Focal Rosai–Dorfman disease coexisting with lymphoma in the same anatomic site: a localized histiocytic proliferation associated with MAPK/ERK pathway activation

Rosai–Dorfman disease is a rare histiocytic disorder shown to have gene mutations that activate the MAPK/ERK pathway in at least one-third of cases. Most patients with Rosai–Dorfman disease present with bulky lymphadenopathy or extranodal disease, but rarely Rosai–Dorfman disease is detected concomitantly with lymphoma in the same biopsy specimen. The underlying molecular mechanisms of focal Rosai–Dorfman disease occurring in the setting of lymphoma have not been investigated. We report 12 cases of Rosai–Dorfman disease and lymphoma involving the same anatomic site. There were five men and seven women (age, 23 to 77 years) who underwent lymph node (n = 11) or skin (n = 1) biopsy; the lymphomas included nodular lymphocyte predominant Hodgkin lymphoma (n = 6), classical Hodgkin lymphoma (n = 4), small lymphocytic lymphoma (n = 1) and extranodal marginal zone lymphoma (n = 1). The foci of Rosai–Dorfman disease in all cases had S100 protein-positive histiocytes undergoing emperipolesis. No patients had Rosai–Dorfman disease at other anatomic sites at initial diagnosis and at last follow-up (median, 40 months). We performed immunohistochemical analysis to assess activity of the MAPK/ERK pathway in the Rosai–Dorfman disease foci. We also micro-dissected disease foci and analyzed 146 genes using next-generation sequencing in four cases with adequate DNA; the panel included genes previously reported to be mutated in Rosai–Dorfman disease. All cases were negative for gene mutations. Nevertheless, all cases were positive for cyclin D1 and most cases showed p-ERK expression indicating that the MAPK/ERK pathway is active in the histiocytes of focal Rosai–Dorfman disease. We conclude that focal Rosai–Dorfman disease coexisting with lymphoma is a clinically benign and localized histiocytic proliferation. These data also indicate that the MAPK/ERK pathway is active in focal Rosai–Dorfman disease although we did not identify activating mutations. These findings suggest that the pathogenesis of focal Rosai–Dorfman disease is different from that of usual cases of Rosai–Dorfman disease.