Lymphoma diagnosis integrates clinical, morphological, immunophenotypical, and molecular genetic features, as shown in WHO classifications of lymphoid malignancies. Diagnosis of lymphoma is challenging. Reactive lesions such as Kikuchi lymphadenitis, infectious mononucleosis, autoimmune lymphoproliferative syndrome, and immunoglobulin G4-related sclerosing disease can be misdiagnosed as lymphomas. Anaplastic large-cell lymphoma variants that are positive for anaplastic lymphoma kinase, classical Hodgkin's lymphoma variants, and infarcted lymphomas might be misdiagnosed as reactive disorders. Difficulties with classification of lymphomas are also encountered, such as the distinction of classical Hodgkin's lymphoma from anaplastic large-cell lymphoma that is negative for anaplastic lymphoma kinase. Interpretation of immunophenotyping results is complicated in some cases by aberrant or cross-lineage expression of lymphoid antigens on lymphomas, and the occasional lymphoid antigen expression on non-lymphoid malignancies. Molecular analysis can help to define clonality and lineage, but can be affected by the sensitivity and specificity of tests and cross-lineage gene rearrangement and pseudoclonality. To resolve these issues, a close collaboration between the clinician, histopathologist, and molecular biologist is needed. The aim of this review is to provide pathologists and clinicians with a concise account of these pitfalls and avoidance strategies.
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