Rosai–Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy or sometimes as Destombes–Rosai–Dorfman disease, is a rare disorder of unknown cause that is characterized by abundant histiocytes in the lymph nodes or other locations throughout the body. Signs and symptoms The histiocytosis of Destombes–Rosai–Dorfman disease can occur in lymph nodes, causing lymphadenopathy, or can occur outside lymph nodes in extranodal disease. Lymphadenopathy Lymphadenopathy can occur in one or more groups of lymph nodes. Among 358 cases of Destombes–Rosai–Dorfman disease that Rosai collected in a disease registry for which the location of lymphadenopathy was specified, 87.3% had cervical lymphadenopathy. Axillary, inguinal, and mediastinal lymphadenopathy are also found in Destombes–Rosai–Dorfman disease. Extranodal disease Accumulation of histiocytes may occur outside of lymph nodes. The most common sites of extranodal disease in Rosai's registry were skin, nasal cavity/paranasal sinuses, soft tissue, eyelid/orbit, bone, salivary glands, central nervous system, and heart. The symptoms of this disease vary with the site of accumulation similar to other regional tumors. For instance, accumulation in closed spaces such as the cranium can lead to poor outcomes compared to growth in the dermis of an extremity where surgical excision is possible. Cause The etiology of the condition is unknown. Possible but unproven infectious causes are Klebsiella, polyomaviridae, Epstein–Barr virus, parvovirus B19, and human herpesvirus 6. Jilin University researchers suggested in 2017 that monocytes recruited to inflammatory lesions could produce macrophage colony-stimulating factor, which leads to a complex signal transduction, which leads to the histiocytosis characteristic of Destombes-Rosai–Dorfman disease. Diagnosis The differential diagnosis of Destombes–Rosai–Dorfman disease includes both malignant and nonmalignant diseases, such as granulomatosis with polyangiitis, Langerhans cell histiocytosis, Langerhans cell sarcoma, lymphoma, sarcoidosis, IgG4-related disease, and tuberculosis. The disease is diagnosed by biopsy of affected tissues. Microscopic examination of stained specimens will show histiocytes with lymphocytes and possibly other types of cells trapped within them, a phenomenon known as emperipolesis. Upon immunohistochemical staining, the histiocytes will be positive for S100, CD68, and CD163 but negative for CD1a. Classification In 2016 the Histiocyte Society proposed a classification of histiocytoses into five groups designated by letters: "C", "H", "L", "M", and "R". Group "R" included Rosai–Dorfman disease and "miscellaneous noncutaneous, non-Langerhans cell histiocytoses". Rosai–Dorfman disease itself was classified into "Familial", "Classical (nodal)", "Extranodal", "Neoplasia-associated", and "Immune disease-associated" subtypes. Treatment Some patients have no symptoms, spontaneous remission, or a relapsing/remitting course, making it difficult to decide whether therapy is needed. In