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2-ALK - REVIEWS The anaplastic lymphoma kinase in the...

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It is now agreed that anaplastic large cell lymphoma (ALCL) is a distinct subset of T-cell non-Hodgkin lym- phomas (NHL) 1 for which a normal cellular counterpart has not yet been established. Morphological, immu- nophenotypical and molecular genetic studies have elucidated many of the pathogenetic events in the devel- opment and progression of ALCL. Prior to the discovery of the CD30 antigen (also known as tumour necrosis factor receptor superfamily, member 8 ( TNFRSF8 )) as a characteristic marker 2 , ALCL was variously mis- interpreted as different diseases: histiocytic lymphoma, malignant histiocytosis, Hodgkin disease, malignant melanoma, metastatic carcinoma or malignant fibrous histiocytoma 3 . The lymphoid origin was finally deter- mined from the presence of clonal T-cell receptor (TCR) gene rearrangements and/or the expression of T-cell lineage-associated antigens. Primary systemic ALCL has a peak incidence in childhood, accounting for approximately 40% of NHL cases diagnosed in paediatric patients 4 , whereas it accounts for <5% of NHL in adults 5 , and it is seen mostly in males. Patients present with stage III to IV disease, often with multiple extranodal sites of involvement 6,7 . In the late 1980s, the t(2;5)(p23;q35) translocation was described by several groups as the most frequent in ALCL 8–10 and in 1994 the product of this translocation was identified as the receptor tyrosine kinase (RTK) ana- plastic lymphoma kinase ( ALK ) fused to nucleophosmin ( NPM1 , also known as NPM and B23) 11 (TIMELINE) . Many groups have since discovered additional translocations in which ALK is fused to other partners (TABLE 1) . Nevertheless, ~15–40% of ALCL 1,3,12 do not express ALK or other recurrent translocations. Although the current World Health Organization classification of lymphomas considers ALK-positive and ALK-negative ALCL to share the same category, it is now suggested that these two types of lymphomas, as well as cutaneous ALCL, might correspond to different entities 12 ( European Association for Haematopathology ). This Review illustrates the translocations involv- ing ALK and the molecular mechanisms that underlie the pathogenesis of ALK-positive ALCL. We will also discuss the potential of ALK as a specific target for the therapy of ALCL and other cancers. ALK and its translocations in NHL ALCL and ALK. There are various morphological subtypes of ALCL. The predominant subtype, also called ‘common’ type, is composed of large, pleomor- phic, atypical tumour cells with an abundant grey-blue cytoplasm. Their nuclei are large, horseshoe- or kidney- shaped, and sometimes have pseudonuclear inclusions (so-called doughnut cells). These hallmark cells are characteristic of ALCL 13 . Rare variants are the ‘small-cell’ subtype, which is composed of a predominant popula- tion of medium and small cells with clear cytoplasm and irregular nuclei, and the ‘lymphohistiocytic’ subtype, in which large numbers of histiocytes are mixed with the tumoural cells. Other even rarer types include the ‘giant-cell-rich’ subtype, with many tumour cells with
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