Rosai-Dorfman disease

Discussion

Rosai-Dorfman disease is a rare disease. Three cases involved the CNS in this series. The first case involved dura and extended to the underlying cortical tissue. The second case involved parietal bone, dural, and extended to subcortical white matter. The third case involved optic chiasm. Previously, we have reported 2 cases of RDD with involvement of spinal dura.¹⁰ Central nervous system involvement usually manifests as dura-based masses and should be considered in the differential diagnosis of a dura-based lesion such as meningiomas. Intracranial and spinal intramedullary involvement by RDD is extremely rare, and lesions can clinically mimic lymphomas. Intraventricular lesions have also been reported.¹¹

There was one case of isolated laryngeal RDD. In a recent review by Wei et al,¹² there were approximately 30 reported cases in English so far. Patients in those cases were treated in different ways. The largest case series was reported by Niu et al¹³ who reviewed 5 laryngeal RDD cases. Thalidomide treatment was found to be effective in the treatment of laryngeal RDD.¹²

One case in the current series was an osseous RDD involving lumbar vertebrae without involvement of spinal dura. The patient presented with lytic lesion. Primary osseous RDD is also very rare and is usually multifocal. The largest case series of osseous RDD was reported by Demicco et al.¹⁴ They reviewed 15 cases, and the lesions in their series arose in various anatomical locations. On radiological assessment, typically, these lesions tended to be lytic with well-defined sclerotic margins.¹⁴ Bone RDD must be differentiated from the pathological mimics of bone lesions, especially in Erdheim-Chester disease.

Only one soft tissue RDD was identified in this study, in the left upper arm. In this patient, the disease was multifocal, with similar masses identified in the left shoulder, and thigh. According to the literature, skin and soft tissue represented the most reported sites of extranodal involvement by RDD. However, a cutaneous disease without lymphadenopathy is extremely rare.^2,15 Skin lesions must be differentiated from different cutaneous mimics, including histiocytosis, lymphoma, sarcoidosis, and infectious processes.¹⁵

A review of the English literature revealed 12 RDD cases reported from Saudi Arabia and is summarized in Table 2.8-10,16-22 In those cases, the age range was between 10 months and 53 years. There were 8 males and 4 females. The tumor site included LNs, cheek, cornea, orbit, and thoracic spine. All patients were adults except one case reported in infancy.²² Three of the cases were reported in association with other diseases, including sickle cell disease and eczema, polyarthritis, and Sjogren’s syndrome.^16,18,23 In those cases, patients were treated by surgical excision alone, surgical excision with systemic steroid, surgery with local steroid, surgery with radiation, steroid alone, and steroid with azathioprine.^{8-10,16-18,20-24}

Nodal RDD frequently mimics other diseases clinically. Because RDD is a rare disease and has various clinical presentations, it can mimic other causes of lymphadenopathy. All 7 cases of nodal RDD in this series were samples for the clinical suspicion of lymphoid neoplasm. Pathological examination is important to distinguish RDD from lymphoma because they are completely different entities. The pathological mimics of RDD include malignancy like lymphoma, histiocytic sarcoma, metastasis or other benign like tuberculosis, sarcoidosis, immunoglobulin G4 (IgG4) related disease, and Erdheim-Chester disease. Two of the cases in the current study have been initially pathologically misdiagnosed outside the institutions, one was labeled as atypical infiltrate suspicious for lymphoma, and the other was called non-caseating granulomatous inflammation suggestive of sarcoidosis. The misdiagnosis of RDD as another entity was well known in the literature. Rosai-Dorfman disease has been misdiagnosed histologically or cytologically as meningioma, rhinoscleroma, toxoplasma lymphadenitis, sarcoidosis, tuberculosis, and lymphoma.²⁵ Careful morphological assessment and proper immunohistochemistry interpretation usually prevent misdiagnosis. Rosai-Dorfman disease has been reported in association with other histiocytic disorders, such as Langerhans cell histiocytosis.²⁶ It can be associated with both Hodgkin’s and non-Hodgkin’s lymphoma, including mantle cell lymphoma, peripheral T-cell lymphoma, small lymphocytic lymphoma, extranodal marginal zone lymphoma, and large-cell anaplastic lymphoma.^27,28 Rosai-Dorfman disease can precede, coincide with, or follow lymphoma diagnosis.²⁷ Rosai-Dorfman disease and lymphoma may involve the same or different anatomic locations. Therefore, the diagnosis of RDD in LN should raise possible associated lymphoma in the same LN or in different anatomical sites.

Among the 25 cases reported from Saudi Arabia (including the patients in this series), 14 were nodal, and 11 cases extranodal with CNS and spine represented the most common site (total of 5 cases). The prognosis in those patients reported from Saudi Arabia was generally very good, with only 3 recurrences of disease and one fatal case, where the patient failed treatment, deteriorated clinically, and died within 4 months after diagnosis.24 Only 2 cutaneous RDD were identified, which suggest that the cutaneous form of RDD is rare among Saudis compared to Asians.

The pathogenesis of RDD is still unclear and likely multifactorial. The relation of RDD with different viruses is a controversial issue. Different viruses have been reported associated with RDD, including Epstein-Barr virus, human herpesvirus-6, and parvovirus B19 infection.^29-31 The possible association between RDD and different autoimmune diseases, IgG4-related diseases, have been also reported.^32,33 Recent studies have shown Kirsten rat sarcoma viral oncogene homolog (KRAS) and mitogen-activated protein kinase 1 (MAP2K1) mutations in some cases of RDD, suggesting that at least a subset of RDD cases may be clonal lesions, which may open new channels for targeted therapy, particularly in refractory cases.^34-37

Pathologically, RDD is characterized by histiocytic proliferation that may show mild to moderate cytologic atypia with nuclear pleomorphism and prominent nucleoli. The pathognomonic histopathological feature is emperipolesis, which is the presence of lymphocytes, plasma cells, red blood cells, and less frequently neutrophils within vacuoles in the cytoplasm of many histiocytes. Although emperipolesis is considered a characteristic feature of RDD, it can rarely be seen in association with lymphomas, with few cases reported in the literature.³⁸ Awareness of this fact is important for the pathologist to avoid misdiagnosis of lymphomas as RDD with subsequent delayed management. Rosai-Dorfman disease may have some overlapping features with IgG4-related disease. However, it lacks other histologic criteria for IgG4-related disease, mainly storiform fibrosis and obliterative phlebitis.

When RDD involves the LN, the germinal centers are usually atrophic, compressed, or lacking in most cases, and the paracortex is attenuated due to the compression effect of the expanded sinusoids. The histiocytes in RDD classically are positive for S100 and CD68, but they lack markers of Langerhans cells (CD1a and langerin) or dendritic cells (CD21, CD23, and CD35). This immunohistochemistry profile is very helpful in differentiating this entity from other histiocytic diseases.

Surgery, steroid, chemotherapy, methotrexate, azathioprine, thalidomide, and radiation have been used to treat RDD. While the optimal treatment remains controversial, surgical resection is generally curative. Abla et al³⁷ and Salama et al³⁵ reported guidelines for clinical evaluation with treatment recommendations for a patient with RDD based on their clinical experience and review of the literature. Targeted therapy with mitogen-activated protein kinase inhibitors is under investigation in those with MAPK/ERK pathway alterations.^36,39 In most cases, RDD has a benign course and treatment is not required. Treatment is indicated for patients with extranodal RDD affecting vital organs or those with nodal RDD associated with serious complications.

Rosai-Dorfman disease reportedly has a benign prognosis with good response to treatment. However, it is unpredictable. Some patients had progressive disease and died.⁴⁰ In others, the disease seemed to regress. Fatalities were reported to be in the range of 5-10%.³⁶ Because of the rarity of this disease, reports of even small patient series will highlight more on this entity in particularly the extranodal type and provided more information on the clinical presentation and management options.