Burkitt’s Lymphoma– Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Mature B-cell neoplasm that arises in lymph node germinal centers
  • Highly aggressive, rapidly growing malignancy
  • Can present as lymphoma or leukemia
  • 3 distinct forms, differing in epidemiology, clinical presentation, and genetics:
    • Endemic, or African
    • Sporadic
    • Immunodeficiency-related
      • HIV/AIDS-related
      • Post solid organ transplant
      • Inherited immunodeficiency
  • Associated with Epstein-Barr virus (EBV)
    • Almost 100% of endemic cases
    • Up to 30% of sporadic cases
  • Specific chromosome translocation [t(8;14)]
  • Similar disease characteristics to diffuse large B cell lymphoma (DLBCL)
  • System(s) affected: Hematologic; Lymphatic
    • Can involve other systems, particularly the ileocecal region, ovaries, kidneys, breasts, and central nervous system [CNS].
  • Synonym(s): Mature B cell high-grade lymphoma; Mature B cell acute lymphoblastic leukemia, L3 type (FAB classification); Burkitt cell leukemia

Pediatric Considerations

Common age group for this disorder (30% of cases in US)

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 4–7 years old.
    • Rare in adults
  • Sporadic (1)
    • In US, trimodal peaks of age incidence around ages 10, 40, and 75
    • More common in Caucasians
    • Male > Female (3:1 or 4:1), more pronounced at younger ages
  • HIV-associated Burkitt occurs mainly in middle-aged adults.

Incidence

Rare in US, incidence 0.27 per 100,000 person-years; about 50 times more common in endemic regions of Africa

Prevalence

Comprises <1% of adult non-Hodgkin lymphoma (NHL); accounts for 30–40% of NHL in children in the US and western Europe

Risk Factors

In endemic areas, children with early acquisition of EBV infection are at increased risk. Coinfection with malaria and EBV 100-fold increase in incidence.

General Prevention

Currently there are no specific measures known to prevent development of Burkitt lymphoma.

Etiology

  • Activation and overexpression of c-myc oncogene
  • 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.
    • Immunodeficiency patients with persistent generalized lymphadenopathy and polyclonal B cell activation.

Commonly Associated Conditions

  • EBV infection
  • Immunodeficiency, especially AIDS

Diffuse large B-cell lymphoma, endemic regions, chromosome translocation, central nervous system, aggressive treatment, neoplasm,

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, gastrointestinal bleeding, symptoms mimicking acute appendicitis or intussusception
  • Endemic (African): Jaw or facial bone tumor, which may present as 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
  • Immunodeficiency-associated: Lymphadenopathy. pallor, petechiae, hepatosplenomegaly

Diagnostic Tests & Interpretation

Lab

Initial lab tests

  • Biopsy of mass lesion
    • Diagnosis is suggested by cellular morphology on histologic examination
  • Complete blood count (CBC) with differential: Anemia, neutropenia, and/or thrombocyptopenia
  • Order electrolytes, BUN, creatinine, calcium, magnesium, phosphorus, serum lactate dehydrogenase (LDH), uric acid: Hypokalemia, hypophosphatemia, hypercalcemia, hyperuricemia, renal insufficiency, elevated LDH
  • Hepatitis B virus serologies prior to rituximab administration

Follow-Up & Special Considerations

  • Diagnosis requires immunophenotypic and cytogenetic data.
  • Immunophenotype studies:
    • Cells express surface IgM 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%)
    • Reciprocal chromosome translocation involving c-myc and 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.

Imaging

Initial approach

  • Chest x-ray
  • CT scan of chest, abdomen, pelvis
  • Imaging of any site suspected to be involved by tumor

Diagnostic Procedures/Surgery

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  • Bone marrow aspiration and biopsy for morphology and flow cytometry
  • Lumbar puncture for CSF cell count, differential, and cytology
  • Lymph node biopsy: Most suggestive lymph nodes should be selected for excisional biopsy.
    • Frozen sections and needle biopsies discouraged as lymph node architecture helpful for diagnosis.
  • Diagnostic laparotomy with resection of localized disease

Pathological Findings

  • Monotonous diffuse infiltrate of medium-size 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 and express Ki-67.
  • Classic “starry sky” histologic appearance
    • Results from the presence of scattered macrophages with phagocytic cell debris
    • Characteristic of, although not pathognomonic, for Burkitt lymphoma
  • Although lymph nodes usually diffusely involved, early lesions may show selective involvement of germinal centers.

Differential Diagnosis

  • Other non-Hodgkin lymphomas
    • Burkitt-like lymphoma:
      • Immunophenotype and molecular characteristics differ from those of classic Burkitt lymphoma
      • Problematic entity with little reproducibility of diagnosis.
      • May be confused with DLBCL.
    • DLBCL: Large, irregular cells, often with BCL rearrangement
    • Precursor B-lymphocytic lymphoma
    • Precursor T-lymphocytic lymphoma
    • Mantle cell lymphoma, blastoid variant
  • Hodgkin’s 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

Treatment

If available, all patients should be offered participation in an appropriate clinical trial.

Medication

  • Intensive, short-term, multiagent chemotherapy administered in cycles (2)[A].
    • Chemotherapeutic agents include cyclophosphamide, methotrexate, vincristine, prednisone, high-dose methotrexate, high-dose cytarabine, etoposide, isophosphamide, and doxorubicin.
    • Type and extent of therapy depend on stage of disease.
  • Rituximab in combination with chemotherapy may improve outcome.
  • CNS prophylaxis for most patients
    • Not necessary for limited disease remote from the CNS.
    • Intrathecal methotrexate, with or without IV methotrexate and cytarabine, may be used for CNS prophylaxis.
    • Routine cranial irradiation does not improve efficacy of treatment.
  • 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 in front-line therapy.
  • Hematopoietic stem cell transplantation in combination with high-dose chemotherapy (3)

Additional Treatment

Issues for Referral

All patients should be managed by a pediatric or adult hematologist/oncologist.

Complementary and Alternative Medicine

Many possible complementary and alternative therapies exist to assist in management of side effects of chemotherapy. These should be considered individually for a risk/benefit discussion with the patient.

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
  • Many patients require placement of a central venous line for administration of chemotherapy.

In-Patient Considerations

Initial Stabilization

  • Burkitt lymphomas have high growth fractions and short doubling times.
    • 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 every 6–8 hours
    • 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 2–3 times per day) if rasburicase not available
      • Consider alkalization of urine with bicarbonate-containing intravenous fluids (goal urine pH 7–8) with allopurinol use
    • Use of phosphate binder if serum phosphorus becomes elevated
    • Medical management of hyperkalemia

IV Fluids

Aggressive IV hydration with first cycle of chemotherapy

  • Typically D5/0.5 NS at 125 cc/m2/hr (twice the maintenance rate)
  • No potassium in IV fluids.
  • Consider addition of NaHCO3 to IV fluids at the direction of the treating oncologist.

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 tests, and renal function should also be closely monitored throughout chemotherapy.
  • Surveillance physical exam and imaging for detection of recurrence
  • All patients, particularly children, should be followed indefinitely for long-term effects of chemotherapy.

Patient Education

Educational materials are available online from the Leukemia and Lymphoma Society (http://www.leukemia-lymphoma.org/hm_lls) and Curesearch (http://www.curesearch.org/).

Prognosis

  • In localized disease, 5-year disease-free survival >90%
  • Aggressive treatment of advanced disease yields >80% 5-year disease-free survival.
  • Recurrent disease tends to be 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) secondary to high tumor burden and rapid cell turnover 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 short- and long-term potential complications of chemotherapy include alopecia, myelosuppression requiring blood transfusion, life-threatening infection, nausea, mucositis, infusion reactions, peripheral neuropathy, seizures, infertility, congestive heart failure, and secondary malignancy.

References

1. Mbulaiteye SM, Anderson WF, Bhatia K, Rosenberg PS, Linet MS, Devesa SS et al. Trimodal age-specific incidence patterns for Burkitt lymphoma in the United States, 1973–2005. Int J Cancer. 2010;126:1732–9.

2. Tauro S, et al. Dose-intensified treatment of Burkitt lymphoma and B-cell lymphoma unclassifiable, (with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma) in young adults (<50 years): a comparison of two adapted BFM protocols. Ameri J Hem. 2010;85(4):261–3.

3. Gross TG, Hale GA, He W, Camitta BM, Sanders JE, Cairo MS, Hayashi RJ, Termuhlen AM, Zhang MJ, Davies SM, Eapen M et al. Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol. Blood Marrow Transplant. 2010;16:223–30.

Codes

ICD9

  • 200.20 Burkitt’s tumor or lymphoma, unspecified site
  • 200.21 Burkitt’s tumor or lymphoma involving lymph nodes of head, face, and neck
  • 200.22 Burkitt’s tumor or lymphoma involving intrathoracic lymph nodes
  • 200.23 Burkitt’s tumor or lymphoma involving intra-abdominal lymph nodes
  • 200.24 Burkitt’s tumor or lymphoma involving lymph nodes of axilla and upper limb
  • 200.25 Burkitt’s tumor or lymphoma involving lymph nodes of inguinal region and lower limb
  • 200.26 Burkitt’s tumor or lymphoma involving intrapelvic lymph nodes
  • 200.27 Burkitt’s tumor or lymphoma involving spleen
  • 200.28 Burkitt’s tumor or lymphoma involving lymph nodes of multiple sites

Snomed

  • 118617000 Burkitt’s lymphoma (disorder)
  • 92512000 Burkitt’s tumor of lymph nodes of head, face AND/OR neck (disorder)
  • 92510008 Burkitt’s tumor of intrathoracic lymph nodes (disorder)
  • 92508006 Burkitt’s tumor of intra-abdominal lymph nodes (disorder)
  • 92511007 Burkitt’s tumor of lymph nodes of axilla AND/OR upper limb (disorder)
  • 92513005 Burkitt’s tumor of lymph nodes of inguinal region AND/OR lower limb (disorder)
  • 92509003 Burkitt’s tumor of intrapelvic lymph nodes (disorder)
  • 92515003 Burkitt’s tumor of spleen (disorder)
  • 92514004 Burkitt’s tumor of lymph nodes of multiple sites (disorder)

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 EBV infection.
  • Burkitt lymphoma is highly treatable with intense multiagent systemic and intrathecal chemotherapy.

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