Rosai-Dorfman disease Dr Shiva Nazari Pediatri Hematologist – Oncology Associate Professor of Shahid Beheshti Medical University Mofid Children Hospital

Patient Introduction A 7-year-old boy referred with headache, fever, imbalance, weight loss, and Speech impairment. The symptoms had begun with speech impairment about 3 months before . Headache had been added and gradually the symptoms had intensified and progressed so that the child was no able to go to school. Examination of head and neck: Inflation of the left parietal, papillary edema Examination of the rest of the body had normal results.

Pre-Operative MRI There are mutilobulated intraventricular masses in lateral ventricles cause hydrocephalus and significant edema in adjucent parenchyma, another extra axial dural base mass located on tentorium is also noted encasing posterior aspect of superior sagital sinus. Mentioned masses appear hyperdense in CT, low signal at T1 and T2 weighted images in MRI were observed, and show avid contrast enhancement after contrast administration

Description of the disease The dural base and the large intraventricular masses were diagnosed with MRI. At that time differential diagnosis included: Brain tumor, Wagner granulomatosis, LCH, Sarcoidosis, TB, lymphoma, glioma, and metastatic events The patient underwent surgery and craniotomy, and the mass was removed.

The pathology Report of removed cerebrovascular lesions showed: Pathologic Report The pathology Report of removed cerebrovascular lesions showed: Proliferation of hystiocytic cells with a relatively large eosinophilic cytoplasm and giant hystiocytic cells, Emperipolesis and lymphoplasma cells in a highly fibrotic area associated with ischemic cores with parts of normal coroid plexus and glyotic tissue of the brain without evidence of high mitotic activity, and the final diagnosis was RosaiDorfman

Family History The boy was the first child of the family. During the infancy and breastfeeding, he had a good growth and development The parents had no kinship relationship

Past History The child had been referred to a hospital 6 months before Symptoms: headache, fever and vomiting Diagnosis: acute bacterial meningitis Treated with antibiotics for 10 days. The cultures of the CSF and blood were negative . Papillary edema , ESR was still high after treatment. Tuberculosis and viral infections were investigated but no positive finding was observed His overall condition improved and the ESR was lowered. Except MRI, MRV and MRA no further examination was done.

Brain MRI When Have Meningitis

Brain MRV and MRA were Reported to be Normal. When Have Menangitis

The history of the patient A noticeable point in this patient was the history of large size of bilateral cervical lymph nodes at the age of two, which was most likely to be treated with an antibiotic. Got smaller after about seven months, which disappeared spontaneously. Biopsy of these large lymph nodes was not performed

The history of the patient At the age of 3, a soft tissue mass in the left lateral femur with the size of 1.5 × 3 cm was observed. MRI reported: A mass in the muscle with invasion of the perivascular fascia and subcutaneous fat The mass was removed by surgery The pathologic outcome of mass was of benign Fibro Histoyo Cystic Tumor

The history of the patient He had Itchy red rashes in the scalp and chest since birth. At the age of 5 rashes were Intensified. investigated for the potential of allergic reactions. At the same time Blood tests for : CBC, serum immunoglobulin's, serum complement , liver and kidney function tests, were reported normal. Food allergy diagnosed After four months, the lesions improved. Biopsy of skin lesions was not performed.

Patient Treatment The patient was treated with Corticosteroid. Due to lack of proper response Brain Radiotherapy was performed . Then the size of the mass was larger and there was an increase in cerebral pressure Treatment is continued with vinblastine - Methotrexate - 6MP( Langerhans Cell Histiocytosis (LCH) 2009).

Rosai-Dorfman disease (RDD) or Sinus histiocytosis with massive lymphadenopathy (SHML) Rare histiocytic disorder Initially described in 1969 by Rosai and Dorfman characterized by a nonmalignant proliferation of histiocytes that can be located in the lymph nodes or extranodal.

Clinical Features Most frequent clinical presentation is a massive bilateral and painless cervical lymphadenopathy with fever, night sweats and weight loss. mediastinal, inguinal and retroperitoneal nodes Extranodal involvement in 40% of cases : Skin, soft tissue, upper respiratory tract, multifocal bone, eye and retro-orbital tissue with lymphadenopathy, gasterintstinal Less than 5% in central nervous system In most of the caaes, the intracranial RDD is associated with nodal involvement.

Intracranial Dissease Usually affects adult males in their 40s and 50s Usually, it presents as a dura based solitary mass, multiple lesions are not common. Common locations are suprasellar region, cerebral convexity, parasagittal region, cavernous sinus. Clinical features depend on location of the tumour: including headache, epilepsy, and cranial nerve deficit Radiologically, intracranial RDD is commonly mistaken for meningioma. This mistake was also made in the present case. both of the conditions show hypointensity or isointensity on T1 and T2 weighted images. They also show marked homogenous enhancement after contrast administration.

Differential Diagnosis Langerhans cell histiocytosis (LCH) : Most affected individuals have single or multiple bone lesions. Meningiomas are benign, slow-growing tumors. Lymphoma, Abnormal enlargement of the lymph nodes. Lyme disease is an infectious disease. Granulomatous inflammation like tuberculosis and sarcoidosis

Causes disease The exact cause of disease is unknown infectious agents, immunodeficiency, autoimmunity are suggested Reported after bone marrow transplant , Hodgkin’s and non-Hodgkin’s lymphoma, autoimmune diseases, hematological malignancies and post-infectious conditions, Herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV)

Histology Lymph nodes show pericapsular fibrosis and dilated sinuses, heavily infiltrated with large histiocytes, lymphocytes and plasma cells. The presence histiocytes that express S-100, is considered diagnostic although not uniquely. Immunohistochemical is also positive for CD68, CD163, α1-antichymotrypsin, α1-antitrypsin, fascin and HAM-56 while CD1a is typically negative

Treatment In the majority of cases, disease has a benign course and treatment is not necessary. Therapy is required, however, for patients with extranodal disease having vital organ involvement or those with nodal disease causing life-threatening complications. Surgery is generally limited to biopsy, but debulking may be required in patients with vital organ compromising such as intracranial dural-based lesions or upper airway obstruction. Radiotherapy has limited efficacy in most cases, although showed benefit in refractory cases.

6-mercaptopurine (6MP) was effective Drug Treatment Systemic corticosteroids are usually helpful in decreasing nodal size chemotherapeutic agents have not been encouraging Antimetabolite therapy with low-dose methotrexate (MTX) and 6-mercaptopurine (6MP) was effective Anthracyclines, alkylating agents and vinca alkaloids have limited efficacy, although some benefit with vinblastine has been reported Drugs that specifically target cytokines (TNF-α and IL-6), such as cladribine (or 2-CDA), have been found to be effective in recurrent, refractory or severe casesTo report the outcome of a patient with Rosai Targeted therapy against MAPkinase pathway is active in refractory disaes Dabrafenib & trametinib. Dabrafenib 75 mg BID and Trametinib 1.5 mg/day

Summary Although Rosai Dorfman Disease is more prevalent in children but the involvement of nervous system is rare in children in a way that only a few cases have been reported Here we present a case who had isolated intracranial disease and had massive lymphadenopathy in his neck with regression 4 years ago. This report describes a case of life-threatening tumor which was treated with radiotherapy and corticosteroid. After a second relapse it was decided to try chemotherapy following the LCH-2009 protocol of weekly vinblastine(6 mg/m2), 6-MP(75 mg/m2), and MTX (25mg/m2)