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Who Should Be Tested for Double-Hit Lymphoma?

Double-hit lymphoma (DHL) is an aggressive variant of B-cell non-Hodgkin lymphoma and is characterized by rearrangements in MYC as well as in BCL2 and/or BCL6. The histologic classification of these lymphomas is typically diffuse large B-cell lymphoma (DLBCL) or B-cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma (BCLU), with up to 15% and 75% of cases, respectively, classified as DHL. Although the frequency of DHL is lower in patients with DLBCL than it is in those with BCLU, it is likely that the greatest number of DHL cases occurs in patients diagnosed with DLBCL because of the higher incidence of DLBCL compared with BCLU. In the article that accompanies this commentary, Staton and Cohen provide a thorough and well-written series of recommendations for the assessment and treatment of patients with DHL. However, as patients with DHL who experience failure of front-line therapy rarely achieve durable responses with subsequent treatments, we cannot effectively apply the management pathway suggested by Staton and Cohen to patients with undiagnosed DHL, or to thosewho are first tested for and diagnosed with DHL at the time of relapsed or refractory disease. Thus, clinicians and pathologists alike must understand the importance of testing for DHL at diagnosis, in particular for cases of DLBCL. Multiple retrospective studies have explored the link between clinicopathologic features and the incidence of DHL. It has been suggested that DHL occurs more frequently in patients with lymphomawho have elevated levels of lactate dehydrogenase or Ki-67 expression or in patients with a history of follicular lymphoma; however, in a review of patients with high-grade lymphoma treated at our center, we did not find any baseline characteristics to be predictive of DHL. Although it seems that most, if not all, cases of MYC/BCL2-rearranged DHL are of germinal centerB-cell origin (GCB), 25% to 45% of MYC/BCL6-rearranged DHL cases are of non-GCB origin; thus, these cases would be missed if only GCB DLBCL tumors were screened for DHL.