Paget's disease is a
skin cancer characterized by characteristic (Paget) cells scattered in the epidermis. Although its prognosis is generally favorable with surgical resection, the clinical outcome turns unfavorable in cases with recurrence and
metastasis. Therefore, establishment of effective therapeutic regimens is required for advanced Paget's disease. The
human epidermal growth factor receptor 2 (HER2)
protein, a transmembrane
growth factor receptor, is frequently overexpressed in
malignancies, causing activation of the
phosphatidylinositol 3 kinase (PI3K) and
extracellular signal-regulated kinase (ERK) signal pathways. Recently, HER2-targeting molecular
therapy using
trastuzumab (
Herceptin; Genentech, Inc, South San Francisco, Calif) was revealed to be effective in advanced breast
cancers overexpressing HER2
protein. Here, we analyzed the correlation between activation of the HER2 signal pathways and clinicopathologic parameters of 36
extramammary Paget's disease samples from 34 Japanese patients, using immunohistochemical analyses for HER2, phosphorylated HER2, phosphorylated AKT, and phosphorylated ERK
proteins. We found overexpression of the HER2
protein in 19.4% (7) of the lesions, 3 of which showed HER2 amplification by chromogenic in situ hybridization. Phosphorylated HER2
protein was detected in 12 lesions (33.3%), including 2 of the 7 HER2-overexpressing lesions. Phosphorylated AKT was detected in approximately 75.0% (27/36) and phosphorylated ERK in 38.9% (14/36). Both HER2 and AKT were simultaneously phosphorylated in 9 cases (25.0%) and HER2 and ERK in 9 cases (25.0%), but all 3 molecules were phosphorylated in only 1 sample. Phosphorylated ERK correlated with the maximum diameter of the
tumors (P < .025), but other immunohistochemical parameters failed to show any correlation with clinicopathologic features. These results suggest the contribution of the HER2 signaling pathway to the pathogenesis and progression of some cases of
extramammary Paget's disease, for which clinical use of molecular target
therapy against the HER2 pathway is warranted.