Expression of C-erbB-2 Oncoprotein in Mammary and Extramammary Paget's Disease

Abstract

Formalin-fixed, paraffin-embedded tissue sections from 45 patients with mammary and extramammary Paget's disease were stained immunohistochemically with the use of a polyclonal antiserum directed against a 14-amino acid segment of the c-erbB-2 oncoprotein. Positive membrane staining, which correlates with gene amplification, was found in 15 of 19 cases (79%) of mammary Paget's disease, 4 of 13 cases (31%) of vulvar Paget's disease, none of 8 cases of scrotal Paget's disease, and none of 5 cases of perianal Paget's disease. Of the 19 patients with mammary Paget's disease, specimens of underlying breast tissue were available from 14; all contained a concurrent ductal adenocarcinoma. Concordance of c-erbB-2 antigen staining between the underlying breast carcinoma and the pagetoid component was observed in 12 cases. Of the 13 patients with vulvar Paget's disease, 2 had superficial stromal invasion, and 3 had underlying, deeply invasive adenocarcinomas. One superficially invasive case was positive for c-erbB-2 expression. One additional case of vulvar Paget's disease had an associated primary pagetoid endocervical adenocarcinoma that spread into the endometrium; both the endocervical and vulvar components stained positively for the c-erbB-2 antigen. The results of this study indicate that the c-erbB-2 oncoprotein may play a role in the pathogenesis of extramammary Paget's disease. These results also suggest that the c-erbB-2 oncoprotein may function in vivo to promote intraepithelial spread of adenocarcinoma cells.

Tumour cells of extramammary Paget's disease do not show either p53 mutation or allelic loss at several selected loci implicated in other cancers

“…As expected, overexpression of c-erbB-2 protein, which reflects c-erbB-2 gene amplification, was observed in 43% of the tumours. The higher prevalence of c-erbB-2 overexpression in our series compared with previous studies (Keatings et al, 1990;Meissner et al, 1990;Wolber et al, 1991;Nishi et al, 1994) may be explained by case selection bias because 9 out of 14 cases investigated in this study were invasive carcinomas, in which c-erbB-2 overexpression is generally more prominent than in in situ lesions (Nishi et al, 1994). Expression of bcl-2 was entirely negative in all cases, suggesting that activation of bcl-2 proto-oncogene does not play a role.…”

“…Finally, we examined the expression of c-erbB-2 protein, a protooncogene product reported to be overexpressed in a subset of extramammary Paget's disease (Keatings et al, 1990;Meissner et al, 1990;Wolber et al, 1991;Nishi et al, 1994), and bcl-2 protein, which belongs to a group of proto-oncogenes that prolong the survival of cells by blocking apoptosis (Lu et al, 1996). As expected, overexpression of c-erbB-2 protein, which reflects c-erbB-2 gene amplification, was observed in 43% of the tumours.…”

“…A variety of cell types have been proposed as the progenitors of extramammary Paget's cells, including pluripotential germinative epidermal cells (Murrell Jr and McMullan, 1962;Jones et al, 1979), and cells of both eccrine and apocrine sweat glands (Demopoulos, 1971; Lee et al, 1977;Roth et al, 1977;Mazoujian et al, 1984;Hamm et al, 1986). Furthermore, extramammary Paget's disease may arise multicentrically within the anogenital area (Gunn and Gallager, 1980) or even in distant anatomical sites known as 'triple' extramammary Paget's disease in which genitalia and both sides of axillae are affected at the same time (Kawatsu and Miki, 1971 al, 1990) and c-erbB-2 proto-oncogene products (Keatings et al, 1990;Meissner et al, 1990;Wolber et al, 1991;Nishi et al, 1994), and altered expression of p53 tumour-suppressor protein (Wienecke et al, 1994;Nakamura et al, 1995). Because of its particular biological properties, we were interested in examining genetic changes in extramammary Paget's disease.…”

Paget disease of the breast: Changing patterns of incidence, clinical presentation, and treatment in the U.S.

“…32 In 1 report, 24 of 37 women (65%) who had Paget disease with underlying invasive cancer had tumors with Grade 3 histology. 3 In another report of 20 patients with who had mammary Paget disease, 80% of tumors showed strong overexpression (3þ) of HER-2 and were negative for ER.…”

p185 overexpression and HER2 oncogene amplification in recurrent vulvar Paget's disease

“…[4][5][6][7][8][9] Tanskanen et al 5 reported HER2 oncogene amplification and p185 Her2 overexpression in seven of 13 primary vulvar Paget's disease, but p185 Her2 expression in recurrent Paget's disease has not been studied. We analyzed p185 Her2 overexpression and HER2 oncogene amplification in six patients with recurrent vulvar Paget's disease.…”