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E.D. McPhail et al.
this issue has been addressed. Previous studies on this matter have yielded conflicting results. Johnson et al., in a retrospective study of 54 DLBCL and BCLU cases with MYC/BCL2 identified by abnormal karyotype, showed that a non-IG/MYC partner was associated with a favor- able clinical outcome.6 However, they also found an asso- ciation between non-IG/MYC partner and DLBCL histo- logical appearance (P<0.001). In contrast, we found no such association in our cohort (P=0.96). This difference may, therefore, in part explain the divergent findings of clinical outcome between the two studies. In addition, case identification by abnormal karyotype may have selected for more aggressive disease. Pedersen et al. prospectively studied a cohort of 237 DLBCL and BCLU cases, including primary, transformed, and relapsed cases.8 They observed that IG/MYC rearrangements (n=9) were associated with a worse OS than were non- IG/MYC rearrangements (n=10). However, only 19 cases were studied, and this analysis included both MYC/BCL2 and MYC single-hit cases but lacked MYC/BCL6 cases. In addition, the patients received various treatment regi- mens, although most included rituximab plus intensive chemotherapy. An additional controversial element was the FISH protocol, because cases that were positive for a MYC rearrangement on the basis of a split MYC break- apart probe but were negative for IGH/MYC fusion were then studied with IGK and IGL break-apart probes rather than IGK/MYC and IGL/MYC dual-fusion FISH probes. Cases with concurrent MYC and IGK or IGL split break- apart probes were presumed to represent fusions, likely overestimating the number of IG/MYC cases.
Copie-Bergman et al. performed interphase FISH using break-apart probes for MYC, BCL2, and BCL6 and dual- fusion FISH probes for IGH/MYC/CEP8, IGK/MYC, and IGL/MYC as needed in 574 de novo DLBCL cases treated with rituximab–anthracycline-based chemotherapy.5 They found that the DH/THL cohort as a whole (n=32) had poorer outcome than the DLBCL cohort that lacked DH/THL rearrangements (P=0.046). However, on evalu- ating the IG/MYC and non-IG/MYC partner cases sepa- rately, Copie-Bergman et al. found that the 12 IG/MYC DH/THL cases had a poorer prognosis than the 19 DH/THL cases without non-IG/MYC rearrangement. They also observed poorer OS and progression-free sur- vival for the 25 MYC/BCL2 cases than for the seven MYC/BCL6 cases, but they did not report the IG gene ver- sus non-IG gene partners for these cases. Therefore, the IG versus non-IG gene results may have been confounded by the number of MYC/BCL2 versus MYC/BCL6 cases in each group. More than 90% of their DH/THL cases had large-cell histological characteristics (3 were reclassified
as high grade on re-review); by comparison, 60% of our cases had high-grade histological characteristics, which may have contributed to the discrepant findings between the two groups.
Other studies have shown no difference in survival between IG/MYC and non-IG/MYC groups. Aukema et al. studied 80 MYC rearrangement-positive B-cell lym- phomas, with exclusion of pediatric cases as well as adult cases with a gene expression profile of molecular BL.9 Most cases had the histological appearance of DLBCL, although some had other histological patterns, such as BCLU and follicular lymphoma. Similar to our study, Aukema et al. found no difference in survival between the IG/MYC and non-IG/MYC groups, both overall and within the MYC/BCL2 (n=26) and MYC/BCL6 (n=14) subgroups. However, various treatment regimens were used, and only some patients received immunotherapy (rituximab). Li et al. also found no significant difference in survival in MYC/BCL2 DH/THL cases with IG (n=23) ver- sus non-IG (n=5) MYC partners.11
More studies are needed to resolve the issue of the prognostic significance of MYC rearrangement partner in DH/THL. Our study, as well as those of Aukema et al.9 and Li et al.,11 suggests that it may not be necessary to identify whether the MYC gene rearrangement partner is an IG gene. Our current approach is to perform FISH on all aggressive B-cell lymphomas. However, in the light of these findings coupled with the association of DH/THL with such features as GCB phenotype, high-grade B-cell lymphoma morphological characteristics, and high MYC expression in immunohistochemistry, further risk-benefit analyses of alternative triage strategies are warranted.
In conclusion, in this large, retrospective, single-institu- tion study of DH/THL, although no differences in sur- vival were seen between the IG/MYC and non-IG/MYC groups, transformation from previously treated and untreated low-grade lymphoma was associated with infe- rior OS, and there was a trend toward inferior OS in patients with high-grade morphological patterns and the presence of a BCL2 rearrangement.
Acknowledgments
We thank Kay M. Ristow for her assistance with database management. This work was supported in part by National Institutes of Health (NIH) Grant no. P50 CA97274 to the University of Iowa and Mayo Clinic Lymphoma Specialized Program of Research Excellence, National Cancer Institute (NCI) Grant n. R01 CA200703, NCI Grant n. U01 CA195568, and the Henry J. Predolin Foundation, Inc. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
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