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Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL), which accounts for 30–40% of adult NHL with 27,650 estimated new cases diagnosed in the United States in 2016. DLBCL is defined as a B-cell neoplasm with a diffuse growth pattern of large tumor cells with a nuclear size larger than that of a histiocyte nucleus or more than twice that of a normal small lymphocyte.

Excisional biopsy of lymph node is a routine procedure for evaluating lymphoid pathology in patients with lymphadenopathy. A standard workup to rule out lymphoma is a comprehensive study, including histologic evaluation, immunohistochemical analysis, flow cytometry, cytogenetic study (i.e., FISH for targeted cytogenetic abnormalities), and/or molecular diagnostic tests. This chapter covers some general principles for handling specimens of lymphoma workup, clinical correlation with types of lymphoma, common morphological patterns of lymphomas or mimics, and judicial application of ancillary tests, based on clinical presentations and initial morphologic evaluation.