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Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease.

ABSTRACT: Rosai-Dorfman disease is a rare subtype of non-Langerhans cell histiocytosis. With the last major report published in 1990, there is a paucity of contemporary data on this disease. Our objective was to report the clinicopathological features, treatments and outcomes of patients seen at a tertiary referral center. Sixty-four patients with histopathological diagnosis of Rosai-Dorfman disease were identified from 1994 to 2017 (median age 50 years; range, 2-79). The median duration from symptom onset to diagnosis was seven months (range, 0-128), which was also reflected in the number of biopsies required to establish the diagnosis (median 2; range, 1-6). The most common presentation was subcutaneous masses (40%). Of the 64 patients, 8% had classical (nodal only) and 92% had extra-nodal disease (67% extra-nodal only). The most common organs involved were skin and subcutaneous tissue (52%), followed by lymph nodes (33%). Three patients had an overlap with Erdheim-Chester disease, which had not been described before. Two of these were found to have MAP2K1 mutations. Commonly utilized first line treatments were surgical excision (38%) and systemic corticosteroids (27%). Corticosteroids led to a response in 56% of the cases. Of those treated initially, 15 (30%) patients developed recurrent disease. The most commonly used systemic agent was cladribine (n=6), with 67% overall response rate. Our study demonstrates that Rosai-Dorfman disease has diverse clinical manifestations and outcomes. While this disease has been historically considered a benign entity, a subset of patients endures an aggressive course necessitating the use of systemic therapies.

SUBMITTER: Goyal G

PROVIDER: S-EPMC7012468 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Project description:ImportanceRosai-Dorfman disease (RDD) is a rare histiocytic neoplasm with recent studies showing alterations in the MAPK pathway, most commonly in the KRAS and MEK genes in about 40% of patients. Reports on the use of MEK-inhibitor therapy in RDD have been limited to small case studies. There are no approved treatments for this neoplasm, and therefore patients with RDD need efficacious treatments.ObjectiveTo study the outcomes after treatment with cobimetinib based on MAPK pathway alterations in patients with RDD.Design, setting, and participantsThis retrospective cohort study conducted at 2 tertiary care centers included patients with RDD who underwent treatment with cobimetinib between January 1, 2013, and December 1, 2021. Cobimetinib was administered at a dosage of 20 to 60 mg orally once daily as a single agent for 21 days in a 28-day cycle. Pathology was centrally reviewed. Response assessment was centrally conducted and was based on the established positron emission radiography response criteria used for clinical trials of targeted therapies in histiocytosis.Main outcomes and measuresMain outcomes were overall response rate (ORR), progression-free survival (PFS), adverse events (AEs) of cobimetinib in the entire cohort, and ORRs and PFS based on MAPK pathway alterations in patients with RDD.ResultsA total of 16 patients (median [range] age at cobimetinib initiation, 57 [31-74] years; 11 [69%] women) were included in the study. The median follow-up duration was 19.0 months (95% CI, 8.4-27.8 months). The ORR was 63% (n = 10), including 5 complete responses and 5 partial responses. Somatic alterations in the KRAS or MEK genes were detected in 8 (50%) patients. Patients with KRAS or MEK alterations had significantly higher ORR (88% vs 38%; P = .03), deeper responses (complete responses among responders: 71% vs 0%; P = .002), and better PFS (at 1 year, 100% vs 29% were free from progression or death, respectively; P < .001) compared with those without such alterations. Grade 2 or higher AEs occurred in 12 (75%) patients, and 9 (56%) required dose reduction or temporary/permanent treatment discontinuation due to AEs.Conclusions and relevanceIn this cohort study, treatment with cobimetinib was associated with positive outcomes in KRAS- or MEK-variant RDD. However, AEs requiring dose modifications were common.

Project description:Background Rosai–Dorfman disease (RDD) is a rare histiocytic proliferative disorder of uncertain pathogenesis. Most patients present with proliferation in the lymph nodes manifesting as adenopathy; however, RDD may primarily arise in a variety of extranodal sites, including the bone, which is a great challenge in the diagnosis. The clinicopathological characteristics and prognostic features of primary intraosseous RDD have not been well characterized. Methods We retrospectively analyzed the clinicopathologic and prognostic features of four cases of primary intraosseous RDD during the past 10 years in our hospital, with a review of an additional 62 cases with complete follow-up data from the literature. Results Primary intraosseous RDD was identified in 0.14% (4/2,800) of total bone biopsies performed at our institution over the study period. According to our retrospective analysis, a total of 18 cases of primary lymph node, skin, or other non-osseous site-based RDD were diagnosed in our hospital. The ages of the 66 total patients ranged from 1.5 to 76 years, with a median age of 25 years. There were 31 male and 35 female patients, with a male-to-female ratio of 0.89:1. Primary intraosseous RDD occurred most often in the bones of the extremities (60.6%, 40/66), with the proximal tibia being the most common location; 39.4% (26/66) of the cases arose in the axial skeleton, predominantly in the vertebra and craniofacial bones. Solitary masses and multiple tumors were present in 84.8% (56/66) and 15.2% (10/66) of the cases, respectively. Pain of the affected area was the most common presenting symptom. Radiographically, the lesions were lytic with well-defined and usually sclerotic margins. Immunohistochemistry showed that large histiocytes from patients with RDD were positive for OCT2, in addition to S100 and CD68. Molecular tests were performed in seven reported cases and four of our cases. All the 11 cases were non-decalcified. PCR results showed that there were no BRAF-V600E, KRAS, or NRAS mutations in primary intraosseous RDD; only one case with both RDD and Langerhans cell histiocytosis showed BRAF-V600E mutation. The survival data showed that 22.7% (15/66) of the patients experienced recurrences or developed RDD at distant sites during the follow-up period (median follow-up, 13 months; range, 1–106 months). The 5-year progression-free survival (PFS) of the patients with primary intraosseous RDD was 57.5%. We found that there was a significant difference in PFS between female and male patients (p = 0.031). However, there was no statistically significant difference in PFS between patients with solitary masses and multiple tumors (p = 0.698). Similarly, no statistically significant differences in PFS were found between the different age groups (p = 0.908) or tumor locations (p = 0.728). Conclusion Primary intraosseous RDD is an extremely rare disease. The diagnosis of RDD may be quite challenging because of its non-specific clinical presentation and imaging. Immunohistochemistry showed that large histiocytes were positive for OCT2 in addition to S100 and CD68, which may be helpful for differential diagnosis. Molecular detection showed that RDD may be related to the MAPK pathway, though these results are also ultimately not specific. The pathogenesis of RDD is yet to be elucidated, but recent studies suggest possible clonality of hyperproliferative histiocytes.

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Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease.

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