RDD disease, known as sinus histiocytosis with massive lymphadenopathy (SHML), is generally a rare benign disorder consisting of a proliferation of histiocytes[1]. First described in 1969, More than 600 cases have been reported worldwide. All age groups and both sexes are affected, but it is more common in children and adolescents and in males. The disease is characterized by painless, bilateral cervical lymphadenopathy in 90% of patients and may be accompanied by low-grade fever. Other common sites of nodal involvement include the axillary, inguinal, paraaortic, and mediastinal regions. Symptoms are also related to the presence and distribution of extranodal disease, which occurs in approximately 43% of cases, with or without lymph node involvement. Common extranodal sites include the skin, central nervous system, bone, soft tissues, upper respiratory tract, and salivary glands[2]. There were very few reports of RDD in the thymus [3–6]. Osama [7]found that most of patients had multiple sites of involvement: of 10 patients, only one had pure lymphadenopathy, and all others had some combination of anatomic sites. All three cases of spinal involvement also had either intracranial involvement (n = 2) or
head and neck involvement (n = 1). If Rosai-Dorfman disease is diagnosed at one site, other sites are also likely to be involved.
The underlying causes of RDD remain unclear. It has been considered a neoplastic, immune, or infectious process in various reports [8, 9]. Several viruses were postulated to be associated with onset of the disease. Epstein-Barr virus and human herpes virus 6 have been detected by in situ hybridization in some patients with RDD [10]. Mehraein et al[8] reported four patients with RDD who had huge numbers of parvovirus B19–positive cells detected in their tissues. B19 has been shown to be associated with a variety of inflammatory vasculitides. Osama reported one patient had concomitant RDD and Takayasu arteritis.
RDD manifested various symptoms in reports, including persistent fever, significant fatigue, poor appetite, noticeable weight loss, and painless neck mass. However, some RDD patients without any symptoms were diagnosed form unexpected finding of enlarged lymph nodes in neck, mediastinum, or other sites, just similar to present case in our report.
Preoperative diagnosis of RDD is very difficult, especially located in anterior mediastinum. It is difficult to distinguish RDD from conventional thymic tumors. There is no specificity in tumor size, relationship with surrounding tissues and CT density value. Preoperative biopsy of all thymic tumors is also impractical and unnecessary.
However, in RDD, the thymic mass was composed of histiocytes, not thymic cells. Kubota et al [11] described in 1992 that macrophages (histiocytes) adjacent to a tumor show higher FDG uptake than viable tumor cells. This finding supports our observation of intensely increased FDG uptake by a histiocytic proliferative disorder. Distinguishing RDD from malignant lesions may be difficult, even with FDG PET study, because proliferative histiocytes in RDD were observed to have higher FDG uptake than tumor cells. Osama A [7]report two of three patients with paranasal sinus involvement had aggressive disease with bony destruction. Such aggressive disease is difficult to differentiate from malignant conditions, making the diagnosis of RDD a mainly histologic diagnosis and not a radiological one.
The histopathology of RDD is very characteristic. Lymph nodes shows massively distended sinuses, presence of numerous large histiocytes with vesicular nuclei, distinct nucleoli and abundant pale cytoplasm and emperipolesis. Emperipolesis, a biological phenomenon defined as the active penetration of one cell by another which remains intact. The histiocytes will be positive for immunohistochemical stains S100 and part of CD68 and are typically negative for CD1a. Laboratory findings in RDD include leukocytosis, neutrophilia, normocytic anemia, thrombocytosis, an elevated C- RP, ESR, ferritin levels and hypergammaglobulinemia[12]. However, these lab findings are unspecific.
The RDD can easily be misdiagnosed as it mimics infections like tubercular adenitis, reactive lymphadenopathies, and malignancies like lymphoma and metastatic carcinoma, which occur more frequently than RDD.
The course of the illness is unclear. Classic symptoms, such as cervical lymphadenopathy, fever, and good general condition, may persist from several weeks to even a few years (the average time is 3–9 months) [13]. Without treatment, relapsing-remitting RDD will occur in 70% of cases, spontaneous regression in 20%, and in 10% there will be a progression of the disease[14]. It is recommended that a clinical examination and laboratory tests be performed every 3–6 months during the first two years following diagnosis, then every year [14].
In 2011 the Histiocyte Society divided RDD patients into three major groups: 1) Patients with sudden enlargement of the lymph nodes, in which spontaneous regression is observed, without any further recurrences – consistent with the best prognosis; 2) Patients with immunological abnormalities, in which lymphadenopathy is more generalised – the prognosis being worse; and 3) Patients with extranodal site involvement and/or multinodal disease, with repeated relapses and remissions over a period of years – the prognosis depends on the type and number of extranodal sites [15].
RDD in most cases is a benign disorder; however, multiorgan involvement or dysfunction and association with immune dysfunction are poor prognostic indicators and may lead to death. The most common causes of reported deaths were identified immunological abnormalities, severe infections, surgical complications, complications after radiotherapy, and the compression of airways by enlarged lymph nodes [13, 16]. There are reports of RDD leading to lymphoma, amyloidosis, and consequently death resulting from these diseases [16].
Because of its rarity and limited experiences in treatment for RDD, there are no commonly accepted therapeutic modality. Because spontaneous remission can be observed in a considerable part of RDD patients, the “watch and wait” principle is recommended [14, 17], only if diagnosis of this disease could be confirmed. Although the majority of patients could be safely administered under this “watch and wait” approach without any therapy, some cases whose vital organs, such as airways or spinal cord are moderately or severely pressed or obstructed require appropriate treatment [14, 15, 18].
Treatments for RDD include surgical resection, chemotherapy, radiotherapy, steroids. low dose interferon are occasionally used in some several patients [19]. Very limited clinical trials about chemotherapy and radiotherapy for RDD have been carried out, so effect of these methods is still ambiguous. According to the latest findings, radiotherapy showed better therapeutic response than chemotherapy in RDD cases [15, 20]. So, radiotherapy was considered preferred procedure for patients with symptomatic RDD, and for steroid-resistant patients [21, 22].There are reports describing RDD patients with a high level of HHV-6/VZV antibody titres, in which there was significant improvement after the application of acyclovir [15, 23, 24]. In other cases, partial remission was observed after using thalidomide[15, 20]. Surgery was also reasonable option for those RDD cases whose great vessels or airway are severely pressed, especially diagnosis could not be ascertained before surgery. In present report, RDD manifested as a solitary, unidentified lump in thymic site, so we performed complete resection of the lesion. And the patient maintains in good conditions for 2 years after surgery, and is still under regular follow-up.
It is difficulty of making a diagnosis before surgery and more cases will need to be reported in order to facilitate the preoperative diagnosis of such a rare tumor.