Evaluation of Immunophenotypic and Molecular Biomarkers for Sézary Syndrome Using Standard Operating Procedures: A Multicenter Study of 59 Patients

Abstract

Differentiation between Sézary syndrome and erythrodermic inflammatory dermatoses can be challenging, and a number of studies have attempted to identify characteristic immunophenotypic changes and molecular biomarkers in Sézary cells that could be useful as additional diagnostic criteria. In this European multicenter study, the sensitivity and specificity of these immunophenotypic and recently proposed but unconfirmed molecular biomarkers in Sézary syndrome were investigated. Peripheral blood CD4(+) T cells from 59 patients with Sézary syndrome and 19 patients with erythrodermic inflammatory dermatoses were analyzed for cell surface proteins by flow cytometry and for copy number alterations and differential gene expression using custom-made quantitative PCR plates. Experiments were performed in duplicate in two independent centers using standard operating procedures with almost identical results. Sézary cells showed MYC gain (40%) and MNT loss (66%); up-regulation of DNM3 (75%), TWIST1 (69%), EPHA4 (66%), and PLS3 (66%); and down-regulation of STAT4 (91%). Loss of CD26 (≥80% CD4(+) T cells) and/or CD7 (≥40% CD4(+) T cells) and combination of altered expression of STAT4, TWIST1, and DNM3 or PLS3 could distinguish, respectively, 83% and 98% of patients with Sézary syndrome from patients with erythrodermic inflammatory dermatoses with 100% specificity. These additional diagnostic panels will be useful adjuncts in the differential diagnosis of Sézary syndrome versus erythrodermic inflammatory dermatoses.

Sézary Syndrome: Translating Genetic Diversity into Personalized Medicine

“…The altered expressions of several biomarkers, including CD26 and/or CD7, in CD4 þ cells was confirmed as specific for SS diagnosis in a multicenter study (Boonk et al, 2016).…”

“…Genetic loss at 6q23e27 of TNFAIP3, initially detected in half of SS samples, has been confirmed only in a single NGS study (Braun et al, 2011;Choi et al, 2015). Finally, except when single nucleotide polymorphism array analysis was associated (Wang et al, 2015), most NGS studies, including the one by Prasad et al (2016), have not reported gain of MYC and/or loss of its antagonist MNT, which have been recovered in 76% of patients with SS (Boonk et al, 2016;Vermeer et al, 2008). Comprehensive and functional analyses are therefore still needed to address the clinical relevance of SS genes.…”

Increased Expression of PLS3 Correlates with Better Outcome in Sézary Syndrome

“…Recently, we investigated the diagnostic significance of a large number of immunophenotypic and molecular biomarkers for SS in a group of patients with SS (Boonk et al, 2016) that fulfilled the diagnostic criteria of the World Health OrganizationeEuropean Organization for Research and Treatment of Cancer classification (Willemze et al, 2005). None of these patients had a history of mycosis fungoides.…”

“…Between September 2009 and October 2013, 64 SS patients from six European Organization for Research and Treatment of Cancer centers, including Helsinki, Finland; London, UK; Leiden, The Netherlands; Mannheim, Germany; Turin, Italy; and Paris, France were included and followed up until January 30, 2015. At the inclusion of the study, clinical variables (sex, age at diagnosis, duration of skin lesions before diagnosis if SS, lymph node involvement, leukocyte count, absolute CD4 count, and Sézary cell count) were recorded, and peripheral blood samples were collected for copy number variation and gene expression quantitative PCR analysis, as described previously (Boonk et al, 2016). Lymph node involvement was defined by presence of enlarged lymph nodes of 1.5 cm or larger in the longest transverse diameter on computed tomography scan or histologically confirmed lymph node involvement.…”

“…In all participating centers the study was approved by their local institutional ethical review boards and written informed patient consent was obtained (Boonk et al, 2016).…”