Highly aggressive B cell malignancy, small non-cleaved-cell lymphoma.
Derived from the mature germinal center B cell.
Among fastest growing malignancies:The most rapid proliferating human cancer.
Less than 2000 cases annually.
30% of patients with BL are 33qsqswrereolder than 60 years.
More than 90% of children and adolescents are cured with high-dose intensive chemotherapy, whereas adults are more susceptible to the toxic effects of treatment and only 70-85% of those have long-term remission.
Nearly all cases of recurrent to Rectory disease or fatal.
Accounts for 20-30% of pediatric lymphomas but only approximately 1%-2 of adult non-Hodgkin lymphomas in the United States for an estimated 1480 cases annually.
There are three major variants: endemic, occurring it Equatorial Africa, sporadic, occurring worldwide, and immunodeficiency associated, occurring in patients with HIV infections.
Endemic BL occurs in geographic regions when malaria is endemic and BUrkitt’s lymphoma is the most common pediatric cancer in these regions.
Endemic BL involves the jaw, orbit, or both, but more contemporary studies show abdominal involvement is now more common.
It has been suggested that jaw involvement is related to poor dentition allowing EBV to enter jaw marrow cells.
The clinical presentation is often dramatic and associated with tumor doubling times of 24 to 48 hours.
Diagnosis requires a high index of clinical suspicion, immediate evaluation and early initiation of care.
Tumor proliferation and growth is advanced by means of the phosphatidyllonisitide 3-kinase pathway and cyclin-dependent kinases.
Characteristically has rapid growth and spread to extranodal anatomical sites, including intra-abdominal organs and the CNS.
About 10% of patients with c-myc gene translocation seen in diffuse large B cell lymphoma.
Must be distinguished from diffuse large B cell lymphoma since it requires high intensity treatment.
It has a hallmark translocation of the MYC oncogene.
The translocation T (8; 14) translocation of MYC from chromosome 8 to the immunoglobulin heavy chain region on chromosome 14, in 70 to 80% of cases, from chromosome 8 to chromosome 2, in 15% of cases or from chromosome 8 to 22 in 5% of cases.
NYC transit locations are nearly universal among Burkitt’s lymphoma variants.
EB virus induces abnormalities involving extra bands on the long arm of chromosome 14 with corresponding loss of material on the long arm of chromosome eight.
The reciprocal translocations that juxtaposed the MYC oncogene on chromosome 8 and immuno globulin loci on chromosomes 2, 14, or 22, result in deregulated MYC expression and uncontrolled tumor proliferation.
Deregulated expression of activation-induced cytidine deaminase within germinal center B cells leads to MYC chromosomal translocations: this explains the elevated risk of Burkitt’s lymphoma in regions with endemic malaria.
The geographic distribution of Burkitt’s lymphoma correlates with areas of endemic infections for plasmodium falciparum malaria.
Prophylactic intrathecal chemotherapy or chemotherapy that crosses the blood brain barrier is needed because of the high risk of involvement of the CNS.
Involvement of the CNS occurs in 15-20% of cases: manifests as cranial nerve palsies or spinal cord compression.
Endemic BL is virtually always associated with EBV infection and elevated titers of EBV antibodies are associated with an increased risk.
Genomics studies show the presence of mutations in p53 and along the phosphatidylinositol 3 kinase (PI3K) signaling pathway that contributes to oncogenesis.
TP53 mutations inactivate the p53 tumor suppressor and its loss promotes MYC induced transformation.
DDX3X tumor suppressor is frequently mutated or deleted in BL promoting the initial transformation of MYC by lowering MYC proteotoxic stress at disease initiation.
Malignant cells increase expression of the Y chromosome and may be account for the higher prevalence of BL among males.
Diagnosis based on morphologic, immunophenotyping and cytogenetic studies.
Morphologically BL tumors show complete effacement of the normal lymph node architecture, with monotonous appearing B cells.
Originates from germinal center B cells.
B cells are small to intermediate in size and have round, basophilic nuclei and coarse chromatin.
B cells show a mature germinal center, typically expressed strong membrane IgM with light chain restriction and are positive for CD 19, CD 20, CD 79A, PAX5, CD 10, and BCL6.
Stains are usually negative for CD5, BCL2, and TdT..
Numerous mitosis are present.
With proliferation rate of nearly 100% the specimen may have a starry sky pattern from numerous benign macrophages that have ingested apoptotic debris.
Frequent mitoses may be present and tumor cells may have small vacuoles, and the proliferation growth rate fractions approach 100%.
Characteristically there is a “starry sky“ appearance produced by intermittent benign histicytes the that have ingested apoptic debris.
Characteristic t(8;14) translocation.
Increased expression of c-myc target gene, decreased expression of major histocompatibility complex class I and nuclear factor κB target genes and expression of germinal center B cell genes.
Includes endemic and sporadic types associated with immunodeficiency and immunosuppression.
The median age a presentation among sporadic BL is 10 years, with an additional peak at 40 and 75 years of age.
Patients older than 60 years of age account for only 20% of cases.
Males are affected 3 to 4 times as often as females
There is no racial or ethnic predisposition.
Sporadic BL can affect virtually any organ but often manifests as avrapidly enlarging abdominal mass, with involvement of the ileocecal region mimicking acute appendicitis or bowel obstruction.
Bone marrow involvement is present in 30 to 35% of cases.
EBV is associated with 20-30% of cases of sporadic Burkitt’s lymphoma, most often in patients over the age of 50 years.
Occurs mostly in pediatric patients and infrequently in adults in the absence of HIV infection or posttransplant setting.
The median age of patients with immuno deficiency associated BL is 40 to 45 years.
BL accounts for nearly 40% of them foam is that a rise in HIV infected patients, and occurs in those were relatively normal CD4 counts.
HIV increases risk by 10 fold.
Young patients with sporadic disease have a favorable outcome with short-term intense chemotherapy, whereas adults patients and those with immunodeficiency related disease have inferior outcomes.
Of the three clinical variants, endemic BL is the most common worldwide with incidence in equatorial Africa of 3-6 children per hundred thousand.
Endemic BL accounts for 30-50% of cases of childhood cancer in this region, with a 2 to 1 male predominance and median age of presentation of 4-7 years.
The incidence of endemic BL is highest in areas with a high prevalence of Plasmodium falciparum malaria and early exposure to Epstein-Barr virus, such as Equatorial Africa, Brazil, and Papua New Guinea.
Virtually all cases of endemic BL are positive for EBV, and a high serologic titer of EBV is associated with an increased risk of BL.
The Epstein –Barr virus what the first virus implicated as a factor in human cancers.
Children with endemic BL present with rapidly growing jaw or periorbital region masses, and extranodal sites including the ileum, cecum, gonads, kidney, and breasts.
In endemic BL the bone marrow is involved in fewer cases than other variants initially, but is often a complication of disease relapse.
CNS involvement is also uncommon at diagnosis in the endemic variant.
Sporadic BL occurs in immunocompetent patients outside of endemic regions.
Sporadic BL is found primarily in orth Africa and western Europe, and accounts for 30 to 50% of pediatric non-Hodgkin lymphomas but only 1 to 2% of adult lymphomas.
Sporadic BL in adults has a slight male predilection, the median age of diagnosis between 30-40 years with bimodal peaks at 10 and 75 years of age.
In contrast to endemic BL, only 40% of cases of sporadic BL are positive for EBV.
In sporadic BL the abdominal region is frequently involved, particularly the ileocecal region.
Sporadic BL patients may present with abdominal pain, nausea, vomiting, and can imitate small bowel obstruction or acute appendicitis prompting surgical attention.
Bone marrow involvement is more common in sporadic BL than in endemic BL, and some cases are categorized as leukemia with extensive involvement of blasts in the bone marrow.
CNS involvement is present at diagnosis in 10 to 20% cases of sporadic BL.
Immunodeficient-associated BL is most commonly in patients infected with HIV, although cases can occur after solid organ or stem cell transplant.
Immunodeficiency-associated BL is the variiant that is seen in approximately 20% of cases in the US annually.
This process can occur even in well-controlled HIV and the incidence has not significantly declined despite the widespread use of highly active anti-retroviral therapy.
HIV-associated BL typically has nodal involvement but ihas a high frequency of dissemination to extra nodal sides, including the CNS, bone marrow, breast, gonads, and adrenal glands.
Staging procedures include a bone marrow biopsy and aspiration, and lumbar puncture for a CSF analysis.
Laboratory testing includes a complete blood count, metabolic panel, LDH and uric acid measurements, and screening for HIV, hepatitis B and C infections.
A large core needle biopsy or surgical biopsy, is necessary to distinguish Burkitt’s lymphoma from other aggressive, lymphomas, and fine needle aspiration is not an adequate diagnostic procedure.
Imaging studies include CT/PET scans:
MRI scans of the brain, spinal cord are indicated for patients with neurologic symptoms.
Adverse patient related factors include 40 years of age or greater, coexistent conditions, tumor burden, performance status, baseline LDH, CNS involvement, and bone marrow status.
Clinical manifestations are often dramatic.
Marked elevation in serum. LDH levels may indicate spontaneous tumor lysis.
Flow cytometry should be performed on CSF to identify low volume disease that requires more aggressive CNS directed therapy.
Laboratory test include: a CBC, comprehensive, metabolic panel, LDH, uric acid levels, screening for HIV, hepatitis B, and C.
The Burkett Lymphoma International Prognostic Index based on four independent risk factors: age of 40 years or older, performance status of two or higher, and LDH level three times the upper limit of the normal range, and CNS involvement.
Patients without any of the factors noted, have a three-year survival rate of 96-98% whereas patients with two or more factors have a three-year overall survival of only 58 to 64%.
TREATMENT:
BL is considered a medical emergency and supportive care to prevent sepsis, intestinal, perforation, and tumor lysis syndrome should be initiated immediately.
Intravenous, hydration and correction of electrolytes are critical since tumor lysis syndrome may worsen with therapy.
Allopurinol is it givem before chemotherapy and recombinant urate oxidase (RAS Uro AEs) may be required as prophylaxis against hyperurecemia.
Treated with intensive chemotherapy, plus agents that penetrate the blood brain barrier because the tumor tend to spread to the CNS.
Surgical debulking is unnecessary and should be avoided.
Highly sensitive to chemotherapy and can be cured with highly intensive combination treatment regimens that include agents that penetrate the CNS, along with intensive supportive care.
Chemotherapy regimens are of short duration, and are designed to achieve high peak drug concentrations to include agents that penetrate the CNS.
Regimens require a prolonged inpatient hospital stay, blood, product support, and antibiotic prophylaxis.
Agents utilized include cyclophosphamide, incristine, doxorubicin, methotrexate, ifosfamide, etoposide, cytarabine, plus intrathecal, methotrexate and cytarabine.
Low risk patient received 2 to 4 courses of chemotherapy, whereas high risk groups receive 5-6; courses with CNS directed therapy such as high dose methotrexate or cytarabine therapy along with a intrathecal therapy.
Patients with high risk disease, those with CNS involvement or extensive leukemic disease receive higher doses of CNS penetrating agents along with more intensive schedules of intrathecal therapy.
Rituximab improve overall survival and should be given to all patients.
Adults may require dose reductions due to higher toxicity rates.
The two year event free survival rates for adults ranges from 65 to 80%.
Cranial radiation in adults is particularly toxic with high rates of severe neurotoxicity.
The anti-CD20 monoclonal antibody rituximab further improves survival when added to standard chemotherapy.
More than 90% of children and adolescents are cured with highly dose intensive chemotherapy.
Only 75 to 85% of adults have long-term remissions.
Nearly all cases of recurrent or refractory disease are fatal.
A large bore needle aspiration is necessary to distinguish BL from other aggressive lymphomas, and a fine needle aspiration is not adequate for diagnostic purposes.
Surgically bulking is a necessary and tumor resection should be avoided.