Rosai–Dorfman Disease between Proliferation and Neoplasia

SIMPLE SUMMARY: Rosai–Dorfman disease (RDD) was a benign histiocytic proliferative disorder rather than a neoplastic process. Emergent molecular studies have shown recurrent somatic gain-of-function mutations in genes of the MAPK pathway (e.g., NRAS, KRAS, MAP2K1, and ARAF) in a subset of RDD, suggesting a clonal histiocytic proliferative process. This review encompasses clinical characteristics, updated subclassification, diagnostic approaches, and treatment strategies, with an emphasis on the molecular profiles of RDD. This study includes the latest international consensus on diagnosing and managing this disease. This review will provide novel insights on the latest discoveries in RDD. ABSTRACT: Rosai–Dorfman disease (RDD) is a rare myeloproliferative disorder of histiocytes with a broad spectrum of clinical manifestations and peculiar morphologic features (accumulation of histiocytes with emperipolesis). Typically, the patient with RDD shows bilateral painless, massive cervical lymphadenopathy associated with B symptoms. Approximately 43% of patients presented with extranodal involvement. According to the 2016 revised histiocytosis classification, RDD belongs to the R group, including familial and sporadic form (classical nodal, extranodal, unclassified, or RDD associated with neoplasia or immune disease). Sporadic RDD is often self-limited. Most RDD needs only local therapies. Nevertheless, a small subpopulation of patients may be refractory to conventional therapy and die of the disease. Recent studies consider RDD a clonal neoplastic process, as approximately 1/3 of these patients harbor gene mutations involving the MAPK/ERK pathway, e.g., NRAS, KRAS, MAP2K1, and, rarely, the BRAF mutation. In addition to typical histiocytic markers (S100/fascin/CD68/CD163, etc.), recent studies show that the histiocytes in RDD also express BCL-1 and OCT2, which might be important in pathogenesis. Additionally, the heterozygous germline mutation involving the FAS gene TNFRSF6 is identified in some RDD patients with an autoimmune lymphoproliferative syndrome type Ia. SLC29A3 germline mutation is associated with familial or Faisalabad histiocytosis and H syndrome.