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Chapter 84 Malignant Lymphomas in Childhood 1333

as compared with 90.7% ± 4.4% for patients with lower degree of BL and DLBCL (gray zone lymphoma). Burkitt-like lymphoma is
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marrow involvement. Minimal disseminated disease at diagnosis rare in children, and the clinical value of this classification is unclear.
was associated with an increased likelihood of BM or distant recur- When there is marrow involvement, it is designated Burkitt leukemia
rence but not local recurrence. In NHL-BFM trials, adolescent (French-American-British [FAB] classification L3 leukemia) but is
girls with T-LBL had poorer outcomes than adolescent boys despite treated similarly to BL. 10,44
similar presenting characteristics. In 45 adolescents with T-LBL, the
5-year EFS was 57% for girls and 92% for boys (p = .004). This Epidemiology
sex difference was not observed in children less than 15 years old in Sporadic BL constitutes approximately 50%% of childhood NHL
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NHL-BFM trials. One adult study of T-cell ALL has demonstrated and is much commoner in boys than in girls (4 : 1 ratio), with a peak
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poorer outcomes in females than in males, but a prognostic impact incidence between 5 and 14 years of age. 11,14 Endemic BL associated
of sex has not been found in other pediatric or adult studies of LBL. with Epstein-Barr virus (EBV) in more than 85% of cases accounts
Whereas adolescent age itself has not been established as a poor for approximately half of all childhood cancers in equatorial Africa.
prognostic factor as it has for ALL, adult outcomes of LBL are inferior In contrast, sporadic BL is most common in the United States and
to pediatric outcomes. 30 Europe and is associated with EBV in only 10% to 15% of cases. 45,46
Therapy Pathobiology
Two potentially life-threatening situations requiring urgent interven- BL is composed of monomorphic, small, noncleaved cells with round
tion must be considered in children with LBL: (1) mediastinal tumor nuclei, clumped chromatin, and basophilic cytoplasm. A high
with airway obstruction or superior vena cava syndrome and (2) uniform proliferation index is seen, with the Ki-67 positivity
tumor lysis syndrome. Owing to the cardiac and respiratory risks of approaching 100%. The classic “starry sky” appearance of BL seen
anesthesia or sedation in children with a large mediastinal mass, the under low-power microscopy is caused by tingible body macrophages
least invasive procedure should be chosen to establish a tissue diag- scattered among malignant cells. BL cells show mature B-cell features
nosis. In children with relevant pleural effusion, pleural puncture and and usually express surface immunoglobulins. B-cell markers such as
morphologic combined with immunologic diagnostics by flow CD19, CD20, and CD22 are usually present, and the majority
cytometry allow adequate diagnosis. In children with peripheral express CD10 (common acute lymphoblastic leukemia antigen). BL
lymphadenopathy, lymph node biopsy under local anesthesia may be is negative for TdT and BCL2. CD21, the EBV receptor, is more
possible. In children who cannot tolerate a procedure, pretreatment commonly seen in endemic BL than in sporadic BL.
with steroids may be necessary to stabilize the patient. Because pre- Characteristic chromosomal translocations suggest that BL
treatment may diminish the ability to accurately diagnose a patient, develops from genetic aberrations during somatic hypermutation
a tissue diagnosis should be obtained as soon as it is possible to do or attempted immunoglobulin class switching in a B-cell precur-
so safely. Tumor lysis syndrome is characterized by metabolic conse- sor. These translocations, usually t(8;14) or infrequently t(8;22) or
quences of the breakdown of lymphoma cells causing renal failure if t(2;8), juxtapose the c-myc gene (involved in cellular proliferation)
severe. Hyperuricemia, hyperkalemia, and hyperphosphatemia must with immunoglobulin locus regulatory elements, resulting in c-myc
be aggressively managed by hyperhydration, rasburicase, and/or overexpression. In sporadic cases, the predominant chromosome
allopurinol, as well as close monitoring. Children with NHL can also 8 breakpoints usually occur within the c-myc gene, whereas they
present with epidural masses and associated neurologic deficits caused are upstream of the gene in endemic cases. For the rare event of
by spinal cord compression. If the diagnosis is known, chemotherapy c-myc–negative BL, characteristic aberrations of chromosome 11q
should be started as soon as possible. If the diagnosis is not known, characterized by interstitial gains, including 11q23.2–11q23.3 and
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or if there is a sluggish response to chemotherapy, low-dose radiation telomeric losses of 11q24.1-qter, were reported. Other cytogenetic
therapy may be considered in consultation with a radiation abnormalities, such as gain of 7q and deletion of 13q, are uncom-
oncologist. mon. 48,49 Recently published large-scale next-generation sequencing
ALL treatment strategies achieved favorable outcome in LBL and studies unveiled sets of recurrently mutated genes in tumor cells
are accepted as standard treatment as, for example, the Berlin- of pediatric and adult patients with B-NHL and introduced
Frankfurt-Münster (BFM) combination chemotherapy with induc- functionally related inhibitor of DNA 3 (ID3), transcription factor
tion, consolidation, and maintenance phases lasting a total of 24 3 (TCF3), and cyclin D3 (CCND3) as potential drivers of BL
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months with 90% 5-year EFS. Even patients with stages III and IV lymphomagenesis. 50–52
LBL had good outcomes on ALL-type therapy. 39,42 This ALL-like
therapy has now become standard for LBL (Table 84.3). CNS pro- Clinical Manifestations
phylaxis is needed for LBL, but chemotherapy prophylaxis has not BL is an extremely fast-growing malignancy. The most common
proven inferior to prophylactic cranial irradiation in CNS-negative primary sites of sporadic BL are the abdomen and the lymph nodes
patients, even those with advanced-stage disease. 22,34,38 Additionally, of the head and neck. 53,54 Abdominal disease presentation, often
the Pediatric Oncology Group did not demonstrate a survival advan- associated with nausea, vomiting, and abdominal pain, carries a risk
tage of high-dose methotrexate for T-LBL, although its utility in of intestinal perforation, obstruction, and gastrointestinal bleeding.
T-ALL is still being evaluated. 39 Abdominal lymphoma often arises from the distal ileum, causing
intestinal obstruction secondary to intussusception or compression
by an expanding mass encasing the bowel (Fig. 84.1E). BL can
Burkitt Lymphoma involve testes, bone, skin, BM, and CNS. CNS involvement at
diagnosis, occurring in about 9% of patients, is associated with a
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Burkitt lymphoma (BL) was first described in Uganda by Dennis worse outcome. Endemic BL frequently involves the abdomen, jaw,
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Burkitt in the 1950s. First thought to be endemic to equatorial paraspinal region, orbit, and CNS.
Africa, it was subsequently observed in Europe and North America.
The WHO classification recognizes three variants: (1) sporadic BL, Differential Diagnosis
occurring throughout the world and more common in children, In DLBCL, another mature B-cell lymphoma, the cells are usually
adolescents, and young adults; (2) endemic BL, occurring primarily larger, and additional cytogenetic abnormalities such as BCL-6 gene
in sub-Saharan Africa and New Guinea, with some unique clinical rearrangements or t(14;18) may be seen, although these abnormalities
features but morphologically identical to sporadic BL; and (3) are more common in adult DLBCL. Ki-67 staining in less than 95%
immunodeficiency-associated BL, observed primarily in patients with of the cells or positivity for BCL2 are helpful in excluding a diagnosis
HIV and less commonly in the setting of other immunodeficiencies. of BL. Burkitt-like lymphoma is a controversial diagnosis with some
The WHO and REAL classifications also recognize the controversial morphologic features more similar to DLBCL, including larger cells,
entity of Burkitt-like lymphoma, with features intermediate between but commonly with c-myc translocations and a clinical behavior