Rare extranodal non-Hodgkin’s lymphoma that can occur in the brain, leptomeninges, spinal cord or eyes and usually remains confined to the CNS.
Accounted for 2.7% of all brain tumors diagnosed form 1995-1999.
The incidence has been rising throughout the past 2 to 3 decades, which may be the result of better diagnostic techniques or may reflect the aging population.
It is rare, with an annual incidence of approximately 4 to 5 new diagnoses per million per year.
Incidence is approximately 0.5 400,000 individuals in is increasing impatiens older than 60 years.
A subtype of diffuse large B cell lymphoma, the most common type of non-Hodgkin’s lymphoma.
Diffuse large B cell lymphoma accounts for at least 95% of the lymphomas that primarily affect the CNS.
The type of diffuse large B cell lymphoma is most similar to the activated B – cell subset and mutations that are common include MYD 88 mutation in up to 3/4 of patients and mutations in parts of the B cell receptors such is CD 79B.
An aggressive lymphoma characterized by early relapses and poor outcomes, with the five-year survival of 20 to 30%.
A diffuse large B-cell lymphoma that is confined to the CNS compartment, without any systemic manifestations.
About 3-4% of cases of diffuse large B cell lymphoma are primary CNS lymphoma.
Estimated annual incidence 0.48 per 100,000 person-years.
Incidence in immunocompetent patients has been increasing, with the highest increase in those patients of advanced age.
This lymphoma starts in the CNS and, in most cases, is confined there.
This lesion occurs with substantially increased incidence in patients with HIV, especially those with less than 50 CD4 cells per millimeter3.
Can be divided into one or two molecular subtypes based on cell of origin: germinal center B-cell subtype and activated B-cell subtype.
Most patients with primary CNS lymphoma have mutations in the B-cell receptor signaling pathway and or in the toll-like receptor signaling pathway.
Most primary CNS lymphomas are of the activated B-cell type of DLBCL, and carry mutations in the MYD88, and CD79B.
Evaluation includes MRI of the brain and spinal fluid analysis for cytology and flow cytometry.
The best imaging modality with contrast enhanced MRI.
Primary CNS lymphoma may be multifocal and demonstrate homogeneous enhancement and fusion restriction on the fusion, weighted imaging.
Data indicate that a recent decrease incidence of disease especially among patients with AIDS related to new antiviral treatments.
Approximately 1000 cases per year in the U.S.
Median age at is 53-57 years for immunocompetent patients with male:female ratio of 1.2-1.7:1.
Most cases are in patients 60 years or older.
These patients frequently have a poor performance status at diagnosis.
Higher risk for patients over age of 60 years.
Incidence 0.43:1,000,000 per year and is increasing.
In western countries the incidence of primary CNS lymphoma is five per one million.
Arises from a cell not normally present in the CNS.
It is suggested that T and B cells enter the CNS normally and it is hypothesized that the process may originate from the systemic lymphoid cells trafficking in and out of the CNS.
It is possible that this lesion may represent a a metastatic process of an occult systemic lymphoma that has been eradicated by an intact immune system except for the CNS.
Resembles the ABC subtype of diffuse large b-cell lymphoma.
A high proportion of patients have a CD79bB mutation in the B-cell receptor and or a MYD88 mutation.
Patients present with the wide range of central neurologic symptoms.
The history of the symptoms spans, weeks to months.
Patients present with behavior, personality, speech, memory, and higher cognitive dysfunctions, especially when the frontal lobe is affected.
Symptoms may be similar to stroke, and include mode weakness in an extremity.
Visual disturbances can be related to the direct infiltration into the visual cortex in the acceptable lobe may present from direct infiltration into the vitreoretinal compartment.
Significant cognitive impairment occurs in patients following whole brain radiation
Median survival up to 42 months with whole brain radiation and intrathecal methotrexate.
Diffuse B cell lymphomas in the vast majority of cases.
In immunocompetent 95% of cases are diffuse large B cell lymphomas.
Remaining cases are T cell lymphomas, 2-5%, and rare cases of low grade B cell lymphomas, or MALTomas.
Much of the tumor resides behind an intact blood brain barrier and cannot be visualized radiographically.
Leptomeningeal involvement occurs in up to 40% of patients and may be the sole manifestation of disease at the time of diagnosis in about 8% of those patients.
Patients mostly present with symptoms of an intracranial mass lesion with motor and sensory focal defects present in about 50% of patients.
This lesion frequently involves the frontal lobes, and may be associated with changes in personality and level of alertness.
Seizures are less common than with CNS cancers other than lymphomas, occurring only in 10% of patients, because most patients lesions involve deep structures.
Extrapyramidal syndrome, brainstem or cerebellum impairments are rarely present at the onset of disease.
As many lesions are located in peri-ventricular sites tumor cells can easily spread to the cerebral spinal fluid, and autopsy studies indicate meningeal involvement in 100% of cases.
Clinical studies that examine the CSF demonstrate lymphoma cells and less than half of the cases.
Direct extension from the nervous system to the eye may result in involvement of the vitreous, retina, choroid and optic nerve.
Eye symptoms may precede CNS symptoms my months or years.
At least 80% of patients with primary lymphoma of the eye will develop cerebral lymphoma, even after prolonged latency.
Of all patients with primary central nervous system 20% have ocular disease at diagnosis.
Patients may present with nonspecific, unilateral uveitis refractory to conventional management.
Primary leptomeningeal in the absence of the brain lymphoma is rare, and accounts for only 7% of primary central nervous system lymphomas, and primary spinal cord lymphoma is even less rare.
Diagnosis: enhanced MRI can provide a high degree of confidence in the diagnosis of primary CNS lymphoma:however tissue biopsy is typically required using CT imaging to guide a biopsy.
Findings on enhanced MRI included single mass or multifocal lesions that avidly enhance with contrast.
The movement of water through the cellular lesion is restricted and produces a distinct type of image on MRI sequence.
Presently there is no consensus on the optimal treatment of these patients.
Surgery has no role in treatment.
Patients older than 60 years that obtain remission when treated with radiation and methotrexate combination have a 70% risk of developing significant dementia.
Treatment of primary CNS lymphoma has two phases: all first phase treatment includes high dose intravenous chemotherapy with methotrexate.
The usual dose of high-dose methotrexate is at least 3 g/m².q
In most treatment protocols methotrexate is combined with anti-CD20 monoclonal antibody, rituximab.
Additional chemo therapy agents include cytarabine and thiotepa.
Second phase, consolidation phase, includes whole-brain radiotherapy, although its toxicity involving memory and other cognitive functions have limited its usefulness.
The preferred second phase option is high-dose chemotherapy with autologous stem cell transplant.
IELSG trial in patients less than 75 years old the combination of high doses of methotrexate and cytarabine results were consistently better in outcome and acceptable toxicity over high-dose methotrexate alone (Ferrari AJ et al).
Methotrexate-cytarabine followed by whole brain radiotherapy associated with a 5 year overall survival of 45%, with a plateau in survival curve after the third year (F2242ari AJ et al).
Regardless of treatment older patients do less well than younger patients with a 5-year survival of 19% for patients over the age of 60 years compared with 75% for younger patients.
The prognosis remains poor for the majority, but 20-30% can be cured.
High-dose methotrexate is the single most active chemotherapeutic agent.
Methotrexate is commonly used in combination with drugs such as vincristine, procarbazine, cytarabine, rituximab or ifosfamide.
Induction is typically followed by consolidation whole brain radiation to maximize responses and improved outcomes.
Rituximab may be effective in refractory cases.
Ibrutinib has a high response rate, but most patients develop relapse or progressive disease within 6 to 8 months.
Ibrutinib Studies showed 50% of patients I have meaningful response is an overall response rate was 77% in PCNSL.
A regimen of temozolamide, etoposide, doxorubicin, dexamethasone, ibrutinib, and rituximubab with intraventricular cytabrine has a high efficacy.
Methotrexate, cytarabrine, thiorepa, and rituximab associated with a complete response rate of 49%.
HOVON 105/ALLG NHL trial for primary CNS lymphoms in patiens treated with Rituximab in addition to high dose methotrexate induction chemotherapy versus chemotherapy alone.
All responding patients received consolidation chemotherapy with cytarabine and those aged 60 years or younger receive additional whole brain radiotherapy, patients older than 60 did not receive radiotherapy.
Results did not significantly favor rituximab group.
Nivolumab efficacy in primary CNS lymphoma.
Temsirolimus has a overall response rate of 54%
A combination of lenalidomide/rituximab had a response rate of 63% and no durable relations were noted.
Approximately 25% of patients with primary CNS lymphoma are alive five years after initial diagnosis and there are high numbers of late relapses.