RS is a heterogeneous entity, which encompasses at least two different conditions: (1) transformation of CLL cells to a clonally related diffuse large B-cell lymphoma (DLBCL) (most common) and (2) development of a DLBCL that is unrelated to the CLL clone. The disease involves most frequently the lymph nodes, but extranodal localizations are also not uncommon and have been reported in the GI tract, skin, liver, tonsil, and bone marrow among other sites. Exact etiology of RS is unclear, but risk factors include trisomy 12, deletion of 11q23, microsatellite instability, mutations in tumor suppressor genes, and Epstein-Barr virus infections. RS is usually heralded by sudden clinical deterioration and a rapid increase in the size of a lymphoid mass at one site. Clinical features include systemic symptoms (59%), progressive lymphadenopathy (64%), extranodal involvement (64%), elevation in lactate dehydrogenase (82%), and a monoclonal gammopathy (44%). The median time for the development of RS is 21.6 months.