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

ObjectiveThere 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. MethodsA 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. ResultsTwenty-six (99%) 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 45 years, a total of 23 malignant PPGLs were documented, including eight (308%) patients in the ERBB-2 overexpression group and 15 (64%) patients in the ERBB-2-negative group. The incidence rate of metastasis was 53 per 100 person-years vs 14 per 100 person-years in the ERBB-2 overexpression and ERBB-2-negative groups (P < 0001), respectively. Kaplan-Meier analysis showed that ERBB-2 overexpression was associated with decreased metastasis-free survival (P = 0001, 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 = 278; 95% CI, 112-690; P = 0028). ConclusionPatients harbouring tumours with ERBB-2 overexpression have a significantly higher risk of developing malignant PPGLs.