Double-hit B-cell lymphomas

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BlankBlood, 24 February 2011, Vol. 117, No. 8, pp. 2319-2331

Double-hit B-cell lymphomas

Sietse M. Aukema1,2, Reiner Siebert3, Ed Schuuring1, Gustaaf W. van Imhoff2,

Hanneke C. Kluin-Nelemans2, Evert-Jan Boerma1, and Philip M. Kluin1

1 Department of Pathology and Medical Biology, University Medical Center

Groningen, University of Groningen, The Netherlands; 2 Department of Hematology,

University Medical Center Groningen, University of Groningen, The Netherlands;

and 3 Institute of Human Genetics, Christian-Albrechts University Kiel and

University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany

In many B-cell lymphomas, chromosomal translocations are biologic and diagnostic

hallmarks of disease. An intriguing subset is formed by the so-called double-

hit (DH) lymphomas that are defined by a chromosomal breakpoint affecting the

MYC/8q24 locus in combination with another recurrent breakpoint, mainly a

t(14;18)(q32;q21) involving BCL2. Recently, these lymphomas have received

increased attention, which contributed to the introduction of a novel category

of lymphomas in the 2008 WHO classification, " B cell lymphoma unclassifiable

with features intermediate between DLBCL and BL. " In this review we explore the

existing literature for the most recurrent types of DH B-cell lymphomas and the

involved genes with their functions, as well as their pathology and clinical

aspects including therapy and prognosis. The incidence of aggressive B-cell

lymphomas other than Burkitt lymphoma with a MYC breakpoint and in particular a

double hit is difficult to assess, because screening by methods like FISH has

not been applied on large, unselected series, and the published cytogenetic data

may be biased to specific categories of lymphomas. DH lymphomas have been

classified heterogeneously but mostly as DLBCL, the majority having a germinal

center phenotype and expression of BCL2. Patients with DH lymphomas often

present with poor prognostic parameters, including elevated LDH, bone marrow and

CNS involvement, and a high IPI score. All studies on larger series of patients

suggest a poor prognosis, also if treated with RCHOP or high-intensity treatment

modalities. Importantly, this poor outcome cannot be accounted for by the mere

presence of a MYC/8q24 breakpoint. Likely, the combination of MYC and BCL2

expression and/or a related high genomic complexity are more important. Compared

to these DH lymphomas, BCL6+/MYC+ DH lymphomas are far less common, and in fact

most of these cases represent BCL2+/BCL6+/MYC+ triple-hit lymphomas with

involvement of BCL2 as well. CCND1+/MYC+ DH lymphomas with involvement of 11q13

may also be relatively frequent, the great majority being classified as

aggressive variants of mantle cell lymphoma. This suggests that activation of

MYC might be an important progression pathway in mantle cell lymphoma as well.

Based on clinical significance and the fact that no other solid diagnostic tools

are available to identify DH lymphomas, it seems advisable to test all diffuse

large B-cell and related lymphomas for MYC and other breakpoints.