A high degree of clinical suspicion is needed to diagnose Rosai–Dorman disease. Eight-Spotted Skimmer. Photograph courtesy of Sherri Damlo. www.damloedits.com. Rosai–Dorfman Disease: Tumor Biology, Clinical Features, Pathology, and Treatment Samir Dalia, MD, Elizabeth Sagatys, MD, Lubomir Sokol, MD, PhD, and Timothy Kubal, MD Background: Rosai–Dorfman disease (RDD) is a rare, nonmalignant clinical entity characterized by a group of clinical symptoms and characteristic pathological features. Methods: Articles that reviewed tumor biology, clinical features, pathology, and treatment for RDD were identified in a search of the literature for the years 1990 to 2014. The results from this body of literature were reviewed and summarized. Results: Patients with RDD generally present with massive, painless cervical lymphadenopathy, fevers, and elevated inflammatory markers. Extranodal disease is typical, with the most common sites being the skin and the central nervous system. Rarely, the gastrointestinal tract is involved. Immunohistochemistry remains the mainstay of diagnosis with S100 and CD68 positive cells while CD1a will be negative of involved histiocytes. Histologically, the disease shows the classical characteristic finding of emperipolesis. Many patients do not require treatment; however, surgical resection remains the mainstay of treatment for symptomatic disease. The role of steroids, chemotherapy, and radiation therapy continue to be based on small case series and case reports. Conclusions: RDD has a variable clinical presentation; therefore, a high degree of suspicion and a thorough pathological review are necessary to diagnose this rare clinical entity. Although some patients will experience spontaneous resolution, others may require surgical resection or steroid therapy and radiation or chemother- apy. Given the rarity of the disease and the lack of a clear therapeutic pathway, referring patients to a tertiary center is recommended for confirming the diagnosis and treatment considerations. Introduction Rosai–Dorman disease (RDD), also known as sinus From the Departments of Medical Oncology (SD), Hematopathology histiocytosis with massive lymphadenopathy, was and Laboratory Medicine (ES), and Malignant Hematology (LS, originally described by Destombes in 1965.1 Subse- TK) at the H. Lee Moffitt Cancer Center & Research Institute and quently, it was characterized as a distinct clinicopatho- the University of South Florida Morsani College of Medicine (SD), 2 Tampa, Florida. logical disorder in 1969 by Rosai and Dorfman. In this Dr Dalia is now affiliated with Mercy Clinic Oncology-Hematology, nonmalignant disorder, patients typically present with Jopin, Missouri. fever, leukocytosis, and nonpainful cervical lymph- Submitted July 5, 2014; accepted August 12, 2014. adenopathy. Although the disease has a predilection Address correspondence to Samir Dalia, MD, Mercy Clinic Oncol- for the lymph nodes in the head and neck, RDD can ogy-Hematology, 3001 McClelland Boulevard, Joplin, MO 64804. also present in any extranodal site, with common sites E-mail: [email protected] including the skin and soft tissue, the central nervous No significant relationships exist between the authors and the com- panies/organizations whose products or services may be referenced system (CNS), and, less commonly, the gastrointestinal in this article. tract.3-9 Histology and immunohistochemistry help 322 Cancer Control October 2014, Vol. 21, No. 4 differentiate RDD from malignant disorders such as often affected than Caucasians and a male predomi- lymphoma and Langerhans cell histiocytosis. Although nance is present.11 Classically, most patients present adenopathy can be significant and disfiguring, RDD is in otherwise good health with symptoms of fever and usually self-limiting and eventually recedes, making massive, nonpainful cervical lymphadenopathy mim- systemic therapy rarely required.10 The aim of this icking lymphoma.2 Patients may have night sweats and review is to provide health care professionals with the weight loss. Painless maculopapular eruptions also scientific framework to gain a better understanding can be reported, and, unlike patients with Langerhans of the tumor biology, clinical features, pathology, and cell histiocytosis, osteolytic bone lesions are rare but treatment for RDD. sclerotic bone lesions sometimes occur.4,11,22,23 The workup of patients with suspected RDD is Tumor Biology similar to that of lymphoma. A detailed history and RDD is a disease of nonmalignant histiocytes that in- physical examination should be performed to exclude filtrate lymph nodes or extranodal tissues. RDD cells other causes of the adenopathy. It is worth noting that exhibit emperipolesis, the nondestructive phagocy- hepatosplenomegaly is rare in RDD, while it is com- tosis of lymphocytes or erythrocytes, which is the monly seen in other histiocytic disorders.11,24 Staging hallmark of the disease and required for diagnosis.2,8 should include contrast computed tomography (CT) The etiology of RDD is unknown and is considered an scans of the neck, chest, abdomen, and pelvis to look idiopathic histiocytosis. The search for an infectious for distant disease. The role of bone marrow biopsy agent linked to RDD has led to conflicting results. is unclear but is usually obtained because primary Some evidence suggests that immune dysfunction and bone marrow disorders are included in the differential viral infections, such as human herpesvirus (HHV), diagnosis of RDD. Laboratory workup should include parvovirus B19, and Epstein–Barr virus (EBV) may screening for EBV, cytomegalovirus, HHV-6, HHV-8, play a role in the pathogenesis.9,11-13 In particular, the and HIV. In addition, the laboratory workup should expression of the HHV-6 antigen has been identified include rheumatoid factor, an antinuclear antibody in the histiocytes present in RDD, while EBV and test, complete blood counts, liver and kidney func- parvovirus have been shown to be present in lympho- tion tests, immunoglobulin levels, and an erythrocyte cytes, which may eventually be phagocytosed by his- sedimentation rate (ESR). A total of 90% of patients tiocytes.13,14 However, in situ hybridization studies for has been reported to have an elevated ESR and poly- EBV-encoded RNA have shown the RDD histiocytes clonal hypergammaglobulinemia with a reversal of to be negative.11,15 In addition, 3 cases of RDD were the albumin:globulin ratio.24 Leukocytosis with neu- demonstrated to be negative for HHV-6.16 Therefore, trophilia, a normochromic normocytic anemia, and the definitive identity of an infectious agent behind a positive rheumatoid factor or antinuclear antibody RDD remains undetermined. value have all been reported.11,13,24 Hemolytic anemia Although RDD has been reported in patients with and eosinophilia are rare.11,24 Ideally, excisional biopsy immunoglobulin (Ig) G4-related disease, no clear ev- should be performed to obtain adequate tissue for idence suggests that these disorders have a common morphological and immunohistochemical analyses etiopathogenesis. In a recent analysis of 29 patients to make a diagnosis. with RDD, low numbers of IgG4-positive plasma cells The differential diagnosis of RDD is broad and and low IgG4/IgG ratios were present when compared is similar to other causes of lymphadenopathy. Non- with IgG4-related disease samples. Forkhead box malignant etiologies include tuberculosis, Wegener P3–positive T-regulatory cells were also lower in granulomatosis, sarcoidosis, IgG4-related disease, ju- number in patients with RDD when compared with venile xanthogranuloma, Erdheim–Chester disease, IgG4-related disease, suggesting that RDD does not fit Gaucher disease, and other histiocytic disorders such into the spectrum of IgG4-related disease.9,17,18 Germ- as Langerhans cell histiocytosis. Malignant etiologies line mutations in SLC29A3, which encodes an intracel- in the differential diagnosis of RDD include Hodgkin lular human equilibrative nucleoside transporter, have lymphoma, non-Hodgkin lymphoma, melanoma, leu- been reported in patients with familial RDD, suggest- kemia, and Langerhans cell sarcoma. ing that RDD may belong to a spectrum of disorders Extranodal involvement by RDD was initially with SLC29A3 mutations, including Faisalabad histio- thought to be uncommon, but some reports suggest cytosis, H syndrome, and pigmented hypertrichosis in that it may be present in up to 40% of cases.4,18 The the setting of insulin-dependent diabetes.19-21 most commonly involved extranodal sites include the skin, CNS, orbit and eyelid, upper respiratory tract, Clinical Features and the gastrointestinal tract.7-9,11-13,17,18,22,25-32 Typically, RDD manifests in childhood and early adult- CNS involvement in the setting of RDD is uncom- hood, with the majority of cases reported in the second mon and has been reported in 210 cases in the English and third decades of life.11 African Americans are more literature.8 The mean age of patients is 39 years and a October 2014, Vol. 21, No. 4 Cancer Control 323 male prevalence has been reported.8 Commonly, RDD RDD; lymph node structures, including sinusoids, presents with dura-based, extra-axial involvement of are absent (Fig 1).2,11 With fewer histiocytes present the cranium; by contrast, spinal cord and intracerebral showing emperipolesis in extranodal tissue, a careful involvement are rare.3,8 Constitutional symptoms are examination of the biopsies is required and immu- usually absent and neurological symptoms depend on nohistochemical stains may be