Hypereosinophilic syndrome (HES) is a rare hematologic disorder characterised by eosinophilia > 1500/mL and/or tissue eosinophilia, leading to organ dysfunction, excluding secondary causes. The 2022 classification includes idiopathic (I-HES), myeloproliferative (M-HES), lymphocytic (L-HES), overlap, associated and familial HES 1. L-HES arises from clonal T cells (CD3− CD4+) producing IL-5, causing eosinophil expansion 1, 2. Skin involvement is common in CD3− CD4+ L-HES, presenting with pruritus, eczema, erythroderma, urticaria and vasculitis-like eruptions 1. In very rare instances, L-HES may overlap with or evolve into cutaneous T-cell lymphomas (CTCL), particularly in cases with atypical or mixed immunophenotypes, posing significant diagnostic challenges. Steroids are first-line therapy, reducing aberrant T-cell populations and eosinophilia, though response varies 3, 4. For steroid-refractory cases, options include IFN-α, steroid-sparing agents and Mepolizumab, an FDA-approved IL-5 inhibitor for idiopathic HES 1. We present a case with significant skin involvement, initially diagnosed as cutaneous T-cell lymphoma (CTCL) based on clinical and histological findings, in which a lymphocytic hypereosinophilic syndrome (L-HES) later emerged during follow-up. The two conditions may have coexisted, contributing to a complex and evolving diagnostic course. A 61-year-old woman was referred to our clinic in 2019 for diffuse pruritus and a severe rash, initially suspected to be CTCL. Clinical examination revealed erythematous plaques on the legs and papular lesions on the forehead and trunk (Figure 1A,B). Initial blood tests showed mild leukocytosis and a slight increase in eosinophils with an absolute value of 0.63 cells per 109/L. A punch biopsy of a leg lesion suggested a T-cell lymphoproliferative disorder with clonal TCR rearrangement Figure 2. Given these findings, she was diagnosed with CTCL and started on methotrexate. For symptomatic relief, pulsed oral prednisone (25 mg for 5 days every fortnight) was introduced, leading to temporary improvement. Over the following 2 years, however, skin manifestations gradually changed. Lesions became progressively less circumscribed and more confluent, eventually forming ill-defined erythematous patches and areas of diffuse homogeneous erythema: this gradual transition from discrete plaques to widespread erythema. Also pruritus worsened significantly, prompting further investigations: blood tests showed a significant increase in eosinophils with an absolute value of 0.92 cells per109/L IgE, and a clonal T-lymphocyte population with an increase from 0.21 cells per 109/L to 1.2 cells per 109/L with CD2+, CD3−, CD4+, CD8−, CD26+/− (63%), CD7+/− (87%) phenotype, findings more consistent with L-HES rather than CTCL 5. At this stage, when cutaneous lesions lose their clear borders and appear as diffuse erythematous areas, morphological features alone no longer allow a reliable distinction between CTCL and eosinophilic dermatoses, emphasising the importance of systemic markers and cytokine profiling in diagnostic reassessment. These findings and the progressive eosinophilia supported a revised diagnosis of aL-HES, likely pre-existing at onset, which progressively came to dominate the clinical picture, requiring a shift in diagnostic and therapeutic focus. The main therapeutic challenge became controlling severe, persistent pruritus and progressive eosinophilia despite multiple treatment attempts, including gabapentin, ondansetron, opioid receptor antagonists, high-dose antihistamines, omalizumab and phototherapy. While pulsed steroids remained the only effective symptomatic treatment, concerns over long-term corticosteroid use necessitated a steroid-sparing strategy. By early 2024, symptoms worsened despite multiple antipruritic therapies, and mepolizumab was initiated, along with gradual steroid tapering to mitigate glucocorticoid-induced osteoporosis. Additionally, a new phototherapy cycle was started in November 2024. After 6 months of Mepolizumab therapy, symptoms and eosinophil counts significantly improved, representing a promising response. From a diagnostic perspective, differential diagnosis of L-HES and CTCL should include not only skin examination but also assessment of systemic features, peripheral eosinophilia, immunophenotype (CD3− CD4+ clones in L-HES versus CD3+ CD4+ in CTCL), lymphadenopathy and internal-organ involvement. While CTCL is primarily confined to the skin in its early stages, L-HES frequently shows extracutaneous manifestations and elevated IgE or IL-5 levels. Therapeutically, CTCL management relies initially on skin-directed treatments like phototherapy, retinoids, steroid creams and in worst cases systemic treatments such as interferon-α, methotrexate or targeted biologics such as mogamulizumab or brentuximab, whereas L-HES treatment centres from the beginning on systemic treatments, corticosteroids, interferon-α and IL-5 inhibitors such as mepolizumab, with immunosuppressants or tyrosine-kinase inhibitors reserved for selected variants. This case highlights how L-HES can be underdiagnosed and related to CTCL presentation, delaying diagnosis. It highlights the diagnostic complexity and underscores the need for advanced immunophenotypic and molecular testing to prevent misdiagnosis. Finally, Mepolizumab proved effective as a long-term therapeutic option 1. The authors have nothing to report. This work was supported by Università di Bologna. The authors have nothing to report. The patients in this manuscript have given written informed consent to publish their case details. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Rizzo et al. (Thu,) studied this question.