Abstract：
BACKGROUND: Previously identified mutually-exclusive driver genes in juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) include mutations in MAP kinase pathway genes such as MAP2K1, BRAF, ARAF, KRAS, NRAS, PIK3CD as well as fusions in BRAF and ALK, with a subset of cases with no identified driver yet. NTRK fusion has been identified in rare cases.
METHODS: We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease.
RESULTS: We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases).
CONCLUSIONS: NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.
METHODS: We identified two consecutive index cases of localized JXG or AXG with NTRK1 fusion by next-generation sequencing (NGS) and confirmed by pan-NTRK immunostain. We expanded the study to a total of 50 cases of JXG and AXG using screening by pan-NTRK immunostain. We confirmed the specificity of our approach with negative results in 5 cases of histiocytic neoplasia lacking an NTRK fusion by NGS and 14 cases of non-neoplastic histiocytic disease.
RESULTS: We found 23 cases of JXG or AXG with overexpression of NTRK by immunostain, and these cases were restricted to localized disease (23 of 43 cases, 53.5%) rather than disseminated disease (zero of seven cases).
CONCLUSIONS: NTRK expression is common in JXG or AXG and associated with localized rather than disseminated disease. We speculate that the potential importance of this in JXG and AXG has not been previously appreciated due to the tendency to focus sequencing studies on disseminated disease. We confirm the presence of an NTRK1 fusion in two positive cases by NGS, however, additional genetic studies are necessary to further explore this.
摘要：
背景：先前在青少年黄色肉芽肿（JXG）和成人黄色肉芽肿（AXG）中鉴定的互斥驱动基因包括MAP激酶途径基因的突变，例如MAP2K1，BRAF，ARAF,KRAS,NRAS,PIK3CD以及BRAF和ALK中的融合，有一部分病例还没有确定的驱动因素。NTRK融合已在极少数情况下被鉴定。
方法：我们通过下一代测序（NGS）确定了两个连续的局部JXG或AXG与NTRK1融合的指标病例，并通过pan-NTRK免疫染色确认。我们通过pan-NTRK免疫染色筛选，将研究扩展到总共50例JXG和AXG。我们证实了我们的方法的特异性，在5例缺乏NGSNTRK融合的组织细胞瘤形成和14例非肿瘤性组织细胞疾病中结果为阴性。
结果：我们发现23例JXG或AXG通过免疫染色过表达NTRK，这些病例仅限于局部疾病(43例中有23例，53.5％），而不是播散性疾病（7例中为零）。
结论：NTRK表达在JXG或AXG中很常见，并且与局部而非播散性疾病相关。我们推测这在JXG和AXG中的潜在重要性以前没有被认识到,因为倾向于将测序研究集中在播散性疾病上。我们通过NGS确认了两个阳性病例中NTRK1融合的存在，然而,更多的遗传研究是必要的，以进一步探讨这一点。
方法：我们通过下一代测序（NGS）确定了两个连续的局部JXG或AXG与NTRK1融合的指标病例，并通过pan-NTRK免疫染色确认。我们通过pan-NTRK免疫染色筛选，将研究扩展到总共50例JXG和AXG。我们证实了我们的方法的特异性，在5例缺乏NGSNTRK融合的组织细胞瘤形成和14例非肿瘤性组织细胞疾病中结果为阴性。
结果：我们发现23例JXG或AXG通过免疫染色过表达NTRK，这些病例仅限于局部疾病(43例中有23例，53.5％），而不是播散性疾病（7例中为零）。
结论：NTRK表达在JXG或AXG中很常见，并且与局部而非播散性疾病相关。我们推测这在JXG和AXG中的潜在重要性以前没有被认识到,因为倾向于将测序研究集中在播散性疾病上。我们通过NGS确认了两个阳性病例中NTRK1融合的存在，然而,更多的遗传研究是必要的，以进一步探讨这一点。
