Rosai Dorfman Disease
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Rosai-Dorfman Disease (“Sinus histiocytosis with massive lymphadenopathy” or SHML) is a rare benign tumor characterized by an abundance of histiocytes (tissue resident macrophages, dendritic cells) in the involved tissue. Typically manifests as painless lymphadenopathy, but extranodal orbital disease also occurs, and may even occur without lymph node involvement.
Rosai-Dorfman Disease (RDD) Other names include Rosai-Dorfman-Destombe Disease as well as Sinus Histiocytosis with Massive Lymphadenopathy (1).
Rare non-malignant histiocyte proliferation, typically presenting with painless bilateral cervical lymphadenopathy (2). Commonly seen with extranodal involvement. Presently designated an R-group histiocytosis (3), previously histiocytosis X.
There are 4 classes, based on predisposing factors (6). Heredity: A number of associated kinase mutations have been identified, including ARAF, MAP2K1, NRAS, KRAS. Germline mutations in SLC29A3 may cause familial RDD. Neoplasia: Hodgkin or non-Hodgkin lymphoma, myelodysplastic syndrome, cutaneous clear cell sarcoma, histiocytosis. Immune-Related: Systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune hemolytic anemia. IgG4-Related: Polyclonal hypergammaglobulinemia has been noted in up to 90% of cases (3).
1 per 200,000 in US (6). 43% of cases have extranodal involvement (3). 11% of cases involve the eye, orbit, or ocular adnexa (5).
Most common in children, young adults. Mean age of onset is 20 (5). More common in males, particularly those of African descent. Cutaneous form more common in women of Asian descent (6). Patients tend to have co-existing, possibly underlying, autoimmunity. Most commonly autoimmune hemolytic anemia, systemic lupus erythematosus, juvenile idiopathic arthritis, and IgG4 related disease (5).
Non-specific inflammatory infiltration of large histiocytic cells with hypochromatic nuclei, abundant emperipolesis. S100 +, CD 68+, CD14+, CD1a -, CD207- (3,4). No specific cytogenetic findings (5). In lymphatic tissue, histiocytes found in sinuses, plasma cells and B-cells seen in cortex (3,4).
Unknown. Proposed mechanisms include chronic occult infection or exaggerated immune response to an undetermined trigger prompting histiocytosis (4, 5).
Painless or painful swelling of the eyelids, conjunctiva, lacrimal gland or orbital soft tissues (6). Mass effect may cause proptosis or dystopia causing symptoms of exposure, diplopia, headaches, symptoms of optic nerve compression in severe cases (9). May be bilateral or unilateral. Painless ipsilateral cervical lymphadenopathy likely present.
Occasionally there is a history of recent fever and upper respiratory infection (5). Less commonly with constitutional symptoms including malaise, night sweats, weight loss. If multi-system, may have other organ systems involved.
Diagnosis is based on correlation of clinical, historical, radiologic, laboratory, and pathologic studies. Histologic examination is required.
Imaging with CT, MRI, and ultrasonography may be helpful to characterize the lesion (7, 8). Osteolytic bone lesions are present in less than 10% of cases (5). Soft tissue lesions are enhancing on CT and MRI. PET imaging demonstrates a hypermetabolic state.
Laboratory findings are non-specific, include elevated ESR, leukocytosis, elevated ferritin (3). Polyclonal hypergammaglobulinemia is present in 90% of cases (5). Rheumatoid factor and ANA may be positive. Normocytic or microcytic anemia may be present if there is associated autoimmune hemolytic anemia.
Given the vague presentation and lack of hard definite clinical characteristics, the differential is necessarily broad.
Consider neoplastic etiologies such as Langerhans cell sarcoma, Hodgkin lymphoma, metastatic carcinoma (5).
Non-neoplastic considerations should include Langerhans cell histiocytosis, granulomatosis with polyangiitis, IgG4 related disease, juvenile xanthogranuloma, Erdheim-Chester disease, sarcoidosis, tuberculosis, histoplasmosis, HHV-6, EBV, HIV.
Evidence to guide treatment is lacking and largely anecdotal, therefore we currently rely on expert recommendations.
Observation without treatment advised when possible, as spontaneous resolution is common (10).
Patients are likely to be corticosteroid responsive (11). Steroid sparing therapies should be pursued if long-term suppression is required, including certain chemotherapeutics and immunomodulatory drugs. Rituximab, imatinib, cyclophosphamide, methotrexate, cladribine, sirolimus, IFN-alpha, have reportedly been used with varying degrees of success (12, 13, 14, 15, 16, 17).
Surgical excision is curative if disease is unifocal (6). Debulking is effective (11, 18, 19), particularly if the tumor is disrupting vision or there is risk or evidence of optic nerve compression. Radiotherapy alone has not shown consistent results and is likely most useful for palliative treatment (20).
Generally self-limiting. Most common outcome is spontaneous remission without recurrence (3).
A subset experience recurrence or persistence (21). Cosmetic appearance may be an issue. In orbital disease, the biggest concerns are mass effect causing diplopia, exposure, and/or optic nerve compression in rapidly progressive cases.
Rarely, the course may be aggressive and fatal (5). Poor prognostic factors include autoimmune cytopenias as well as disseminated involvement including kidneys, lower respiratory tract, liver.
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15. Utikal J, Ugurel S, Kurzen H, et al. Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses. Arch Dermatol. 2007;143(6):736-740.
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21. Agarwal A, Pathak S, Gujral S. Sinus histiocytosis with massive lymphadenopathy--a review of seven cases. Indian J Pathol Microbiol. 2006;49(4):509-515.