Department of Anatomical Pathology, Royal North Shore Hospital, Sydney 2065, Australia.
Hum Pathol. 2010 Jun;41(6):805-14. doi: 10.1016/j.humpath.2009.12.005. Epub 2010 Mar 17.
Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (SDHB mutations) or significant multiorgan disease (RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.
多达 30%的嗜铬细胞瘤和副神经节瘤与胚系 RET、Von Hippel-Lindau(VHL)、神经纤维瘤病 1 型(NF1)和琥珀酸脱氢酶亚基(SDHB、SDHC 和 SDHD)突变有关。遗传检测可进行家族咨询,并确定具有恶性肿瘤高风险(SDHB 突变)或多器官疾病显著(RET、VHL 或 NF1)的患者。然而,对所有基因座进行常规遗传检测既繁琐又昂贵。我们对 58 例已知 SDH 突变状态的肿瘤进行了 SDHB 的免疫组织化学检测。我们将阳性定义为颗粒状细胞质染色(线粒体模式),弱弥漫性为缺乏明确颗粒的细胞质晕染,阴性为在存在内部阳性对照的情况下完全不存在染色。所有 12 例 SDH 突变肿瘤(6 例 SDHB、5 例 SDHD 和 1 例 SDHC)均显示弱弥漫性或阴性染色。已知 VHL、RET 或 NF1 突变的 10 例肿瘤中的 9 例显示阳性染色。1 例 VHL 相关肿瘤显示弱弥漫性染色。在 36 例无胚系突变的肿瘤中,34 例显示阳性染色。1 例无已知 SDH 突变但具有家族性疾病临床特征的副神经节瘤为阴性,1 例显示弱弥漫性染色。我们还对 143 例连续未选择的肿瘤进行了 SDHB 的免疫组织化学检测,其中 21 例为弱弥漫性或阴性。由于 SDH 突变几乎总是胚系突变,我们得出结论,大约 15%的嗜铬细胞瘤或副神经节瘤与胚系 SDH 突变有关,免疫组织化学可用于基因检测的分类。完全缺失染色更常见于 SDHB 突变,而弱弥漫性染色常发生于 SDHD 突变。
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