Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease

Abstract

Rosai-Dorfman disease is a histiocytic disorder with a poorly defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3-82). In all, 13 had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 vs 53 years, P=0.0347) with more pediatric patients (4/7 vs 1/14, P=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated vs 1/14 (7%) unmutated cases (P=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (P=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7-352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contribute to the understanding of the biology of Rosai-Dorfman disease and point to potential diagnostic and therapeutic targets.

Figure 1

KRAS-mutated Rosai-Dorfman disease, soft tissue of trunk (Case 3). (a) Medium power image of soft tissue with aggregates of abnormal emperipoletic histiocytes (200X). (b) Some areas show dense fibrosis where emperipoletic histiocytes are less obvious to identify (400X). (c) Immunostain for S-100 is positive in Rosai-Dorfman histiocytes and negative in engulfed lymphocytes (400X). (d) Immunostain for p-ERK is negative in emperipoletic histiocytes (endothelial cells are positive) (1000X).

Figure 2

MAP2K1-mutated Rosai-Dorfman disease, nodal (case 11). (a) Low power image of a lymph node with markedly expanded sinuses by numerous emperipoletic histiocytes, lymphocytes and plasma cells (100X). (b) High power magnification of a distended sinus with a histiocyte engulfing numerous lymphocytes (1000X). (c) Immunostain for S-100 highlights Rosai-Dorfman histiocytes and provides contrast with numerous negatively outlined lymphocytes (1000X). (d) Immunostain for p-ERK is positive in histiocytes in a nuclear and cytoplasmic pattern (1000X).

Figure 3

MAP2K1-mutated Rosai-Dorfman disease, nasopharynx (case 12). (a) Medium power image of nasopharynx with sheets of histiocytes admixed with lymphocytes and plasma cells (200X). (b) Higher magnification shows numerous histiocytes engulfing lymphocytes, plasma cells and neutrophils (400X). (c) Immunostain for S-100 is positive in histiocytes and negative in engulfed lymphocytes (400X). (d) Immunostain for p-ERK is positive in the nucleus and cytoplasm of a subset of Rosai-Dorman histiocytes (500X).