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Prognostic markers of double-/triple-hit lymphomas
outcome.43 In contrast, Petrich et al., in their retrospective study of 311 DH/THL patients, reported that histological appearance had no effect on OS; however, theirs was a multicenter study across 23 medical centers without cen- tral pathological review.13 Our cases were derived from a single institution, and outcome analysis was restricted to cases with a consensus re-review diagnosis among four expert hematopathologists, lending support to the validi- ty of this finding.
The clinical significance of high-grade histological char- acteristics underscores the importance of the revised WHO recommendation to note morphological appearance in all DH/THL cases.1 Furthermore, because DH/THL cases often show morphological characteristics of DLBCL (40% in this series), a complete interphase FISH analysis to exclude DH/THL is important for all cases with large-cell or high-grade morphological appearance. Also, low MYC expression by immunohistochemistry does not reliably predict absence of a MYC rearrangement. In the present series, 14% of evaluable cases, all with a MYC rearrange- ment by definition, had fewer than 40% MYC-positive cells by immunohistochemistry. However, these cases were too few to analyze outcome, and it is not known whether absence of MYC expression in DH/THL has a favorable impact on survival.
Third, clinical and pathological differences were report- ed and depended on whether a BCL2 rearrangement was present. BCL2-rearranged cases [i.e., MYC/BCL2, MYC/BCL2/BCL6, or MYC/BCL2 (BCL6 unknown)] showed heterogeneous presentation as de novo, recurrent, or transformation events but were uniformly of GCB type. The latter finding has been previously described.4,5,7,9,26 Conversely, MYC/BCL6 cases uniformly developed de novo but were equally likely to be GCB or non-GCB type. Thus, all patients with non-GCB DH/THL in our cohort had MYC/BCL6. Although the association between non-GCB subtype and MYC/BCL6 has been reported previously,5,9 this is the largest cohort to date to investigate this issue.
Clinically, our 12 MYC/BCL6 cases with outcome analysis showed a nonsignificant tendency to superior OS and EFS12, regardless of whether only the de novo cases were evaluated. Previous studies have yielded con-
flicting results. Two studies showed an association between MYC/BCL6 and poor prognosis.9,14 In the first study, only six FISH-confirmed cases were evaluated.14 In the second study, the MYC/BCL6 group, which had older patients with uniformly large-cell histological features, was compared with a MYC/BCL2 group that was younger and had various histological patterns, including low-grade lymphoma.9 Two other studies reported improved survival of patients with MYC/BCL6 compared to those with MYC/BCL2 DH/THL, but only seven and four cases, respectively, were studied.5,44 Another group showed better survival in de novo MYC/BCL6 with large- cell morphological features compared with MYC/BCL2 DH/THL combined with MYC-rearranged single-hit DLBCL.12 Four additional studies – three included patients with large-cell lymphomas and high-grade histological characteristics13,15,25 and one comprised only subjects with large-cell histological features26 - showed no difference in survival between MYC/BCL2 and MYC/BCL6 DH/THL. However, the former two studies also included cases of follicular lymphoma,13,15 and the third study included cases with extra intact signals, as well as rearrangements of MYC, BCL2, and BCL6.25 This lack of uniformity may have affected the outcome data. More studies are needed to resolve the issue of the prognostic significance of MYC/BCL6 in DH/THL.
Some groups have suggested that it may not be neces- sary to perform interphase FISH studies to exclude DH/THL in large-cell or high-grade B-cell lymphomas of non-GCB phenotype. However, if this approach were fol- lowed, about one-half of MYC/BCL6 DH/THL would fail to be identified. The MYC/BCL6 cases in our study showed a tendency toward superior OS and EFS12. Nevertheless, in the light of conflicting outcome data in the literature, potential for poor clinical outcome, and suggested benefit from more aggressive therapy in this cohort, we advocate the performance of interphase FISH to exclude DH/THL in all large-cell and high-grade B-cell lymphomas, regardless of their cell of origin.
Fourth, we found no association between MYC partner (IG gene versus non-IG gene) and clinical outcome. To our knowledge, our study represents the largest (n=87) and most comprehensively studied cohort to date in which
Figure 5. Overall survival according to treatment regimen. Patients treated with R-CODOX-M/R- IVAC had superior overall survival, although the difference was not statistically significant (hazard ratio 0.37, P=0.10). DA-EPOCH-R: dose-adjusted etoposide, prednisone, vincristine, cyclophos- phamide, doxorubicin, and rituximab; R-CHOP: rit- uximab, cyclophosphamide, doxorubicin, and vin- cristine; R-CODOX-M/IVAC: rituximab, cyclophos- phamide, vincristine, doxorubicin, and high-dose methotrexate alternating with rituximab, ifos- famide, etoposide, and high-dose cytarabine; R- hyper-CVAD: rituximab, cyclophosphamide, vin- cristine, doxorubicin, and dexamethasone.
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