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E.D. McPhail et al.
rearrangements of MYC and BCL2 or BCL6, or both, besides those that meet criteria for follicular or lym- phoblastic lymphoma. It encompasses some cases previ- ously called ‘B-cell lymphoma, unclassifiable, with fea- tures intermediate between diffuse large B-cell lym- phoma (DLBCL) and Burkitt lymphoma (BL) (BCLU)’, in accordance with the 2008 WHO classification.2 These cases were considered clinically aggressive but were diffi- cult to diagnose because of vague diagnostic criteria.
By morphological evaluation, DH/THL may show a cytological spectrum. The spectrum can range from (i) monotonous medium-sized cells with round nuclei, fine- ly dispersed chromatin, and starry sky appearance, resembling BL, to (ii) intermediate-sized cells with slight pleomorphism and slightly irregular nuclear contours, resembling BCLU,2 to (iii) large lymphoid cells with round to irregular nuclear contours, variably sized nucleoli, and varying amounts of cytoplasm, resembling DLBCL. Experts have recommended that during evaluation, details of the morphological appearance be added in a comment to the record because of the potential prognos- tic importance of morphological characteristics.1 Yet, few studies have specifically addressed morphological appear- ance as a prognostic indicator.
MYC is a powerful transcriptional factor that helps to drive the cell from G0/1 phase to S phase and promotes cell proliferation and growth, DNA replication, and protein biosynthesis. It was identified initially as the molecular target of the 8q24 rearrangement characteristic of BL but was subsequently identified in various B-cell lymphomas, including 5% to 15% of DLBCL and 30% to 60% of high- grade B-cell lymphomas.3-5 The MYC rearrangement part- ner in BL is almost invariably an immunoglobulin (IG) gene (IGH, IGK, or IGL), whereas in DLBCL and high- grade B-cell lymphoma it is a non-IG gene in about 40% of cases.5-9 Common non-IG MYC partners include lym- phomagenesis-related genes, such as BCL6, BCL11A, PAX5, and IKAROS.10 In IG/MYC rearrangements, MYC is juxtaposed to an IG enhancer, usually resulting in pro- nounced amplification of MYC protein expression, whereas MYC expression and MYC transcript levels are often less robust in the clinical setting of non-IG/MYC rearrangements.5,9 The prognostic significance of the MYC partner gene is controversial. Some groups found that a non-IG MYC partner was a survival advantage,5,6,8 while other groups observed no significant difference between IG and non-IG partner cases.9,11
DH/THL was established as a new diagnostic category in part because of its aggressive clinical behavior. However, most DH/THL cases have a BCL2 rearrange- ment (i.e., MYC/BCL2 or MYC/BCL2/BCL6). The clinical behavior of those lacking the BCL2 rearrangement (i.e., MYC/BCL6 cases) is not well understood because a limit- ed number are available for analysis. At present, the prog- nostic significance of MYC/BCL6 in this context is con- troversial, with different groups identifying superior out- come,5,12 no difference in outcome,13 or inferior out- come.9,14,15 However, fewer than 100 cases have been described in the literature.
The reported median overall survival (OS) for DH/THL in different series range from 4.5 to 34 months.6,10,13,16-26 Patients were treated primarily with rituximab, cyclophosphamide, doxorubicin, and vincristine (R- CHOP)27; dose-adjusted etoposide, prednisone, vin- cristine, cyclophosphamide, doxorubicin, and rituximab
(EPOCH-R)28; rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper CVAD); methotrexate; cytarabine25; and rituximab, cyclophos- phamide, vincristine, doxorubicin, and methotrexate/rit- uximab, ifosfamide, etoposide, and cytarabine (R- CODOX-M/IVAC)29 with or without an autologous stem cell transplant in first complete remission. The median progression-free survival and OS were not improved in some series,13,23,25 but were improved in one series.30 Autologous stem cell transplantation in the relapse setting is associated with poor outcomes.31-33 Few studies have addressed the prognostic significance of transformation of low-grade lymphoma to DH/THL.34
In the light of the controversy surrounding these issues, the present study investigated the prognostic significance of several of these parameters, including morphological evaluation, IG/MYC versus non-IG rearrangement part- ner, presence or absence of a BCL2 rearrangement, trans- formation from low-grade lymphoma, and therapeutic regimens in diagnostic cases of DH/THL at the Mayo Clinic in Rochester, Minnesota. To our knowledge, this study represents the largest single-institution study of these characteristics among contemporary DH/THL patients.
Methods
The Mayo Clinic Institutional Review Board approved this study and all patients provided consent. Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines were followed. Cases were identified through review of Mayo Clinic patients in the Mayo Clinic Lymphoma Database (1998-2015) and the Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource (2002- 2015). Five cases were identified from the Molecular Epidemiology Resource through fluorescence in situ hybridiza- tion (FISH) performed for other studies.35 The therapeutic regi- mens were R-CHOP, dose-adjusted EPOCH-R, R-CODOX- M/IVAC, R-hyper-CVAD, methotrexate, cytarabine, and non– anthracycline-based treatment. Additional information regard- ing case identification and case criteria is detailed in the Online Supplementary Appendix.
All cases were diagnosed initially by a Mayo Clinic hematopathologist as either DLBCL or BCLU according to the 2008 WHO criteria;2 all were reclassified as DH/THL according to the 2016 WHO criteria.1 Morphological re-review to assess high-grade versus large-cell histological characteristics was per- formed by four Mayo Clinic hematopathologists (ALF, PJK, WRM, and EDM). Definitions of high-grade and large-cell cyto- logical features are detailed in the Online Supplementary Appendix. For outcome analysis, only cases with a consensus re- review diagnosis were used.
Cell of origin was determined according to the Hans classifier.36 Immunohistochemical methods and criteria are detailed in the Online Supplementary Appendix. Interphase FISH was performed on either paraffin sections of tissue specimens or smears of bone marrow aspirate specimens according to previ- ously described methods37,38 using break-apart probes for MYC and BCL6; dual-fusion FISH probes for IGH/MYC, IGL/MYC, and IGK/MYC; and either a BCL2 break-apart probe or an IGH/BCL2 dual-fusion FISH probe. Further details are provided in the Online Supplementary Appendix. Because of tissue limita- tions, not all probe sets were performed in all cases. Specifically, in some cases, the MYC rearrangement partner could not be
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haematologica | 2018; 103(11)