Human epidermal growth factor receptor 2 protein overexpression and gene amplification in extramammary Paget disease.
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.


OBJECTIVE
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.
Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan. ryota621@hotmail.co.jp
R
R
Tanaka
Y
Y
Sasajima
H
H
Tsuda
K
K
Namikawa
A
A
Tsutsumida
F
F
Otsuka
N
N
Yamazaki
D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D005786:Gene Expression Regulation / Q000502:physiology*; D018734:Genes, erbB-2 / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010145:Paget Disease, Extramammary / Q000235:genetics* / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D012878:Skin Neoplasms / Q000235:genetics* / Q000276:immunology
D015415:Biomarkers; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human