Tzankov, Alexandar5; Xu-Monette, Zijun Y6; Gerhard, Marc7; Visco, Carlo8; Dirnhofer, Stephan7; Gisin, Nora7; Dybkær, Karen9; Orazi, Attilio10; Bhagat, Govind11; Richards, Kristy L12; Hsi, Eric D13; Choi, William Wl14; van Krieken, J Han15; Ponzoni, Maurilio16; Ferreri, Andrés Jm16; Ye, Qing17; Winter, Jane N18; Farnen, John P19; Piris, Miguel A22; Møller, Michael Boe21; You, M James6; McDonnell, Timothy6; Medeiros, L Jeffrey6; Young, Ken H6
1 The Faculty of Medicine, Aalborg University, VBN2 Aalborg University Hospital, The Faculty of Medicine, Aalborg University, VBN3 Klinik Diagnostik, The Faculty of Medicine, Aalborg University, VBN4 Patologi, The Faculty of Medicine, Aalborg University, VBN5 1] Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA  Department of Pathology, University Hospital, Basel, Switzerland.6 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.7 Department of Pathology, University Hospital, Basel, Switzerland.8 Department of Hematology, San Bortolo Hospital.9 Department of Clinical Medicine, The Faculty of Medicine, Aalborg University, VBN10 Department of Pathology, Weill Medical College of Cornell University, New York, NY, USA.11 Department of Pathology, Columbia University Medical Center and New York Presbyterian Hospital, New York, NY, USA.12 Department of Hematology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.13 Department of Clinical Pathology, Cleveland Clinic, Cleveland, OH, USA.14 Department of Pathology, University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, China.15 Department of Pathology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.16 Unit of Lymphoid Malignancies, San Raffaele H Scientific Institute, Milan, Italy.17 Department of Pathology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China.18 Department of Hematology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.19 Department of Hematology, Gundersen Lutheran Health System, La Crosse, WI, USA.20 Hospital Universitario Marques de Valdecilla21 Patologi22 Hospital Universitario Marques de Valdecilla
In order to address the debatable prognostic role of MYC rearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYC rearrangements by fluorescence in situ hybridization in 563 cases using break-apart probes and IGH/MYC dual-fusion probes. Concurrent BCL2 and BCL6 aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYC rearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYC rearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYC rearrangements were more likely to be treatment resistant (P<0.0001). All types of MYC rearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYC rearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2 aberrations but not of BCL6 aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYC rearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYC rearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYC rearrangements. We conclude that MYC rearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.
Modern Pathology, 2014, Vol 27, Issue 7, p. 958-971