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A Comparison of Morphologic and Molecular Features of BRAF, ALK, and NTRK1 Fusion Spitzoid Neoplasms.

BRAF、ALK及NTRK1融合的Spitzoid肿瘤中形态和分子特征比较

Amin SM,Haugh AM,Lee CY,Zhang B,Bubley JA,Merkel EA,Verzì AE,Gerami P

Abstract

Recent studies have identified translocations involving the kinase domains of ALK, NTRK1, BRAF, RET, and ROS in spitzoid neoplasms. Subsequent studies have also characterized morphologic features corresponding to ALK and NTRK1 translocations. In this study, we sought to further compare morphologic features across a range of 49 genetically defined spitzoid neoplasms with ALK, NTRK1, BRAF, or RET fusions to determine discriminating features. We also compared them with a group of 22 spitzoid neoplasms, which were confirmed to be negative for fusions in ALK, NTRK1, BRAF, and RET. Features with the highest discriminatory value included diameter of the lesion, dermal architecture, and certain cytomorphologic features. Specifically, cases with a large diameter (≥9 mm) and wedge-shaped, plexiform dermal architecture of nests of large, spindle-shaped cells were most likely to have an ALK fusion. NTRK1-fused cases were most likely of the fusions to have Kamino bodies and were typically arranged in smaller nests with smaller predominantly spindle-shaped cells, occasionally forming rosettes. BRAF fusion cases were the only fusion subtype to have a predominance of epithelioid cells, were less organized in nests, and commonly had a sheet-like growth pattern or dysplastic Spitz architecture. BRAF fusion cases were most likely to have high-grade nuclear atypia, to be diagnosed as spitzoid melanoma, to have a positive result by melanoma fluorescence in situ hybridization assay, and to develop copy number gains in the kinase domain of the fusion protein. On the basis of experience from this cohort, BRAF-fused cases appear most likely to progress to melanoma.

摘要

最新研究表明Spitzoid肿瘤中存在ALKNTRK1BRAFROS1融合。亚组分析也已确认ALKNTRK1融合的形态特征。作者通过包括ALKNTRK1BRAF以及RET在内的49个基因对比来确定Spitzoid肿瘤中这些基因亚型的形态特征,作者又通过对一组22例已确认ALKNTRK1BRAFRET融合阴性的Spitzoid肿瘤作对比,发现病灶直径、真皮结构和一定的细胞特征对ALK融合的Spitzoid肿瘤有更高的甄别价值。尤其是直径超过9mm、楔形、巨大的巢状真皮结构、梭形细胞的Spitzoid肿瘤最有可能存在ALK融合。NTRK1融合的Spitzoid肿瘤形态学特征经常出现Kamino结构和小梭形细胞为主小巢状结构,偶尔形成玫瑰型。BRAF融合的Spitzoid肿瘤是仅有的以上皮细胞占主导亚型,并较少有巢存在,通常有一个片状生长或发育异常的Spitzoid结构。BRAF融合的Spitzoid肿瘤最有可能存在高级别的核异型性,被诊断为Spitzoid黑色素瘤,黑色素瘤原位杂交阳性,融合蛋白的基因拷贝数增加。在这项研究中,BRAF融合的Spitzoid肿瘤最有可能发展成为黑色素瘤。

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