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1674 Part XI: Malignant Lymphoid Diseases Chapter 102: Burkitt Lymphoma 1675

diameter on a blood or marrow film) with a high nuclear-to-cytoplas- diagnosis of BL has been refined and diagnostic criteria have been tight-
mic ratio. Nuclear contours are round to oval without cleaves or folds, ened. Although the majority of BL cases, even in the adult, possess all of
a key feature in the distinction from DLBCL. Nucleoli are typically the criteria for the diagnosis: high mitotic rate in an appropriate mor-
multiple, small-to-intermediate in size, and the nuclear chromatin is phologic and immunophenotypic setting, together with an Ig-positive
relatively immature, being finely granular. Along with a high prolifer- MYC translocation, significant overlap exists with DLBCL and a minor-
ation rate these cells are characterized by a high rate of spontaneous ity of cases do not fit neatly into the diagnosis of either. Typically, this
apoptosis leading to the characteristic “starry sky” pattern in marrow arises because of the absence of key morphologic features in a lesion
and lymph nodes—a monomorphic diffuse background of lymphoma that otherwise resembles BL: a nonmonomorphic nuclear morphol-
cells that is interspersed with reactive macrophages engulfing cellular ogy; fewer tingible-body macrophages than is typical; or an abnormal
debris (so-called tingible-body macrophages) (see Fig. 102–1). immunophenotype. Terms that were once frequently used to describe
such cases, such as “atypical” BL or “Burkitt-like lymphoma,” have fallen
IMMUNOPHENOTYPE out of favor for diagnostic purposes, and these cases may be best classi-
BL cells are mature B cells, positive for CD19, CD20, CD22, and CD79a, fied as an intermediate or unclassifiable B-cell lymphoma (see “B-Cell
Lymphoma, Unclassifiable” below). Consequently the term “Burkitt
and have monotypic surface IgM; they lack CD5 and CD23. BL cells also lymphoma” is now reserved for a more pathologically uniform tumor
show immunologic similarity to germinal center cells of B-cell follicles type, and thus BL now arguably comprises one of the most homoge-
rather than activated B cells, being positive for BCL6, CD10, Tcl1, and neous subtypes of aggressive B-cell NHL.
CD38, negative for Mum-1, CD44, CD138, TdT (terminal deoxynu-
cleotidyl transferase), and importantly little to no expression of BCL2.
However, germinal center cells markers are not specific for BL, since a sig- B-CELL LYMPHOMA, UNCLASSIFIABLE
nificant proportion of DLBCL also has this germinal center cell signature. To address the spectrum of overlapping clinicopathologic features
exhibited by some cases that fall outside BL, the WHO developed a
EPSTEIN-BARR VIRUS STUDIES mixed classifier, termed “B-cell lymphoma, unclassifiable, (BCL-U)
with features intermediate between diffuse large B-cell lymphoma and
Although EBV is associated with 98 percent of eBL, it is also seen in Burkitt lymphoma.” Although some propose that this category rep-
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20 percent of sporadic cases, and in 30 to 40 percent of HIV-associated resents a distinct clinicopathologic entity, this designation is primarily
cases. It can be detected using in situ hybridization for EBER. Although reserved for cases with morphologic and/or immunophenotypic fea-
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EBV likely plays a key role in B-cell stimulation during a prelymphoma tures that preclude more specific classification into either group. The
stage, the role for EBV after lymphoma development is unclear, as is BCL-U category is not intended simply to include otherwise conven-
whether EBV positivity is clinically meaningful. In EBV-positive tional DLBCL that harbor a MYC translocation, or conversely BL for
endemic cases, CD21 (the EBV receptor) is expressed and is negative in which a MYC translocation cannot be demonstrated.
most EBV-negative nonendemic BL cases. In contrast to primary effu-
sion lymphomas and DLBCL, EBV-positive, HIV-associated BL does not
express LMP1 or EBNA2. DOUBLE-HIT LYMPHOMA
Another diagnostic term that has recently gained widespread use is
CYTOGENETICS “double-hit lymphoma” (DHL). Although not a formal diagnostic cat-
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Virtually all cases of BL have a translocation between the long arm of egory, DHL refers to a subset of aggressive mature B-cell (non-Burkitt)
chromosome 8, the site of the MYC protooncogene (8q24), and one of lymphomas that harbor translocations of MYC as well as at least one
three translocation partners: the Ig heavy-chain region on chromosome other protooncogene (most commonly BCL2 or BCL6). Distinction
14; the κ light-chain locus on chromosome 2; or the λ light-chain locus of such a subset is warranted given that DHL, empirically, has among
on chromosome 22. The translocations involving MYC can be detected the worst prognosis of any NHL and patients may benefit from more
by fluorescence in situ hybridization (FISH) using so-called MYC “break intensive chemotherapy. The prognostic implication for DLBCLs that
apart” probes: a set of two fluorescently tagged DNA probes of two differ- overexpress both MYC and BCL2 (i.e., “double-hit” patterns of pro-
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ent colors that hybridize to the upstream and downstream side of the gene. tein expression as determined by immunohistochemistry) is similar.
In an unperturbed gene, they hybridize together within interphase cells Whereas DHL most frequently exhibits histomorphologic features of
giving a composite color, whereas with translocation, the two fluorescently DLBCL or BCL-U, and the importance of BCL2 activity clearly distin-
labeled probes are separated. A key feature of BL is the relative simplicity of guishes it from BL, the clinical aggressiveness of these tumors and critical
their karyotype; in the majority of cases, the MYC translocation is the sole importance of MYC dysregulation have prompted comparisons to BL.
abnormality. This relatively limited degree of chromosomal change has
been confirmed by microarray studies which can detect submicroscopic B-CELL LYMPHOBLASTIC LYMPHOMA
chromosomal alterations. 39,40 Among the few changes repeatedly seen by Despite the fact that B-cell lymphoblastic lymphoma (B-LBL; a.k.a.
microarray, MYC amplification is found in mBL cases that lack Ig-MYC B-cell acute lymphoblastic leukemia [B-ALL]) is a malignant neoplasm
translocation. In general, this noncomplex cytogenetic profile for BL dis- of immature B-cell precursors, numerous features warrant its consid-
tinguishes it from DLBCL, which is among one of the primary consider- eration in the differential diagnosis with BL, including: anatomic dis-
ations in the differential diagnosis with BL, as discussed below. tribution (marrow, soft tissues, and nodes), high proliferation index,
overlapping histomorphology (medium-size round-cell morphology,
finely dispersed nuclear chromatin, high nuclear-to-cytoplasmic ratio,
DIFFERENTIAL DIAGNOSIS and occasional “starry sky” pattern), immunophenotype (CD10-posi-
tive/CD20-variable), and propensity to occur in young patients. Dis-
DIFFUSE LARGE B-CELL LYMPHOMA tinctive features include the expression of TdT, absence of mature B-cell
The primary pathologic diagnosis in the differential diagnosis of BL markers (e.g., surface immunoglobulin expression and BCL6), and the
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is DLBCL. Since the publication of the 2008 WHO guidelines, the distinctive cytologic and flow cytometric features of immature blasts.

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