Identification of a 3-gene model as a powerful diagnostic tool for the recognition of ALK-negative anaplastic large-cell lymphoma

Abstract

IntroductionSystemic anaplastic large-cell lymphomas (ALCLs) are a peripheral T cell-derived malignancy accounting for approximately 12% of all T-cell non-Hodgkin lymphomas (T-NHLs). 1 Originally described by Stein et al in 1985 as ALCL-expressing CD30, 2 its definition and relationship with other T-NHLs has undergone a series of revisions. 1,3,4 Based on genetic and clinical features, 2 different entities are now recognized as systemic forms, the ALK-positive (ALK ϩ ) and ALK-negative (ALK Ϫ ) ALCL. 1,5 The first entity is characterized by recurrent chromosomal translocations involving the Anaplastic Lymphoma Kinase (ALK) gene, which leads to the expression and constitutive activation of anaplastic lymphoma kinase (ALK) fusion proteins. 6,7 Whereas ALK ϩ ALCL are readily diagnosed by anti-ALK Abs, the recognition of ALK Ϫ ALCL is in some instances subjective. In fact, immunophenotypic or genetic features that define ALK Ϫ ALCL precisely are missing; accordingly, ALK Ϫ ALCL has been considered a provisional entity by the World Health Organization (WHO) classification. 1 Although all ALCLs display strong and diffuse immunoreactivity for CD30, the expression of this marker is not specific for ALCL. Indeed, CD30 is found also in activated nonneoplastic lymphoid cells, in a subset of peripheral T-cell lymphoma not otherwise specified (PCTL-NOS), in Hodgkin lymphoma, and other neoplasms such as embryonal carcinoma. 8 At present, the diagnosis of ALCL relies on the application of a panel of Abs for B-and T cell-restricted antigens, epithelial membrane antigen (EMA), granzyme B, perforin, and T cell-restricted intracellular antigen-1 (TIA1). 5 ALCLs usually show an aberrant T-cell phenotype with frequent loss of the common T-cell markers such as the pan-T-cell antigens, 9 although in approximately 85%-90% of ALCL clonal TCR gene rearrangement can be detected by PCR. Furthermore, PAX5 negativity is critical for the differentiation of ALCL from common Hodgkin lymphoma and CD30 ϩ diffuse large B-cell lymphoma. 10 Recently, chromosomal translocations affecting 6p25.3, which targets DUSP22 and/or IRF4 have been described in a subset of ALK Ϫ ALCLs, with predominant cutaneous involvement 11,12 ; however, the effects on the pathogenesis of this lymphoma are still largely unknown. ALK Ϫ ALCL distinction is supported by genetic criteria, epidemiologic data, and clinical features. The crude 5-year overall survival of this lymphoma is 49%, a value intermediate between 70% for ALK ϩ ALCL and 32% for PTCL-NOS. 1 Nevertheless, when patients are stratified according to the clinical parameters The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 12, 2018. by guest www.bloodjournal.org From (ie, age and/or stage), ALK ϩ and ALK Ϫ ALCL patients display a similar prognosis in terms of f...

CD30-positive peripheral T-cell lymphomas share molecular and phenotypic features

“…Interestingly however, when we excluded these "borderline" samples from the analyses, only the score of pSTAT3 was significantly different between CD30 + PTCL, NOS and ALK -ALCL (data not shown), enabling us to exclude the hypothesis of an eventual bias introduced by the inclusion of these six cases. Moreover, when applying the molecular classifiers developed by Piva et al 13 and Agnelli et al 14 to discriminate ALCL from PTCL, NOS, we found that the levels of mRNA expression of three of the four genes which could be analyzed in our dataset (TMOD1, PERP, TNFRSF8) were significantly lower in CD30 + PTCL, NOS than in ALK -ALCL, while one of the genes (BATF3) was expressed at similar levels in CD30 + PTCL, NOS and ALCL. Interestingly, the levels of expression of TMOD1, PERP and TNFRSF8 were also significantly different between CD30 -and CD30 + PTCL, NOS, being lower in the CD30 -subgroup (data not shown).…”

ALK-Dependent Control of Hypoxia-Inducible Factors Mediates Tumor Growth and Metastasis

“…Gene-expression profiling and GSEA Gene-expression profiling (GEP) data from T-cell lymphomas were generated by our group (19). Expression data for NSCLC are publicly available (20,21).…”

A novel immunohistochemical classifier to distinguish Hodgkin lymphoma from ALK anaplastic large cell lymphoma

“…Several attempts have been made to establish classifiers differentiating between ALK À anaplastic large cell lymphoma and peripheral T-cell lymphoma not otherwise specified, [24][25][26] but to our knowledge this has not been achieved for differential diagnosis of classical Hodgkin lymphoma and ALK À anaplastic large cell lymphoma. The aim of the present study was to find new immunohistochemical markers which can be applied in the differential diagnosis of ALK À anaplastic large cell lymphoma and classical Hodgkin lymphoma in daily routine practice.…”