Chapter 64: Burkitt Lymphoma

Burkitt lymphoma (BL) may present in three distinct forms: endemic (African), sporadic, and immunodeficiency-associated.

The endemic form is found in eastern equatorial Africa, with a peak age incidence at 4 to 7 years, and it is nearly twice as frequent in boys as in girls.

Sporadic BL, defined as cases outside of endemic African regions, accounts for 1% to 2% of all patients with non-Hodgkin lymphoma (NHL).

The incidence is higher in males than in females, and the median age of onset is 30 years.

Immunosuppression-related BL increased in incidence during the AIDS epidemic.

The unifying feature of all three types of BL is activation of the c-MYC gene, typically resulting from translocations involving the long arm of chromosome 8, which carries c-MYC.

— Such translocations commonly involve also the long arm of chromosome 14, which carries the immunoglobulin heavy chain gene complex, but might instead involve chromosome 2 or 22, which carries the immunoglobulin kappa or lambda light chain gene complex, respectively.

— The constitutive activation of c-MYC increases the expression of a number of genes encoding proteins involved in cell proliferation.

Translocations are thought to occur via double-strand breaks that occur during the normal B-cell class-switch reaction and somatic hypermutation.

Up to one-third of cases also might have alterations involving the short arm of chromosome 17 at 17p13.1, involving the TP53 gene encoding p53. Loss of p53 function might be selected in BL cells that otherwise would be induced to undergo apoptosis in response to overexpression of c-MYC.

Next-generation sequencing has found frequently occurring mutations in ID3, TCF3, and CCND3.

Evidence of Epstein-Barr virus (EBV) is found in essentially all patients with African BL, one-third of patients with immunosuppression associated BL, and in one-fifth of patients with nonendemic form of disease.

The endemic (African) form often presents as a jaw or facial bone tumor. It may spread to extranodal sites, especially to the marrow and meninges. Almost all cases are EBV positive.

The nonendemic or American form presents as an abdominal mass in approximately 65% of cases, often with ascites. Extranodal sites, such as the kidneys, gonads, breast, marrow, and central nervous system (CNS) may be involved. Involvement of the marrow and CNS is much more common in the nonendemic form.

Tumor lysis syndrome is very common following induction chemotherapy but also can occur spontaneously prior to therapy, especially in patients with a high tumor burden. Spontaneous tumor lysis is a poor prognostic indicator.

The syndrome results in some or all of the following: hyperuricemia and hyperuricosuria, hyperkalemia, hyperphosphatemia, hypocalcemia, metabolic acidosis, and uric acid nephropathy with renal failure as a result of the extraordinary proliferative nature of BL cells.

Patients with bulky disease may have BL cells in marrow and blood with accompanying suppression of normal blood counts.

— Marrow involvement is characteristically extensive with replacement by Burkitt-type lymphoblasts with a very high nuclear:cytoplasmic ratio, deep blue rim of cytoplasm, and often prominent cellular vacuolization (Figure 64–1).

Rare cases, often males, may present principally with marrow and blood involvement, so-called Burkitt cell leukemia.

The serum lactic acid dehydrogenase is often elevated as a reflection of the high cell turnover, especially in patients with bulky disease.

BL cells are mature B cells that typically express CD19, CD20, CD22, CD79a, and surface IgM. BL cells lack expression of CD5 or CD23.

All cases of BL have a translocation between the long arm of chromosome 8, the site of the c-MYC proto-oncogene (8q24), and one of three translocation partners: the Ig heavy-chain region on chromosome 14, the κ light-chain locus on chromosome 2, or the λ light-chain locus on chromosome 22.

The translocations involving c-MYC can be detected by fluorescence in situ hybridization (FISH) (Figure 64–2).

Although virtually all lymphoma is staged with a uniform set of parameters, staging in BL employs a distinct system (Table 64–1).

BL is a highly aggressive tumor; however, therapy with multiagent chemotherapeutic programs results in excellent long-term remission rates and long-term survival of up to 85% of children.

Risk stratification allows patients with limited disease to be treated with less intensive therapy than more advanced cases and still achieve very high responses.

Regimens used for BL and treatment results are found in Table 64–2.

There are no studies directly comparing regimens, with most employing cyclophosphamide, doxorubicin, vincristine, methotrexate, ifosfamide, etoposide, high-dose cytarabine, rituximab, but always with intrathecal chemotherapy.

In general, shorter durations of chemotherapy (ie, 6 months or less) are as good as longer (18 months) periods of treatment.

BL has a high proliferative rate, so subsequent chemotherapy cycles should be started as soon as hematologic recovery occurs. Waiting for a fixed period between cycles may lead to regrowth of resistant tumor cells between cycles.

Given the high proliferative rate of the tumor, and the effect of chemotherapy, upfront treatment for tumor lysis syndrome should occur, especially in patients with a high lactic acid dehydrogenase level or bulky disease.

— Carefully monitored hydration (~3 liters of saline per day)

— Allopurinol or rasburicase, the latter especially useful in high-risk or spontaneous tumor lysis cases because of rapid onset of action

— Continuous venovenous hemofiltration, which has been very useful in permitting concomitant full-dose chemotherapy, while preventing lysis syndrome and renal failure

In the highly active antiretroviral therapy era, HIV-positive patients with BL should be treated similarly to immunocompetent patients.