Burkitt Lymphoma

MYC translocation is the defining event

• The t(8;14)(q24;q32) translocation, present in roughly 80% of cases, moves MYC from chromosome 8 next to the immunoglobulin heavy chain (IgH) enhancer on chromosome 14
• Variant translocations account for most of the remainder: t(2;8) places MYC under the kappa light chain locus, t(8;22) under the lambda locus
• In every version, MYC is placed under the control of an immunoglobulin enhancer that is constitutively and powerfully active in B cells. MYC is not mutated — it is deregulated, transcribed relentlessly in a cell type built to express immunoglobulin at high level
• MYC is a master transcription factor driving ribosome biogenesis, glycolysis, nucleotide synthesis and cell cycle entry. Unopposed, it produces the extraordinary proliferation rate that defines the disease
• Cooperating lesions are needed because MYC alone also drives apoptosis: TP53 mutations (~35%), and ID3, TCF3 and CCND3 mutations that sustain tonic B-cell receptor signalling

Why EBV matters, and why malaria matters more than it looks

• Epstein-Barr virus is present in nearly 100% of endemic, roughly 20-30% of sporadic, and 25-40% of immunodeficiency-associated cases
• EBV establishes latency I in Burkitt cells — expressing only EBNA-1 — which is immunologically near-silent and allows infected cells to persist
• In endemic regions, **holoendemic Plasmodium falciparum malaria is the essential co-factor. Chronic malaria causes sustained polyclonal B-cell expansion, increasing the pool of cells in which a translocation can occur, while simultaneously impairing EBV-specific cytotoxic T-cell surveillance. Malaria also induces AID (activation-induced cytidine deaminase)**, the enzyme that normally mediates class-switch recombination and which can mediate the illegitimate MYC-IgH recombination itself
• This is why endemic Burkitt maps onto the malaria belt rather than onto EBV distribution — EBV infects most of the world's population, but only where chronic malaria coexists does Burkitt become common

Why tumor lysis happens before treatment

• With a near-100% growth fraction and a large tumor burden, spontaneous cell turnover alone releases enough intracellular contents to produce hyperuricemia, hyperkalemia and hyperphosphatemia at presentation
• The released purines are metabolized to uric acid; phosphate binds calcium, causing hypocalcemia and calcium phosphate deposition in tubules; the combination precipitates acute kidney injury, which then impairs clearance and accelerates the whole process

Endemic (African) variant

• Geographically restricted to equatorial Africa and Papua New Guinea, overlapping the belt of holoendemic malaria
• Peak age 4-7 years, male predominance
• The most common childhood malignancy in these regions
• EBV-positive in essentially all cases; chronic P. falciparum malaria is the necessary co-factor

Sporadic (American/Western) variant

• Occurs worldwide with no geographic clustering
• Children and young adults; accounts for roughly 30-40% of childhood lymphomas in the United States, and a small minority of adult NHL
• EBV-positive in only about 20-30%

Immunodeficiency-associated variant

• Chiefly HIV infection, where Burkitt is an AIDS-defining malignancy
• Distinctively, HIV-associated Burkitt tends to occur at relatively preserved CD4 counts — often above 200 — unlike primary CNS lymphoma, which is a disease of CD4 counts below 50. It may be the presenting manifestation of HIV
• Also seen after solid organ and stem cell transplantation and in congenital immunodeficiency

Risk factors overall

• Chronic malaria exposure in endemic regions
• EBV infection, necessary but far from sufficient
• HIV infection and iatrogenic immunosuppression
• No established familial predisposition, occupational exposure or lifestyle risk factor

The tempo is the diagnosis

• Symptoms measured in days to a few weeks, not months. A patient describing a mass that was not there a fortnight ago has an aggressive lymphoma until proven otherwise
• B symptoms — fever, drenching night sweats, weight loss — are common
• Markedly elevated LDH and uric acid at presentation reflect tumor burden and turnover

Endemic variant

• Rapidly growing mass of the jaw and facial bones, or of the orbit — the classic and near-signature presentation, with loosening of teeth and facial distortion
• Abdominal and CNS involvement also occur

Sporadic variant

• Abdominal mass, characteristically in the ileocecal region, presenting with pain, distension, a palpable mass, ascites, or as intussusception in a child — Burkitt is the most common cause of intussusception in children old enough that idiopathic intussusception is unusual
• Involvement of ovaries, kidneys, retroperitoneum and breast (the last notably in pregnancy or lactation)
• Bowel obstruction or perforation may be the presenting event

Immunodeficiency-associated variant

• More often nodal, with bone marrow and central nervous system involvement at diagnosis

Sites and complications to look for in all variants

• CNS involvement — cranial neuropathies, leptomeningeal disease, cord compression — is common and drives mandatory prophylaxis
• Bone marrow involvement; extensive infiltration overlaps with the leukemic form (formerly "L3 ALL")
• Waldeyer ring, testes, bone and skin less commonly
• Superior vena cava syndrome, airway compromise, ureteric obstruction or spinal cord compression from rapid mass expansion — any of which converts this into an immediate emergency
• Tumor lysis syndrome at presentation: nausea, arrhythmia, tetany, seizures, oliguria — before a drop of chemotherapy is given

Tissue diagnosis, urgently

• Excisional or generous core biopsy is strongly preferred; fine-needle aspiration alone is inadequate because architecture and ancillary studies are both needed. Do not let the pursuit of a perfect specimen delay treatment in an unstable patient
• Histology: sheets of monomorphic, medium-sized cells with basophilic cytoplasm, multiple small nucleoli, and numerous mitotic and apoptotic figures. Interspersed tingible-body macrophages phagocytosing apoptotic debris create pale gaps against the dark tumor — the "starry sky" pattern, where the macrophages are the stars
• Ki-67 proliferation index approaching 100% — a defining feature. Anything substantially below that argues against Burkitt

Immunophenotype

• Positive: CD19, CD20, CD22, CD10, BCL6, surface IgM, and monotypic light chain — a germinal-centre B-cell phenotype
• BCL2 negative — this is the critical discriminator. A MYC-rearranged, BCL2-positive aggressive lymphoma is a different disease with different therapy
• TdT negative — separating Burkitt from lymphoblastic lymphoma/ALL, which is TdT positive
• CD5 and CD23 negative, distinguishing it from CLL/SLL and mantle cell lymphoma

Cytogenetics and molecular studies

• FISH for MYC rearrangement is essential, along with BCL2 and BCL6 to exclude the double-hit lymphomas below
• Karyotype: t(8;14) in ~80%, t(2;8) or t(8;22) in most of the rest
• Burkitt has a simple karyotype; complex cytogenetics suggests an alternative diagnosis

The differential that changes treatment

• High-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double-hit" lymphoma) — morphologically overlapping, but BCL2 positive, occurring in older adults, with substantially worse prognosis and requiring different, generally intensive therapy. This is the single most important distinction to make, and it rests on FISH plus BCL2 immunohistochemistry, not on morphology
• Diffuse large B-cell lymphoma — larger, more pleomorphic cells, lower Ki-67, frequently BCL2 positive
• B-lymphoblastic lymphoma/leukemia — TdT positive, immature phenotype
• Blastoid mantle cell lymphoma — cyclin D1 positive, CD5 positive, t(11;14)

Staging and baseline studies

• PET-CT for staging; bone marrow aspirate and biopsy; lumbar puncture with cytology and flow cytometry in every patient
• LDH and uric acid — both prognostic and a measure of immediate tumor lysis risk
• HIV testing in every patient, plus hepatitis B and C serology before rituximab
• Baseline potassium, phosphate, calcium, creatinine and, if rasburicase is contemplated, G6PD status
• Echocardiogram before anthracycline exposure

Treat tumor lysis before, and while, treating the lymphoma

• Aggressive intravenous hydration is the foundation, aiming for high urine output. Start it before cytotoxic therapy
• Rasburicase (recombinant urate oxidase) converts uric acid to soluble allantoin and is the agent of choice for high-risk patients or established hyperuricemia, working within hours. It is contraindicated in G6PD deficiency, where the hydrogen peroxide generated causes severe hemolysis and methemoglobinemia — screen before giving it in at-risk populations
• Allopurinol blocks new uric acid formation and suits lower-risk patients, but does nothing to existing uric acid
• Routine urinary alkalinization is no longer recommended — raising urine pH increases uric acid solubility but promotes calcium phosphate precipitation in tubules
• Laboratory monitoring every 6-8 hours through the initial period, with correction of hyperkalemia as a priority and cautious treatment of hypocalcemia (correcting it in the presence of hyperphosphatemia risks precipitation — treat only symptomatic hypocalcemia)
• Have renal replacement therapy available; a nephrology conversation early is prudent
• Some protocols begin with a low-dose prednisone and cyclophosphamide prophase specifically to reduce burden gradually before full-intensity therapy

Chemotherapy — short, intensive, and always with CNS prophylaxis

• Standard CHOP is inadequate. Burkitt requires dose-intense, short-duration regimens
• DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, with rituximab) — effective with a favourable toxicity profile, and particularly well suited to HIV-associated disease and to lower-risk or older adults
• CODOX-M/IVAC (the Magrath regimen: cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate, alternating with ifosfamide, etoposide and cytarabine), with rituximab added — used for higher-risk disease
• Hyper-CVAD with rituximab is an alternative
• Rituximab improves outcomes and is standard in CD20-positive disease
• Intrathecal chemotherapy is mandatory in every patient, given the high rate of CNS relapse; systemic high-dose methotrexate and cytarabine contribute CNS penetration
• Therapy is brief — a few months — rather than prolonged maintenance, exploiting the tumor's chemosensitivity
• Growth factor support and infection prophylaxis are needed given profound expected myelosuppression

Special situations

• HIV-associated disease: give concurrent antiretroviral therapy with chemotherapy; outcomes now approach those of HIV-negative patients. Watch for drug interactions with the regimen
• Relapsed or refractory disease carries a poor prognosis; salvage chemotherapy followed by stem cell transplantation is attempted, and clinical trial enrolment is appropriate
• Surgery has essentially no therapeutic role beyond biopsy and management of an acute abdominal complication; debulking does not improve outcome

Prognosis

• Children: cure rates exceed 90% with modern protocols
• Adults: roughly 60-90%, depending on age, stage, LDH, performance status and CNS or marrow involvement
• Relapse occurs early, almost always within the first year. A patient disease-free at two years is very likely cured — an unusually reassuring natural history that follows directly from the tumor's kinetics

• Tumor lysis syndrome — hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, acute kidney injury, arrhythmia, seizures. Occurs spontaneously and worsens sharply on treatment initiation; the leading early cause of death
• Acute kidney injury from urate and calcium phosphate nephropathy, from ureteric obstruction by retroperitoneal mass, or from both
• Bowel obstruction, intussusception, perforation and hemorrhage from ileocecal disease — occasionally requiring emergency laparotomy
• Airway obstruction, superior vena cava syndrome, and spinal cord compression from rapidly enlarging masses
• CNS relapse, the principal pattern of treatment failure when prophylaxis is inadequate
• Profound myelosuppression with neutropenic sepsis, and mucositis, from dose-intense regimens
• Rasburicase-induced hemolysis and methemoglobinemia in G6PD deficiency
• Hepatitis B reactivation after rituximab in patients not screened and prophylaxed
• Late effects in cured children: anthracycline cardiomyopathy, infertility, and secondary malignancy
• Facial disfigurement and dental loss from endemic jaw disease, with reconstructive and psychosocial consequences

• "Starry sky" on histology = sheets of monomorphic blue tumor cells with pale tingible-body macrophages as the stars. Ki-67 approaches 100% — the fastest-growing human tumor, doubling in about 24 hours
• t(8;14) juxtaposes MYC (chromosome 8) with the IgH enhancer (chromosome 14). Variants are t(2;8) with kappa and t(8;22) with lambda. MYC is deregulated, not mutated
• Jaw or orbital mass in an African child = endemic Burkitt — EBV-positive in nearly all cases, with holoendemic malaria as the essential co-factor through polyclonal B-cell expansion and impaired EBV-specific T-cell surveillance
• Ileocecal abdominal mass in a Western child or young adult = sporadic Burkitt, EBV-positive in only 20-30%. A cause of intussusception in older children
• BCL2 is negative in Burkitt. A MYC-rearranged lymphoma that is BCL2 positive is "double-hit" high-grade B-cell lymphoma — a different disease, older patients, worse prognosis, different therapy. Always send FISH for MYC, BCL2 and BCL6
• TdT is negative, which separates Burkitt from lymphoblastic lymphoma/ALL; CD5 and CD23 negative separates it from CLL/SLL and mantle cell
• Tumor lysis syndrome can occur before treatment starts. Hydrate aggressively and give rasburicase for high-risk disease — but never in G6PD deficiency, where it causes hemolysis and methemoglobinemia
• Do not routinely alkalinize the urine — it increases uric acid solubility but precipitates calcium phosphate in the tubules
• CHOP is not enough. Burkitt needs short, dose-intense therapy — DA-EPOCH-R or CODOX-M/IVAC — with rituximab and mandatory intrathecal CNS prophylaxis
• Test every patient for HIV. HIV-associated Burkitt appears at relatively preserved CD4 counts, unlike primary CNS lymphoma, which requires CD4 below 50
• It is an oncologic emergency but a curable one — over 90% in children, 60-90% in adults. Relapse is almost always within the first year, and two years disease-free usually means cured