A New Subtype of Large B-Cell Lymphoma Expressing the ALK Kinase and Lacking the 2; 5 Translocation

Abstract

Seven cases of large B-cell lymphoma which define a previously unrecognized subgroup are reported. Morphologically they are comprised of monomorphic large immunoblast-like cells, containing large central nucleoli, which tend to invade lymphatic sinuses. Superficially they resemble anaplastic large cell lymphoma (ALCL) but they lack CD30. These lymphomas express epithelial membrane antigen (as do ALCL), but also contain intracytoplasmic IgA of a single light chain type (five cases) and an endoplasmic reticulum–associated marker detected by antibody VS38. They lack lineage-associated leukocyte antigens with the exception of CD4 (5 of 5 cases) and CD57 (5 of 7 cases). They are labeled by antibodies detecting both the intracytoplasmic and extracellular regions of the ALK receptor kinase, suggesting that they express the full-length form of this molecule. This was confirmed by Western blotting (in the one case tested) which showed a band of 200 kD in tumor cell lysates, and by polymerase chain reaction (PCR) amplification of mRNA encoding intracellular and extracellular ALK sequences (in the two cases tested). There was no evidence by cytogenetics (one case analyzed) or reverse transcriptase-PCR (three cases tested) of the 2; 5 translocation or the resultant NPM-ALK gene, as is commonly found in ALCL. All but one of the patients were male and all but one were adults, and in all but the latter case the disease followed an aggressive course.

Aggressive B‐cell lymphomas: a review based on the workshop of the XI Meeting of the European Association for Haematopathology

“…42 DLBCL with expression of ALK ALK+ DLBCL was originally described in 1997 as a rare subtype of lymphoma expressing the full-length ALK protein. 43 However, full-length ALK protein lacks tyrosine kinase activity and the mechanism of oncogenesis has remained elusive. Recently these ALK+ DLBCL have been shown to carry a single or complex t(2;17)(p23;q23) involving the Clathrin gene at chromosome band 17q23 and the ALK gene at chromosome band 2p23.…”

Activity of second‐generation ALK inhibitors against crizotinib‐resistant mutants in an NPM‐ALK model compared to EML4‐ALK

“…The first evidence of ALK oncogenic properties emerged in 1994, when the fusion protein nucleophosmin (NPM)-ALK originated by the chromosomal translocation t(2;5)(p23;q35) was identified and associated with an aggressive form of non-Hodgkin T-cell lymphoma, known as anaplastic large-cell lymphoma (ALCL) [3]. Several dysregulated or aberrant ALK forms have since been discovered as the cause of hematopoietic and non-hematopoietic malignancies, such as diffuse large B-cell lymphoma (DLBCL) [4], inflammatory myofibroblastic tumor (IMT) [5], neuroblastoma [6], anaplastic thyroid cancer [7], rhabdomyosarcoma [8], non-small-cell lung cancer (NSCLC) [9], and other diseases [10][11][12][13][14][15][16][17]. In particular, about 5% of NSCLC cases carry the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein resulting from inv(2)(p21; p23) [9].…”

ALK‐positive large B‐cell lymphoma with strong CD30 expression; a diagnostic pitfall and resistance to brentuximab and crizotinib

“…ALK-LBCL is a rare variant of diffuse large B-cell lymphoma (DLBCL), and was first described in 1997. 2 Since then, <100 cases have been described. The lymphoma has a bimodal age distribution, with primarily nodal involvement, and shows aggressive behaviour, resulting in a median survival time of 12 months.…”