Showing papers by "Setsuko K. Chambers published in 2004"

Endometrial Glandular Dysplasia: A Newly Defined Precursor Lesion of Uterine Papillary Serous Carcinoma. Part I: Morphologic Features

Abstract: Dysplastic epithelium frequently bridges the changes between normal epithelium and noninvasive carcinoma. However, such a dysplastic lesion has not been previously described in the development of uterine papillary serous carcinoma (UPSC) or between resting endometrium and serous endometrial intraepithelial carcinoma (EIC), which is composed of indisputably malignant noninvasive cancer cells. In this study, we hypothesize that there is a lesion bridging benign endometrium and serous EIC. Based on current understanding of carcinogenesis in general, the lesion should exhibit dysplastic features that are more atypical than "resting endometrium" but fall short of serous EIC. If the putative dysplastic endometrial lesion exists, it should be highly associated with UPSC rather than uterine endometrioid carcinoma (UEC). We examined the morphologic appearance of the endometrium from 32 uteri with UPSC, 16 with serous EIC, and 60 with UEC. The endometrial dysplastic lesions were identified and their pathologic features were characterized. Immunohistochemical staining with p53 and MIB-1 were performed in all sections containing endometrial dysplastic lesions, serous EICs, and benign areas. In addition, 25 postmenopausal endometrial biopsies including 6 benign resting endometria, 8 dysplastic lesions, and 11 serous EICs were also compared for the level of p53 overexpression and cellular proliferative activity. We found that endometrial dysplastic lesions do exist in the endometrial specimens we speculated and examined. We designate it as endometrial glandular dysplasia (EmGD). EmGD was present in 17 (53%) uteri with UPSC compared with 1 (1.7%) uterus removed for UEC (p = 0.001). EmGD was identified in 12 (75%) of 16 serous EIC uteri. Areas of both EmGD and serous EIC were found in 15 (47%) of the 32 UPSC uteri. Transitions from either EmGD to serous EIC or serous EIC to UPSC were present in 8 (25%) of the UPSC cases. No transitions from EmGD to UPSC were identified in any hysterectomy specimen. EmGD was frequently found in endometrial polyps. There was no statistically significant difference between EmGD in a polyp (48%) and EmGD in nonpolypoid endometrium (52%). The majority of EmGDs were multifocal and involved superficial endometrial glands. However, single glandular involvement and endometrial surface epithelial involvement were also seen. Immunohistochemically, EmGD lesions mostly showed intermediate scores/indices of p53 and MIB-1 in comparison with serous EIC and resting endometrium. EmGD is a morphologically distinct entity, which is commonly and specifically associated with uterine tumors with serous differentiation. EmGD may represent the earliest identifiable morphologic change in the development of UPSC. Characteristics of p53 and MIB-1 immunostains of EmGD may be of diagnostic usage in surgical pathology practice. Recognition of EmGD may provide an opportunity to improve the management of UPSC.

Endometrial glandular dysplasia: a putative precursor lesion of uterine papillary serous carcinoma. Part II: molecular features.

Abstract: Endometrial glandular dysplasia (EmGD) may be a newly defined precursor lesion of uterine papillary serous carcinoma (UPSC) by morphology. In this report, we studied molecular changes present in EmGD by the loss of heterozygosity (LOH) approach using laser capture microdissected tissue samples. Nineteen uteri showing at least 1 focus of EmGD by morphology were selected. These cases were 12 UPSC, 2 clear cell carcinomas, 1 mixed uterine papillary serous and endometrioid carcinoma, 1 uterine carcinosarcoma, 1 serous endometrial intraepithelial carcinoma (EIC), and 2 EmGD involving endometrial polyps. Seven microsatellite polymorphic DNA markers (TP53 at 17p, D1S211, and D1S162 at 1p32, D17S1323 at 17q21, D17S1330 at 17q25, D5S346 at 5q, and D2S123 at 2p) were utilized. A total of 123 laser-captured microdissection samples from 19 cases was studied with LOH method. The frequencies and patterns of LOH were analyzed and compared among benign resting endometrium (RE), EmGD, serous EIC, and UPSC. LOH was observed for at least 1 of the 7 markers in all categories of lesions, EmGD, serous EIC, and UPSC. The frequency of LOH for EmGD ranged from 4.2% to 31.3%; the range for serous EIC was 5.9% to 78.6%; and that for UPSC was 7.7% to 62.5%. The most frequent LOH in the 3 above-cited categories of lesions was identified at 17p (TP53) and 1p (D1S162). The frequency of LOH in EmGD with markers of TP53 and D1S162 was significantly higher than in RE (p < 0.05). With markers of D1S211 and D2S123, LOH in EmGD was higher than RE, approaching to a statistically significant level. Compared with foci of serous EIC and UPSC, however, the rate of LOH in EmGD was significantly lower only with TP53 locus (31.3% vs more than 60%, p < 0.05). The difference of LOH frequency with other chromosomal markers between EmGD and serous EIC/UPSC did not reach a statistically significant level. A significantly high concordant LOH pattern was found between foci of EmGD and serous EIC/UPSC (p = 0.05). We conclude that EmGD frequently shows LOH at multiple chromosomal loci, particularly at 17p and 1p. Significantly high concordant LOH frequency between EmGD and paired serous EIC or UPSC strongly suggests that EmGD is a noncancerous precursor lesion of UPSC, probably also of serous EIC. The clinical significance of EmGD needs further studies.

SGK1, a potential regulator of c-fms related breast cancer aggressiveness.

Abstract: The aggressive behavior of breast cancer cells can at times be modulated by hormonal mechanisms. Exposure to glucocorticoids (GC) has been shown to stimulate the invasiveness, motility and adhesiveness of breast cancer cells containing the glucocorticoid receptor. This is largely explained by GC-associated overexpression of the c-fms proto-oncogene, which encodes the receptor for the colony stimulating factor-1 (CSF-1). Our objective is to investigate additional GC-associated genetic alterations that could modulate c-fms related malignant behavior in breast cancer cells. A microarray technique using an oligonucleotide array representing 16,700 known expressed human genes was used to analyze the gene expression profile of breast cancer cells exposed to dexamethasone (Dex) or vehicle. Results were confirmed by western blot analysis. Six genes were found to be consistently differentially overexpressed in the Dex-exposed cells compared to control. We focused on serum-glucose kinase 1 (SGK1), a serine-threonine kinase known to be involved in intracellular signal transduction pathways and induced by GC and serum. An adhesion assay was performed on extracellular matrix after exposing the breast cancer cells to Dex, CSF-1 or to Dex or CSF-1 plus LY294002, a functional inhibitor of SGK1 action. Exposure to LY294002 significantly decreased both CSF-1 and Dex-induced adhesiveness to the level of control cells. SGK1 may act as a downstream intracellular regulator of c-fms, particularly of c-fms-induced adhesiveness of breast cancer cells after exposure to GC or CSF-1. This finding may have implications for potential therapeutic interventions aimed at decreasing the aggressiveness of breast cancer cells.

Carboplatin/Paclitaxel as adjuvant therapy for stage III endometrial adenocarcinoma

Abstract: 5071 Background: The standard therapy for stage III endometrial adenocarcinoma (EAC) has been surgical staging followed by adjuvant radiation therapy. Recent trials have suggested that platinum-bas...

Retrospective analysis of topotecan administered weekly in heavily pretreated recurrent epithelial ovarian carcinoma patients

Abstract: 5079 Background: The established regimen of topotecan (1.5 mg/m2 on days 1 - 5 of a 21-day cycle) in recurrent ovarian cancer may be limited by noncumulative myelosuppression. Limited clinical data...