Rosai-Dorfman Disease (RDD) was described by Rosai and Dorfman in 1969 as a rare, benign, idiopathic and often self-limiting proliferation of histiocytes. More recently, RDD is classified as a non-Langherhans cell histiocytosis belonging to the R group. The classical presentation of RDD involves massive, painless cervical lymphadenopathy, although case reports show a heterogeneous disease. Extranodal disease has been reported in 43% of cases, with skin being the most common. Both nodal and extranodal presentations were seen in 28% of patients.

A 60-year-old mixed-race woman, with no known comorbidities other than a history of tobacco and alcohol use, presented with skin lesions, involuntary weight loss of 7 kg and leukocytosis, prompting referral to our service for further evaluation. Physical examination revealed indurated, erythematous plaques and nodules with central necrosis on the face, which were painless. Peripheral blood analysis confirmed leukocytosis with neutrophil predominance. Bone marrow examination demonstrated hypercellularity with granulocytic and megakaryocytic hyperplasia, as well as marked histiocytosis. Immunohistochemical staining was positive for CD68, S100, and CD4, and negative for CD1a and Langerin. Molecular testing was negative for the BCR-ABL fusion gene and the JAK2 V617F mutation. Imaging studies showed splenomegaly and mediastinal lymph nodes measuring up to 9 mm. Initial treatment with prednisone at a dose of 1 mg/kg resulted in partial improvement. However, disease flares occurred with every attempt to taper the dosage, and no response was observed upon the third re-escalation, with significant lesion progression involving the entire left hemiface and portions of the thorax. Subsequently, combination therapy with methotrexate (20 mg/m² weekly), mercaptopurine (50 mg/m² daily), and a single dose of vincristine (1.4 mg/m²) was initiated. After one month of treatment, complete clinical resolution was achieved, along with normalization of laboratory parameters. The response was sustained during progressive dose reduction, and no treatment-related toxicity was observed.

The case described emphasizes the diagnostic challenges of RDD and its potential resistance to corticosteroid therapy. It reinforces the importance of considering RDD in the differential diagnosis of leukocytosis accompanied by systemic symptoms, especially when cutaneous involvement is present. The favorable response to combined immunosuppressive and chemotherapeutic agents after the loss of response to corticosteroid highlights the potential role of alternative therapies in corticosteroid-resistant cases.