ERBB-2过表达作为恶性嗜铬细胞瘤和副神经节瘤的一个危险因素。

ERBB-2 overexpression as a risk factor for malignant phaeochromocytomas and paraganglinomas.

作者信息

Wang Weiqing, Zhong Xu, Ye Lei, Qi Yan, Su TingWei, Wei Qing, Xie Jing, Jiang Lei, Jiang Yiran, Zhou Weiwei, Cui Bin, Ning Guang

机构信息

Shanghai Key Laboratory for Endocrine Tumors, Shanghai Clinical Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of Chinese Health Ministry, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, China.

Laboratory for Endocrine & Metabolic Diseases of Institute of Health Science, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 227 South ChongQing Road, Shanghai, China.

出版信息

Clin Endocrinol (Oxf). 2016 Jun;84(6):822-9. doi: 10.1111/cen.13019. Epub 2016 Feb 25.

DOI:10.1111/cen.13019

PMID:26749044

Abstract

OBJECTIVE

There are currently no good histological or molecular markers to differentiate benign from malignant phaeochromocytomas and paraganglinomas (PPGLs). Our previous cross-sectional study observed that ERBB-2 overexpression was associated with malignant PPGLs. This study aimed to evaluate the predictive value of ERBB-2 overexpression for metastasis in PPGLs in a large population.

METHODS

A total of 262 patients diagnosed as PPGLs in our institution between 2002 and 2012 were included. We analysed ERBB-2 protein expression in the primary PPGL tumours by immunohistochemistry (IHC) and ERBB-2 amplification by fluorescence in situ hybridization (FISH). Direct Sanger sequencing was performed to examine ERBB-2 exon 20 mutations. The occurrence of malignant PPGLs was documented in the follow-up period. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate the association between ERBB-2 overexpression and metastasis of PPGLs.

RESULTS

Twenty-six (9·9%) patients had ERBB-2 overexpression in their primary PPGL tumours, which was significantly associated with ERBB-2 amplification (17/25, 68%). No ERBB-2 mutation was found. At a median follow-up of 4·5 years, a total of 23 malignant PPGLs were documented, including eight (30·8%) patients in the ERBB-2 overexpression group and 15 (6·4%) patients in the ERBB-2-negative group. The incidence rate of metastasis was 5·3 per 100 person-years vs 1·4 per 100 person-years in the ERBB-2 overexpression and ERBB-2-negative groups (P < 0·001), respectively. Kaplan-Meier analysis showed that ERBB-2 overexpression was associated with decreased metastasis-free survival (P = 0·001, log-rank test). After adjusting for primary tumour size and location, Cox regression analysis revealed that ERBB-2 overexpression was independently associated with risk of malignant PPGLs (HR = 2·78; 95% CI, 1·12-6·90; P = 0·028).

CONCLUSION

Patients harbouring tumours with ERBB-2 overexpression have a significantly higher risk of developing malignant PPGLs.

摘要

目的

目前尚无良好的组织学或分子标志物来区分良性与恶性嗜铬细胞瘤和副神经节瘤（PPGLs）。我们之前的横断面研究观察到ERBB-2过表达与恶性PPGLs相关。本研究旨在评估在大量人群中ERBB-2过表达对PPGLs转移的预测价值。

方法

纳入2002年至2012年间在本机构诊断为PPGLs的262例患者。我们通过免疫组织化学（IHC）分析原发性PPGL肿瘤中ERBB-2蛋白表达，并通过荧光原位杂交（FISH）分析ERBB-2扩增情况。采用直接桑格测序法检测ERBB-2外显子20突变。随访期间记录恶性PPGLs的发生情况。采用Kaplan-Meier分析和Cox比例风险模型评估ERBB-2过表达与PPGLs转移之间的关联。

结果

26例（9.9%）患者的原发性PPGL肿瘤中存在ERBB-2过表达，这与ERBB-2扩增显著相关（17/25，68%）。未发现ERBB-2突变。中位随访4.5年时，共记录到23例恶性PPGLs，其中ERBB-2过表达组有8例（30.8%）患者，ERBB-2阴性组有15例（6.4%）患者。ERBB-2过表达组和ERBB-2阴性组的转移发生率分别为每100人年5.3例和每100人年1.4例（P<0.001）。Kaplan-Meier分析显示，ERBB-2过表达与无转移生存期缩短相关（P = 0.001，对数秩检验）。在调整原发性肿瘤大小和位置后，Cox回归分析显示ERBB-2过表达与恶性PPGLs风险独立相关（HR = 2.78；95%CI，1.12 - 6.90；P = 0.028）。