Molecular Analysis of Primary Cutaneous Aggressive T-Cell Lymphomas: the Epidermotropic CD8+, the Pleomorphic CD8+ and the Gamma Delta Subsets.

Abstract 2713

Primary cutaneous T-cell lymphomas (CTCL) are usually characterized by a T-helper CD4+ immunophenotype and show an indolent clinical course; on the contrary, cases harbouring a CD8+ cytotoxic immunophenotype exhibiting epidermotropism (AECTCL) or pleomorphic morphology (PTL-NOS), as well as cases with gamma-delta + (CGDL) immunophenotype, display a very different course. Clinically, these tumours are very aggressive, with poor outcome in adults. Chemotherapy, preferably based on intensive CHOP-like regimens, represents the mainstay of treatment, when possible followed by stem cell transplantation. Histologically, tumour cells constitute a population of pleomorphic medium-large size elements. In these rare CTCL subtypes few reports have been published dealing with oncogenomic investigations. With this study, by array-based comparative genomic hybridization (a-CGH) and gene expression profiling (a-GEP), we aimed to explore genomic alterations possibly involved in tumorigenesis of aggressive CTCL referred to our department. We focused on 9 cases of CD8+ AECTCL, 3 cases of CD8+ PTL-NOS and 4 cases of CGDL, who were extensively investigated by a-CGH; a-GEP was applied in 5 cases of AECTCL to further expose genomic profile of neoplastic cells. Among AECTCL patients, immunophenotype was always typical and EBV was demonstrated only in one case. Results were assessed by statistical analysis to reveal more significant common chromosomal aberrations. By a-CGH investigations, we found the presence of extensive gains and losses of both large and small chromosomal regions; copy number gains were more frequent than losses. In CD8+ cases, we observed gains of 3p21.33-p21.2 in 10 out of 12 cases, 6p21.2-p21.1 in 8/12, 7q11.23 in 9/12, 7q21.2-q22.1 in 10/12, 7q36.1-q36.3 in 7/12, 8q24.3 in 8/12, 11pter in 11/12, 11q12.3-q13.2 in 10/12, 16p13.3 in 10/12, 17q in 10/12, trisomy 19 (as a mosaic aberration) in 12/12, and trisomy 22 in 8/12; losses involved 4q12-q22.2 in 8/12, 9p21.3 in 10/12 (homozygous in 7) and 14q11.2 in 9/12. In CGDL, recurrent copy number alterations (observed in 50% to 75% of cases) were gains of 2q13-qter, 17q21.3, 19 (trisomy, as mosaic) and 22q11.21, along with losses of 4q12-q22, 6q23.3 and 9p21.3. Summarizing, most of our genomic results have been previously described in other cutaneous lymphomas: gains of 3p21 in diffuse large B-cell lymphomas (DLBCL), of 7q21 in mycosis fungoides (MF), of 8q24 in PTL-NOS and in Sézary syndrome (SS), of 11q22-q13 in DLBCL, of 16p in DLBCL and in angioimmunoblastic T-cell lymphoma (AITL), of 19p in AITL and natural killer lymphomas, trisomy 22 in AITL, PTL-NOS and SS, gain of 17q in SS and in ALCL, MF and PTL-NOS. However, we underline the loss of p21.3, determining CDKN2A deletion, as a common alteration in these three CTCL entities. We also found other common anomalies in AECTCL and PTL-NOS, with particular interest with regard to gain of 17q, 19p13 and 19q13.11-q32, which associate with the JAK/STAT signaling pathway activation. Other alterations in AECTCL cases involve c-MYC (8q24), CCND1/CDK4–6 (11q13) and IL21R (16p13.3). Worth mentioning, GEP analysis in AECTCL confirmed altered expression of CDKN2A, JAK3 and STAT6 genes. Although most genetic aberrations detected in our study have already been described in other lymphoproliferative disorders, we conclude that the combination of aberrations appears characteristic in these aggressive disorders.