Primary central nervous system lymphoma
Encyclopedia
A primary central nervous system lymphoma (PCNSL), also known as microglioma and primary brain lymphoma, is a primary intracranial tumor
appearing mostly in patients with severe immunosuppression
(typically patients with AIDS
). PCNSLs represent around 20% of all cases of lymphoma
s in HIV
infections (other types are Burkitt's lymphoma
s and immunoblastic lymphomas). Primary CNS
lymphoma is highly associated with Epstein-Barr virus
(EBV) infection (> 90%) in immunodeficient
patients (such as those with AIDS and those iatrogenically
immunosuppressed), and does not have a predilection for any particular age group. Mean CD4
+ count at time of diagnosis is ~50/uL. In immunocompromised patients, rognosis is usually poor. In immunocompetent patients (that is, patients who do not have AIDS or some other immunodeficiency), there is rarely an association with EBV infection or other DNA viruses. In the immunocompetent population, PCNSLs typically appear in older patients in their 50's and 60's. Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. The cause for the increase in incidence of this disease in the immunocompetent population is unknown.
, cranial nerve findings, altered mental status, or other focal neurological deficits typical of a mass effect
. Systemic symptoms may include fever, night sweats, or weight loss.Other symptoms include
MRI or contrast enhanced CT
classically shows multiple ring-enhancing lesion
s in the deep white matter
. The major differential diagnosis
(based on imaging) is cerebral toxoplasmosis
, which is also prevalent in AIDS patients and also presents with a ring-enhanced lesion, although toxoplasmosis generally presents with more lesions and the contrast enhancement is typically more pronounced. Imaging techniques
cannot distinguish the two conditions with certainty, and cannot exclude other diagnoses. Thus, patients undergo a brain biopsy
.
is usually ineffective because of the depth of the tumor. Treatment with irradiation
and corticosteroid
s often only produces a partial response and tumor recurs in more than 90% of patients. Median survival is 10 to 18 months in immunocompetent
patients, and less in those with AIDS. The addition of IV methotrexate
and folinic acid
(leucovorin) may extend survival to a median of 3.5 years. If radiation is added to methotrexate, median survival time may increase beyond 4 years. However, radiation is not recommended in conjunction with methotrexate because of an increased risk of leukoencephalopathy
and dementia
in patients older than 60. In AIDS patients, perhaps the most important factor with respect to treatment is the use of highly active anti-retroviral therapy
(HAART), which affects the CD4+ lymphocyte population and the level of immunosuppression. The optimal treatment plan for patients with PCNSL has not been determined. Combination chemotherapy and radiotherapy at least doubles survival time, but causes dementia and leukoencephalopathy in at least 50% of patients who undergo it. The most studied chemotheraputic agent in PCNSL is methotrexate
(a folate analogue that interferes with DNA
repair). Methotrexate therapy in patients with PCNSL typically requires hospitalization for close monitoring and intravenus fluids. Leucovrin is often given for the duration of the therapy. Standard chemotherapeutic regimens for lymphoma such as CHOP
are ineffective in PCNSL, probably due to poor penetration of the agents through the blood brain barrier.
Newer treatments, such as high dose chemotherapy combined with stem cell transplant are proving to increase survival by years.
and PCNSL have a median survival of only 4 months with radiotherapy alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself. Extended survival has been seen, however, in a subgroup of AIDS patients with CD4
counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either methotrexate monotherapy or vincristine
, procarbazine, or whole brain radiotherapy. These patients have a median survival of 10–18 months. Of course, highly active antiretroviral therapy (HAART) is critical for prolonged survival in any AIDS patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and PCNSL.
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
appearing mostly in patients with severe immunosuppression
Immunosuppression
Immunosuppression involves an act that reduces the activation or efficacy of the immune system. Some portions of the immune system itself have immuno-suppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other...
(typically patients with AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
). PCNSLs represent around 20% of all cases of lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
s in HIV
HIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
infections (other types are Burkitt's lymphoma
Burkitt's lymphoma
Burkitt's lymphoma is a cancer of the lymphatic system...
s and immunoblastic lymphomas). Primary CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
lymphoma is highly associated with Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
(EBV) infection (> 90%) in immunodeficient
Immunodeficiency
Immunodeficiency is a state in which the immune system's ability to fight infectious disease is compromised or entirely absent. Immunodeficiency may also decrease cancer immunosurveillance. Most cases of immunodeficiency are acquired but some people are born with defects in their immune system,...
patients (such as those with AIDS and those iatrogenically
Iatrogenesis
Iatrogenesis, or an iatrogenic artifact is an inadvertent adverse effect or complication resulting from medical treatment or advice, including that of psychologists, therapists, pharmacists, nurses, physicians and dentists...
immunosuppressed), and does not have a predilection for any particular age group. Mean CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
+ count at time of diagnosis is ~50/uL. In immunocompromised patients, rognosis is usually poor. In immunocompetent patients (that is, patients who do not have AIDS or some other immunodeficiency), there is rarely an association with EBV infection or other DNA viruses. In the immunocompetent population, PCNSLs typically appear in older patients in their 50's and 60's. Importantly, the incidence of PCNSL in the immunocompetent population has been reported to have increased more than 10-fold from 2.5 cases to 30 cases per 10 million population. The cause for the increase in incidence of this disease in the immunocompetent population is unknown.
Clinical manifestations
A primary CNS lymphoma usually presents with seizure, headacheHeadache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...
, cranial nerve findings, altered mental status, or other focal neurological deficits typical of a mass effect
Mass effect (medicine)
In medicine, a mass effect is the effect of a growing mass , for example the consequences of a growing cancer....
. Systemic symptoms may include fever, night sweats, or weight loss.Other symptoms include
- diplopiaDiplopiaDiplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
- dysphagiaDysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
- vertigoVertigoVertigo is a form of dizziness.Vertigo may also refer to:* Vertigo , a 1958 film by Alfred Hitchcock**Vertigo , its soundtrack** Vertigo effect, or Dolly zoom, a special effect in film, named after the movie...
- monocular visionMonocular visionMonocular vision is vision in which each eye is used separately. By using the eyes in this way, as opposed by binocular vision, the field of view is increased, while depth perception is limited. The eyes are usually positioned on opposite sides of the animal's head giving it the ability to see two...
loss - progressive dementiaDementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
or stuporStuporStupor is the lack of critical cognitive function and level of consciousness wherein a sufferer is almost entirely unresponsive and only responds to base stimuli such as pain. This is often mistaken for delirium and treated with Haldol and or other anti-psychotic drugs...
in patients with a nonfocal neurologic exam and minimal abnormalities on MRI (more common in AIDSAIDSAcquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients) - facial hypoesthesiaHypoesthesiaHypoesthesia refers to a reduced sense of touch or sensation, or a partial loss of sensitivity to sensory stimuli....
Diagnosis
The definitive diagnosis is arrived at from tissue, i.e. a biopsy, by a pathologist.MRI or contrast enhanced CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
classically shows multiple ring-enhancing lesion
Ring-enhancing lesion
A ring-enhancing lesion is an abnormal finding on CT scan obtained using radiocontrast. On the image there is an area of decreased density surrounded by a bright rim from concentration of the enhancing contrast dye. This can be a finding in numerous disease states...
s in the deep white matter
White matter
White matter is one of the two components of the central nervous system and consists mostly of myelinated axons. White matter tissue of the freshly cut brain appears pinkish white to the naked eye because myelin is composed largely of lipid tissue veined with capillaries. Its white color is due to...
. The major differential diagnosis
Differential diagnosis
A differential diagnosis is a systematic diagnostic method used to identify the presence of an entity where multiple alternatives are possible , and may also refer to any of the included candidate alternatives A differential diagnosis (sometimes abbreviated DDx, ddx, DD, D/Dx, or ΔΔ) is a...
(based on imaging) is cerebral toxoplasmosis
Toxoplasmosis
Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. The parasite infects most genera of warm-blooded animals, including humans, but the primary host is the felid family. Animals are infected by eating infected meat, by ingestion of feces of a cat that has itself...
, which is also prevalent in AIDS patients and also presents with a ring-enhanced lesion, although toxoplasmosis generally presents with more lesions and the contrast enhancement is typically more pronounced. Imaging techniques
Medical imaging
Medical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...
cannot distinguish the two conditions with certainty, and cannot exclude other diagnoses. Thus, patients undergo a brain biopsy
Brain biopsy
Brain biopsy is the removal of a small piece of brain tissue for the diagnosis of abnormalities of the brain. It is used to diagnose Alzheimer's disease, tumors, infection, inflammation, and other brain disorders....
.
Treatment
Surgical resectionSegmental resection
Segmental resection is a surgical procedure to remove part of an organ or gland. It may also be used to remove a tumor and normal tissue around it. In lung cancer surgery, segmental resection refers to removing a section of a lobe of the lung.- External links :* entry in the public domain NCI...
is usually ineffective because of the depth of the tumor. Treatment with irradiation
Radiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
and corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s often only produces a partial response and tumor recurs in more than 90% of patients. Median survival is 10 to 18 months in immunocompetent
Immunocompetence
Immunocompetence is the ability of the body to produce a normal immune response following exposure to an antigen. Immunocompetence is the opposite of immunodeficiency or immuno-incompetent or immuno-compromised...
patients, and less in those with AIDS. The addition of IV methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
and folinic acid
Folinic acid
Folinic acid or leucovorin , generally administered as calcium or sodium folinate , is an adjuvant used in cancer chemotherapy involving the drug methotrexate. It is also used in synergistic combination with the chemotherapy agent 5-fluorouracil.Levofolinic acid and its salts are the enantiopure...
(leucovorin) may extend survival to a median of 3.5 years. If radiation is added to methotrexate, median survival time may increase beyond 4 years. However, radiation is not recommended in conjunction with methotrexate because of an increased risk of leukoencephalopathy
Leukoencephalopathy
The term Leukoencephalopathy is a broad term for leukodystrophy-like diseases . It is applied to all brain white matter diseases, whether their molecular cause is known or not...
and dementia
Dementia
Dementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
in patients older than 60. In AIDS patients, perhaps the most important factor with respect to treatment is the use of highly active anti-retroviral therapy
Antiretroviral drug
Antiretroviral drugs are medications for the treatment of infection by retroviruses, primarily HIV. When several such drugs, typically three or four, are taken in combination, the approach is known as Highly Active Antiretroviral Therapy, or HAART...
(HAART), which affects the CD4+ lymphocyte population and the level of immunosuppression. The optimal treatment plan for patients with PCNSL has not been determined. Combination chemotherapy and radiotherapy at least doubles survival time, but causes dementia and leukoencephalopathy in at least 50% of patients who undergo it. The most studied chemotheraputic agent in PCNSL is methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
(a folate analogue that interferes with DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
repair). Methotrexate therapy in patients with PCNSL typically requires hospitalization for close monitoring and intravenus fluids. Leucovrin is often given for the duration of the therapy. Standard chemotherapeutic regimens for lymphoma such as CHOP
CHOP
CHOP is the acronym for a chemotherapy regimen used in the treatment of non-Hodgkin lymphoma. CHOP consists of:* Cyclophosphamide, an alkylating agent which damages DNA by binding to it and causing cross-links...
are ineffective in PCNSL, probably due to poor penetration of the agents through the blood brain barrier.
Newer treatments, such as high dose chemotherapy combined with stem cell transplant are proving to increase survival by years.
In immunocompetent patients
The initial response to radiotherapy is often excellent, and may result in a complete remission. However,the duration of response with radiotherapy alone remains short, with median survival after treatment with radiotherapy just 18 months. Methotrexate based chemotherapy markedly improves survival,with some studies showing median survival after methotrexate chemotherapy reaching 48 months.In AIDS patients
Patients with AIDSAIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
and PCNSL have a median survival of only 4 months with radiotherapy alone. Untreated, median survival is only 2.5 months, sometimes due to concurrent opportunistic infections rather than the lymphoma itself. Extended survival has been seen, however, in a subgroup of AIDS patients with CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
counts of more than 200 and no concurrent opportunistic infections, who can tolerate aggressive therapy consisting of either methotrexate monotherapy or vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
, procarbazine, or whole brain radiotherapy. These patients have a median survival of 10–18 months. Of course, highly active antiretroviral therapy (HAART) is critical for prolonged survival in any AIDS patient, so compliance with HAART may play a role in survival in patients with concurrent AIDS and PCNSL.
External links
- MedPix Teaching File MR Scans of Primary Brain Lymphoma