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Scientific Institute, Milan, Italy; 12Department of Hematology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 13Department of Pathology, Odense University Hospital, Odense, Denmark; 14Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Introduction: In diffuse large B-cell lymphoma (DLBCL), multiple extranodal sites of involvement and MYC/BCL2 translocations (double-hit lymphoma) are associated with a poor clinical outcome. The association between the pattern of extranodal involvement and MYC/BCL2 protein co-expression, as well as their prognostic significance, is unknown. Methods: We analyzed the clinical data of 487 DLBCL patients treated with R-CHOP. Immunohistochemical (IHC) studies were performed for MYC and BCL2. A double-hit score (DHS) was assigned to all patients based on expression of MYC and BCL2. Those with http://www.selleckchem.com/products/ly2109761.html both MYC and BCL2 were DHS 2, with MYC or BCL2 was DHS 1, and neither was DHS 0. Cell-of-origin (COO) classification was achieved by combining gene expression profiling (GEP) and IHC data with GEP as the gold standard. Results: Approximately half of the patients (n?=?251; 51.5%) had at least one extranodal site of involvement. In this group, the clinical features were median age of 63?years (range, 12�C88), male (58.6%), stage III/IV (63.2%), elevated serum LDH (66.8%), and international prognostic index (IPI) of 3�C5 (48.5%). IHC features were MYC (64.9%), BCL2 (49.8%), MYC?/BCL2? (DHS 0; 20.3%), MYC/BCL2? or MYC?/BCL2 (DHS 1; 44.6%), and MYC/BCL2 (DHS 2; 35.1%). The common http://www.selleckchem.com/products/epz-5676.html extranodal sites of http://www.selleck.cn/products/Staurosporine.html involvement were genitourinary, gastrointestinal, and sinonasal tracts. MYC expression was associated with bone marrow (p?=?0.01) and skin (p?=?0.04) involvement, BCL2 with sinonasal (p?=?0.03) involvement, and MYC/BCL2 with skin/soft tissue (p?=?0.04) and lung (p?=?0.04) involvement. Non-germinal centre B-cell like (GCB) subtype was associated with genitourinary tract (p?