erbB-2 overexpression but no activation of beta-catenin gene in extramammary Paget's disease

Our previous study in extramammary Paget's disease showed neither p53 mutat ions nor allelic loss at selected loci implicated in other cancers, suggest ing a pathogenesis of this skin cancer different from other common epitheli al malignancies. To examine further the genetic defects in extramammary Pag et's disease, we carried out molecular genetic analyses in 31 tumor samples obtained from 27 cases of extramammary Paget's disease without underlying malignancies, Immunohistochemistry using CB-11 monoclonal antibody revealed either membrane or cytoplasmic erbB-2 oncoprotein overexpression in none o f the 13 primary in situ tumors, but in one recurrent in sib tumor, 10 of 1 3 invasive primary tumors and two of four lymph node metastases. Sensitive dual color fluorescence in sih hybridization analysis using probes for eubB -2 gene locus and chromosome 17 pericentromere, however, revealed different erbB-2 gene status in the erbB-2 overexpressing tumors, One recurrent in s itu tumor and one lymph node metastasis showed definite gene amplification characterized by multiple scattered signals or a few large clustered erbB-2 signals, whereas four tumors with predominantly cytoplasmic erbB-2 overexp ression were thought to have low-grade gene amplification. The remaining si x tumors overexpressing erbB-2 showed no increase of erbB-2 copy numbers. N o evidence of abnormal activation of the beta-catenin gene, a critical medi ator of Wnt signaling pathway, in any tumor by immunohistochemical staining and by direct sequencing and reverse transcription-polymerase chain reacti on analysis was found, Frequent overexpression of erbB-2 by either gene amp lification or possible transcriptional activation in invasive primary tumor s and metastases suggests an important part for this oncogene in the progre ssion of extramammary Paget's disease.