The Clinical Features of Recurrent Endometrial Cancer in Japan: Chemotherapy Instead of Radiotherapy as Postoperative Adjuvant Treatment.

OBJECTIVE: Chemotherapy is a standard adjuvant treatment after primary surgery for endometrial cancer in Japan. We aimed to characterize the clinical features of recurrent endometrial cancer (REC) patients in Japan. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 112 REC patients who were primarily treated at 1 of 3 university hospitals in Japan from 2005 to 2012. We analyzed overall survival since the first recurrence (R-OS) in accordance with several factors. RESULTS: Median patient age was 64 years. The median follow-up period was 48 months. The distributions of cancer stage and histological subtype lacked distinctive features, and most patients had a high risk for recurrence at the time of the primary surgery. Although approximately 78% of patients received adjuvant chemotherapy, 85/112 patients (76%) experienced recurrence within 2 years after the initial treatment ended. For patients receiving adjuvant chemotherapy, regional lymph node (LN) and distant-site recurrence were more frequent (>40%) than vaginal or intra-abdominal recurrence. Median survival and 5-year R-OS were 27 months and 26.1%, respectively. The R-OS was significantly better for patients aged 65 years or older, those with negative peritoneal cytology at the time of primary surgery, those with recurrence within regional LN (eg, pelvic LN or para-aortic LN under the renal vein) and/or vagina, and those who underwent surgery and/or radiotherapy after recurrence. A multivariate analysis indicated that positive peritoneal cytology, a disease-free interval of less than 12 months, recurrent lesions in 2 or 3 areas, and treatment excluding surgery or radiotherapy were independent predictors of poor prognosis after recurrence. CONCLUSIONS: Adjuvant chemotherapy was insufficient to reduce the incidence of distant recurrence. The prognosis of patients recurred within regional LN and/or vagina was significantly better than that of patients with recurrence in other lesions because of treatment with surgery and/or radiotherapy. The disease-free interval was a significant prognostic factor for REC patients.

Transcriptional upregulation of HIF-1α by NF-κB/p65 and its associations with ß-catenin/p300 complexes in endometrial carcinoma cells.

The hypoxia-inducible factor (HIF)-1α, which has a major role in cell adaptation to hypoxia, is mainly regulated at post-translational levels. Recently, HIF-1α mRNA was also shown to be upregulated by several signal pathways under normoxic conditions. Here we focused on relationships of HIF-1α with NF-κB and ß-catenin signaling in endometrial carcinomas (Em Cas). Long-term exposure of Ishikawa cells to cobalt chloride (CoCl2), which is known to mimic the effect of hypoxia, caused a decrease in the growth, along with increased HIF-1α protein but not mRNA expression. In contrast, short-term exposure resulted in a rapid and transient increase in HIF-1α mRNA expression along with stabilization of nuclear NF-κB/p65 (p65). Transfection of p65 increased HIF-1α expression through activation of the promoter, whereas overexpression of HIF-1α also activated NF-κB-dependent transcription, indicating the existence of a positive feedback loop. In addition, HIF-1α was indirectly associated with nuclear ß-catenin through interactions with p300, leading to slight enhancement of both HIF-1α- and ß-catenin-mediated transcriptional activity. In clinical samples, biphasic upregulation of HIF-1α expression was observed in normal endometrial glandular components during the menstrual cycle, with the labeling indices showing significantly higher values in the early secretory stage. Significantly higher values for phosphorylated p65 and nuclear ß-catenin were also observed in HIF-1α-positive than -negative lesions of Em Cas, in contrast to significantly lower Ki-67 status. These data therefore suggest that transcriptional associations with HIF-1α and NF-κB, as well as ß-catenin/p300 complexes, may contribute to modulation of changes in tumor cell kinetics in response to a hypoxic condition in Em Cas.

Relevance of frozen sections and serum markers in invasive squamous cell carcinoma arising from ovarian mature cystic teratoma: two case reports.

BACKGROUND: Ovarian mature cystic teratoma (MCT) is a common neoplasm in women. While malignant transformation of MCT is relatively rare, squamous cell carcinoma is the most frequent malignant neoplasm arising from MCT. Some tumor markers have been reported to be useful for prediction of MCT malignant transformation prior to operation. However, widely accepted use of these markers remains to be established. In the present study, we report the usefulness of frozen section assessment during operation, as well as preoperative measurement of tumor marker levels. CASE PRESENTATION: We present two cases of squamous cell carcinoma arising from ovarian MCT. The first case was a 45-year-old Asian woman referred to our hospital after her periodical company medical checkup, due to possible ovarian tumor. Image analysis suggested a dermoid cyst, and left salpingo-oophorectomy was performed. Because the cyst was histologically diagnosed as an invasive squamous cell carcinoma arising from an MCT, our patient underwent an additional preventative operation. The TNM classification and FIGO stage were T1aNXM0 and Ia, respectively. The second case was a 53 -year-old Asian woman who visited our hospital due to complaints of abdominal pain and urinary retention. Image analysis and laboratory data showing high serum levels of SCC antigen (normal range: < 1.5 ng/mL) and CA19-9 (normal range: < 37 U/mL), which strongly suggested malignant transformation of MCT. Frozen sections obtained during the operation were histologically analyzed to confirm malignancy, and our patient underwent an additional operation. The TNM classification and FIGO stage were T1aNXM0 and Ia, respectively. CONCLUSIONS: We report the usefulness of frozen section assessment during operation, as well as preoperative measurement of tumor marker levels.

Bifunctional roles of survivin-ΔEx3 and survivin-2B for susceptibility to apoptosis in endometrial carcinomas.

PURPOSE: Alternative splicing variants of survivin have different biological roles on cell kinetics. Here, we focused on the effects of different variants, including wild type (wt), survivin-ΔEx3, and survivin-2B, on apoptosis and cell proliferation in endometrial carcinomas (Em Cas). METHODS: Expression of survivin-wt, survivin-ΔEx3, and survivin-2B with reference to cell death and proliferation was investigated, using Em Ca cell lines and its clinical tissues. RESULTS: Ishikawa cells stably overexpressing either survivin-ΔEx3 (Surv-ΔEx3#34) or survivin-2B (Surv-2B#17) demonstrated considerably lower proliferative activity, along with up-regulation of p21waf1. After TNF-α treatment, Surv-ΔEx3#34 cells showed an increase in apoptotic cells, while the effects were relatively minor in Surv-2B#17 cells. In contrast, doxorubicin treatment resulted in increased apoptotic cells in Surv-2B#17 but not Surv-ΔEx3#34 cells, along with decreased expression of bcl-2 relative to bax. Control Ishikawa cells also showed relatively higher endogenous mRNA expression of survivin-ΔEx3 and survivin-2B during treatment of TNF-α and doxorubicin, respectively. In addition, exogenous overexpression of each survivin variant resulted in inhibition of other endogenous isoforms, indicating that the relative proportion may contribute to regulation of the splicing machinery. In clinical samples, level of survivin-ΔEx3 relative to either survivin-wt or survivin-2B was significantly higher in Em Cas than non-neoplastic lesions. Moreover, survivin-ΔEx3 and survivin-wt were positively correlated with apoptosis and cell proliferation, respectively, in Em Cas. CONCLUSIONS: These findings provided evidence that the balance among expression level of survivin variants may contribute to modulation of cell kinetics in Em Ca cells.

Frequent ß-catenin gene mutations in atypical polypoid adenomyoma of the uterus.

Atypical polypoid adenomyoma (APA) is an uncommon polypoid lesion of the uterus. To clarify the mechanism of its histogenesis, we examined the functional role of ß-catenin, with reference to expression of p21(waf1), cyclin D1, cyclin E, CD10, and α-smooth muscle actin (SMA), as well as cell proliferation, in 7 lesions. In the epithelial components, expression of nuclear ß-catenin, p21(waf1), and cyclin D1 was increased in a stepwise fashion from normal tissue through complex atypical hyperplasia and adenomyoma to APA lesions, particularly in squamous morular areas, whereas cell proliferation, as well as cyclin E expression, was significantly decreased in the latter. Similar findings were evident in the stromal lesions, with the exception of a case of nuclear ß-catenin. In addition, coexpression of CD10 and α-SMA markers was observed in the stromal components in 3 APA cases, in line with the results of normal secretory endometrial and adenomyoma samples, suggesting that cells progress to myofibromatous cells in response to differentiation-promoting events. Finally, ß-catenin gene (CTNNB1) mutations were detected in all APA cases, the single nucleotide substitutions being in the epithelial but not the stromal components. These findings suggest that activation of ß-catenin signaling, probably secondary to the gene abnormalities, plays an important role in the formation of the complex epithelial architecture in APAs, leading to inhibition of cell proliferation through overexpression of p21(waf1). In contrast, changes in the stromal cell phenotype may occur through a shift from CD10 to α-SMA immunopositivity, independent of CTNNB1 status.

Transcriptional regulation of the alpha-1 type II collagen gene by nuclear factor B/p65 and Sox9 in the chondrocytic phenotype of uterine carcinosarcomas.

Uterine carcinosarcomas (U-CSs) are considered monoclonal in origin, but little is known about the mechanisms for establishment of heterologous sarcomatous components. Here, we examine the functional roles of nuclear factor κB (NF-κB)/p65 and Sox9 in the transcriptional regulation of alpha-1 type II collagen (COL2A1), a hallmark of chondrogenesis, during morphologic change in the direction of the chondrocytic phenotype. In 32 cases of U-CS, both phosphorylated p65 and Sox9 expression were colocalized in Col2A1-positive sarcomatous components, particularly in cartilaginous elements, with strongly positive correlation (ρ = 0.72, P = .005). A positive association of Col2A1 expression between protein (immunohistochemistry) and messenger RNA (in situ hybridization) assays was evident in sarcomatous components, whereas 9 cases also showed distinct positive signals for the messenger RNA without protein expression in carcinomatous elements, probably through a posttranscriptional and/or posttranslational modulation mechanism. In the Ishikawa endometrial cancer line, overexpression of p65 could activate transcription of COL2A1 promoter-intron reporters through binding to specific NF-κB sites in the first intron, along with up-regulation of Sox9. Exogenous induction of Sox9 also caused an increase in transcription of COL2A1, in contrast to a repression of the p65-mediated COL2A1 transcription, suggesting the existence of a negative feedback loop. These data, therefore, suggest that NF-κB/p65 signaling, as well as Sox9, may contribute to changes in the morphology of U-CS cells toward the chondrocytic phenotype through modulation of COL2A1 transcription.