Takata M, Lin J, Takayanagi S, Suzuki T, Ansai S, Kimura T, Cerroni L, Saida T
Department of Dermatology, Shinshu University School of Medicine, Asahi 3-1-1, Matsumoto 390-8621, Japan.
Br J Dermatol. 2007 Jun;156(6):1287-94. doi: 10.1111/j.1365-2133.2007.07924.x.
The histopathological differentiation of malignant melanoma and Spitz naevus often presents diagnostic problems.
We aimed to find out applicable diagnostic parameters other than routine pathology.
The cases included conventional melanomas and Spitz naevi as well as atypical spitzoid lesions that had posed diagnostic difficulties. We examined hotspots of mutation in the BRAF, NRAS and HRAS genes by polymerase chain reaction-based direct sequencing. We also analysed DNA copy number aberrations and the methylation of CpG sequences in several cancer-related genes by utilizing a novel methylation-specific multiplex ligation-dependent probe amplification method.
Twenty three of 24 conventional melanomas showed at least one of the genetic and epigenetic alterations examined, although one acral melanoma did not show any alteration. By sharp contrast, 12 Spitz naevi with an unambiguous histopathology showed no or few chromosomal aberrations, no oncogene mutations and no methylation of CpG sequences. Of the 16 ambiguous spitzoid lesions, most of which were designated atypical Spitz tumour by one of the authors, all but one showed no mutations, no methylations and few copy number aberrations. However, three tumours showed copy number loss of the cyclin-dependent kinase inhibitor 2A gene (CDKN2A), an alteration observed frequently in melanomas but not found in conventional Spitz naevi. These results show that, although most atypical Spitz tumours do not differ from conventional Spitz naevi showing virtually no genetic and epigenetic aberrations, some cases may have chromosomal aberrations that include copy number loss of the CDKN2A gene.
Genetic and epigenetic analyses may be useful as an additional diagnostic tool to distinguish between melanoma and Spitz naevus, and may help to define subgroups in atypical Spitz tumours.
恶性黑色素瘤和斯皮茨痣的组织病理学鉴别常常带来诊断难题。
我们旨在找出常规病理学以外适用的诊断参数。
病例包括传统黑色素瘤、斯皮茨痣以及曾造成诊断困难的非典型斯皮茨样病变。我们通过基于聚合酶链反应的直接测序检测BRAF、NRAS和HRAS基因的突变热点。我们还利用一种新型甲基化特异性多重连接依赖探针扩增方法分析了几个癌症相关基因的DNA拷贝数畸变和CpG序列的甲基化情况。
24例传统黑色素瘤中有23例显示出至少一种所检测的基因和表观遗传学改变，尽管有一例肢端黑色素瘤未显示任何改变。形成鲜明对比的是，12例组织病理学明确的斯皮茨痣未显示或仅有很少的染色体畸变、没有癌基因突变且CpG序列未发生甲基化。在16例不明确的斯皮茨样病变中，其中大多数被作者之一诊断为非典型斯皮茨肿瘤，除一例之外其余均未显示突变、甲基化且仅有很少的拷贝数畸变。然而，有三例肿瘤显示细胞周期蛋白依赖性激酶抑制剂2A基因（CDKN2A）的拷贝数缺失，这种改变在黑色素瘤中经常观察到，但在传统斯皮茨痣中未发现。这些结果表明，尽管大多数非典型斯皮茨肿瘤与几乎未显示基因和表观遗传学畸变的传统斯皮茨痣没有差异，但一些病例可能存在包括CDKN2A基因拷贝数缺失在内的染色体畸变。
基因和表观遗传学分析可能作为区分黑色素瘤和斯皮茨痣的额外诊断工具有用，并且可能有助于界定非典型斯皮茨肿瘤中的亚组。
