Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Instituto Oncológico Nacional Dr Juan Tanca Marengo, Guayaquil, Ecuador.
Mod Pathol. 2017 Oct;30(10):1367-1377. doi: 10.1038/modpathol.2017.55. Epub 2017 Jun 30.
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.
罗道氏病（Rosai-Dorfman disease）是一种组织细胞增生症，其发病机制尚不清楚。最近的分子研究揭示了朗格汉斯细胞组织细胞增生症和 Erdheim-Chester 病中涉及 MAPK/ERK 通路的基因的反复突变。然而，罗道氏病的病例很少被评估。我们对 21 例罗道氏病进行了下一代测序，评估了 134 个基因，包括 13 名女性和 8 名男性，中位年龄为 43 岁（范围为 3-82 岁）。共有 13 例为结外疾病，5 例为结内疾病，3 例为结内和结外同时存在疾病。头颈部是最常见的受累部位（n=7）。突变分析在 7 例（33%）中检测到点突变，包括 KRAS（n=4）和 MAP2K1（n=3）。未在评估的 ARAF、BRAF、PIK3CA 或任何其他基因中发现突变。免疫组化显示 3 例存在 p-ERK 过表达，均携带 MAP2K1 突变。携带突变基因的患者年龄较小（中位年龄，10 岁 vs 53 岁，P=0.0347），且更多为儿科患者（4/7 例 vs 1/14 例，P=0.0251）。存在突变与头颈部更常见的位置相关；7 例突变（86%）vs 14 例未突变（7%）（P=0.0009）。所有 5 例（100%）具有可获得分期信息的突变病例均为多灶性表现，而 11 例（27%）未突变患者中仅有 3 例为多灶性疾病（P=0.0256）。10 例患者中有治疗信息，包括根治性切除术（n=4）、切除术加放疗（n=3）和克拉屈滨化疗（n=3）。中位随访时间为 84 个月（范围为 7-352），7 例仍处于临床缓解期，3 例仍有疾病持续存在。未观察到突变状态与临床结局之间的相关性。总之，我们在三分之一的罗道氏病病例中检测到相互排斥的 KRAS 和 MAP2K1 突变，这表明该亚组是克隆性的，并涉及 MAPK/ERK 通路的激活。我们的数据有助于了解罗道氏病的生物学特性，并指出潜在的诊断和治疗靶点。
