/AIDS, are at an increased risk of developing a primary CNS lymphoma. PCNSL is an AIDS-defining illness, meaning that a HIV-positive individual with a PCNSL will be considered to have AIDS. The symptoms of PCNSL are similar to those of other brain tumors and can include arm and leg weakness, cognitive and behavioral changes, brain swelling, language deficits, and vision changes. Chemotherapy, notably with high-dose methotrexate (HD-MTX) is the main treatment modality for PCNSL and might be combined with radiation therapy in certain cases. Corticosteroids are also often used as an adjunct treatment.
The potential symptoms of primary CNS lymphoma are varied and mostly depend on the anatomical location of the tumor. Symptoms typically develop over weeks (subacute). Most patients present with focal neurological deficits such as asymmetric upper and/or lower extremity weakness or impaired movement (paresis). Many patients also develop neurocognitive deficits, especially in the case of AIDS-related PCNSL. Personality, language, and behavioral changes can also occur. Bladder and bowel dysfunction can develop and lead to incontinence. Pressure from the mass and fluid that surrounds it (edema) can lead to brain swelling and increased pressure inside the skull (intracranial pressure), which is associated with symptoms such as headaches, vomiting (emesis), and vision changes (papilledema). Seizures can occur and are more common in patients with AIDS-related PCNSL.
If specific structures within the brain (such as the pituitary gland and hypothalamus) are damaged, PCNSL can be associated with excessive eating (hyperphagia), decreased libido (hyposexuality), central diabetes insipidus, and syndrome of inappropriate antidiuretic hormone secretion (which leads to a decreased concentration of sodium in the blood, a condition known as hyponatremia). (For more information on central diabetes insipidus, choose “central diabetes insipidus” as your search term in the Rare Disease Database.)
Involvement of the brainstem, which connects the brain and the spinal cord, can lead to gait imbalance (ataxia), vertigo, impairment of eye movements (dysconjugate gaze), and intractable vomiting.
Spinal cord involvement is rare in PCNSL. When the spinal cord is compressed and damaged (myelopathy) by a mass, affected individuals can experience weakness, loss of sensation, and bladder and bowel dysfunction. Other structures that can be compromised by a primary CNS lymphoma include the coverings of the brain (meninges) and the peripheral and cranial nerves (neurolymphomatosis). The latter can lead to nerve pain and deficits specific to the function of the cranial nerve affected (for instance, face droop if the facial nerve is affected).
As primary CNS lymphomas are malignant tumors, they can spread to other sites of the body. Eye (ocular) involvement is present in 20 to 40% of patients at presentation and in almost all patients later in the course of the disease. Blurry vision and floaters are the most common visual symptoms. Systemic dissemination is rare but can notably affect the prostate, the skin, and the gastrointestinal tract. Systemic spread of a PCNSL can lead to weight loss, fever, and night sweats. Those symptoms are known as constitutional or B symptoms and are present in most patients with AIDS-related PCNSL even in the absence of systemic spread.
Primary CNS lymphoma most commonly occurs in individuals around age 60, but rare cases have also been described in children. AIDS-related PCNSL tends to develop around age 45 and is typically more aggressive. With proper treatment, primary CNS lymphoma regresses in around 85% of patients. However, relapse occurs in 50% of cases, most often within two years. The average survival after a diagnosis of PCNSL is 44 months. Overall, 30% of affected individuals survive more than five years after diagnosis, and long-term survival is achieved in 15 to 20% of patients. Age under 60 years and high level of autonomy and functioning are associated with increased survival, while HIV infection and involvement of deep regions of the brain are associated with lower survival. Elevated blood levels of lactate dehydrogenase (LDH) and elevated protein concentration in the cerebrospinal fluid, both of which are usually measured during diagnostic workup, are also associated with lower survival.
Primary CNS lymphomas most often develop from the uncontrolled proliferation of cells derived from B lymphocytes (also known as B cells), which are a type of immune cell. More rarely, PCNSL can also develop from T lymphocytes (also known as T cells), but our understanding of prognosis and therapies for PCNSL is based on patients who specifically have primary diffuse large B-cell lymphoma of the CNS. The exact mechanism by which malignant lymphocytes invade the brain is not understood yet, but two main hypotheses prevail: lymphocytes might be drawn to the CNS and then replicate and lead to a malignant tumor. Alternatively, already malignant lymphocytes might be drawn to the CNS via the expression of specific adhesion molecules that mediate traffic to the brain.
Several molecular processes are thought to be involved in the malignant transformation of cells of primary CNS lymphomas. These processes lead to uncontrolled cell proliferation and avoidance of destruction of malignant cells, notably by evasion of the immune system (which would normally destroy abnormal cells). Gain and loss of genetic material is also involved in the development of primary CNS lymphoma. The net result of these genetic changes is to allow malignant cells to escape from regulation of the immune system and to proliferate, notably via amplification of a molecular pathway known as NF-κB. Silencing of tumor suppressor genes is also one of the mechanisms by which PCNSL develops.
In addition to the malignant cells themselves, the environment in which the tumor grows might also play a role in PCNSL development. The vasculature of the brain might be involved, as PCNSL cells tend to accumulate around blood vessels. Evidence also shows that the tumor cells and surrounding cells secrete B cell surviving factors (notably interleukin-4) and promote a local inflammatory response.
A feature of primary CNS lymphoma that is mostly identified in immunocompromised individuals (such as those living with HIV/AIDS) is the presence of genetic material of the Epstein-Barr virus (EBV; which is the virus involved in most cases of infectious mononucleosis). EBV infection is thought to lead to malignancy by the excessive activation of human cell growth factors, activation of viral cell growth factors, and chronic stimulation of the immune system.
Primary central nervous system lymphoma constitutes 4% of all brain tumors and develops in around five individuals per million each year, for a total of approximately 1,500 new cases per year in the United States. PCNSL is slightly more common in males. The most common risk factor for the development of a primary CNS lymphoma is an impaired immune system (immunosuppression). This is notably the case of patients living with HIV/ AIDS, especially those who are not treated who have a high viral load and low CD4+ cell count. Other immunosuppressed groups include organ transplant recipients and individuals with congenital immunodeficiency syndromes. In fact, primary CNS lymphoma is the most common brain tumor in immunosuppressed patients. The other main risk factor for developing a PCNSL is age. Most immunocompetent patients are diagnosed around age 60, although cases of PCNSL have also been reported in children. AIDS-related PCNSL most often develop during the fifth decade of life (age 40-49).
The diagnosis of primary CNS lymphoma is complex and requires a combination of patient history, physical examination, laboratory testing, medical imaging, as well as microscopic, cellular and genetic (cytogenetic) analysis of the tumor cells.
Initially, history from the patient and a physical examination performed by a physician might identify signs and symptoms that are suggestive of a brain lesion (see “Signs & Symptoms” section for more detail). If such signs and symptoms are identified, medical imaging of the brain will be performed, notably by computed tomography (CT) scan or magnetic resonance imaging (MRI). Imaging of the spine can also be performed if the symptoms suggest spinal involvement. While medical imaging can lead to suspicion of a primary CNS lymphoma, definitive diagnosis is only possible by analysis of the cells of the tumor. A lumbar puncture, which is a procedure where a needle is placed in the spinal column of the patient to collect cerebrospinal fluid (CSF), is typically performed to look for the presence of tumor cells. Fluid from the eye (vitreous fluid) can also be collected for the same reason. If tumor cells are not identified in these fluids, a neurosurgeon will have to perform a brain biopsy to extract a piece of the lesion.
Once tumor cells are obtained, they can be analyzed in multiple ways to confirm the diagnosis of primary CNS lymphoma. Flow cytometry is a laboratory method that allows identification of cells based on their size, shape, and the presence of specific markers. Immunohistochemistry can complement microscopic analysis by staining cells based on their origin. The DNA of tumor cells can also be analyzed to identify the presence of specific alterations (mutations).
The diagnosis of primary CNS lymphoma is usually followed by an extensive workup to evaluate the severity and spread of the disease. Patients are usually tested for HIV due the association between HIV infection and PCNSL. A full eye examination with a slit lamp is performed to see if there is eye (ocular) involvement, as this can occur even in the absence of visual symptoms. The level of protein in CSF and of lactate dehydrogenase (LDH) in the blood can be measured and are markers of aggressive disease when they are elevated. The CSF can also be tested for the presence of Epstein-Barr virus, which is associated with PCNSL in immunocompromised individuals. A full body CT or PET scan, a testicular ultrasound (in male patients) and a bone marrow biopsy are also part of the diagnostic workup and are useful to determine if other organs are involved. If a patient is found to have lymphoma outside of the brain, spinal cord, spinal fluid or eyes, then they will be diagnosed with a systemic lymphoma and the brain involvement is considered a secondary CNS lymphoma.
Many other general tests are also typically performed to evaluate the baseline health of the patient and to determine the best treatment options. These tests might include blood tests to look for blood cells (complete blood count) and level of different electrolytes (biochemical serum profile), cognitive function test, renal function test, liver (hepatic) function tests, and cardiac function tests.
Treatment & Management
Unlike most other brain tumors, surgery is typically avoided in primary central nervous system lymphoma. The mainstay of treatment is based on chemotherapy, notably with high-dose methotrexate (HD-MTX). Leucovorin (folinic acid) is often added to prevent systemic and bone marrow toxicity from MTX. Depending on the patient, HD-MTX can be combined with other chemotherapeutic drugs such as alkylating agents, cytarabine, and rituximab. Chemotherapy regimens also vary depending on the center where the patient is treated, as many experimental treatments are being investigated. In certain cases, whole-brain radiation can be performed but is used with caution due to an association with increased neurocognitive deficits, especially in elderly patients. Corticosteroids such as dexamethasone can be used to decrease fluid accumulation (edema) around the tumor but are usually only administered after definitive diagnosis as they can decrease diagnostic accuracy by altering the tumor. Anticonvulsants are used for patients that develop seizures. Highly active antiretroviral therapy (HAART) should be initiated or optimized in HIV-positive patients. Treatment of Epstein-Barr virus (EBV) with ganciclovir or zidovudine might be beneficial, although this as yet to be confirmed and clinical trials are needed.
The treatment of relapsing primary CNS lymphoma is based on the characteristics of the patients and on the response of previous treatment. Whole-brain radiation can be considered in patients that have not previously received such treatment. High-dose chemotherapy can also be combined with autologous stem cell transplant, especially in younger patients. Autologous stem cell transplant is a medical procedure where healthy stem cells from a person’s own body are used to replace bone marrow cells damaged by chemotherapy.
Therapy of primary central nervous system lymphoma is a very active and constantly evolving field of medical research. Multiple molecular pathways involved in the development of primary CNS lymphoma are being targeted by medication tested in clinical trials.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Cai Q, Fang Y, Young KH. Primary Central Nervous System Lymphoma: Molecular Pathogenesis and Advances in Treatment. Transl Oncol 2019;12:523-38.
Grommes C, Rubenstein JL, DeAngelis LM, Ferreri AJM, Batchelor TT. Comprehensive approach to diagnosis and treatment of newly diagnosed primary CNS lymphoma. Neuro Oncol 2019;21:296-305.
Grommes C, Nayak L, Tun HW, Batchelor TT. Introduction of novel agents in the treatment of primary CNS lymphoma. Neuro Oncol 2019;21:306-13.
Labak CM, Holdhoff M, Bettegowda C, et al. Surgical Resection for Primary Central Nervous System Lymphoma: A Systematic Review. World Neurosurg 2019.
Brandsma D, Bromberg JEC. Primary CNS lymphoma in HIV infection. Handb Clin Neurol 2018;152:177-86.
Grommes C, DeAngelis LM. Primary CNS Lymphoma. J Clin Oncol 2017;35:2410-8.
Hoang-Xuan K, Bessell E, Bromberg J, et al. Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology. Lancet Oncol 2015;16:e322-32.
Abla O, Weitzman S, Blay JY, et al. Primary CNS lymphoma in children and adolescents: a descriptive analysis from the International Primary CNS Lymphoma Collaborative Group (IPCG). Clin Cancer Res 2011;17:346-52.
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;101:257-65.
Ferreri AJ. How I treat primary CNS lymphoma. Blood 2011;118:510-22.
Villano JL, Koshy M, Shaikh H, Dolecek TA, McCarthy BJ. Age, gender, and racial differences in incidence and survival in primary CNS lymphoma. Br J Cancer 2011;105:1414-8.
Bhagavathi S, Wilson JD. Primary central nervous system lymphoma. Arch Pathol Lab Med 2008;132:1830-4.
Hochberg FH, Baehring JM, Hochberg EP. Primary CNS lymphoma. Nat Clin Pract Neurol 2007;3:24-35.
Rubenstein JL, Fridlyand J, Shen A, et al. Gene expression and angiotropism in primary CNS lymphoma. Blood 2006;107:3716-23.
INTERNET
Autologous Transplantation, Memorial Sloan Kettering Cancer Center. https://www.mskcc.org/cancer-care/diagnosis-treatment/cancer-treatments/blood-stem-cell-transplantation/autologous Accessed Sept. 24, 2019.
Batchelor T. Treatment and prognosis of primary central nervous system lymphoma, UpToDate. Last updated: 02/06/2019. https://www.uptodate.com/contents/treatment-and-prognosis-of-primary-central-nervous-system-lymphoma Accessed Sept. 24, 2019.
Batchelor T, Loeffler JS. Clinical presentation, pathologic features, and diagnosis of primary central nervous system lymphoma, UpToDate. Last updated: 12/04/2018. https://www.uptodate.com/contents/clinical-presentation-pathologic-features-and-diagnosis-of-primary-central-nervous-system-lymphoma Accessed Sept. 24, 2019.
Brook I. Brain Abscess Differential Diagnoses, Medscape. Last updated: Oct 27, 2017.
https://reference.medscape.com/article/212946-differential Accessed Sept. 24, 2019.
Gandhi RT, Toxoplasmosis in HIV-infected individuals, UpToDate. Last updated: 05/20/2019. https://www.uptodate.com/contents/toxoplasmosis-in-hiv-infected-patients Accessed Sept. 24, 2019.
Kaplan LD, AIDS-related lymphomas: Primary central nervous system lymphoma, UptoDate. Last updated: 04/30/2019. https://www.uptodate.com/contents/aids-related-lymphomas-primary-central-nervous-system-lymphoma Accessed Sept. 24, 2019.
McPherson C, DiNapoli V. Brain biopsy, Mayfield Brain & Spine. Last updated: https://mayfieldclinic.com/pe-brainbiopsy.htm Accessed Sept. 24, 2019.
Primary central nervous system lymphoma. Genetic and Rare Diseases Information Center. Last updated: 01/11/2016. https://rarediseases.info.nih.gov/diseases/9318/primary-central-nervous-system-lymphoma Accessed Sept. 24, 2019.
Primary central nervous system lymphoma, Orphanet. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=46135 Accessed Sept. 24, 2019.
Primary central nervous system lymphoma, Canadian Cancer Society. https://www.cancer.ca/en/cancer-information/cancer-type/non-hodgkin-lymphoma/non-hodgkin-lymphoma/more-types-of-nhl/primary-cns-lymphoma/?region=ab Accessed Sept. 24, 2019.
Primary CNS Lymphoma Treatment. National Cancer Institute. Last updated: May 24, 2019. https://www.cancer.gov/types/lymphoma/hp/primary-cns-lymphoma-treatment-pdq Accessed Sept. 24, 2019.
Uppal G, Thomas TP. CNS Toxoplasmosis in HIV, Medscape. Last updated: 07/11/2017. https://emedicine.medscape.com/article/1167298-overview#a4 Accessed Sept. 24, 2019.
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