Targetable driver mutations in multicentric reticulohistiocytosis

Multicentric reticulohistiocytosis (MRH) is a very rare systemic disease, characterized by multiple destructive arthritic and papulonodular skin lesions that can also affect other organs including the lungs and heart. MRH is classified as a group C histiocytosis (cutaneous and mucocutaneous histiocytosis) with typical histopathological findings such as histiocytic infiltration, particularly of multinucleated giant cells with eosinophilic cytoplasms. From the first report in 1937, only 200-300 cases of MRH have been reported, and the molecular pathogenesis of MRH remains poorly understood. Given that its clinical manifestations are similar to those of rheumatoid arthritis (RA), it has been suspected that MRH is an autoimmune or inflammatory disease, and treatments similar to those for RA, including administration of corticosteroids, methotrexate, bisphosphonates, and several biological anti-inflammatory agents (etanercept, adalimumab, and infliximab), have been tried. Although spontaneous remission is occasionally observed during the first ten years after diagnosis, functional prognosis is usually poor; joint replacement surgery has often been required because of the progression of destructive arthritis, and current treatment is inadequate, especially in severe cases. In this study, we performed a comprehensive genetic analysis in two MRH patients to help elucidate its molecular pathogenesis. We studied specimens from two patients with MRH and from 13 patients with Langerhans cell histiocytosis (LCH). One of our patients with MRH has been reported elsewhere. Patients provided written informed consent. The Ethics Committee of the Nagoya University Graduate School of Medicine approved this study, which was conducted in accordance with the principles of the Declaration of Helsinki. We performed whole-exome sequencing (WES) and RNA sequencing in two patients with MRH. We performed PCR–amplicon-based targeted deep sequencing covering BRAF and MAP2K1, and RNA sequencing in 13 patients with LCH. Details of these analyses are provided in the Online Supplementary Methods. A 60-year old female (unique patient number 1, UPN1) visited our hospital because of multiple skin lesions that had first appeared when she was 52 years old. She had a history of breast cancer at the age of 48. Her family history was unremarkable. Fluorodeoxyglucose (FDG) positron-emission tomography (PET) showed the accumulation of FDG in the polyarticular lesions of bilateral upper and lower extremities (Figure 1A). The histological findings of periarticular lesions showed infiltration of histiocytes and multinucleated giant cells (Figure 1C). Immunohistochemical analysis showed CD68 was positive in these cells, whereas LCH markers such as CD1a and Langerin were negative. No abnormalities were revealed in her blood test results, and no blasts appeared in her peripheral blood (Online Supplementary Table S1). We diagnosed the patient as having MRH based on the clinical and pathological features. UPN2 was a 39-year old male who visited our hospital because of disturbances in his daily activities caused by polyarticular nodular lesions and arthralgia in addition to multiple skin lesions (erythematous papules) (Online Supplementary Figure S1). He had no remarkable family history. At the age of 30, abnormal chest shadows were found on X-ray images at routine medical examination. A bronchoscopic biopsy revealed the infiltration of histiocytic cells. The disease was followed up without any intervention because of the lack of subjective symptoms. FDG-PET showed abnormal accumulation of FDG in the large and small joints of the body (including phalangeal joints) (Figure 1). We performed a biopsy of a periarticular lesion of the left elbow and diagnosed him as having MRH based on the typical histological findings similar to those of UPN1 (Figure 1C). We performed WES using biopsy specimens containing histiocytic cells and peripheral blood mononuclear cells derived from the two patients with MRH. We identified eight non-synonymous somatic mutations in the histiocytic cells of each specimen, which were suggestive of clonal expansion (Table 1). While to the best of our