Identification of Succinate Dehydrogenase-deficient Bladder Paragangliomas
Identification of Succinate Dehydrogenase-deficient Bladder Paragangliomas
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DOI：
10.1097/pas.0b013e318293d83c
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发表时间：
2013-10-01
影响因子：
5.6
通讯作者：
Barletta, Justine A.
中科院分区：
文献类型：
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作者：
Mason, Emily F.;Sadow, Peter M.;Barletta, Justine A.
大量副神经节瘤患者的琥珀酸脱氢酶 (SDH) 基因（SDHA、B、C 或 D）之一存在种系突变。可以使用免疫组织化学来鉴定具有 SDH 基因突变的肿瘤。 SDHB 染色缺失可见于任一 SDH 基因突变的肿瘤，而 SDHB 和 SDHA 表达缺失仅见于 SDHA 突变情况。识别 SDH 缺陷的肿瘤对于预后具有重要意义，因为具有 SDHB 突变的肿瘤更有可能发展为恶性病程。虽然已知副神经节瘤中 SDH 缺陷的发生率一般约为 30%，但 SDH 缺陷的膀胱副神经节瘤的报道却很少。因此，本研究的目的是确定膀胱副神经节瘤中 SDH 缺陷的发生率。确定了 11 例膀胱副神经节瘤病例。检查所有肿瘤的苏木精和伊红染色载玻片，并对 SDHB 和 SDHA 进行免疫组织化学分析。对于免疫组织化学显示 SDHA 表达缺失的病例，进行 SDHA 基因突变分析。 3 例 (27%) 病例出现 SDHB 染色丢失（2 例仅丢失 SDHB，1 例丢失 SDHB 和 SDHA）。 SDH 缺陷肿瘤患者比 SDH 表达完整肿瘤患者更年轻（就诊时的平均年龄分别为 39 岁和 58 岁）。 2 例 SDHB 缺陷且 SDHA 完整的肿瘤患者中，1 例被发现存在种系 SDHB 突变，另一例有恶性副神经节瘤家族史。两名患者均出现转移性疾病。一名患有 SDHB 和 SDHA 缺陷的肿瘤患者没有副神经节瘤家族史，也没有转移性疾病的证据。该肿瘤的测序显示肿瘤和正常组织中 SDHA 外显子 10 (c. 1340 A > G; p.His447Arg) 中存在有害杂合单碱基对替换，表明存在种系 SDHA 突变，并且仅在肿瘤的 1 个等位基因中 SDHA 外显子 5 (c. 484 A > T; p.Arg162*) 中存在有害单碱基对替换。 SDH 表达完整的患者没有副神经节瘤家族史； 1 人患有同时性副神经节瘤，但没有人出现转移性疾病。膀胱副神经节瘤的一个重要子集是 SDH 缺陷的。识别 SDH 缺陷肿瘤至关重要，因为 SDH 突变的存在具有预后意义，并且对于指导遗传咨询很重要。
A significant number of patients with paragangliomas harbor germline mutations in one of the succinate dehydrogenase (SDH) genes (SDHA, B, C, or D). Tumors with mutations in SDH genes can be identified using immunohistochemistry. Loss of SDHB staining is seen in tumors with a mutation in any one of the SDH genes, whereas loss of both SDHB and SDHA expression is seen only in the context of an SDHA mutation. Identifying an SDH-deficient tumor can be prognostically significant, as tumors with SDHB mutations are more likely to pursue a malignant course. Although the rate of SDH deficiency in paragangliomas in general is known to be approximately 30%, there are only rare reports of SDH-deficient bladder paragangliomas. Therefore, the aim of this study was to determine the rate of SDH deficiency in bladder paragangliomas. Eleven cases of bladder paragangliomas were identified. Hematoxylin and eosin-stained slides of all tumors were reviewed, and immunohistochemical analysis for SDHB and SDHA was performed. For cases with loss of SDHA expression by immunohistochemistry, mutation analysis of the SDHA gene was performed. Loss of SDHB staining was seen in 3 (27%) cases (2 with loss of SDHB only, 1 with loss of SDHB and SDHA). Patients with SDH-deficient tumors were younger than those with tumors with intact SDH expression (mean age at presentation 39 y and 58 y, respectively). Of the 2 patients with SDHB-deficient and SDHA-intact tumors, one was found to have a germline SDHB mutation, and the other had a family history of a malignant paraganglioma. Both patients developed metastatic disease. The one patient with a tumor that was deficient for both SDHB and SDHA had no family history of paragangliomas and no evidence of metastatic disease. Sequencing of this tumor revealed a deleterious heterozygous single-base pair substitution in exon 10 of SDHA (c. 1340 A > G; p.His447Arg) in both the tumor and normal tissue, indicative of a germline SDHA mutation, and a deleterious singlebase pair substitution in exon 5 of SDHA (c. 484 A > T; p.Arg162*) in 1 allele of the tumor only. No patients with intact SDH expression had a family history of paragangliomas; 1 had a synchronous paraganglioma, but none developed metastatic disease. A significant subset of bladder paragangliomas is SDH deficient. It is essential to identify SDH-deficient tumors, as the presence of an SDH mutation has prognostic implications and is important in guiding genetic counseling.