CLINICAL: ALK-positive large B-cell lymphoma is a highly aggressive subtype of large B-cell lymphoma that expresses anaplastic lymphoma kinase (ALK) gene. It occurs in young patients (median age 36 years; one-third cases occur in children) with a male:female ratio of 3:1. There is no association with immunosuppression. Most patients present with advanced nodal disease and succumb to the tumor within a year of diagnosis. MORPHOLOGY: The lymph node architecture is effaced by sheets of high-grade tumor cells with immunoblastic or plasmablastic features. The cells may be deceptively cohesive with an epithelioid appearance and may be misinterpreted as carcinoma. IMMUNOPHENOTYPE: The tumor cells are usually positive for CD45 with absent or weak positivity for CD20, CD79a, and CD30. There is strong immunoreactivity for CD138, kappa or lambda light chains (usually IgA), and EMA (as well as cytokeratin in some cases). Expression of CD4 and CD57 is seen in 40% to 60% of cases. By definition, this tumor expresses ALK with granular cytoplasmic staining. EBV is negative. GENETICS: Overexpression of ALK gene is due to t(2;17)(p23;q23) translocation which fuses CLTC (clathrin) gene on 17q23 with the ALK gene on 2p23. CLTC encodes the clathrin heavy polypeptide which is the main structural protein of coated vesicles. ALK codes for anaplastic lymphoma kinase which is a receptor tyrosine kinase. Rare cases show the t(2;5)(p23;q35) translocation (seen in ALK+ anaplastic large cell lymphoma of T/null phenotype) which fuses NPM and ALK genes leading to the nuclear as well as cytoplasmic expression of ALK protein.