Clinical Features

The clinical characteristics of BL differ between endemic and sporadic cases, although there is some overlap between these two entities. Frequent extran-odal sites of involvement are seen in all cases. The classical presentation of endemic BL, with a jaw tumor, is seen in 50% to 70% of endemic cases, but less than 10% of sporadic BL.39'43'44

The majority of cases (around 90%) of sporadic BL present with abdominal masses, frequently involving the ileocecal region.45 Common presenting symptoms therefore include abdominal pain and distension, change in bowel habit, nausea and vomiting, and occasionally, gastrointestinal bleeding or perforation. Abdominal obstruction secondary to intussusception may also occur. Retroperitoneal disease is common, and may result in extradural extension and spinal cord compression. Other frequent sites of involvement in sporadic BL include bone marrow (20%), pleural effusions (20%), and CNS disease (15%). Breast involvement, although uncommon, is associated with onset of the disease at puberty, or during pregnancy and lactation, and is typically bilateral, and often very bulky.46,47

CNS disease most commonly presents either with cranial nerve palsies or with cerebrospinal fluid pleo-cytosis.48 Numbness of the lip and chin, associated with compression of the inferior alveolar nerve is relatively frequent in patients with bone marrow disease, presumably because this nerve passes through the mandible. Although this is not, in itself, indicative of CNS disease, it is a well-documented risk factor for involvement of the CNS.49

PATHOLOGY AND PATHOGENESIS Classical Burkitt's lymphoma

This pattern is seen in almost all cases of endemic BL, most cases of sporadic BL, and many cases of immunodeficiency-associated disease. Affected tissues are diffusely infiltrated by monomorphic, medium-sized cells. A distinct "starry sky" pattern can be seen as a result of the presence of benign macrophages ingesting nuclear debris resulting from the apoptotic death of the lymphoma cells. A very high proliferation rate is characteristic of BL. "Squaring off" of the cytoplasm is a common feature, especially using mercury-based fixatives such as B5.1

Variant BL with plasmacytoid differentiation

This variant is most commonly seen in BL associated with HIV infection. Pleomorphism in nuclear shape and size is more common than in classical BL. Nuclei are often slightly eccentric, and nucleoli are frequently single and central, giving the appearance of plasmacy-toid immunoblasts.150 This results in a morphology that has some features of diffuse large B-cell lymphoma.

Atypical Burkitt's and Burkitt-like lymphoma

Atypical BL is characterized by a very high proliferation fraction (close to 100% Ki-67 or MIB-1 positive) in association with evidence of the presence of c-myc translocation.151 It differs from classical BL morphologically in that there is greater nuclear pleomor-phism and nucleoli are more prominent, but present in lower numbers. The atypical morphologic features are probably related more to tissue processing artifact than to true biologic differences, and all other features of this entity are identical to classical BL, with the typical immunophenotype, including presence of CD10, absence of bcl-2, and cytogenetic or molecular evidence of a myc translocation as a single genetic abnormality.

Cases designated as Burkitt-like lymphoma are biologically distinct from classical BL, and have some features more consistent with diffuse large B-cell lym-phoma.152 As such they represent "gray zone" cases. Although these cases usually show a diffuse pattern of lymph node infiltration, cases with a follicular pattern are sometimes seen. High mitotic rates and a starry sky pattern are common, but large centroblasts are nearly always present. These cases usually have a lower proliferation rate by MIB-1 or Ki-67, and may either lack c-myc translocations or show c-myc and bcl-2 rearrangements in the same cells.

The typical immunophenotype for BL is summarized in Table 56.4. Tumor cells in classical and atypical BL are mature B cells that express CD19, CD20, CD22, and Cd79a, along with surface IgM, commonly with light chain restriction. Their germinal center origin is confirmed by frequent expression of CD10 and bcl-6.

All cases of BL have a translocation of myc at band q24 from chromosome 8 either to the Ig heavy chain region on chromosome 14 [t(8;14)] or to the light chain loci on chromosome 22q11 [t(8;22)] or chromosome 2q11 [t(2;8)].1 For those cases with t(8;14) translocations,

Cytogenetics t(8;14) or t(2;8) or t(8;22) t(8;14) or t(2:8) or t(8;22) Variable. Myc translocation may be present and may coexist with Bcl-2 translocation

Molecular Myc rearrangement Myc rearrangement Bcl-2 +/-, myc =/-

features

Immunophenotype and genetic/molecular features of Burkitt's lymphoma and variants

Classical Burkitt's Atypical Burkitt's Burkitt-like lymphoma lymphoma lymphoma the breakpoint varies between sporadic and endemic cases. In endemic cases, the breakpoint is at the heavy chain joining region, characteristic of a relatively early B cell. In sporadic cases, the translocation affects the Ig switch region, which characterizes a later stage of B-cell development.53 The myc gene becomes constitutively expressed with the result that the cells progress through the cell cycle. This is thought to be the critical event in lymphomagenesis in this disease, although myc activation also activates various target genes that are involved in the regulation of apoptosis.

The role of Epstein-Barr virus

The Epstein-Barr virus (EBV) is known to be an important factor in the development of endemic BL, where it is present in the majority of tumor cells. It is thought that the development of the lymphoma in this case is preceded by a long period of polyclonal B-cell activation secondary to multiple infective events, including the presence of EBV as well as malaria. Subsequent abnormal T-cell regulation of EBV infected cells may then lead to the development of lymphoma.4454

In contrast to endemic disease, the incidence of EBV in sporadic BL is less, at about 30% in immunocompetent patients, and about 25-40% in those who are immunosuppressed.4255 Although EBV is implicated in the etiology of BL, its exact role remains unclear.

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