The facts that
cancer represents tissues consisting of heterogeneous neoplastic, as well as reactive, cell populations and that
cancers of the same histotype may show profound differences in clinical behavior have long been recognized. With the advent of new technologies and the demands of
precision medicine, the investigation of
tumor heterogeneity has gained much interest. An understanding of intertumoral heterogeneity in patients with the same disease entity is necessary to optimally guide personalized treatment. In addition, increasing evidence indicates that different
tumor areas or primary
tumors and
metastases in an individual patient can show significant intratumoral heterogeneity on different levels. This phenomenon can be driven by
genomic instability, epigenetic events, the tumor microenvironment, and stochastic variations in cellular function and antitumoral
therapies. These mechanisms may lead to branched subclonal evolution from a common progenitor clone, resulting in spatial variation between different
tumor sites,
disease progression, and treatment resistance. This review addresses
tumor heterogeneity in
lymphomas from a pathologist's viewpoint. The relationship between morphologic, immunophenotypic, and genetic heterogeneity is exemplified in different
lymphoma entities and reviewed in the context of high-grade transformation and transdifferentiation. In addition, factors driving heterogeneity, as well as clinical and therapeutic implications of
lymphoma heterogeneity, will be discussed.