para>Common age group (30% of cases in the United States)
Geriatric Considerations
Unusual in this age group. Toxicity with chemotherapy may be increased in the elderly.
Pregnancy Considerations
With aggressive treatment, good maternal, and fetal outcome
EPIDEMIOLOGY
- Varies by disease form
- Endemic
- One of most common tumors of childhood in Africa, most frequently occurring in children age 4 to 7 years
- Rare in adults
- Sporadic
- In the United States, trimodal peaks of age incidence around ages 10, 40, and 75 years
- More common in Caucasians
- Predominant sex: male > female (3:1 or 4:1)
Incidence
Rare in the United States, incidence 0.27 per 100,000 person-years; 50 times more common in endemic regions of Africa
Prevalence
Composes <1% of adult non-Hodgkin lymphoma (NHL); accounts for 30 " 40% of NHL in children in the United States and Western Europe
ETIOLOGY AND PATHOPHYSIOLOGY
- Activation and overexpression of c-Myc oncogene (1)
- Monoclonal proliferation of B lymphocytes resulting from dysregulation of c-Myc
- Translocation of c-Myc to immunoglobulin coding regions results in constitutive expression of gene product.
- EBV-infected cells in germinal center reactions may increase the risk of translocation.
- Poorly regulated proliferation of genetically unstable B cells increases chance of translocations:
- Immunodeficient patients with persistent generalized lymphadenopathy and polyclonal B-cell activation
RISK FACTORS
Pediatric Considerations
Endemic: Children with early acquisition of EBV infection are at increased risk. Coinfection with malaria and EBV increases incidence 100-fold.
GENERAL PREVENTION
No known methods to prevent Burkitt lymphoma
COMMONLY ASSOCIATED CONDITIONS
- EBV infection
- Immunodeficiency, especially AIDS
DIAGNOSIS
HISTORY
- Rapidly progressive bulky adenopathy or extranodal mass
- Symptoms of bone marrow involvement
- Fatigue, exercise intolerance, bruising, epistaxis, other bleeding, fever
- Abdominal presentation
- Abdominal pain, nausea, vomiting, bowel obstruction, GI bleeding, symptoms mimicking acute appendicitis or intussusception
- Endemic (African): jaw or facial bone tumor, with mouth pain, loose teeth, or jaw mass
- Nonendemic: extranodal disease, abdominal presentation typical
- Can present as acute leukemia (L3-ALL) with predominant bone marrow involvement and no mass lesions
- Renal function impairment and significant metabolic derangement may quickly manifest due to the rapid progression and spread of the tumor.
PHYSICAL EXAM
- Endemic: mass on jaw or facial bone, pallor, petechiae, hepatosplenomegaly
- Sporadic: lymphadenopathy, any mass lesion, abdominal tenderness, pallor, petechiae, hepatosplenomegaly
DIFFERENTIAL DIAGNOSIS
- Other NHLs
- Burkitt-like lymphoma: intermediate immunophenotype and molecular characteristics between classic Burkitt lymphoma and DLBCL
- DLBCL: large, irregular cells, often with B-cell lymphoma (BCL) rearrangement
- Precursor B-lymphoblastic lymphoma
- Precursor T-lymphoblastic lymphoma
- Mantle cell lymphoma, blastoid variant
- Hodgkin lymphoma
- Acute lymphoblastic leukemia
- Other causes of lymphadenopathy
- Infection (e.g., bacterial lymphadenitis, mononucleosis, tuberculosis, atypical mycobacterium, cat-scratch disease)
- Reactive lymphoid hyperplasia
- Histiocytosis
- Other primary malignancies of childhood (e.g., Wilms tumor, neuroblastoma, peripheral neuroectodermal tumor)
- Other metastatic malignancies
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Biopsy of mass lesion: diagnosis by cellular morphology on histologic examination
- CBC with differential: anemia, neutropenia, or thrombocytopenia
- Tumor lysis syndrome: hyperkalemia, hyperphosphatemia, hyperuricemia, renal failure. Order electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, serum lactate dehydrogenase (LDH), uric acid.
- Consider hepatitis B virus serologies prior to rituximab
- Chest x-ray
- CT scan of chest, abdomen, pelvis
- Consider whole body PET to identify active disease.
- Dedicated imaging of any site suspected to be involved by tumor
Follow-Up Tests & Special Considerations
- Diagnosis requires immunophenotypic and cytogenetic data.
- Immunophenotype studies
- Cells express surface immunoglobulin (Ig) M- and B-associated antigens (CD19, CD20, CD22, CD79a), as well as CD10, HLA-DR, and CD43.
- Cells also show nuclear staining for BCL-6 protein.
- Cytogenic studies to visualize chromosomal translocation
- Reciprocal chromosome translocation involving c-Myc and immunoglobulin heavy chain (IgH) gene (t[8;14]) (80% of cases) or immunoglobulin light chain (IgL) genes (t[2;8] or t[8;22])
- Fluorescence in situ hybridization (FISH) or long-segment polymerase chain reaction (PCR) may be necessary to identify translocation.
- EBV testing in lesional cells
- Gene expression profiling can help distinguish Burkitt lymphoma from DLBCL.
Diagnostic Procedures/Other
- Bone marrow aspiration and biopsy for morphology and flow cytometry
- Lumbar puncture for CSF cell count, differential, and cytology
- Lymph node biopsy: Most lymph nodes suggestive of disease should be selected for excisional biopsy.
- Frozen sections and needle biopsies discouraged because lymph node architecture helpful for diagnosis.
- Diagnostic laparotomy with resection of localized disease
Test Interpretation
- Monotonous diffuse infiltrate of medium-sized round cells, with round or oval nuclei, several nucleoli, and coarse chromatin. Cytoplasm is intensely basophilic and moderately abundant.
- Mitotic rate is high; close to 100% of viable cells will be actively engaged in cell cycle.
- Classic starry-sky histologic appearance
- Results from the presence of scattered macrophages with phagocytic cell debris
- Characteristic of, although not pathognomonic for, Burkitt lymphoma
TREATMENT
If available, all patients should be offered participation in an appropriate clinical trial.
MEDICATION
First Line
- Intensive, short-term, multiagent chemotherapy administered in cycles (2)[A]
- Chemotherapeutic agents include cyclophosphamide, methotrexate, vincristine, prednisone, high-dose methotrexate, high-dose cytarabine, etoposide, ifosfamide, and doxorubicin.
- Type and extent of therapy depend on stage of disease.
- Rituximab in combination with chemotherapy may improve outcome (3)[B].
- Nonintensive chemotherapy protocols used in developing countries can be effective (4)[B].
- Cyclophosphamide, methotrexate
- Areas with limited financial and medical resources
- CNS prophylaxis for most patients
- Not necessary for limited disease far from CNS
- Intrathecal methotrexate, cytarabine, and hydrocortisone, with or without IV methotrexate and cytarabine, may be used for CNS prophylaxis.
- Prophylactic irradiation does not improve outcome.
- Chemotherapy cycles should be initiated as soon as hematologic recovery permits.
- Delay of chemotherapy may result in regrowth of resistant tumor between cycles.
- Management of tumor lysis syndrome with initial cycle of chemotherapy
Second Line
- Rituximab may be effective if not used previously.
- Hematopoietic stem cell transplantation in combination with high-dose chemotherapy (5,6)[B]
ISSUES FOR REFERRAL
All patients should be treated by a pediatric or adult oncologist.
SURGERY/OTHER PROCEDURES
- Biopsy and staging
- All patients require a biopsy to establish the diagnosis pathologically.
- Surgical resection
- Treatment for small, completely resectable abdominal tumors (in addition to chemotherapy)
- For patients with intestinal obstruction who cannot begin chemotherapy immediately
- Aggressive upfront resection of disease is not indicated.
- Patients require placement of a central venous line for administration of chemotherapy.
COMPLEMENTARY & ALTERNATIVE MEDICINE
Many complementary therapies exist to assist in management of side effects of chemotherapy.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Almost all patients should be admitted to the hospital for initial care.
- Burkitt lymphoma has high-growth fraction and short doubling time.
- Rapid initiation of definitive chemotherapy is essential.
- Management of tumor lysis syndrome with initial cycle of chemotherapy
- Aggressive hydration without potassium
- Close monitoring of electrolytes, renal function, and uric acid initially q6 " 8h.
- Rasburicase (0.2 mg/kg IV once daily for up to 5 days, depending on response to therapy) to break down uric acid
- Allopurinol (10 mg/kg PO divided 2 to 3/day) if rasburicase not available
- Consider alkalization of urine with bicarbonate-containing IV fluids(goal urine pH 7 to 8) when using allopurinol.
- Phosphate binder if serum phosphorus becomes elevated
- Avoid supplemental calcium unless symptomatic hypocalcium develops.
- Medical management of hyperkalemia
IV Fluids
Aggressive IV hydration with first cycle of chemotherapy
- Typically D5/0.5 NS at 125 mL/m2/hr (twice the maintenance rate)
- No potassium in IV fluids
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Close monitoring of serum chemistries is critical due to high risk of tumor lysis syndrome and uric acid nephropathy.
- CBC, liver function, and renal function should also be closely monitored throughout chemotherapy.
- Surveillance history and physical exam for detection of recurrence
- Consideration of routine imaging for detection of recurrence (7)[B]
- All patients, particularly children, should be followed indefinitely for long-term effects of chemotherapy.
PATIENT EDUCATION
Educational materials are available online from
- Leukemia and Lymphoma Society (www.leukemia-lymphoma.org)
- CureSearch (www.curesearch.org)
PROGNOSIS
- Low-stage localized disease, 5-year event-free survival >95%
- Aggressive treatment of advanced disease yields >90% 5-year event-free survival (8).
- Additional chromosomal abnormalities may be associated with poorer prognosis (9).
- Recurrent disease more resistant to therapy
- Mortality for endemic form remains high where access to health care is limited.
COMPLICATIONS
- Complications of extensive abdominal disease include obstructive jaundice and pancreatitis, bowel obstruction, and intestinal perforation.
- Tumor lysis syndrome with renal failure (uric acid nephropathy) may occur prior to, and especially following, the start of chemotherapy.
- Rituximab has been associated with reactivation of hepatitis B virus resulting in fulminant liver failure.
- Other effects of chemotherapy include alopecia, myelosuppression, life-threatening infection, nausea, mucositis, infusion reactions, peripheral neuropathy, seizures, infertility, congestive heart failure, and secondary malignancy.
REFERENCES
11 Said J, Lones M, Yea S. Burkitt lymphoma and MYC: what else is new? Adv Anat Pathol. 2014;21(3):160 " 165.22 Okebe JU, Skoetz N, Meremikwu MM, et al. Therapeutic interventions for Burkitt lymphoma in children. Cochrane Database Syst Rev. 2011;(7):CD005198.33 Rizzieri DA, Johnson JL, Byrd JC, et al. Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and leukemia Group B study 10 002. Br J Haematol. 2014;165(1):102 " 111.44 Beogo R, Nacro B, Ouedraogo D, et al. Endemic Burkitt lymphoma of maxillofacial region: results of induction treatment with cyclophosphamide plus methotrexate in West Africa. Pediatr Blood Cancer. 2011;56(7):1068 " 1070.55 Gross TG, Hale GA, He W, et al. Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant. 2010;16(2):223 " 230.66 Maramattom LV, Hari PN, Burns LJ, et al. Autologous and allogeneic transplantation for burkitt lymphoma outcomes and changes in utilization: a report from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant. 2013;19(2):173 " 179.77 Eissa HM, Allen CE, Kamdar K, et al. Pediatric Burkitt 's lymphoma and diffuse B-cell lymphoma: are surveillance scans required? Pediatr Hematol Oncol. 2014;31(3):253 " 257.88 El-Mallawany NK, Cairo MS. Advances in the diagnosis and treatment of childhood and adolescent B-cell non-Hodgkin lymphoma. Clin Adv Hematol Oncol. 2015;13(2):113 " 123.99 Lones MA, Sanger WG, Le Beau MM, et al. Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children 's Cancer Group Study CCG-E08. J Pediatr Hematol Oncol. 2014;26(3):169 " 178.
CODES
ICD10
- C83.70 Burkitt lymphoma, unspecified site
- C83.71 Burkitt lymphoma, lymph nodes of head, face, and neck
- C83.73 Burkitt lymphoma, intra-abdominal lymph nodes
- C83.79 Burkitt lymphoma, extranodal and solid organ sites
- C83.77 Burkitt lymphoma, spleen
- C83.76 Burkitt lymphoma, intrapelvic lymph nodes
- C83.74 Burkitt lymphoma, lymph nodes of axilla and upper limb
- C83.72 Burkitt lymphoma, intrathoracic lymph nodes
- C83.75 Burkitt lymphoma, nodes of inguinal region and lower limb
- C83.78 Burkitt lymphoma, lymph nodes of multiple sites
ICD9
- 200.20 Burkitt 's tumor or lymphoma, unspecified site, extranodal and solid organ sites
- 200.21 Burkitt 's tumor or lymphoma, lymph nodes of head, face, and neck
- 200.23 Burkitt 's tumor or lymphoma, intra-abdominal lymph nodes
- 200.28 Burkitt 's tumor or lymphoma, lymph nodes of multiple sites
- 200.27 Burkitt 's tumor or lymphoma, spleen
- 200.26 Burkitt 's tumor or lymphoma, intrapelvic lymph nodes
- 200.24 Burkitt 's tumor or lymphoma, lymph nodes of axilla and upper limb
- 200.22 Burkitt 's tumor or lymphoma, intrathoracic lymph nodes
- 200.25 Burkitt 's tumor or lymphoma, lymph nodes of inguinal region and lower limb
SNOMED
- Burkitt 's lymphoma - disorder
- Burkitt 's tumor of lymph nodes of head, face AND/OR neck
- Burkitt 's tumor of intra-abdominal lymph nodes
- Burkitt 's tumor of lymph nodes of multiple sites
- Burkitt 's tumor of lymph nodes of inguinal region AND/OR lower limb
- Burkitt 's tumor of intrathoracic lymph nodes
- Burkitt 's tumor of lymph nodes of axilla AND/OR upper limb
- Burkitt 's tumor of spleen
- Burkitt 's tumor of intrapelvic lymph nodes
CLINICAL PEARLS
- Burkitt lymphoma is an aggressive, mature B-cell malignancy most commonly diagnosed in childhood.
- Burkitt lymphoma is strongly associated with t(8;14) and with EBV and malaria infections.
- Burkitt lymphoma is highly treatable with intense multiagent systemic and intrathecal chemotherapy.