Monika Pilichowska1, Stefania Pittaluga2, Judith A. Ferry3, Jessica Hemminger4, Hong Chang5, Jennifer A. Kanakry6, Laurie H. Sehn7, Tatyana Feldman8, Jeremy S. Abramson9, Athena Kritharis9, Francisco J. Hernandez-Ilizaliturri10, Izidore S. Lossos11, Oliver W. Press12, Timothy S. Fenske13, Jonathan W. Friedberg14, Julie M. Vose15, Kristie A. Blum16, Deepa Jagadeesh17, Bruce Woda18, Gaurav K. Gupta1, Randy D. Gascoyne7, Elaine S. Jaffe2, Andrew M. Evens19
1 Department of Pathology and Laboratory Medicine, Tufts Medical Center, Boston, Massachusetts, USA, 2 Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA, 3 Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA, 4 Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, Ohio, 5 Johns Hopkins University School of Medicine, Baltimore, MD, Institute for Clinical Research and Health Policy Studies and the Biostatistics, Epidemiology, and Research Design (BERD) Center at Tufts Medical Center, Boston, Massachusetts, 6 Study affiliation: Johns Hopkins University School of Medicine, Baltimore, MD (current: Experimental Transplantation & Immunology Branch, National Cancer Institute, Washington, DC), 7 Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada, 8 Hackensack University Medical Center, Hackensack, NJ, 9 Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, 10 Roswell Park Cancer Institute, Buffalo, NY, 11 University of Miami School of Medicine, Miami, FL, 12 Hutchinson Cancer Research Center, Seattle, WA, 13 Medical College of Wisconsin, Milwaukee, WI, 14 University of Rochester, Rochester, NY, 15 University of Nebraska Medical Center, Omaha, NE, 16 Division of Hematology, The Ohio State University, Columbus, Ohio, 17 Cleveland Clinic, Cleveland, OH, 18 Department of Pathology, UMASS Medical School, 19 Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA
Purpose: GZL is described as sharing features with cHL and DLBCL. However, there remains complexity in establishing diagnosis, delineating prognosis, and determining optimum therapy.
Methods: 68 cases diagnosed as GZL at 15 North American academic centers were evaluated by central pathologic review to achieve consensus. The recommended immunohistochemical (IHC) panel included: CD20, CD79a, PAX5, MUM1, CD30, CD15, CD3 and EBV (EBER) in situ hybridization. Beyond IHC, diagnostic morphologic criteria included: tumor cell density, fibrosis, necrosis and microenvironment. Survival differences were assessed using the log-rank test. Univariate associations of survival were derived using Cox proportional hazards model and entered into multivariate model.
Results: Of the original 68 cases, only 26 (38%) were confirmed as GZL on consensus review. Morphology was critical to GZL consensus diagnosis (e.g., tumor cell richness); IHC showed universal B-cell derivation, frequent CD30 expression, and rare EBV positivity (CD20+ 83%; PAX5+ 100%; BCL6+ 20%; MUM1+ 100%; CD30+ 92%; EBV+ 4%). 42 cases were reclassified: nodular sclerosis (NS) cHL, n = 27 (including n = 10 NS grade-2); lymphocyte predominant HL, n = 4; DLBCL, n = 4; EBV+ DLBCL, n = 3; primary mediastinal BCL n = 2; lymphocyte-rich cHL and BCL-NOS, n = 1 each. GZL consensus-confirmed vs re-classified cases more often had mediastinal disease (69% vs 41%, P = 0.038) and less likely >1 extranodal site (0 vs 25%, P = 0.019). With 44-month median follow-up, the 3-year progression-free survival (PFS) and overall survival for GZL patients were 39% and 95%, respectively, vs 58% and 85%, respectively, for re-classified cases (P = 0.19 & P = 0.15, respectively). Interestingly, NS grade-2 re-classified patients had similar PFS as GZL consensus-confirmed cases. For prognostication of GZL cases, hypoalbuminemia was a negative factor (3-year PFS 12% vs 64%, P = 0.01), while frontline cyclophosphamide, doxorubicin, vincristine, prednisone +/- rituximab was associated with improved 3-year PFS vs non-CHOP therapy (primarily ABVD): 70% vs 20%, P = 0.03. Both factors remained significant on multivariate analysis.
Conclusions: Altogether, the pathologic diagnosis of GZL remains challenging. High tumor cell content was extremely helpful in establishing diagnosis. Additionally, our results suggest that treatment with DLBCL-based regimens are most effective and we identified clinical factors that identified GZL patients with divergent clinical outcome.