Rosai-Dorfman Disease between Proliferation and Neoplasia

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.

Keywords: MAPK pathway; Rosai–Dorfman disease; gene mutation; histiocytic disorder; sinus histiocytosis.

Figure 1

The selected images show a case of nodal Rosai–Dorfman disease with concurrent IgG4-related disease. (A) Low-power magnification shows effacement of normal lymph-node architecture by histiocytes (H & E, magnification 40×). (B) Higher-power magnification demonstrates increased plasma cells arranged in nests and singly associated with background fibrosis and histiocytes (immunoperoxidase, magnification 200×). (C) Loaded histiocytes with emperipolesis and (D) an increased number of plasma cells (immunoperoxidase, magnification 600× and 600×, respectively).

Figure 2

Routine immunohistochemical stains for Rosai–Dorfman disease. (A) S-100 immunohistochemical stain highlighting the histiocytes, which also demonstrates emperipolesis (immunoperoxidase, magnification 600×). (B) CD68 immunohistochemical stain highlighting the histiocytes (immunoperoxidase, magnification 600×). (C,D) BCL-1 and Oct2 immunohistochemical stains are positive for histiocytes of Rosai–Dorfman disease (immunoperoxidase, magnification 600×).

Figure 3

Representative images of IgG4 disease in a patient with Rosai–Dorfman disease (refer to Figure 1): increased plasma cells in a background of fibrosis. (A,B) Immunohistochemical stains demonstrate plasma cells positive for IgG and proportionally positive forIgG4 (A,B). immunoperoxidase 100×, respectively). (C,D) In situ hybridization using kappa and lambda light chain probes reveal the plasma cells to be polyclonal (in situ hybridization 100×, respectively).