Joseph R. Kallini
M. Yadira Hurley
Rosai–Dorfman disease (RDD), also referred to as Destombes–Rosai–Dorfman syndrome, is a benign proliferative disorder of histiocytes. It is also termed sinus histiocytosis with massive lymphadenopathy, although this phrase does not appropriately reflect the extranodal manifestations of the disease. Extranodal sites of involvement include the skin, oral and nasal cavities, respiratory tract, eyelid, and periorbital soft tissue. Systemic RDD (SRDD) most commonly presents with fever and massive, painless, bilateral, cervical lymphadenopathy. Usual laboratory abnormalities include anemia, elevated erythrocyte sedimentation rate (ESR), neutrophilia, and polyclonal hypergammaglobulinemia. Cutaneous lesions are uncommon but can occur in conjunction with severe systemic disease. Rosai and Dorfman first described the cutaneous manifestations of RDD among 10 patients, 7 of whom were children.1 Rarely, RDD can present solely with cutaneous lesions without systemic findings; this is known as cutaneous RDD (CRDD).2,3
RDD is uncommon; 600 cases have been reported in the medical literature. It is most common in the West Indies, though it has spanned many geographical regions. About 80% of cases develop in the first two decades of life.3 SRDD with cutaneous manifestations occurs in one-third of patients.4 CRDD (disease without any other manifestations) is extremely rare.5 SRDD favors young adult men and male children,2 whereas CRDD favors adult white women, thus making it appear to be a distinct entity.2,3,5
The etiology of RDD is not fully understood. The association with histiocytosis and reactive proliferation of Langerhans cells may play a role in its development.3 The detection of human herpesvirus 6 (HHV-6) in the lymph nodes of affected patients suggests a possible viral etiology. However, HHV-6 has also been found in lymph nodes of patients with many other reactive disorders; thus, there is no definite correlation between this virus and the disease.2,6 Parvovirus B19 has also been proposed as an etiology because of recent studies reporting parvovirus-related antigens in the tissue of affected individuals. More recent studies suggest a possible relationship between RDD and autoimmune lymphoproliferative syndrome (ALPS), a hereditary disease of Fas-mediated apoptosis.2,7
A group of diseases known as IgG-related disease, which includes autoimmune pancreatitis and various extrapancreatic sclerosing lesions, has shown an increased number of IgG4+ plasma cells in the lesions and is associated with tissue sclerosis and elevated serum IgG4 concentrations. It has been proposed that type T helper cells and regulatory T cells regulate IgG4 expression. A recent study demonstrated that a proportion of both nodal and extranodal RDD may have features of IgG4-related disease, which may correlate with disease progression, recurrent disease, and sclerosis.8
CLINICAL PRESENTATION AND PROGNOSIS
SRDD is benign and self-limited, but can run a long course with multiple exacerbations and remissions. It most commonly presents with fever and massive, nontender, bilateral cervical lymph node enlargement. However, lymphadenopathy may be unilateral or nonexistent. Over 40% of patients will have extranodal involvement, the most common locations being the skin, soft tissues (including around the orbit), upper respiratory tract, salivary glands, central nervous system, and bone. There has been one case of a 10-year-old girl in India who presented with bilateral eyelid swelling consistent with ocular involvement.9 Intrathoracic manifestations of SRDD are relatively common and present as mediastinal lymphadenopathy, airway disease, pleural effusion, cystic lung disease, and interstitial lung disease. These usually have a good prognosis.10 There has been one rare case of cerebellar extranodal involvement that responded well to suboccipital craniotomy.11 Involvement of the lower respiratory tract, liver, and kidney portends a poor prognosis.2 Some patients can present with bone pain.
Immunologic features are associated with 15% of patients with SRDD. These commonly include autoimmune hemolytic anemia and neutrophilia.12 Laboratory analysis of the hemolytic anemia reveals normal mean corpuscular hemoglobin volume with increased reticulocytosis. Patients may also present with elevated ESR, anti–red blood cell antibodies, and polyclonal hypergammaglobulinemia. Immune disease is a sign of poor prognosis.2,13,14,15 Though RDD is usually benign, it may run a protracted course that can result in significant morbidity and mortality. Death can be a result of multiorgan infiltration or immunologic disturbances.2
Cutaneous lesions associated with SRDD usually present on the eyelids and malar region. These are often nonspecific and appear as multiple, focal, erythematous, brown, or xanthomatous macules, papules, pustules, nodules, or plaques. Some of these lesions can be as large as 4 cm in diameter.
In the rare cases of purely CRDD, the clinical findings are variable but most commonly present as a central plaque or nodule with satellite papules or as multiple papules and nodules that coalesce into plaques13,14 (Figs. 68-1, 68-2 and 68-3). Some studies have shown that there is no specific site predilection for the cutaneous lesions,15 although recent studies found frequent involvement of extremities.16 Its clinical presentation has been divided into three subtypes. The most common is the papulonodular subtype, representing 80% of cases (Fig. 68-1). Following this are the indurated plaque type and the tumor type17 (Figs. 68-2 and 68-3).