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Int J Clin Exp Pathol 2(5),411-432;2009

Review Article
Insights into Endometrial Serous Carcinogenesis and Progression

Oluwole Fadare and Wenxin Zheng

Department of Pathology, Wilford Hall Medical Center, Lackland Air Force Base, San Antonio, Texas, USA; Department of Pathology, University
of Texas Health Science Center at San Antonio, San Antonio, Texas, USA; Department of Pathology, University of Arizona College of Medicine,
Tucson, Arizona, USA; Department Obstetrics and Gynecology, University of Arizona College of Medicine, Tucson, Arizona, USA; Arizona Cancer
Center, University of Arizona, Tucson, AZ, USA and College of Medicine, Shandong University, China

Received 04 January 2009; Accepted and available online 10 January 2009

Abstract: Endometrial serous carcinomas (ESC) constitute only approximately 10% of endometrial cancers, but have a substantially higher
case-fatality rate than their more common endometrioid counterparts. The precise composite of factors driving endometrial serous
carcinogenesis and progression remain largely unknown, but we attempt to review the current state of knowledge in this report. ESC probably
do not evolve through a single pathway, and their underlying molecular events probably occur early in their evolution. TP53 gene mutations
occur in 22.7 to 96% of cases, and p53 protein overexpression is seen in approximately 76%. By gene expression profiling, p16 is upregulated
in ESC significantly above both normal endometrial cells and endometrioid carcinomas, and 92-100% of cases display diffuse expression of
the p16 protein by immunohistochemistry (IHC). Together, these findings suggest dysregulation of both the p16INKA/Cyclin D-CDK/pRb-E2F
and the ARF-MDM2-p53 cell cycle pathways in ESC. By IHC, HER2/neu is overexpressed (2+ or 3+) in approximately 32.1% of ESC, and
approximately 54.5% of cases scored as 2+ or 3+ by IHC display c-erbB2 gene amplification as assessed by fluorescent in situ hybridization.
Genetic instability, typically manifested as loss of heterozygosity in multiple chromosomes, is a common feature of ESC, and one study found
loss of heterozygosity at 1p32-33 in 63% of cases. A subset of ESC display protein expression patterns that are characteristic of high grade
endometrial carcinomas, including loss of the metastasis suppressor CD82 (KAI-1) and epithelial-to-mesenchymal transformation, the latter
manifested as E-cadherin downregulation, P-cadherin upregulation, and expression of epithelial-to-mesenchymal transformation-related
molecules such as zinc-finger E-box-binding homeobox 1 (ZEB1) and focal adhesion kinase. Preliminary data suggests differential patterns of
expression in ESC of some isoforms of claudins, proteases, the tumor invasiveness and progression-associated oncofetal protein insulin-like
growth factor II mRNA-binding protein 3 (IMP3), as well as a variety of other molecules. At the morphologic level, evidence that indicates that
endometrial glandular dysplasia (EmGD) is the most likely morphologically recognizable precursor lesion to ESC is presented. We advocate
use of the term endometrial intraepithelial carcinoma (EIC, or its other appellations) only as a morphologic descriptor and never as a
diagnostic/pathologic statement of biologic potential. Given its potential for extrauterine extension, we consider the lesions described as EIC,
when present in isolation, as examples of localized ESC, and patients should be managed as such. Morphologically normal, p53
immunoreactive endometrial cells (the so-called “p53 signatures”), show a statistically significant association with ESC, display p53 mutations
in a significant subset, and form the start of a progression model, outlined herein, from p53 signatures to EmGD to localized ESC to the more
conventionally invasive neoplasm. The identification of a morphologically-recognizable precursor holds the promise of early detection of ESC,
with the attendant reduction in its overall associated mortality rate. Deciphering the molecular basis for endometrial serous carcinogenesis
should uncover potential targets for diagnosis, therapy, and/or disease surveillance. (IJCEP901001).

Key Words: Endometrial serous carcinoma, endometrial glandular dysplasia, endometrial intraepithelial carcinoma, p53, cadherins, claudins,
CDKs, MDM2 and HER2/neu (erb-B2)

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Address all correspondence to: Oluwole Fadare, MD. Director of Surgical Pathology, Wilford Hall Medical Center, 2200 Bergquist Dr., Ste 1,
Lackland AFB, TX 78236. E-mail:
oluwolefadare@yahoo.com or Wenxin Zheng, MD, Professor of Pathology and Obstetrics and Gynecology,
University of Arizona College of Medicine, Tucson, AZ 85724. E-mail:
zhengw@email.arizona.edu