Burkitt lymphoma

Overview

• About 1 to 2% of adult lymphomas, but the most common NHL in children. Driven by EBV and MYC (chromosome 8). Extremely high TLS risk (treat with allopurinol, IVF, plus/minus rasburicase). Highly curable. Classic "starry sky" histology.
• Board vignette: an 18-year-old woman with a rapidly enlarging jaw mass, early satiety, and fevers; biopsy shows a high mitotic index with apoptotic remnants, CD20+, BCL2−, MYC+, Ki-67 about 100%; the expected cytogenetic finding is t(8;14) MYC translocation (note that t(2;5) is seen in anaplastic large cell lymphoma, not Burkitt).

Epidemiologic Subtypes

• Endemic (African): equatorial Africa; pediatric (median 4 to 7 years); EBV+ in nearly 100%; classically a jaw or facial mass (mandible, maxilla, orbit), and can involve abdominal viscera, kidneys, ovaries, adrenals, ileum, and cecum. Linked to chronic malaria plus EBV co-infection.
• Sporadic: Western, US, Europe; the most common pediatric non-Hodgkin lymphoma (Western populations) but affects all ages; EBV+ in about 15 to 20%; carries IgH-locus translocations, usually t(8;14); most often an ileocecal or abdominal (peritoneal) mass with B symptoms, and intussusception in children.
• Immunodeficiency-associated: HIV (can occur with relatively preserved CD4 counts, unlike most AIDS-defining lymphomas), post-transplant, and congenital immunodeficiency; EBV+ in about 25%; often nodal/extranodal and advanced.

Pathology and Genetics

• Morphology: nodal architecture effaced by a diffuse infiltrate of intermediate-sized, monomorphic cells with round or oval nuclei; very high mitotic index and numerous apoptotic cells; nuclear remnants are phagocytosed by benign macrophages, producing the "starry sky" pattern (the tingible-body macrophages are the stars).
• Immunophenotype: CD19+, CD20+, CD10+, BCL6+; BCL2− (or weak); TdT− (distinguishes from immature lymphoid neoplasms); MUM1−; Ki-67 about 95 to 100% (a defining feature). Almost never expresses BCL2, which helps distinguish it from double-hit lymphoma; if BCL2 or BCL6 is rearranged, it is not Burkitt.
• MYC translocations (the defining lesion): MYC is a proto-oncogene transcription factor that, when constitutively expressed, upregulates genes for proliferation, growth, apoptosis, differentiation, and stem-cell self-renewal. FISH for MYC rearrangement is the key diagnostic tool.
  • t(8;14)(q24;q32) IGH-MYC, about 80% (most common).
  • t(2;8)(p12;q24) IGK (kappa)-MYC, about 15%.
  • t(8;22)(q24;q11) IGL (lambda)-MYC, about 5%.
• Cooperating mutations: TP53, TCF3, and ID3.
• WHO 2022 / ICC 2022: Burkitt lymphoma remains a separate entity; HGBL/LBCL with 11q aberration (formerly Burkitt-like with 11q): WHO-HAEM5 recognizes it as a definite entity, ICC 2022 keeps it provisional; both are characteristically MYC-rearrangement negative with partial 11q gain/loss and more pleomorphic morphology.
• Distinguish from HGBL with MYC and BCL2 rearrangements (double-hit; triple-hit if BCL6 also rearranged) per WHO-HAEM5; MYC plus BCL6 without BCL2 is now DLBCL/HGBL, NOS (ICC 2022 keeps a provisional MYC/BCL6 entity): those are usually BCL2+, but BCL2 and Ki-67 are not reliable discriminators (MYC/BCL6 double-hit may be BCL2 negative; double-hit Ki-67 can approach 100%); diagnosis needs FISH for MYC, BCL2, and BCL6, and are treated as DLBCL, not as Burkitt.

Workup

• Imaging: PET-CT (highly FDG-avid), CT chest/abdomen/pelvis.
• Bone marrow biopsy and LP are mandatory (extranodal involvement is common; CSF involvement upstages and worsens prognosis).
• Labs: CBC, CMP, LDH (often very high), uric acid, phosphate, lactate; HIV, HBV, HCV, EBV; pregnancy test; baseline echo.
• TLS labs at baseline and serially during the pre-phase.

Tumor Lysis Syndrome

• Highest TLS risk of any lymphoma, often spontaneous before therapy.
• Prophylaxis is mandatory before cytotoxic therapy: aggressive IVF, rasburicase (especially uric acid >7.5 or pre-existing hyperuricemia/renal impairment; check G6PD first), allopurinol, and electrolyte monitoring every 6 to 12 hours.
• Pre-phase: low-dose cyclophosphamide, vincristine, and prednisone (COP) for about 7 days to debulk before full-dose chemotherapy, reducing TLS in high-tumor-burden disease.

Frontline Treatment (adult)

• DA-EPOCH-R (Roschewski JCO 2020; PMID 32453640): risk-adapted; low-risk (normal LDH, ECOG 0 to 1, stage I/II, no mass ≥7 cm) gets 3 cycles without IT; high-risk gets 6 cycles plus IT methotrexate prophylaxis. 4-year EFS about 85%, OS about 87%; effective regardless of HIV status, age, or IPI, and now widely used in US adults for its favorable toxicity profile (NCCN lists it alongside R-CODOX-M/IVAC and R-hyperCVAD).
• R-CODOX-M/IVAC (Magrath regimen): alternating CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate) and IVAC (ifosfamide, etoposide, high-dose cytarabine). Effective but very toxic; limited to fit younger patients. Monitor closely for TLS.
• R-hyperCVAD: alternating course A (cyclophosphamide, vincristine, doxorubicin, dexamethasone) and course B (high-dose methotrexate plus cytarabine) with rituximab; CNS prophylaxis is built in.
• CNS-directed therapy is used in nearly all Burkitt regimens, but low-risk DA-EPOCH-R is an exception: low-risk patients received 3 cycles without CNS prophylaxis (high-risk received intrathecal prophylaxis) (intrathecal methotrexate and/or cytarabine, plus high-dose IV methotrexate in high-risk regimens). Inadequate CNS coverage leads to relapse.
• No maintenance therapy is used in Burkitt lymphoma.
• HIV+ Burkitt: DA-EPOCH-R is well tolerated with concurrent ART, with outcomes equivalent to HIV-negative patients.

Relapsed / Refractory

• Relapse is usually early (<1 year) and CNS-prone, carrying a poor prognosis.
• Salvage with high-dose chemo (R-ICE, R-DHAP) then auto-HSCT if chemosensitive; allo-HSCT in young fit patients with refractory disease.
• CD19 CAR-T (axi-cel, liso-cel) is not specifically approved for Burkitt but is used off-label in select R/R cases.

Prognosis and High-Yield Pearls

• EFS: low-risk DA-EPOCH-R 100%; high-risk about 82% (Roschewski 2020).
• CSF involvement is the single strongest adverse predictor.
• Ki-67 about 100%, BCL2−, MYC+ is the classic board triad; TdT− separates it from lymphoblastic disease.
• t(8;14) is the most common translocation; t(2;5) is ALCL, not Burkitt.
• TLS prophylaxis (IVF, allopurinol, plus/minus rasburicase) must precede any cytotoxic treatment, including a cytotoxic COP pre-phase; rasburicase is favored for high TLS risk or hyperuricemia but is contraindicated in G6PD deficiency. Pre-phase use is protocol-dependent.
• HGBL with 11q behaves like aggressive B-cell lymphoma and is treated on Burkitt-type protocols, but is a separate MYC-negative WHO 2022 entity.