Revisiting the initial diagnosis and blood staging of mycosis fungoides and Sézary syndrome with the KIR3DL2 marker

Abstract

Background: The early diagnosis of Sézary syndrome (SS) is challenging. Loss of CD7 and CD26 expression on CD4⁺ T cells is the currently used criterion in the initial diagnosis and staging of patients with SS.

Objectives: Our aim was to evaluate the respective value of CD26, CD7 and KIR3DL2 expression on CD4⁺ T cells and total lymphocytes at initial diagnosis of SS.

Methods: This prospective study included 254 patients with clinical features consistent with cutaneous T-cell lymphoma seen at our institution between March 2014 and February 2019. Peripheral blood analysis by flow cytometry was performed for each patient at the time of diagnosis and during follow-up. The diagnosis of SS was based on ISCL/EORTC criteria.

Results: The presence of KIR3DL2⁺ Sézary cells (SCs) ≥ 200 μL^-1 correlated with the diagnosis of SS, with sensitivity of 88·6% and specificity of 96·3%. All 154 patients with either inflammatory skin disease or other haematological disease had KIR3DL2⁺ cells < 200 μL^-1 , while eight of them had CD4⁺ CD26^- T cells ≥ 1000 μL^-1 . Of five patients with SS and lymphopenia, four had CD4⁺ CD7^- T cells < 1000 μL^-1 and three had CD4⁺ CD26^- T cells < 1000 μL^-1 . However, all of them had KIR3DL2⁺ CD4⁺ T cells ≥ 200 μL^-1 . Among patients with available samples during evolution, all B1-staged patients with ≥ 200 μL^-1 KIR3DL2⁺ SCs at diagnosis evolved to B2 stage within 7 months.

Conclusions: KIR3DL2 expression on T cells is highly specific and helps the early diagnosis of SS, especially in those patients with lymphopenia. What's already known about this topic? In the ISCL/EORTC cutaneous T-cell lymphoma (CTCL) categorization of blood involvement (B0-B2), B2 is defined as a T-cell receptor clonal rearrangement in blood, associated with high blood-smear Sézary cell (SC) count. Flow cytometry was developed to circumvent interobserver variability of SC manual counts; however, it mostly relies on detection of cells lacking CD7 and/or CD26 expression. We previously reported the reliability of KIR3DL2 as the first positive SC marker. What does this study add? Based on our analysis of 254 patients, we propose that KIR3DL2 be added to the ISCL/EORTC criteria for initial diagnosis of Sézary syndrome (SS) and B2 staging. This marker improved sensitivity of SS B2-stage CTCL diagnosis with a specificity > 95%, especially for patients with lymphopenia. We found KIR3DL2 helped early diagnosis of SS and was more reliable than CD26 in assessing blood tumour burden during therapy. What is the translational message? SC quantification is the major means of staging at initial diagnosis and monitoring blood tumour burden in a clinical trials setting. We recommend using a threshold value of KIR3DL2⁺ SCs ≥ 200 μL^-1 or KIR3DL2⁺ SCs/lymphocytes ≥ 10% in the diagnostic criteria of SS and propose a novel algorithm for CTCL B2 blood staging.