琥珀酸脱氢酶B、C免疫组化在鉴别良恶性嗜铬细胞瘤和副神经节瘤中的应用

Application of SDHB and SDHC immunohistochemistry in the differentiation of malignant and benign pheochromocytoma and paraganglioma

目的探讨琥珀酸脱氢酶（SDH）B、SDHC在嗜铬细胞瘤（PCC）和副神经节瘤（PGL，合称PPGL）的表达及与肿瘤遗传背景、临床-病理特征间的关系，为良、恶性PPGL的早期鉴别提供病理诊断依据。 方法对126例PPGL患者（PCC 62例、PGL 61例、PCC＋PGL 3例）的140份肿瘤标本进行SDHB、SDHC免疫组化染色。分析肿瘤染色结果与患者临床表现、基因背景、实验室检查、病理结果之间的关系。 结果（1）67例患者进行了基因检测，37例（55.2%）结果异常：SDHA基因突变2例（3.0%）、SDHB基因突变18例（26.9%）、SDHC基因突变2例（3.0%）、SDHD基因突变5例（7.5%）、VHL基因突变2例（3.0%）、RET基因突变7例（10.4%）、NF1基因突变1例（1.5%）；余30例（44.8%）未测得上述胚系突变。（2）27例SDH相关基因（SDHx）胚系突变患者的30份肿瘤标本中，96.7%（29/30）SDHB染色阴性，76.7%（23/30）SDHC染色阴性；而40例非SDH基因突变和无基因突变患者的49份肿瘤标本中，SDHB染色阴性为28.6%（14/49, P〈0.05），SDHC染色阴性为18.4%（9/49, P〈0.05）。（3）PPGL肿瘤SDHB、SDHC免疫组化结果用于诊断患者有无SDHx基因突变的敏感性分别为96.7%、76.7%，特异性分别为71.4%、81.6%。（4）SDHB染色阴性肿瘤中22.9%为恶性，而染色阳性肿瘤仅3.8%为恶性（P〈0.05）。 结论肿瘤标本SDHB、SDHC免疫组化可作为筛查PPGL患者有无SDHx基因胚系突变的方法。对SDHB染色阴性的PPGL患者应密切随访，除外恶性肿瘤。

ObjectiveTo evaluate the expression profile of succinate dehydrogenase （SDH）B and SDHC in pheochromocytoma （PCC） and paraganglioma（PGL） （collectively abbreviated as PPGL）, and their value in the early diagnosis of malignancy. MethodsSDHB and SDHC immunohistochemistry were performed on 140 tumor specimens from 126 PPGL patients （PCC n=62, PGL n=61, PCC＋ PGL n=3）. Results（1） Germline mutation status of 67 patients were determined, of which, identifying 37（55.2%） patients with germline mutation： 2 （3.0%） SDHA, 18 （26.9%） SDHB, 2 （3.0%） SDHC, 5 （7.5%） SDHD, 2 （3.0%）VHL, 7 （10.4%） RET, and 1（1.5%） NF1; and 30 （44.8%） individuals without known mutation. （2） Among 30 PPGLs from 27 patients with SDH-related （SDHx） mutations, 96.7% （29/30） stained negative for SDHB, 76.7% （23/30） stained negative for SDHC, while only 28.6% （14/49） and 18.4% （9/49） stained negative for SDHB and SDHC respectively in the 49 PPGLs without SDHx mutation （P〈0.05）. （3） The sensitivity of the SDH immunostaining in detecting the presence of germline SDHx mutation was 96.7% for SDHB and 76.7% for SDHC, while the specificity was 71.4% for SDHB and 81.6% for SDHC. （4） Among PPGLs without SDHB expression, 22.9% were malignant. This percentage is significantly higher than that in PPGLs with preserved SDHB expression （3.8%, P〈0.05）. ConclusionSDHB and SDHC immunohistochemistry may serve as post-surgical screening tools to predict the presence of germline SDHx mutation in PPGLs. Negative SDHB expression calls for intense follow-up to rule out malignancy.