NRAS Mutations May Be Involved in the Pathogenesis of Cutaneous Rosai Dorfman Disease: A Pilot Study.

Kuan-Jou Wu,Chien-Chin Chen,Shu-Hao Li,Jia-Bin Liao,Chieh-Shan Wu,Chien-Chun Chiou

doi:10.3390/biology10050396

Abstract

Background: Purely cutaneous Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder limited to the skin. To date, its pathogenesis remains unclear. Owing to recent findings of specific mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in histiocytic proliferative disorders, it provides a novel perspective on the pathomechanism of cutaneous RDD. We aim to investigate the genomic mutations in MAPK/ERK pathway in cutaneous RDD. Methods: We retrospectively recruited all cases of cutaneous RDD from two hospitals in Taiwan from January 2010 to March 2020 with the clinicopathologic features, immunohistochemistry, and treatment. Mutations of neuroblastoma RAS viral oncogene homolog (NRAS), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) in MAPK/ERK pathway were investigated by the highly sensitive polymerase chain reaction with Sanger sequencing. Results: Seven patients with cutaneous RDD were recruited with nine biopsy specimens. The median age was 46 years (range: 17–62 years). Four of seven patients (57.1%) received tumor excision, while the other three chose oral and/or topical or intralesional steroids. NRAS mutation was detected in 4 of 7 cases (4/7; 51.7%), and NRAS A146T was the most common mutant point (n = 4/7), followed by NRAS G13S (n = 2/7). There is no KRAS or BRAF mutation detected. Conclusions: We report the NRAS mutation is common in cutaneous RDD, and NRAS A146T was the most frequent mutation in this cohort. Mutations in the NRAS gene can activate the RAS/MAPK signaling and have been reported to be associated with various cancers. It indicates that NRAS mutation in MAPK/ERK pathway may involve the pathogenesis of cutaneous RDD.

Highlights

Rosai–Dorfman disease (RDD), known as “sinus histiocytosis with massive lymphadenopathy”, is a rare histiocytic proliferative disorder
Some specific mutations in the MAPK/ERK pathway have been identified in LCH, Erdheim–Chester disease (ECD), and other non-LCH diseases [20,21,22,23,24,25,26,27,28]. These results indicated that the genomic mutation in the MAPK/ERK pathway may play a role in the pathogenesis of these histiocytic disorders
Our results indicate that neuroblastoma RAS viral oncogene homolog (NRAS) mutation in MAPK/ERK pathway may be involved in the pathogenesis of Rosai-Dorfman disease (RDD), especially in cutaneous RDD

Summary

Introduction

Rosai–Dorfman disease (RDD), known as “sinus histiocytosis with massive lymphadenopathy”, is a rare histiocytic proliferative disorder. It was first described in 1965 by Destombes, and later recognized as a distinct clinicopathologic entity of pale-staining histiocytes in 1969 by Rosai and Dorfman [1,2]. Owing to recent findings of specific mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway in histiocytic proliferative disorders, it provides a novel perspective on the pathomechanism of cutaneous RDD. Mutations in the NRAS gene can activate the RAS/MAPK signaling and have been reported to be associated with various cancers It indicates that NRAS mutation in MAPK/ERK pathway may involve the pathogenesis of cutaneous RDD

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