Funding sources This work was supported in part by the National Cancer Center Research and Development Fund (23-A-22).
CLINICAL AND LABORATORY INVESTIGATIONS
Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease
Article first published online: 5 JUN 2013
© 2013 The Authors. BJD © 2013 British Association of Dermatologists
British Journal of Dermatology
Volume 168, Issue 6, pages 1259–1266, June 2013
How to Cite
Tanaka, R., Sasajima, Y., Tsuda, H., Namikawa, K., Tsutsumida, A., Otsuka, F. and Yamazaki, N. (2013), Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease. British Journal of Dermatology, 168: 1259–1266. doi: 10.1111/bjd.12249
Conflicts of interest None declared.
- Issue published online: 5 JUN 2013
- Article first published online: 5 JUN 2013
- Accepted manuscript online: 29 JAN 2013 10:10AM EST
- Accepted for publication 16 January 2013
Background Several recent studies have reported on the overexpression of human epidermal growth factor receptor (HER)2 in extramammary Paget disease (EMPD). However, there are only a few cases in which both overexpression and gene amplification of HER2 have been examined.
Objectives To evaluate the overexpression and gene amplification of HER2 using a standardized method with a large number of cases of EMPD.
Methods Immunohistochemically, the overexpression of the HER2 protein was examined in 104 cases of EMPD, including 31 intraepithelial cases and 73 invasive cases (35 superficially invasive and 38 deeply invasive). When the HER2 protein was overexpressed or potentially overexpressed, further analysis of amplification of the gene encoding HER2, ERBB2, was undertaken using fluorescence in situ hybridization.
Results The HER2 protein was overexpressed in 16 cases (15%) in total, and in 13 of 73 cases (18%) of invasive EMPD. The ERBB2 gene was amplified in all cases with a HER2 score of 3+. A HER2 score of 3+ or 2+, and ERBB2 amplification were significantly more frequent in the cases of deeply invasive EMPD than in intraepithelial/superficially invasive EMPD (24% vs. 6%/3%, P = 0·012) and were correlated with a larger number of lymph-node metastases (P = 0·047). Log-rank tests for survival curves showed that lymph-node metastasis and ERBB2 amplification were significant prognostic factors (P = 0·0001 and P = 0·043, respectively). However, by a multivariate analysis, only lymph-node status was a significant indicator of Paget-disease-specific survival (P = 0·0001).
Conclusions A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.