Burkitt Lymphoma: Types and Introduction

Introduction to Burkitt Lymphoma

• Highly aggressive mature B-cell lymphoma (non-Hodgkin's).
• Accounts for less than 2% of all NHL diagnoses in the UK.
• Most frequent B-cell lymphoma in children, representing 30–50% of pediatric lymphomas.
• Three clinical variants: endemic, sporadic, and immunodeficiency-associated.

Types of Burkitt Lymphoma

• Endemic BL: Most common pediatric malignancy in sub-Saharan Africa, predominantly in equatorial Africa and Papua New Guinea.
  • Median age of 4-7 years.
  • Epstein-Barr virus (EBV) association about 95%.
  • Presents characteristically as a jaw or facial bone tumor.
• Sporadic BL: More commonly seen in pediatric patients (20-30% of lymphomas), rare in adults (~1% of NHL cases in the US).
  • Is distributed worldwide
  • Median age of 30 years.
  • EBV association in 20% of cases.
  • Occurs predominantly as an abdominal mass in ~65% of cases, often with ascites.
• Immunodeficiency-associated BL: Linked to immunodeficiency, such as HIV or post-organ transplant scenarios with inherited immune deficiencies.
  • Associated with the AIDS epidemic.
  • Median age of 10-19 years
  • EBV association of 30-40%.
  • Manifests with organ and nodal involvement.

Etiology

• Idiopathic
• EBV
• Malaria (especially endemic type)
• HIV
• Chromosomal abnormalities: t(8,14), t(8,2), t(8,22).
• Oncogene involvement includes c-myc, TP53, CCND3, and TCF3 aberrations.

Pathology

• Displays a diffuse, monomorphic population of medium-sized cells featuring:
  • Round nuclei
  • Multiple nucleoli
  • Prominent vacuoles
  • Basophilic cytoplasm, effacing normal nodal architecture.
• High rate of spontaneous apoptosis, creating a characteristic "starry sky" appearance.
• Burkitt lymphoma cells are mature B cells typically expressing CD19, CD20, CD22, CD79a, BCL6, BCL10, and surface IgM.
• BL cells lack expression of CD5 or CD23, Mum-1, and terminal deoxynucleotidyl transferase (TdT).

Laboratory Features

• Patients with bulky disease show BL cells in marrow and blood, coupled with suppressed normal blood counts.
• Marrow involvement is characteristically extensive.
  • Burkitt-type lymphoblasts with very high nuclear:cytoplasmic ratio.
  • Deep blue rim of cytoplasm.
  • Frequent prominent cellular vacuolization.
• Rare cases, often in males, present primarily with marrow and blood involvement, termed Burkitt cell leukemia.
• Serum lactic acid dehydrogenase is frequently elevated, reflecting the high cell turnover, particularly in patients with bulky disease.

CNS Involvement

• Is a poor prognostic factor in BL.
• High risk of CNS involvement
  • Up to 20% of patients presenting with CNS involvement at diagnosis
  • Leptomeningeal involvement more common than parenchymal disease.
• Without prophylaxis, 30-50% develop CNS disease.
• CNS involvement correlates with poorer outcomes.

Diagnosis of High-Grade Lymphoma

• Diagnosis is based on a combination of clinical features, histological findings, and molecular confirmation.
• Key Translocations:
  • t(8;14)(q24;q32): Involves c-MYC and IgH, accounting for 100% of cases with these translocations.
  • t(8;2)(p11/q24): Involves c-MYC and Igκ.
  • t(8;22)(q24; q11): Involves c-MYC and Igλ,.
    • All three result in cell proliferation, differentiation, and apoptosis alteration.
• IG-MYC translocation is thought to occur early in lymphomagenesis.
  • Subsequent MYC and TP53 mutations occur in approximately 60% and 40% of BL cases.
• Recent studies show novel activating mutations in TCF3 and inactivating mutations in ID3 (negative regulator), affecting up to 70% of cases.
• Activating mutations in CCND3 (encoding cyclin D3) found in 38% of sporadic BL cases.
• Recurrent oncogenic mutations cooperate with MYC to promote proliferation, survival, and growth of BL cells.
• An aggressive lymphoma type, lacking MYC gene rearrangement.
  • Morphologically and immunophenotypically similar to BL.
  • With recurrent gains/losses of chromosome 11.
  • Recognized in the WHO 2022 classification (5th edition).
  • Provisionally named "Burkitt-like lymphoma with 11q aberration".

Murphy Staging System for Burkitt Lymphoma

• Stage I: Single nodal or extranodal site, excluding mediastinum or abdomen.
• Stage II: Single extranodal tumor with regional nodal involvement.
  • Two extranodal tumors on one side of the diaphragm.
  • Primary gastrointestinal tumor with or without associated mesenteric nodes.
  • Two+ nodal areas on one side of the diaphragm.
• Stage IIR: Completely resected intra-abdominal disease.
• Stage III: Two single extranodal tumors on opposite sides of the diaphragm.
  • All primary intrathoracic tumors.
  • All paraspinal or epidural tumors.
  • Extensive primary intra-abdominal disease.
  • Two+ nodal areas on both sides of the diaphragm.
• Stage IIIA: Localized, nonresectable abdominal disease.
• Stage IIIB: Widespread multi-organ abdominal disease.
• Stage IV: Initial central nervous system or marrow involvement (<25%).

Differential Diagnosis

• Burkitt Lymphoma:
  • Clinical features: Occurs in children and adults with male predominance, presenting bulky, rapidly growing masses predominantly in extranodal sites.
  • Morphology: Uniform or slightly pleomorphic medium-sized cells with a starry sky appearance.
  • Immunophenotype: CD19+, CD20+, CD10+, BCL6+, BCL2-, TDT-, Ki67~100%, monotypic sIg+.
  • Genotype: Characterized by t(8,14), t(8,2), t(8,22), without bcl2 or bcl6 translocation.
• Diffuse Large B-Cell Lymphoma:
  • Clinical features: more common in adults than children, with nodal or extranodal large masses that are often localized.
  • Morphology: Large oval, irregular, or lobated nuclei with scant cytoplasm.
  • Immunophenotype: CD20+, CD10-/+, BCL6+/-, BCL2+/-, monotypic sIg+.
  • Genotype: Often associated with BCL2 and BCL6 abnormalities, and sometimes MYC abnormalities in minority.
• B-Lymphoblastic Lymphoma:
  • Clinical features: More common in children than adults, associated with leukemia.
  • Morphology: Small to medium-sized cells of variable size and shape.
  • Immunophenotype: CD19+, CD20-/+, TDT+.
  • Genotype: Variable, often hyperdiploidy.
• T-Lymphoblastic Lymphoma:
  • Clinical features: More common in adolescents and young adults and older adults, with male predominance and mediastinum involvement.
  • Morphology: Small to medium-sized cells of variable size and shape.
  • Immunophenotype: CD3+, TDT+.
  • Genotype: Variable.
• Mantle Cell Lymphoma:
  • Clinical features: Occurs mostly in middle-aged and older adults, male to female ratio, widespread disease.
  • Morphology: Medium to large-sized lymphoblastic-like cells with scanty cytoplasm.
  • Immunophenotype: CD20+, CD5+, CD10-, BCL6-, BCL2+, CCD1+, monotypic sIg+.
  • Genotype: Characterized by t(11,14) involving bcl1 and IGH.
• Florid Follicular Hyperplasia:
  • Clinical Features: Can occur in children and adults,
  • Morphology: large irregular follicles
  • Immunophenotype: , CD20+,CD10+,BCL6+,BCL2+
  • Genotype: No clonal Abnormalities

Treatment

• Burkitt Lymphoma: Highly aggressive, but responds well to multi-agent chemotherapeutic programs, leading to excellent long-term survival.
• Rituximab: Commonly used with combination chemotherapy because of high CD20 expression on BL cells.
• Chemotherapy Regimens: Most regimens include:
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Methotrexate
  • Ifosfamide
  • Etoposide
  • High-dose cytarabine -Rituximab in combination with intrathecal chemotherapy.
• Dose-Intense, Short-Duration Strategy: Used due to high tumor proliferation.
  • This minimizes rapid growth and resistance development between cycles.
• G-CSF (Granulocyte Colony-Stimulating Factors): It helps to keep the dose high and treat severe neutropenia.
• HIV-Positive Patients: Should be treated like immunocompetent patients in the era of highly active antiretroviral therapy.
• Tumor Lysis Syndrome (TLS): High risk due to high tumor cell proliferation and levels acid dehydrogenase
  • Manage with careful hydration (~3 L of saline per day).
  • Allopurinol or rasburicase (for rapid onset of action in high-risk and spontaneous cases).
  • Short-term continuous veno-venous hemofiltration to allow concomitant full-dose chemotherapy, preventing lysis syndrome and renal failure.

Prognosis

• Overall, intensive chemotherapy regimens can cure approximately 50–80% of adult patients.
  • Cure rates higher in pediatric populations.
  • Overall survival is age-dependent.
    • OS in children is approximately 90%.
    • OS in adults less than 70 years is approximately 50%.
    • OS in adults greater than 70 years is 25% to 30%.
• Rituximab-Containing Regimens:
  • Complete response (CR) rates: 80–94%.
  • 3-year progression-free survival (PFS) rates: 70–90%.
• Relapses: Typically occur within the first 12 months post-treatment; rare after 1 year.
• Prognosis for relapsed or refractory BL is poor.