Table 2.
Clinical and molecular features of Sézary syndrome and lymphocytic-variant hypereosinophilic syndrome (HES).
| Clinical Features | Sézary Syndrome | Lymphocytic-Variant HES |
| Classification | lymphoma, stage IV | benign lymphoproliferation |
| Diagnostic criteria | Sézary cells > 1000/µL (or, CD4/CD8 ratio ≥ 10, CD4+CD7− cells ≥ 40%, CD4+CD26− cells ≥ 30%), with identical T-cell clone in blood + skin [6,55] | Rule out other causes of HES. Blood eosinophilia >1500/µL, abnormal T cells with no standardized threshold, frequent T-cell clonality, T cells secrete IL-5 [25,35,56]. |
| Clinical course | moderately aggressive | indolent |
| Skin and physical symptoms | widespread erythroderma, pruritus, lymphadenopathy | limited erythroderma, urticaria, pruritus [24,27] |
| Residence of T cells | blood, skin, lymph node | blood, skin, lymph node, soft tissue [25] |
| Skin pathology | epidermotropic Sézary cells with cerebriform nuclei, eosinophils in some patients | abundant eosinophils, and perivascular, dermal infiltrate of small-medium size T cells with irregular nucleus and scarce cytoplasm [25,35] |
| Eosinophilia | some patients, late, moderate complications uncommon [29] >700/µL poor prognostic indicator [46] | all patients, early, severe, can cause organ damage |
| First line therapy | Systemic immunomodulation: ECP combined with interferons or other systemic (bexarotene, romidepsin, low dose methotrexate) and/or skin-directed (topicals, TSEBT) therapy [57,58] | systemic corticosteroids [35,59,60] |
| Second line therapy | Targeted and immune enhancing/sparing therapies preferred: mogamulizumab. romidepsin, alemtuzumab, intermediate dose methotrexate. Refractory disease: clinical trials, allogeneic HCT, chemotherapy [57,58] | IFN-α + glucocorticoids Steroid-sparing: mepolizumab, alemtuzumab, mycophenolate mofetil, cyclosporin, methotrexate, JAK kinase inhibitors (ruxolitinib, tofacitinib) [35,59,60] and imatinib, despite lack of FIP1L1-PDFGRA fusion, for patients who fail other tharapies [61] |
| Follow up | Monitor complete blood count with differential, liver function, LDH, flow cytometry for Sezary cells [33] in blood, physical examination for nodes, viscera and skin infections [62]. | monitor T-cell lymphoma risk with lymphocyte counts, PB flow cytometry, BM cytogenetics [59] |
| Progression symptoms | Increases in pruritus, erythroderma, or skin tumor burden, enlarging lymph nodes, visceral organ involvement, immune suppression [63] | 10–25% progress to T-cell lymphoma, cytogenetic changes Nonspecific symptoms: rapid increase in lymphocytosis, lymph node involvement, infiltrative nodules [25] |
| Molecular Features | Sézary Syndrome | Lymphocytic-Variant HES |
| T-cell phenotype | memory T cell with heterogeneous molecular phenotype [43,64] | memory T cell [30,42] |
| T-cell surface antigens | CD3+/−CD4+, CD7 and/or CD26 loss CLA+, CCR7+, CCR4+, CCR10+ [65,66] |
CD3−CD4+CD7−CD5++, CD3+CD4+CD7−, or, CD3+CD4−CD8− [23,35] |
| Cytokines | Th2 (IL-4, IL-5, IL-13), suppressive (IL-10), autocrine or paracrine growth stimulation (IL-15, IL-16, IL-32) [67,68] | Th2 (IL-4, IL-5, IL-13) [28,42] |
| Molecular drivers | Mutations in pathways related to DNA damage repair (TP53), apoptosis, (FAS), cell cycle (MYC, RB1), epigenetic modulators (DNMT3A, TET2), JAK/STAT (JAK3, STAT3, STAT5B), ARID1A, NF-κB (NFKB2, CARD11), TCR-signaling (CD28, PLCG1) [37,38,69,70] | IL-5, GATA3, JAK/STAT, IL17RB, TGFβ signaling [30,53] |
| Genetic abnormalities | Frequent SNV and CNV, C > T transitions consistent with UV damage, recurrent 10q and 17p deletions, recurrent 8q and 17q amplifications [37,38]; gene fusions [68] | Seldom reported, partial 6q deletion and other karyotype abnormalities [23] |
BM, bone marrow; CNV, copy number variation; ECP, extracorporeal photopheresis; HCT, hematopoietic stem cell transplant; LDH, lactate dehydrogenase; ND, normal donor; PB, peripheral blood; PUVA, psoralen plus ultraviolet A; SNV, single nucleotide variation; TCR, T-cell receptor; TSEBT, total skin electron beam therapy.