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Aim: We sought to compare survival and toxicity between paclitaxel/carboplatin (TC) and doxorubicin/cisplatin (AP) for concurrent chemoradiation (CCR) in intermediate- or high-risk endometrioid endometrial cancer., Methods: The clinical data of 40 patients with intermediate- (FIGO stage IC-IIB, n = 12) or high-risk endometrioid endometrial cancer (FIGO stage IIIA-IVA, n = 28) were reviewed retrospectively between March 2000 and December 2007, who were treated with TC (n = 23, group 1) or AP (n = 17, group 2) for CCR after surgery., Results: Progression-free survival (PFS) and overall survival (OS) were not different between groups 1 and 2 (median PFS and OS; 35 vs 24 and 76 vs 39 months, respectively, P > 0.05). However, >or=6 cycles of chemotherapy improved PFS compared with 3-5 cycles of chemotherapy (51 vs 21 months, P = 0.04), suggesting that >or=6 cycles of chemotherapy was an independent prognostic factor improving PFS (adjusted HR, 0.27; 95% CI, 0.08 to 0.91; P = 0.04). Grade 3 or 4 hematological and non-hematological, especially, gastrointestinal, toxicities related with chemotherapy during CCR were more common in group 2 than in group 1, whereas there was no difference in grade 3 or 4 late complication by CCR between the 2 groups., Conclusion: These findings suggest that TC may have comparable efficacy to AP for CCR with lesser toxicity, and >or=6 cycles of chemotherapy may be more beneficial than 3-5 cycles of chemotherapy in intermediate- or high-risk endometrioid endometrial cancer. However, large-scale randomized controlled trials are needed to support these results.

Background: To determine the accuracy of several preoperative tests in predicting lymph node (LN) metastases and the feasibility of doing a routine lymphadenectomy in clinical stage-I endometrial cancer., Material/methods: We reviewed 132 patients with clinical stage-I endometrial cancer. The preoperative tests used to predict LN metastases were serum CA-125 level, histologic type and grade, LN status assessed by pelvic magnetic resonance image (MRI) or computed tomography (CT), and depth of myometrial invasion assessed only by pelvic MRI. The cutoff value of the serum CA-125 level was determined using receiver operating characteristic curves. Multivariate logistic regression analyses were used to determine which tests are good predictors of LN metastases., Results: Of 132 patients, 13 (9.8%) had LN metastases. On univariate logistic regression analysis, a high CA-125 level and preoperative LN evaluation by pelvic MRI or CT were significant predictors for LN metastases (OR=17.41, 95% CI: 4.36-69.56 and OR=14.30, 95% CI: 4.02-50.63, respectively). However, on multivariate logistic regression analysis adjusted for age and all preoperative tests, a high CA-125 level was the most significant predictor (OR=13.73, 95% CI: 2.03-92.73). Among the 97 patients with no significant predictor of LN metastases, pelvic LN metastases were observed in 3 patients (3.1%) and para-aortic LN metastases were observed in 1 patient (1.1%). Surgical complications were mild (lymphocele, n=9; lymphedema, n=2; wound problem, n=2)., Conclusions: Considering the importance of LN metastases as an indicator of prognosis, and the relatively low surgical risk of lymphadenectomy, clinicians should cautiously consider routine lymphadenectomy in patients with clinical stage-I endometrial cancer.

Endometrial cancer is the second most common cancer in hereditary nonpolyposis colorectal cancer (HNPCC). It has often been overlooked to explore the possibility of HNPCC in endometrial cancer patients. Our study was to investigate how many HNPCC patients existed among endometrial cancer patients. Among patients who underwent hysterectomy for endometrial cancer at Seoul National University Hospital from 1996 to 2004, 113 patients were included, whose family history and clinical data could be obtained and tumor specimens were available for microsatellite instability (MSI) testing and immunohistochemical (IHC) staining of MLH1, MSH2 and MSH6 proteins. There were 4 (3.5%) clinical HNPCC patients fulfilling the Amsterdam criteria II, and 2 (2/4, 50%) of them carried MSH2 germline mutations. There were also 8 (7.1%) suspected HNPCC (s-HNPCC) patients fulfilling the revised criteria for s-HNPCC, and one (1/8, 12.5%) of them revealed MLH1 germline mutation. In 101 patients, who were not clinical HNPCC or s-HNPCC, 11 patients showed both MSI-high and loss of expression of MLH1, MSH2 or MSH6 proteins, and 2 (2/11, 18.2%) of them showed MSH6 germline mutations. In 113 patients with endometrial cancer, we could find 5 (4.4%) HNPCC patients with MMR germline mutation and 2 (1.8%) clinical HNPCC patients without identified MMR gene mutation. Family history was critical in detecting 3 HNPCC patients with MMR germline mutation, and MSI testing with IHC staining for MLH1, MSH2 and MSH6 proteins was needed in the diagnosis of 2 HNPCC patients who were not clinical HNPCC or s-HNPCC, especially for MSH6 germline mutation., ((c) 2007 Wiley-Liss, Inc.)

Objectives: To retrospectively evaluate the accuracy of magnetic resonance (MR) imaging for the prediction of depth of myometrial invasion in the preoperative assessment of women with endometrial carcinoma., Methods: We retrospectively reviewed the medical records and MR imaging reports of 120 women with pathologically-proven endometrial carcinoma who underwent preoperative pelvic MR imaging between June 1997 and February 2006. Tumor signal intensity, the appearance of the junctional zone (JZ), the presence of large polypoid tumors and leiomyomas were analyzed. Univariate logistic-regression analysis was performed to identify associations between incorrect MR staging and the study variables., Results: Data from 120 patients were registered for the current study and analyzed. The sensitivity, specificity and accuracy of the MR imaging in assessment of myometrial invasion among patients with endometrial carcinoma were: 50.6%, 89.2% and 62.5% respectively. MR differentiation of deep myometrial invasion from superficial disease had an 83.3% accuracy (100 of 120 cases). Isointense JZ to myometrium (P<0.001), and the presence of polypoid tumors (P=0.037) on MR imaging were significantly associated with an underestimation of myometrial invasion by endometrial carcinoma., Conclusions: Isointense JZ to myometrium and polypoid tumors are difficult to accurately evaluate for myometrial invasion of endometrial carcinoma by MR imaging.

Objectives: Our objective was to determine the frequency of a coexisting ovarian malignancy and to evaluate the feasibility of ovarian preservation in patients with early stage endometrial carcinoma., Methods: Endometrial cancer patients who received primary surgical treatment between 1992 and 2004 were identified using the institution's tumor registry. Information regarding patient age, preoperative and intraoperative evaluations, pathologic reports, and follow-up results was abstracted from medical records., Results: Coexisting ovarian malignancy was detected in 19 (7.31%) of 260 patients who underwent surgical treatment (12 metastatic and 7 synchronous primaries). The independent risk factors of a coexisting ovarian malignancy, as determined using a logistic regression model, were intraoperative extrauterine disease, non-endometrioid histology, lymph node metastasis, and patient age, and the presence of intraoperative extrauterine disease was found to most significantly predict ovarian involvement (OR=542.1; 95% CI, 57.18 to 5139.23). Seventeen of the 19 cases showed abnormal intraoperative gross findings around adnexa or other sites. Among the 206 patients without any evidence of intraoperative extrauterine disease, the coexisting ovarian malignancy rate was 0.97% (2/206), and zero for those under age of 45. In 35 patients, grossly normal ovaries were selectively saved, and no recurrence or cancer-related death occurred (median duration of follow-up: 76 months, range 3-121)., Conclusions: The risk of coexisting malignancy in patients without predictable risk factors is minimal. Therefore, it is possible to preserve ovaries in young women with early stage endometrial carcinoma with a thorough preoperative evaluation and extensive intraoperative exploration.

Background: Excision repair cross-complementing group 1 (ERCC1) is a major DNA repair protein. Recent studies have addressed the association between ERCC1 polymorphism and carcinogenesis., Methods: We investigated a polymorphism of ERCC1 at nucleotide 19007 (C-->T, Asn118Asn) in 94 epithelial ovarian cancer patients, 102 endometrial cancer patients, and in 329 control subjects., Results: We observed no evidence of associations between the C19007T ERCC1 polymorphism and risk of epithelial ovarian or endometrial cancer, which had the same adjusted odds ratios of 0.91 (p = 0.711, 0.691 respectively)., Conclusion: Our findings suggest that the C19007T ERCC1 polymorphism is unlikely to play an important role in epithelial ovarian or endometrial cancer in Korean women., (2007 S. Karger AG, Basel)

Several studies suggested that aromatase could play an important role in tumor progression and prognosis in endometrial cancer because androstenedione is converted to estrogen by the enzyme. For better understanding of the aromatase expression in endometrial cancer and its relation to diverse clinicopathological parameters, we conducted this study. This study was carried out with 141 endometrial cancer patients, all of whom had undergone operations in our institution from 1993 to 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal antiaromatase antibody using human placental tissue as positive control. Clinicopathological variables of all patients were also reviewed. Despite quite a high aromatase expression in positive control, there was no endometrial cancer specimen showing the enzyme expression. Our result, although needs further investigation on the cause of the difference from other studies, suggested that aromatase might not have an important role in endometrial cancer.

The evaluation of expression levels of the estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer is a very common procedure in modern practice. However, the significance of such tests remains controversial, and the evaluation of the status of steroid receptors seems to be a more thoroughly justified practice. The present study was carried out with 145 endometrial cancer patients, all of whom had undergone operations at the Seoul National University Hospital, from 1993 to 2002. Paraffin-embedded tissue blocks were sectioned and immunostained with monoclonal anti-ER and anti-PR antibodies. Clinicopathological variables were also analyzed, with 10% cutoff values for ER and PR positivity. A multivariate Cox regression analysis was performed in order to estimate the influences of several clinicopathological and immunohistochemical covariates on patient survival. Forty seven specimens (32.4%) stained as ER positive, and 110 (75.9%) stained as PR-positive. Patients with PR-positive tumor tended to be both younger and more obese than patients with PR-negative tumors (P=0.020, 0.016). Well-differentiated tumors were found to be positive for ER or PR more frequently (P=0.015, <0.001). ER or PR-positive tumors exhibited significantly less myometrial invasion (P=0.042, 0.002). However, multivariate Cox regression analyses revealed that the expressions of ER and PR were not significantly associated with patient survival, and only advanced FIGO stage constituted an independent prognostic factor. Our results suggested that the evaluation of steroid receptors might prove helpful prior to surgery. Low ER and high PR values suggest that racial differences and/or sequential loss of receptors during carcinogenesis might be involved in the expression of steroid receptors in cases of endometrial cancer.

The incidence of cervical adenocarcinoma (CA) is rising, whereas the incidence of cervical squamous cell carcinoma (CSCC) continues to decrease. However, it is still unclear whether different molecular characteristics underlie these 2 types of cervical carcinoma. To better understand the epigenetic characteristics of cervical carcinoma, we investigated the DNA promoter hypermethylation profiles in CA and CSCC. In addition, we investigated whether DNA hypermethylation patterns might be used for the molecular diagnosis of CA and endometrial adenocarcinoma (EA). Using the bisulfite-modification technique and methylation-specific PCR, we examined the aberrant promoter hypermethylation patterns of 9 tumor suppressor genes (APC, DAPK, CDH1, HLTF, hMLH1, p16, RASSF1A, THBS1 and TIMP3) in 62 CSCCs, 30 CAs and 21 EAs. After Bonferroni correction adjustment (statistically significant at p < 0.0055), we found that the aberrant hypermethylations of CDH1 and DAPK were more frequent in CSCCs than in CAs (80.6% vs. 43.3%, p = 0.001; 77.4% vs. 46.7%, p = 0.005), whereas HLTF and TIMP3 were more frequently methylated in CAs (3.2% vs. 43.3%, p < 0.001; 8.1% vs. 53.3%, p = 0.001). The hypermethylations of RASSF1A and APC were more frequent in CAs than in CSCCs, but this was not significant (9.7% vs. 33.3%, p = 0.008; and 14.5% vs. 40.0%, respectively, p = 0.009). In addition, RASSF1A hypermethylation was significantly more frequent in EAs than in CAs (81.0% vs. 33.3%, p = 0.001). In conclusion, the existence of these unique methylation patterns in these cancers suggests that their tumorigenesis may involve different epigenetic mechanisms., (2005 Wiley-Liss, Inc.)

Background: The purpose of this study was to evaluate the predictive value of preoperative serum CA-125 levels in the assessment of disease extent and clinical outcome of endometrial cancer., Method: This retrospective study evaluated 92 women with pathologically proven endometrial carcinoma scheduled for treatment that had preoperative serum CA-125 levels between January 1999 and February 2006. The association of preoperative serum CA-125 with a variety of histopathologic factors was evaluated. Statistical analysis was performed using chi2/Fisher's exact test and a logistic regression. Survival was studied with the Kaplan-Meier method and Cox regression models., Results: Elevated serum CA-125 levels were significantly correlated with advanced-stage disease (p<0.001), lymph node metastases (p<0.001), increased depth of myometrial invasion (p=0.001), and positive peritoneal cytology (p=0.026). Multivariate analyses using logistic regression showed that lymph node metastases had the most significant effect on the elevation of preoperative serum CA-125 levels (p=0.004). Patients with a serum CA-125 < or =28.5 U/ml had a significantly better five-year disease-free survival than those with an elevated level in this study: 85.6% versus 60.0% (p=0.004)., Conclusions: The preoperative serum CA-125 level appears to be a significant independent predictor of lymph node metastasis and prognosis after surgical intervention. Therefore, preoperative serum CA-125 may be a useful tool, in the clinical setting, for optimal individualized patient management.

RASSF1A is a tumor suppressor gene that is frequently hypermethylated in various human cancers. In the present study, we examined RASSF1A methylation status in 70 patients with endometrial cancer to search for correlations between the promoter hypermethylation of RASSF1A and the clinicopathologic parameters. Thirty-six of 70 endometrial cancers demonstrated hypermethylation of the RASSF1A promoter. Advanced stage disease (FIGO stage III, IV), lymph node involvement, and high grade (G3) are more frequent in patients with RASSF1A hypermethylation than in those without. We also observed a higher incidence of recurrences and lower disease-free survival (DFS) in patients with RASSF1A hypermethylation (77.8% and 97.0% at 5 years for methylated and unmethylated patients, respectively, p = 0.039). Our results suggest that RASSF1A hypermethylation might be a useful indicator of tumor aggressiveness in endometrial cancer patients.

Objectives: The common G to A single nucleotide polymorphism (G870A) in the splice donor region of exon 4 enhances alternate splicing, and produces a longer half-life cyclin D1 (CCND1). This study was aimed at investigating the possible association between the G870A polymorphism in CCND1 and the risk of endometrial cancer., Methods: We assessed the association between the CCND1 G870A polymorphism and the risk of endometrial cancer in a hospital-based case-control study among 231 Korean women (77 cases; 154 matched controls). Controls were matched to cases with respect to age, menopausal status, and hormone therapy status., Result: The allele frequencies of the case subjects (A, 0.45; G, 0.55) were significantly different from those of control subjects (A, 0.58; G, 0.42) (P = 0.008). All case and control subjects were in Hardy-Weinberg equilibrium. The AA genotype was associated with a significantly elevated odds ratio (OR) of 3.18 [95% confidence interval (CI) 1.38-7.37, P = 0.007], and the AG genotype was associated with an OR of 1.38 (95% CI 0.65-2.89). When we combined the GG and AG genotypes as a reference genotype, we found that the OR for the AA genotype was 2.53 (95% CI 1.34-4.80, P = 0.004), supporting a recessive model for the A allele. Conditional logistic regression adjusted for various risk factors of endometrial cancer revealed positive associations between the AA genotype and an increased risk of endometrial cancer (OR 3.16, 95% CI 1.18-8.43, P = 0.022). However, no significant difference in endometrial cancer stage or grade was observed between the CCND1 genotypes., Conclusion: Our data suggest that the CCND1 polymorphism is associated with an increased risk of endometrial cancer. To validate this association, a large-scale population-based study is needed.

Cyclooxygenase-2 (COX-2) has been known to be related with various types of carcinoma, but we have insufficient knowledge about the association between COX-2 and endometrial cancer. Many have reported a close relationship between p53 expression and a poor prognosis in endometrial cancer, but it is unclear whether p53 is an independent prognostic factor. To clarify these uncertainties, we examined the expressions of COX-2 and p53 in endometrial cancer tissues. The study was carried on 152 endometrial cancer patients who had operation at Seoul National University Hospital. Paraffin-embedded tissue blocks were sectioned and immunostained using monoclonal anti-COX-2 and anti-p53 antibodies. Twenty-seven (17.8%) specimens stained as COX-2 positive. COX-2 positivity was more frequently observed in postmenopausal patients than in premenopausal patients (8.8% versus 25.0%; P = 0.009). However, COX-2 positivity did not show a statistically significant association with any other clinicopathologic characteristic (parity, body mass index, histotype, International Federation of Gynecology and Obstetrics stage, grade, lymph node metastasis, deep myometrial invasion, or p53 overexpression). Thirty-one (20.4%) specimens showed p53 overexpression and this was significantly correlated with an advanced stage (P = 0.001), poor differentiation (P < 0.001), lymph node metastasis (P = 0.012), and deep myometrial invasion (P < 0.001). Multivariate Cox regression analysis showed that advanced stage was an independent prognostic factor of survival, but p53 overexpression was not. COX-2 may be associated with endometrial cancer carcinogenesis during the postmenopausal period but not with tumor aggressiveness and p53 overexpression. The p53 overexpression was found to be strongly associated with endometrial cancer aggressiveness.

Objective: Recently, there has been considerable interest in the association of specific cancers with single nucleotide polymorphisms (SNPs). In this regard, genetic polymorphism at codon 72 (CCC/proline to CGC/arginine [Pro(72)Arg]) of the p53 gene is one of the most frequently studied subjects. An association between endometrial cancer and the polymorphism at codon 31 (AGC/serine to AGA/arginine [Ser(31)Arg]) of the p21 gene, which is known to be a downstream mediator of p53, has also been reported., Methods: The authors designed a hospital-based case-control study of 95 endometrial cancer patients and 285 non-cancer controls. For the determination of p53 and p21 polymorphism, allele-specific polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism assay was applied, respectively., Results: We found statistically significant differences in the frequency of the p53 and p21 genotypes between these two groups (P < 0.001), respectively. The p53 genotypes containing the Pro allele were significantly associated with endometrial cancer with an odds ratio (OR) of 3.56 (95% confidence interval [CI] 2.10-6.04). Also, homozygous carriers of the p21 Ser allele showed a substantially increased risk of developing endometrial cancer (OR 2.68, 95% CI 1.59-4.51) as compared to homozygous and heterozygous carriers of the Arg allele. In addition, the combination of the pro allele containing genotypes of p53 and the Ser homozygous genotype of p21 posed a remarkably increased risk (OR 9.55, 95% CI 4.30-21.24) of endometrial cancer development. These significant differences were maintained throughout the groups after they were stratified by menopausal status., Conclusions: These data suggest that there is a significant association between the genetic polymorphisms of p53, p21, and specific combinations of the at-risk genotypes of these genes and the risk of developing endometrial cancer in Korean women.

Objective: The aim of this study was to compare the accuracy of transvaginal US (TVUS), CT, and MRI in detecting deep myometrial invasion in endometrial carcinoma., Materials and Methods: Twenty-six patients with endometrial carcinoma were evaluated with TVUS, CT, and MRI. The depth of myometrial invasion was estimated in each examination. The invasion depth was categorized into no/superficial and deep and was compared to surgical and pathologic findings., Results: At pathologic examination, the depth of myometrial invasion was no/superficial in 16 patients and deep in 10. The accuracy/sensitivity/specificity of TVUS, CT, and MRI in detecting deep myometrial invasion were 69/50/81, 61/40/75, and 89%/90%/88%, respectively. The sensitivity and accuracy of MRI in detecting deep myometrial invasion were significantly higher than those of TVUS and CT (p = 0.049 for both sensitivity and accuracy)., Conclusion: We recommend MRI instead of CT or TVUS for the evaluation of the depth of myometrial invasion in endometrial carcinoma.