Rosai-Dorfman disease (RDD) is a rare nodal or extranodal disorder defined by an accumulation of atypical histiocytes exhibiting emperipolesis, admixed with other hematopoietic elements, particularly, plasma cells and lymphocytes. The disease was established as a distinct clinical entity by Juan Rosai and Ronald Dorfman in two publications in 1969 and 1972 (Rosai and Dorfman 1969, 1972). Although “sinus histiocytosis with massive lymphadenopathy” (SHML) was the original name proposed by Rosai and Dorfman, the eponym “Rosai-Dorfman disease” (RDD) was later used to refer to the extranodal manifestations of this disease. Both names are currently used interchangeably. Rosai and Dorfman also established an SHML registry, which allowed them to collect and study 423 cases and their clinicopathologic characteristics in 1990 (Foucar et al. 1990). More recently, RDD has been shown to be associated with various immune diseases and neoplasia as well as inherited, familial genetic conditions. Given the heterogeneity of RDD in both localization and various clinical contexts, the Histiocyte Society has recommended that “classic” Rosai-Dorfman disease involving a single lymph node or regional lymph nodes be distinguished from extranodal RDD and RDD-like features seen in association with other conditions (Emile et al. 2016).
The incidence of RDD is unknown, but occurs more frequently in men and individuals of African descent. RDD has been found in association with several immune disorders (e.g., SLE, idiopathic juvenile arthritis, autoimmune hemolytic anemia, HIV), IgG4 syndrome, and various types of neoplasia (e.g., postleukemia, postlymphoma, Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD)). While the majority of RDD cases are believed to be sporadic, two inherited conditions have been shown to predispose to RDD or RDD-like lesions. Specifically, 20% of patients with H (Faisalabad) syndrome and 41% of patients with autoimmune lymphoproliferative syndrome (ALPS) develop features consistent with RDD (Foucar et al. 1990; Emile et al. 2016) (Table 1).
RDD can occur at any age; however, there is a tendency for classic or nodal disease to present in younger individuals in their second or third decades of life and extranodal disease, particularly at CNS, skin, and soft tissue sites, to present later in life, such as the fifth decade.
Slight male predominance (M:F of 3.2).
Among patients with nodal RDD, the cervical lymph nodes (87%) are most commonly involved followed by the inguinal (26%), axillary (24%), and mediastinal (15%) lymph nodes. Extranodal RDD occurs in 43% of cases, often involving more than one extranodal site (Foucar et al. 1990). The most frequent sites of extranodal disease are the nasal cavity, paranasal sinuses, salivary gland, skin, soft tissue, upper respiratory tract, bone, retro-orbital tissue, or CNS. While extranodal disease typically presents with concurrent lymph node involvement, extranodal disease can occur in the absence of any nodal disease or nodal disease may develop later in the clinical course. Specifically, intracranial RDD usually occurs without extracranial localization; however, the frequency of isolated extranodal involvement at this site and others is unclear.
Classic or nodal RDD is clinically characterized by painless, massive lymphadenopathy usually involving the cervical lymph nodes. Less frequently, the axillary, hilar, peritracheal, and inguinal nodes are involved. Patients often experience constitutional symptoms such as fever, night sweats, fatigue, and weight loss. Laboratory abnormalities are nonspecific and can include normochromic or microcytic anemia, polyclonal hypergammaglobulinemia, hypoalbuminemia, and elevated erythrocyte sedimentation rate (ESR). While patients with extranodal disease may experience similar clinical features to those described above with simultaneous nodal involvement, constitutional symptoms and lab abnormalities are less commonly seen in isolated, extranodal RDD. Extranodal RDD often presents as a mass with or without secondary complications, such as compression or organ damage. In fact, extranodal RDD may be incidentally detected during routine screening radiography, such as in a case of extranodal breast RDD detected by screening mammography. CNS disease will often show a lymphocytic pleocytosis in the CSF when there is meningeal involvement.
Most cases of RDD are self-limited and require no additional treatment. However, in cases in which the disease is multifocal, systemic or involving vital organs, such as the liver, upper airway, or CNS, therapeutic intervention is required. No standard treatment has been established and will vary based on site, extent of disease, and the presence of secondary complications. Surgical debulking is often required in situations of vital organ compromise as well as intracranial or orbital involvement by RDD. Additionally, systemic corticosteroids can be helpful in reducing nodal size and alleviating symptoms, such as fevers, tracheal compression, and bulky organ disease; however, recurrence can occur after cessation. While chemotherapy has yet to show significant promising results, several chemotherapies have been used as second-line therapies in refractory cases. Cladribine, clofarabine, imatinib, rituximab, methotrexate, oral 6-mercaptopurine, and azathioprine have all been reported to have some efficacy in treating widespread, nonresectable, refractory, and/or relapsing RDD. Radiotherapy can be beneficial in refractory orbital disease but has shown minimal utility at other sites. Recent genomic analysis showed that one-third of RDD cases harbor mutually exclusive mutations in KRAS and MAP2K1 genes, raising the possibility that these are clonal neoplasms that may benefit from targeted therapy in the future (Garces et al. 2017).
The clinical course of RDD is unpredictable and varies from mild to life threatening. While the majority of RDD cases spontaneously regress and require no therapeutic intervention, some cases can have a more severe and prolonged course with alternating episodes of exacerbation and remission. In particular, cases with more widespread nodal or systemic disease tend to have a more aggressive clinical course, often requiring treatment. Features associated with poor prognosis include simultaneous autoimmune disease or neoplasia, widespread nodal or extranodal involvement, and involvement of vital organs (e.g., liver, kidney, and upper respiratory tract). Death occurs in 5–11% of cases.
Intranodal disease consists of a single or multiple enlarged firm lymph nodes often with capsular and pericapsular fibrosis. When multiple lymph nodes are involved, they are often matted together as a conglomerate. Cut surfaces are yellow-white and granular in appearance. Extranodal disease can vary grossly depending on the site, but typically consist of a white-yellow firm mass. Imaging studies are nonspecific for RDD, but often mimic malignancy.
Extranodal RDD demonstrates inflammatory infiltrates resembling dilated lymph node sinuses with similar histologic features to those observed in nodal RSS described above (Fig. 2a–h). Importantly, there are often fewer histiocytes and less robust emperipolesis. Unique features more often observed in extranodal RDD include prominent germinal centers, fibrosis, and a more edematous background. At skin and soft tissue locations, a storiform pattern is often observed in areas where histiocytic and lymphoplasmacytic infiltrates abut and alternate.
Immunohistochemistry for S100 is uniformly positive in RDD histiocytes and can be useful in highlighting emperipolesis when difficult to confirm by H&E. Although RDD histiocytes express S100 suggestive of a more dendritic cell lineage, overall, their expression profiles are believed to be most similar to activated macrophages. For instance, varying immunopositivity with macrophage markers, including CD68, CD163, lysozyme, fascin, CD14, HLA-DR, MAC-137, alpha-1 anti-trypsin, and alpha-1 antichymotrypsin, has been reported. Importantly, RDD histiocytes are negative for CD1a, which is positive in both Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD), as well as Langerhin/CD207, which is positive in LCH. Additionally, RDD histiocytes are negative for cytokeratins and other melanocytic markers, such as SOX10, HMB-45, and MelanA.
The cause of RDD remains enigmatic. Historically, RDD has been considered reactive in nature and a nonneoplastic, polyclonal disorder. Specifically, it has been hypothesized that immune dysregulation secondary to autoimmune disease, hematological malignancy, or a postinfectious condition underlies RDD and leads to the accumulation of activated histiocytes. In fact, RDD has been reported to concomitantly occur in patients with immune disorders, IgG4-related disease, and neoplasia. Several groups have examined the association between RDD and Epstein-Barr virus, human herpes virus-6, and parvovirus B19 in relation to RDD; however, results are conflicting and no definitive relationship has been established. A genetic basis for RDD has only more recently been investigated. Mutational analysis performed on a cohort of 21 RDD cases (13 extranodal, 5 nodal, 3 nodal and extranodal sites) identified mutually exclusive point mutation in either KRAS or MAP2K1 suggesting the possibility that at least a subset of RDD cases is clonal in nature (Garces et al. 2017). In addition, two rare inherited conditions have been shown to predispose to RDD or RDD-like lesions. Patients with H (Faisalabad) syndrome, an autosomal recessive genetic condition caused by mutations in the nucleoside transporter SCL29A3, have been shown to develop pathologic findings at nodal and extranodal sites compatible with RDD. In addition, 41% of patients with autoimmune lymphoproliferative syndrome (ALPS) type IA lymphoproliferative syndrome type IA, with heterozygous germline mutations in the TNFRSF6 gene encoding FAS, have lymph node histologic findings (Emile et al. 2016). Mutations in these genes have not been associated with sporadic cases of RDD. Further molecular studies are required to better understand and further subclassify RDD.
Types of Rosai-Dorfman disease (Adapted from Emile et al. 2016)
Described in association with H (Faisalabad) syndrome, FAS deficiency, and autoimmune lymphoproliferative syndrome (ALPS). May be unassociated with other conditions (familial RDD, not otherwise specified)
Classical (nodal) RDD
A subset of cases is associated with IgG4-related disease
Most commonly involve CNS, skin, bone, and less commonly, single organs. May in addition be associated with IgG4-related disease; cases of disseminated RDD have been reported
Described in association with lymphoma, leukemia, malignant histiocytoses, Langerhans cell histiocytosis, and Erdheim-Chester disease
Immune disease-associated RDD
Described in association with systemic lupus erythematosus, idiopathic juvenile arthritis, autoimmune hemolytic anemia, and human immunodeficiency virus
- Emile, J.-F. F., Abla, O., Fraitag, S., Horne, A., Haroche, J., Donadieu, J., Requena-Caballero, L., Jordan, M. B., Abdel-Wahab, O., Allen, C. E., et al. (2016). Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood, 127, 2672–2681.CrossRefPubMedPubMedCentralGoogle Scholar
- Garces, S., Medeiros, J., Patel, K., Li, S., Pina-Oviedo, S., Li, J., Garces, J., Khoury, J., & Yin, C. (2017). Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. Modern Pathology. https://doi.org/10.1038/modpathol.2017.55.