Determination of HER2/neu status in uterine serous papillary carcinoma: Comparative analysis of immunohistochemistry and fluorescence in situ hybridization
Introduction
Cancer of the uterine corpus is the most prevalent gynecologic tumor in women, with an estimated 40,320 cases and 7090 deaths in the United States in 2004 [1]. Uterine serous papillary carcinoma (USPC) represents the second most common histologic type of endometrial cancer, constituting up to 10% of all endometrial tumors [2], [3], [4], [5]. The microscopic criteria for diagnosis of USPC were first outlined by Hendrickson in 1982 [5]. Typically, the neoplastic epithelium is characterized by serous differentiation with psammoma bodies present and with predominantly papillary architecture [5]. Prominent nucleoli and a high mitotic activity are commonly detected in this tumor. Clinically, USPC has a propensity for early intraabdominal and lymphatic spread even at presentation and is characterized by a highly aggressive biologic behavior [2], [3], [4], [5]. Unlike the histologically indistinguishable high grade serous ovarian carcinomas, USPC is a chemoresistant disease from onset, with responses to combined cisplatinum-based chemotherapy in the order of 20% and of short duration [2], [3], [4], [5]. The survival rate is dismal, even when USPC is only a minor component of the histologically more common endometrioid adenocarcinoma, and widespread metastasis and high mortality may occur even in those cases in which tumor is confined to the endometrium or to an endometrial polyp [2], [3], [4], [5]. The overall 5-year survival is about 30% for all stages and the recurrence rate after surgery is extremely high (50% to 80%). A better understanding of the molecular basis of the aggressive biologic behavior of USPC and the development of novel, more specific, and more effective treatment modalities against this variant of endometrial cancer remain a high priority.
The human HER-2/neu (c-erbB2) gene product, like the epidermal growth factor receptor, is a transmembrane receptor protein that includes a cysteine-rich extracellular ligand binding domain, a hydrophobic membrane-spanning region, and an intracellular tyrosine kinase domain [6]. With no direct ligand identified to date, HER-2/neu functions as a preferred partner for heterodimerization with other members of the EGFR family (namely HER-1 or ErbB1, HER-3 or ErbB3, and HER-4 or ErbB4), and thus plays an important role in coordinating the complex ErbB signaling network that is responsible for regulating cell growth and differentiation [6]. Importantly, HER2/neu overexpression has been previously suggested to represent a major prognostic factor in several human cancers including endometrial, breast, and ovarian carcinomas [7], [8], [9], [10]. It is only recently, however, that a striking overexpression of the HER2/neu receptor in USPC has been identified [11]. In this regard, HER2/neu overexpression (i.e., 2+ and/or 3+) has been reported with figures ranging from 18% to 80% in different series of USPC tested by immunohistochemical techniques (IHC) [11], [12], [13], [14], [15]. Furthermore, a significantly higher frequency of HER2/neu overexpression has recently been demonstrated in African-American patients harboring USPC when compared to Caucasian patients [16]. These data thus suggesting the consistently reported striking racial disparity in endometrial cancer survival rates in the United States between black and white women [17], [18] may be at least partially correlated to the overexpression of the HER2/neu oncogene [16].
High overexpression of HER2/neu provides support for the proposal that trastuzumab (Herceptin, Genentech, San Francisco, CA), a humanized anti-HER2/neu antibody that is showing great promise for treatment of metastatic breast cancer patients overexpressing HER2/neu protein [19], may be a novel, potentially highly effective therapy against USPC. In agreement with this view, the clinical efficacy of Herceptin therapy is currently being tested by the Gynecologic Oncology Group (GOG) in the GOG181B trial which is actively enrolling patients with advanced or recurrent endometrial cancer showing amplification of the HER2/neu gene by fluorescent in situ hybridization (FISH). Unlike human breast cancer, however, whether the correlation between HER2/neu protein overexpression by IHC and FISH has been extensively studied [20], [21], [22], [23], such correlation remains poorly defined in USPC. To fill this gap in knowledge in this study, we have used IHC and FISH assays to evaluate and compare HER2/neu protein expression and gene amplification, respectively, in paraffin blocks from 26 women harboring stage IA to IV USPC treated at the University of Arkansas for Medical Sciences from 1997 to 2004.
Section snippets
Patient population
Paraffin blocks of endometrial adenocarcinomas were retrieved for 26 women who underwent treatment for International Federation of Gynecology and Obstetrics (FIGO) stage IA to IV serous papillary endometrial adenocarcinoma at the University of Arkansas for Medical Sciences (UAMS) between 1997 and 2004. Study records were reviewed according to IRB guidelines. The patient characteristics are described in Table 1. A total abdominal hysterectomy with bilateral salpingo oophorectomy, pelvic
Immunohistochemistry
Twenty-six specimens were available for both IHC and FISH analysis and therefore satisfied study inclusion criteria. The breakdown by surgical stage was I = 3, II = 1, III = 12, IV = 10. Table 1 shows the distribution of patient characteristics and adjuvant therapy received. Moderate-to-strong expression of HER2/neu protein was noted in 16 (62%) of 26 USPC samples evaluated, with 7 (27%) samples showing moderate staining (2+) and 9 (35%) showing strong staining (3+) for HER2/neu (Table 2). The
Discussion
Our group has recently reported a striking HER2/neu overexpression by IHC in a large percentage of USPC patients [11]. These findings have highlighted the potential of targeting HER2/neu oncogene as a novel therapeutic and prognostic marker in USPC patients [11], [16]. Consistent with this view, in analogy to breast cancer patients harboring disease with proven amplification or strong HER2/neu overexpression, USPC patients with disease refractory to standard treatment modalities may potentially
Acknowledgments
This work was supported in part by grants from the Angelo Nocivelli and the Camillo Golgi Foundation, Brescia, Italy, and a grant from the Istituto Superiore di Sanita' (Italian National Institute of Health) to AS.
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