Progress in the identification of subgroups in ALK-negative anaplastic large-cell lymphoma.

Abstract

Classification of anaplastic large cell lymphoma: historical background Anaplastic large cell lymphoma (ALCL) represents a group of non-Hodgkin lymphomas of mature T-cell origin (peripheral T-cell lymphomas [PTCLs]) that share common pathologic features, especially the presence of large lymphocytes that often involve lymph node sinuses and express the Ki-1 antigen, now designated CD30 [1]. A chromosomal rearrangement in a subset of these cases, t(2;5)(p23;q35), was found to involve the nucleophosmin gene, NPM1, and a novel tyrosine kinase gene, designated anaplastic lymphoma kinase or ALK [2]. Immunohistochemical staining for ALK allowed recognition that cases with several histologic patterns as well as cases with variant, nonNPM1 partner genes could be unified into a common clinicopathologic entity, ALK-positive ALCL [3]. An additional group of cases lacked ALK rearrangements, and these ALKnegative ALCLs occurred in older patients and had inferior outcomes compared with ALK-positive ALCLs [4]. The fourth edition of the WHO classification of lymphomas provisionally classified ALK-negative ALCL as a distinct entity separate from ALK-positive ALCL [5], and this provisional status is likely to be dropped in a forthcoming WHO update. Nevertheless, diagnostic criteria for ALK-negative ALCL still are evolving, particularly to distinguish it from other CD30positive PTCLs [5–7]. Primary cutaneous ALCL is recognized separately by the WHO and represents ALCLs that present in the skin and typically have excellent long-term outcomes [5]; these tumors share some genetic features with systemic ALCLs, as discussed below. The pathogenic role of ALK fusions in ALK-positive ALCL has been studied extensively; however, the pathobiology of ALKnegative ALCL remains incompletely understood [6]. Gene expression profiling studies have identified a molecular signature for ALK-positive ALCL and another signature common to all ALCLs [7]. This latter signature can help distinguish ALCL from other PTCLs, but identifying a signature specific for ALK-negative ALCL has proved challenging. This difficulty likely relates in part to intrinsic molecular heterogeneity within the category of ALK-negative ALCL.