Naïve/memory T-cell phenotypes in leukemic cutaneous T-cell lymphoma: Putative cell of origin overlaps disease classification

Background: Mycosis fungoides (MF) and Sézary Syndrome (SS) are clinically distinct cutaneous T-cell lymphomas with strikingly similar morphologic and phenotypic features. Prior studies have suggested phenotypic differences based on markers of antigen experience, suggesting a different cell of origin. Methods: Seventy-nine involved peripheral blood or bone marrow samples from 33 patients with SS and 19 patients with MF were studied by 10-color flow cytometry, including CD62L, CD45RA, CCR4, and PD-1. Gated tumor events were classified as naïve (T_N), central memory (T_CM), effector memory (T_EM), or effector memory with reacquired CD45RA (T_EMRA); based on CD62L⁺/CD45RA⁺, CD62L⁺/CD45RA⁻, CD62L⁻/CD45RA⁻, or CD62L⁻/CD45RA⁺ phenotype, respectively. Sequential specimens were compared to assess for phenotypic stability. Results: The naïve/memory phenotype of the neoplastic T-cells was markedly heterogeneous, with a dominant T_N, T_CM, T_EM, or T_EMRA subset on 11 (14%), 32 (41%), 30 (38%), and 6 (8%) cases, respectively. There was no correlation between the diagnosis of MF or SS and putative cell of origin (P = 0.4). Overexpression of CCR4 and PD1 was observed in most cases, with higher intensity in SS compared to MF. The naïve/memory phenotype remained the same for 10 patients up to 273 days after the initial analysis; while on six patients, the naïve/memory phenotype was different from the original phenotype. Conclusions: Both SS and MF can have phenotypic features of any of the major naïve/memory T-cell subsets, which questions the current principle of “cell-of-origin” distinction between SS and MF. Phenotypic shifts within these subsets are common, suggesting a functional state rather than a cell-of-origin surrogate.