Severe Persistent Hypereosinophilia of Undetermined Significance: Diagnostic Challenges in Clinical Practice and Two-Year Follow-Up.

Hypereosinophilia of undetermined significance (HE-US) represents a rare subtype of hypereosinophilia (HE) defined by a persistent absolute eosinophil count (AEC) ≥ 1500/uL without an identifiable reactive or clonal cause, and importantly, without evidence of eosinophil-mediated end-organ damage. Long-term structured follow-up is essential due to its unpredictable outcome and the risk of transition into overt hypereosinophilic syndrome (HES) or occult malignancies. We report the case of a 47-year-old woman with severe, persistent blood hypereosinophilia (up to 13600/uL) accompanied by chronic inconstant fixed erythematous-violaceous skin lesions. Extensive diagnostic evaluation for secondary, autoimmune, and clonal etiologies was negative, including fluorescence in situ hybridization (FISH) for FIP1L1-PDGFRA mutation. Bone marrow biopsy showed granulocytic hyperplasia with eosinophils <10% and mild reticulin fibrosis (MF-1). Whole-body computed tomography (CT) revealed small generalized lymphadenopathy (≤ 11mm) without parenchymal infiltration. The patient declined lymph-node biopsy. Although skin biopsy revealed eosinophilic infiltration, it was characterized as a non-specific reactive pattern without objective evidence of eosinophil-mediated cytotoxicity. The case was provisionally diagnosed as HE-US, acknowledging that lymphoproliferative disease could not be definitively excluded in the absence of the lymph-node biopsy. Intermittent systemic corticosteroids provide rapid hematologic response, but prompted immediate recurrence when tapered. The reported case underscores the diagnostic complexity and difficulties in managing hypereosinophilia of undetermined significance in clinical practice. While current evidence suggests a generally benign course, rare progression to hypereosinophilic syndrome or other malignancies requires structured long-term monitoring and individualized therapeutic decision-making.