Sézary syndrome (SS) is a rare cutaneous T-cell lymphoma characterized by blood involvement and considered with Mycosis fungoides (MF) in international prognostic classification. Widely reported in literature, large cell transformation (LCT) is correlated with a poor outcome in MF. However, LCT has never been specifically studied in a large cohort of patients with SS. The objective of our study is to describe the frequency and prognostic impact of LCT in Sezary syndrome.

We retrospectively collected clinical, histological, biological and cytometric data at baseline and during follow-up of all patients with SS diagnosed between 1998 and 2020 according to WHO/EORTC criteria and followed up at Saint-Louis hospital (AP-HP, Paris). All skin biopsy samples were independently analyzed by two pathologists and digitally analyzed (Innate Pharma, Marseille).

117 patients were included in the study. Median follow-up was 41 months [IQR:1-81]. Median age at diagnosis was 65 years [IQR:50-80]. LCT in the skin occurred in 6% (6/100) of patients at diagnosis and 20% (18/91) during follow-up. Interrater reliability Cohen’s kappa coefficient for LCT diagnosis was 0.88 (95%CI[0,78-0,98]). Computational analysis on digitized slides (n=190) showed that the mean surface of the upper quartile largest cells of each biopsy was 32 µm2 [SD=5.1] on LCT+ vs 26 µm2 [SD=3.2] on LCT- biopsies; p <0.001 (Fig. 1). In flow cytometry, the size of circulating tumoral cells was not different in LCT+ and LCT- patients (p= 0.37). Median survival in LCT+ vs LCT- patients at diagnosis was 35 months vs 80 months (HR =9.5, CI95[1.9-47.1], p= 0.006). Median overall survival after LCT during follow-up was 21 months with a 5-year survival of 12% (CI95[1-38]). In multivariate analysis, age >60 years, elevated LDH level, circulating CD3+ CD4+ CD26- cells ≥10,000/mm3 and LCT at diagnosis were independently associated with a reduced overall survival.

LCT in SS is an independent poor prognostic factor, unrelated to the size of circulating tumor cells. Histological evaluation of LCT is reliable, using the same criteria than in MF, and highly recommended during follow-up. Our study is, to our knowledge, the first to describe the frequency and the prognostic impact of LCT in a large and homogeneous cohort of SS contributing to a better understanding of this rare disease.