Diffuse large B-cell lymphoma (DLBCL) is the most common histotype of non-Hodgkin lymphoma among adults,1 with a median age at diagnosis of approximately 70 years and an annual incidence of 7–8 cases per 100,000 people in the United States of America.23 The overall 5-year survival rate for older adults is about 60%, while for children ranges from 70% to 90%.4 It can arise in any body site as a rapidly growing lymph node or mass, sometimes associated with B symptoms (fever, weight loss, night sweats) and/or serum elevation of lactate dehydrogenase.5 Actually, DLBCL encloses a wide spectrum of aggressive, variably responding, lymphomas, different in terms of biology and clinical practice, many of which cannot be separated from one another by well-defined and widely accepted criteria.6 In this regard, the 2016 World Health Organization (WHO) classification of lymphoid neoplasms recognizes several variants of LBCL on the basis of tumor location (central nervous system, skin, mediastinum, serous cavities, inside the vessels), cell background (T cell / histiocyte-rich, chronic inflammation) and concomitant or coexisting diseases (Epstein-Barr virus, Kaposi's sarcoma virus, Castleman disease).7 In some circumstances, DLBCL can also share many features with Hodgkin's lymphoma, being encoded as ‘B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Hodgkin's lymphoma’.7 However, the vast majority of DLBCL cases fall into the ‘not otherwise specified’ (NOS) category. Current efforts are precisely intended to better characterize this still heterogeneous group by evaluating cellular morphology (centroblastic, immunoblastic, plasmablastic, anaplastic) and gene expression (germinal center B-cell-like, activated B-cell-like).6789 Over the years, researchers have realized that important distinctions can be quickly achieved by exploiting immuhistochemistry, and, so, the products of prognostically relevant genes, such as ALK, IRF4, CCND1, LEU1 (CD5), MYC, BCL2 and BCL6 are entered in the diagnostic procedure.101112 This has led to the nosological introduction of ‘ALK positive large B-cell lymphoma’, of ‘large B-cell lymphoma with IRF4 rearrangement’ and of ‘de novo CD5-positive DLBCL’,713 together with the widespread adoption of new terminologies, such as ‘double-hit’ and ‘triple-hit’, referring to those lymphomas characterized by a double synchronous genetic mutation, involving MYC and BCL2 or BCL6, or by a triple synchronous rearrangement of MYC, BCL2 and BCL6.14 These subcategories have replaced the provisional entity of ‘B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt's lymphoma’, dating back to the 2008 WHO classification.15 Double-hit lymphomas are often diagnosed at advanced stages, they show high recurrence rates, despite high-intensity chemotherapy, and are almost always fatal.16 Triple-hit lymphomas are characterized by an aggressive clinical behavior, with frequent dissemination to extranodal sites (e.g. bone marrow, central nervous system), and the standard chemotherapy, used for DLBLC or Burkitt's lymphoma, results ineffective.17 Similarly, the patients affected by de novo CD5-positive DLBCL usually suffer from poor performance status and extranodal involvement, like the central nervous system, and are penalized by an inferior response to rituximab-containing regimens.13 Recently, in an 87-year-old male patient who was submitted to emergency surgery for perforated ulcer (3 cm in size) of the stomach, I diagnosed a de novo CD5-positive primary gastric DLBCL coexpressing Myc and Bcl6; the cytoproliferative index, evaluated by immunohistochemistry for Ki67 antigen, reached the 80% (Fig. 1). The patient died 4 months after surgery despite the administered chemotherapy (R-CHOP). Therefore, there are all the biological and clinical conditions to consider this particular subset of lymphoma a proper triple-hit lymphoma. A final question consequently arises: does quadruple-hit lymphoma involving de novo CD5 (CD5 positive, Myc positive, Bcl2 positive, Bcl6 positive) exist? Just this year, Xiao and colleagues have reported the case of a de novo CD5-positive primary cardiac DLBCL coexpressing Myc and Bcl2.18 Noteworthily, even in this occurrence, the lymphoma developed in an extranodal site. Previously, four lymphoma-specific genetic events (MYC, BCL2, BCL6, CCND1) have been identified in parallel in three patients affected by high grade mature B-cell lymphomas, two of whom died 6 and 9 days from diagnosis.1920 Hence, from a theoretical point of view, there are the assumptions for an affirmative answer.