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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Gland Neoplasms / diagnosis
  • Adrenal Gland Neoplasms / pathology
  • Adult
  • Diagnosis, Differential
  • Female
  • Gene Amplification
  • Genes, erbB-2 / genetics
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization, Fluorescence
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Metastasis / genetics
  • Paraganglioma / diagnosis*
  • Paraganglioma / pathology
  • Pheochromocytoma / diagnosis*
  • Pheochromocytoma / pathology
  • Receptor, ErbB-2 / analysis*
  • Receptor, ErbB-2 / genetics
  • Risk Factors

Substances

  • ERBB2 protein, human
  • Receptor, ErbB-2

Associated data

  • GENBANK/NM_001289937