Mutational Profiling of Rosai-Dorfman Disease and Association with Phenotype: A Multi-Institutional Study

Background: Rosai-Dorfman disease (RDD) is a rare histiocytic disorder with variable characteristics. The clinical presentation is varied, with patients having nodal and/or extranodal involvement. Recently, mutations in the mitogen-activated protein kinase (MAPK) pathway have been reported in a small series of RDD cases. Herein, we report the mutational profiling data by using next-generation sequencing (NGS) among 38 patients with RDD, including associations with clinical phenotype.

Methods: This study was approved by the Institutional Review Board. Patients with RDD who were seen at Mayo Clinic and the University of Alabama at Birmingham (UAB) from January 2017 to December 2021 were included in this study. Data for NGS with an oncogene panel were abstracted where available. A mutation was considered pathogenic if an oncogene had a gain-of-function mutation or if a tumor suppressor gene had a loss-of-function mutation. Patients were considered to have disseminated disease if they had 2 or more extranodal organs involved. Fischer's exact test was used to compare categorical parameters and the Wilcoxon rank sum test was used to compare continuous variables. Time to systemic therapy was calculated using the Kaplan-Meier method. Systemic therapies included prednisone, cobimetinib, cladribine, or rituximab.

Results: A total of 54 patients with RDD were identified. NGS was performed on 47 patients (87%). NGS for nine patients (19%) was unsuccessful because of the small biopsy size or low cellularity that yielded an insufficient quantity of DNA for testing. Among the 38 patients who had successful NGS and were included in this study, the median age at diagnosis was 56 years (range 25-79) with the majority (n=30, 79%) being females. The median follow-up duration was 3.3 years (95% CI: 1.75-4.1). 37 patients (97%) had extranodal disease with the following sites of involvement: disseminated (n=20, 53%), skin (n=9, 24%), central nervous system (n=2, 5%), bone (n=1, 3%), and other (n=5, 13%). One patient had nodal-only disease.

No patients had neoplasia-associated RDD, while 2 patients had IgG4-related RDD and 1 patient had immune-related RDD. A total of 2 patients died. Two patient deaths were reported including one RDD- and one MDS-associated deaths. First-line therapies included prednisone (n=10, 26%), observation (n=10, 26%), cobimetinib (n=5, 13%), topical therapies (n=4), surgery (n=3), radiation therapy (n=3), cladribine (n=2), or rituximab (n=1). The median OS for the overall cohort was not reached (NR) [95% CI: 5.2 - NR].

Of the 38 patients who had a successful NGS, 20 out of 38 (53%) had a pathogenic mutation, which included missense KRAS mutations (n=10, 26%) and missense MAP2K1 mutations (4, 11%) [Figure]. The majority of KRAS mutations occurred at exon 3 (8/10), including p.K117N (5) and p.A146T (3). Other mutations occurred in PTEN, SMARCA4, ARAF, PIK3CA, IDH2, and NF1 genes. Among the two patients with IgG4-related disease, one had an ARAF p.S214F mutation while the other had no identifiable mutations. Among the patient with immune-related RDD, the patient had a KRAS p.A146P mutation.

On univariate analysis, patients with a pathogenic mutation were more likely to have disseminated RDD compared to patients with no pathogenic mutation (80% vs. 22%, p=0.0009; odds ratio 14, 95% CI: 3-67) but age, C-reactive protein, gender, and other sites of organ involvement were not significant (Table). Patients with disseminated disease were more likely to have a pathogenic mutation compared to patients without disseminated disease (80% vs. 22%, p=0.0009). The median time to systemic therapy for patients with a pathogenic mutation was 12 months (95% CI: 2-45) versus 15 months (95% CI: 4-20) for patients without a pathogenic mutation (p=0.66).

Conclusions: In our study of 38 patients, 53% of patients with RDD were found to have a known pathogenic mutation, with missense mutations in KRAS being the most frequent followed by MAP2K1. Unlike other histiocytic disorder subtypes, kinase fusions were not detected in any case. One in five patients had NGS test failure due to insufficient DNA. Patients with disseminated RDD were more likely to have a pathogenic mutation compared to those without disseminated disease but there was no difference in time to systemic therapy. Further studies are necessary to define the molecular underpinnings of non-disseminated RDD.

Shah:Astellas: Research Funding; Marker Therapeutics: Research Funding; Celgene: Research Funding. Vassallo:Bristol Myers Squibb: Research Funding; Sun Pharma: Research Funding; Pfizer: Research Funding.