HER-2/neu expression in Paget disease of the vulva and the female breast
Introduction
Paget disease of the vulva is a rare lesion that accounts for <1% of vulva neoplasms [1]. It is a manifestation of extramammary Paget disease. Mammary Paget disease was originally described as a breast lesion with associated underlying invasive ductal adenocarcinoma. According to the location, it is classified as mammary or extramammary disease [2]. Although controversy still exists as to the true nature of vulvar Paget disease, the majority of lesions appear to be an intraepithelial form of malignancy of apocrine origin involving the skin and its appendages. Paget disease of the vulva is an epidermal neoplasm. During embryological development, the cells of the stratum germinativum give rise to the skin appendages including the apocrine glands and the overlying mature squamous epithelium [3]. Also, the mammary gland is an apocrine differentiated skin appendage. The appearance of apocrine differentiated Paget cells as a neoplasm of the nipple as well as a disease of the vulva evidences this embryological kinship. A 12% prevalence of invasive vulva Paget disease and a 4% prevalence of associated vulva adenocarcinoma are described [1]. There is also an association with other malignancy in 20% of the cases [2]. After surgical treatment, which appears to be the established primary therapy, 30% of the patients experience local recurrences within 8 years [1], [4]. In excising the lesion, it is important to recognize that the lesion frequently extends beyond the clinically apparent borders. Due to the high recurrence rate, different therapeutic options like reexcision, chemotherapy (5-FU), and x-ray therapy have been discussed. Since these are burdening therapies for a noninvasive disease, it is crucial to search for therapeutic strategies with higher tolerability.
HER-2/neu, also known as c-erbB-2, is a transmembrane receptor with overexpression in 25–30% of primary breast carcinomas [5], [6]. HER-2/neu receptor protein has tyrosine kinase activity [7], [8]. Prior studies demonstrate a 95% positivity for HER-2/neu in Paget disease of the nipple with underlying intraductal and invasive carcinomas [9]. It has been demonstrated that HER-2/neu overexpression in breast carcinomas is associated with poor patient prognosis and aggressive disease potential [6], [10], [11], [12], [13]. Similar results could be found in the majority of extramammary vulva Paget disease [14], [15], [16], [17].
Trastuzumab (Herceptin™, Gentech, South San Francisco L.A.) is a recombinant monoclonal antibody against HER-2/neu for the treatment of patients with metastatic breast carcinoma, with overexpression of HER-2/neu. Initial clinical trials with Trastuzumab suggest a prolongation of survival for patients with advanced metastatic breast cancer [18]. The U.S. FDA approved the usefulness of a standardized diagnostic kit for detection of HER-2/neu overexpression. This test is an immunohistochemical staining system for semiquantitative evaluation of HER-2/neu expression. The standardized results of the HercepTest™ correspond with the therapeutic effect of Trastuzumab against breast cancer [19], [20].
It is the objective of this study to evaluate the HER-2/neu expression status in Paget disease of the vulva using the HercepTest™ as a standardized detection system. For a possible new indication for Herceptin™ treatment, it is crucial to demonstrate a HER-2/neu overexpression in Paget disease of the vulva.
Section snippets
Materials and methods
Paraffin blocks from 15 cases (n = 15) with Paget disease were chosen from the archive of the Department of Pathology/University of Hanover.
Seven patients were diagnosed by the histopathologist with noninvasive and two patients with invasive Paget disease of the vulva. One patient showed noninvasive Paget disease of the vulva with underlying adenocarcinoma. It is a small group but a rare disease. These 10 cases represent all patients with this diagnosis in our Colposcopy Clinic from 1996 to
Noninvasive Paget disease of the vulva
Using HercepTest™ and the U.S. FDA-approved scoring system, overexpression of HER-2/neu was demonstrated in six out of seven cases: five cases with 3+, one case with 2+. Staining was visible exclusively in the membranes of Paget cells, whereas normal epithelium was negative (Fig. 1, Fig. 2). Case number 7 showed a 1+ score (Table 1).
Invasive Paget carcinoma
Two cases of invasive Paget carcinoma showed clear membrane signals, scoring 3+ in all Paget cells (invasive as well as intraepithelial tumor areas). Normal
Discussion
At the time of initial presentation, most patients with Paget disease of the vulva are misdiagnosed, because biopsies are usually not performed [21], [22]. Application of steroid creams and antifungal or antibiotic agents are usually the first therapies. The average interval from symptom onset to histological diagnosis is 3 years [21], [22], [23]. Because of the intraepithelial nature of the disease, tumor markers such as squamous cell carcinoma (SCC) antigene, Ca 19-9, or carcinoembryogenic
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