Rosai-Dorfman disease with

Rosai-Dorfman disease (RDD) is a rare histiocytic disorder, usually benign but may follow an aggressive and treatment-refractory course in a subset of patients. Somatic mutations involving the MAPK/ERK pathway, particularly KRAS and MAP2K1, have been increasingly recognized and provide a rationale for targeted therapy. We report the case of a 41-year-old woman with a two-year history of progressive, multisystem RDD presenting with cervical and mediastinal lymphadenopathy and laryngeal involvement, who was refractory to multiple conventional treatments, including corticosteroids, immunosuppressive agents, immunomodulatory drugs, and chemotherapy. Next-generation sequencing identified a pathogenic MAP2K1 c.607G > A mutation, leading to initiation of MEK inhibition with cobimetinib. The patient achieved complete clinical and radiological response, which has been sustained for more than three years after treatment discontinuation. This case highlights the importance of molecular profiling in refractory RDD and supports MEK inhibition as a promising therapeutic strategy in patients with actionable MAPK pathway mutations.