Department of Oncology and Pathology, Karolinska Institutet, SE-17176, Stockholm, Sweden.
Endocr Pathol. 2015 Mar;26(1):9-14. doi: 10.1007/s12022-014-9348-1.
Pheochromocytomas (PCCs) are tumors originating from the adrenal medulla displaying a diverse genetic background. While most PCCs are sporadic, about 40 % of the tumors have been associated with constitutional mutations in one of at least 14 known susceptibility genes. As 25 % of sporadic PCCs harbor somatic neurofibromin 1 gene (NF1) mutations, NF1 has been established as the most recurrently mutated gene in PCCs. To be able to pinpoint NF1-related pheochromocytoma (PCC) disease in clinical practice could facilitate the detection of familial cases, but the large size of the NF1 gene makes standard DNA sequencing methods cumbersome. The aim of this study was to examine whether mutations in the NF1 gene could be predicted by immunohistochemistry as a method to identify cases for further genetic characterization. Sixty-seven PCCs obtained from 67 unselected patients for which the somatic and constitutional mutational status of NF1 was known (49 NF1 wild type, 18 NF1 mutated) were investigated for NF1 protein immunoreactivity, and the results were correlated to clinical and genetic data. NF1 immunoreactivity was absent in the majority of the PCCs (44/67; 66 %), including 13 out of 18 cases (72 %) with a somatic or constitutional NF1 mutation. However, only a minority of the NF1 wild-type PCCs (18/49; 37 %) displayed retained NF1 immunoreactivity, thereby diminishing the specificity of the method. We conclude that NF1 immunohistochemistry alone is not a sufficient method to distinguish between NF1-mutated and non-mutated PCCs. In the clinical context, genetic screening therefore remains the most reliable tool to detect NF1-mutated PCCs.
嗜铬细胞瘤（PCCs）起源于肾上腺髓质，具有多样化的遗传背景。虽然大多数 PCC 是散发性的，但约 40%的肿瘤与至少 14 个已知易感性基因中的一个的组成突变有关。由于 25%的散发性 PCC 存在体细胞神经纤维瘤 1 基因（NF1）突变，NF1 已被确立为 PCC 中最常突变的基因。在临床实践中能够精确定位与 NF1 相关的嗜铬细胞瘤（PCC）疾病，可以促进家族病例的检测，但 NF1 基因的大小使得标准 DNA 测序方法变得繁琐。本研究旨在检查 NF1 基因的突变是否可以通过免疫组化来预测，作为一种识别进一步遗传特征的病例的方法。对 67 例来自 67 例未经选择的患者的 PCC 进行了 NF1 基因的体细胞和组成突变状态的研究（49 例 NF1 野生型，18 例 NF1 突变型），并对 NF1 蛋白免疫反应性进行了检测，并将结果与临床和遗传数据进行了相关性分析。大多数 PCC（67 例中的 44 例；66%）中 NF1 免疫反应性缺失，包括 18 例中的 13 例（72%）有体细胞或组成 NF1 突变。然而，只有少数 NF1 野生型 PCC（49 例中的 18 例；37%）显示保留的 NF1 免疫反应性，从而降低了该方法的特异性。我们的结论是，NF1 免疫组化单独不足以区分 NF1 突变和非突变的 PCC。在临床环境中，遗传筛查仍然是检测 NF1 突变型 PCC 的最可靠工具。
