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Background: Tumor-to-tumor metastasis (TTM) is a rare but well-established phenomenon where histologically distinct tumors metastasize within each other. Here we report the first "known" case of follicular lymphoma that metastasized and extended to a mature ovarian teratoma., Case Presentation: A 59-year-old Japanese postmenopausal woman visited our hospital for a detailed examination of an ovarian tumor. Clinical imaging suggested it to be either teratoma-associated ovarian cancer with multiple lymph node metastases, or tumor-to-tumor metastasis from malignant lymphoma to ovarian teratoma. A bilateral adnexectomy and retroperitoneal lymph node biopsy were performed. Lined with squamous epithelium, the cyst constituted a mature ovarian teratoma, and the solid part showed diffuse proliferation of abnormal lymphoid cells. Immunohistochemically, the abnormal lymphoid cells were negative for CD5, MUM1, and CyclinD1, and positive for CD10, CD20, CD21, BCL2, and BCL6. Genetic analysis using G-banding and fluorescence in situ hybridization identified a translocation of t(14;18) (q32;q21), and we diagnosed tumor-to-tumor metastasis from nodal follicular lymphoma to mature ovarian teratoma. Twelve months after surgery, the patient showed no progression without adjuvant therapy., Conclusions: The present case suggests that molecular approaches are useful in the diagnosis of TTM in mature ovarian teratomas when morphologic and immunohistochemical findings alone are insufficient for diagnoses., (© 2023. The Author(s).)

Background: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis., Methods: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS)., Results: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01)., Conclusion: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors., (© 2020 S. Karger AG, Basel.)

Rationale: The malignant potential and the appropriate treatment of uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is controversial. Although these tumors generally have benign outcomes, several reports have described recurrences, metastases, and deaths associated with this disease., Patient Concerns: A 57-year-old Japanese woman (gravida 2, para 2) was referred to our hospital for the evaluation and treatment of uterine fibroids. Magnetic resonance imaging revealed a right ovarian mass and multiple fibroids in the uterine myometrium., Diagnoses: The patient was diagnosed with UTROSCT with sarcomatous features., Interventions: She initially underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by second-stage surgery comprising pelvic and para-aortic lymphadenectomy and subtotal omentectomy., Outcomes: No postoperative recurrence was observed in the patient in 36 months., Lessons: In this case, extended radical surgery prevented the development of recurrent disease in a patient with UTROSCT with sarcomatous features. These clinicopathological findings suggest that UTROSCT is associated with several risk factors, including older age, presence of necrosis, lymphovascular invasion, significant nuclear atypia, and significant mitotic activity. This lesion type should be considered malignant and treated with curative intent.

Sclerosing stromal tumours (SSTs) are rare benign tumours and are generally observed in individuals in their teens to 20 s. Many cases are suspected as malignant tumours pre-operatively, owing to their high vascularity on diagnostic imaging. Herein, we aimed to evaluate the expressions of various angiogenic factors in SSTs. The expressions of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and hepatocyte growth factor (HGF) were examined by immunohistochemical staining. Upon immunohistochemistry, overexpressions of VEGF, bFGF, and HGF in the ovarian stroma were observed in SSTs. In the normal ovary, the expressions were strong around the vessels and weak in the stroma of the ovary, while a Sertoli-Leydig cell tumour showed weak staining with VEGF, locally strong staining with bFGF and negative staining with HGF. This is the first report about angiogenic factors such as bFGF, and HGF in SST. Impact statement What is already known on this subject? Sclerosing stromal tumour (SST) is a rare benign tumour with high vascularity. The high vascularity of SSTs are reported to be related to the overexpression of vascular endothelial growth factor (VEGF). But there is no study on the expressions of other angiogenic factors in SST. What do the results this study add? In the immunohistochemical analysis, VEGF, bFGF and HGF were found to be widely stained in SSTs. This results suggest the possibility that the high vascularity seen on diagnostic imaging, and the many small vessels observed microscopically may be related to the expressions of VEGF, bFGF and HGF in SSTs. What are the implications of these findings for clinical practice and/or further research? Our results suggest the possibility that the combined expression pattern of VEGF, bFGF, and HGF may be used as marker of SSTs.

Ruptured pseudoaneurysm following pelvic surgery is a rare and fatal complication. Because of its rarity, existing evidence is limited to a small case series. A 60-year-old woman underwent staging laparotomy, including pelvic and para-aortic lymphadenectomy, for ovarian cancer. On the 11th day, the patient developed a sudden lumbar pain and loss of consciousness, which resulted in a state of shock. She was diagnosed as having a pelvic abscess and ruptured external iliac artery pseudoaneurysm. We performed ligation of the external iliac artery to restrain hemorrhage and femoro-femoral artery bypass to prevent infection, which saved the patient's life. Our study had two findings. First, this is the first reported case of ruptured external iliac artery pseudoaneurysm following surgery for ovarian cancer. Second, treatment of ruptured pseudoaneurysm requires rapid hemostasis, prevention of infection, and revascularization., (© 2017 Japan Society of Obstetrics and Gynecology.)

Background: This study aimed to evaluate the current status of secondary debulking surgery (SDS) and tertiary debulking surgery (TDS; performed for recurrence after SDS) and to assess the overall survival after recurrence of Müllerian epithelial cancer in Japan. We also evaluated the data of patients who underwent a fourth debulking surgery (i.e., quaternary debulking surgery (QDS))., Methods: We conducted a retrospective study of 164 patients with recurrent Müllerian epithelial cancers (i.e., ovarian, tubal, and peritoneal cancers). The SDS was performed between January 2000 and September 2014 in 20 Japanese hospitals. Clinicopathological data were collected and analyzed., Results: Of the 164 patients, 66 patients did not have a recurrence or died after SDS. Ninety-eight patients had a recurrence after SDS. Forty-three of the 98 patients underwent TDS; 55 of the 98 patients did not undergo TDS and were classified into the non-TDS group. The overall survival (OS) after SDS was significantly better in the TDS group than in the non-TDS group. The median OS after SDS was 123 and 42 months in the TDS group and non-TDS group, respectively. Of the 43 patients who received TDS, 11 patients were further treated with QDS. The median OS after SDS was 123 months for patients who underwent QDS., Conclusions: This multicenter study on the prognosis of post-SDS is apparently the first report on QDS in Japan. Patients undergoing TDS have a good prognosis, compared to patients in the non-TDS group. Novel drugs are being evaluated; however, debulking surgery remains a necessary treatment for recurrence.

Grade 3 immature teratoma of the ovary is rare and has a poor prognosis due to early recurrence. This report describes a case of grade 3 immature teratoma of the ovary that recurred 16 years after the last treatment. The patient underwent abdominal simple total hysterectomy, bilateral salpingo-oophorectomy, pelvic-para-aortic lymphadenectomy, and adjuvant chemotherapy under the diagnosis of grade 3 immature teratoma of the ovary when she was 15 years old, and complete remission was achieved. Sixteen years after the initial treatment, the tumor relapsed in her liver and pleura. She was treated by 10 courses of tri-weekly paclitaxel and carboplatin, and was alive with stable disease for 12 months after the disease relapse. After 1 year, the tumor progressed, and she died 16 months after the relapse. This is the first report of grade 3 immature teratoma of the ovary that relapsed more than 5 years after the prior treatment., (© 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.)

Aim: Ovarian cancer is the second most common gynecological malignancy, yet it has the highest case-fatality ratio of all gynecologic malignancies. Surgery followed by combination platinum-taxane chemotherapy is the standard approach to the management of primary epithelial ovarian cancer. However, standard treatment of patients with recurrent ovarian cancer remains poorly defined. Secondary cytoreductive surgery (SDS) at the time of relapse has been proposed as a means of improving the prognosis of recurrent ovarian cancer patients with a treatment-free interval of at least 6 months., Methods: In the present study, we retrospectively collected 16 patients with recurrent epithelial ovarian cancer who might benefit most from SDS and evaluated the impact of SDS on the outcomes for this highly select patient group., Results: We found that SDS led to excellent outcomes, with a 73.1% 8-year overall survival rate after initial treatment, a 67.9% 5-year overall survival rate after prior SDS, and a 31.3% 5-year progression-free survival rate after prior SDS. Although the findings were not significant, these results suggest that repeated SDS might improve outcomes for this patient group., Conclusion: The present study may provide a platform for discussion of the impact of aggressive or repeated SDS on the survival of patients with recurrent epithelial ovarian cancer and favorable prognostic factors. Further multi-institutional studies with larger number of patients are mandatory to confirm the present findings., (© 2013 The Authors. Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology.)

Purpose: Mucinous epithelial ovarian tumors generally have estrogenic stroma, although the frequency of endometrioid adenocarcinoma with functioning stroma is very low. And while synchronous development of carcinomas in the endometrium and ovaries is a fairly common phenomenon, the distinction of a single clonal tumor with metastasis from two independent primary tumors may present a diagnostic challenge. We present a rare case of a 31-year-old woman with endometrioid adenocarcinoma of the ovary with functioning stroma and endometrial endometrioid adenocarcinoma who showed symptoms of virilization. Her preoperative levels of serum testosterone and estradiol were as high as 553 ng/dL and 177 pg/mL, respectively, and her serum gonadotropin levels were suppressed. After surgery, the serum levels of testosterone and estradiol decreased and that of follicle-stimulating hormone increased., Methods: To develop a mean of differentiating a single tumor with metastasis from synchronous primary ovarian and endometrial cancers, we performed a microsatellite analysis. Twenty-five dinucleotide microsatellite markers were selected, and microsatellite analysis was performed by a high-resolution method using fluorescence-labeled polymerase chain reaction and laser scanning., Results: In this case, both ovarian carcinoma and endometrial carcinoma demonstrated loss of heterozygosity (LOH). However, the LOH findings of the ovarian tumor and endometrial tumor were different., Conclusions: Loss of heterozygosity analysis may be helpful to differentiate synchronous primary ovarian and endometrial cancers from a single tumor with metastasis.

Purpose: The aims of this study were to compare the usefulness and reliability of integrated whole-body positron emission tomography/computed tomography (PET/CT) using (18)F-fluorodeoxyglucose (FDG) with those of contrast-enhanced multidetector CT during regular follow-up in patients after initial treatment of ovarian cancer, to assess the impact of FDG-PET/CT on the confirmation of recurrence, restaging, and clinical management of patients, and to determine the incremental information provided by PET/CT., Methods: A retrospective review was performed on 19 ovarian cancer patients who underwent a total of 30 FDG-PET/CT and contrast-enhanced multidetector CT scans. The following information was obtained: the clinical information of the patients; the results of FDG-PET/CT and contrast-enhanced multidetector CT, particularly with regard to the impact on the diagnosis of recurrence; information on the localization and number of diseases; and the impact on subsequent clinical management., Results: Both FDG-PET/CT and contrast-enhanced multidetector CT had very high sensitivity and specificity for the detection of recurrent ovarian cancer. Contrast-enhanced multidetector CT was considered the more accurate imaging modality for detecting recurrence, whereas FDG-PET/CT was proven more effective for detecting large numbers of small lesions. When comparing the impact on the choice of a management plan, both FDG-PET/CT and contrast-enhanced multidetector CT were found to be significantly effective at predicting the locations of recurrence., Conclusions: Both integrated FDG-PET/CT and contrast-enhanced multidetector CT are sensitive surveillance modalities for the detection of recurrent ovarian cancer; the use of both modalities aids decisions on treatment plans and may ultimately have a favorable impact on prognosis. However, contrast-enhanced multidetector CT is recommended for the regular follow-up for ovarian cancer patients after initial treatment.

The potential anticancer agent 1-(2-chlorophenyl-N-methylpropyl)-3-isoquinolinecarboxamide (PK11195), a translocator protein ligand, facilitates the induction of cell death by a variety of cytotoxic and chemotherapeutic agents in various human tumor cell lines. The purpose of this study was to elucidate the effect of PK11195 on three endometrial cancer cell lines, two ovarian cancer cell lines and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of PK11195 alone or in combination with chemotherapeutic drugs (cisplatin, paclitaxel), and its effect on cell growth, the cell cycle, apoptosis and related measurements was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of PK11195, although normal endometrial epithelial cells were viable after treatment with the same doses of PK11195 that induced growth inhibition in endometrial and ovarian cancer cells. Synergistic anti-neoplastic effects were obtained by a combination of PK11195 with cytostatic drugs. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to apoptosis. These results suggest that PK11195 alone or in combination with chemotherapeutic drugs might be a new therapeutic option for the treatment of endometrial and ovarian cancers.

Objectives: A membrane-targeted, lipophilic ether lipid of synthetic phospholipid analog, erucylphosphocholine (ErPC) induces apoptosis in some lines of human tumor cells. We investigated the effect of ErPC on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells., Methods: Endometrial and ovarian cancer cells were treated with various concentrations of ErPC, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated., Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of ErPC, although normal endometrial epithelial cells were viable after treatment with the same doses of ErPC that induced growth inhibition in endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to ErPC decreased the proportion of cells in the S-phase and increased the proportion in the G2/M phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis., Conclusions: These results suggest that the anticancer activity of ErPC may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that ErPC may become a useful adjuvant therapy for endometrial and ovarian cancers.

Bufalin is a traditional Chinese medicine and it induces apoptosis in certain human tumor cell lines. We investigated the effect of bufalin on three endometrial cancer cell lines, two ovarian cancer cell lines, and on normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of bufalin, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of bufalin, although normal endometrial epithelial cells were viable after treatment with the same doses of bufalin that induced growth inhibition in endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to bufalin decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with the altered expression of genes related to cell cycle and apoptosis. These results suggest that bufalin may become a useful adjuvant therapy for endometrial and ovarian cancers with minimal side effects.

Objectives: Beta-hydroxyisovalerylshikonin (beta-HIVS), a compound isolated from the traditional oriental medicinal herb Lithospermum radix, is an ATP non-competitive inhibitor of protein-tyrosine kinases, such as v-Src and EGFR, and it induces apoptosis in some lines of human tumor cells. We investigated the effect of beta-HIVS on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells., Methods: Endometrial and ovarian cancer cells were treated with various concentrations of beta-HIVS, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated., Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of beta-HIVS, although normal endometrial epithelial cells were viable after treatment with the same doses of beta-HIVS that induced growth inhibition in endometrial and ovarian cancer cells. Cell-cycle analysis indicated that their exposure to beta-HIVS decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis., Conclusions: These results suggest that the anticancer activity of beta-HIVS may occur with higher sensitivity of cancer cells compared with normal healthy cells, when using low concentration, rising hopes that beta-HIVS may become a useful adjuvant therapy for endometrial and ovarian cancers.

Adult granulosa cell tumors (GCTs) are the most common type of ovarian sex cord tumors. Menstrual irregularity, menorrhagia, or even secondary amenorrhea is frequently observed in premenopausal women bearing GCTs with hormonal activity. We report herein a case of GCT in a patient presenting with secondary amenorrhea and serum luteinizing hormone elevation. A 28-year-old primigravid Japanese woman was admitted complaining of secondary amenorrhea of 2 years' duration. Pelvic examination, transvaginal ultrasonography, and magnetic resonance imaging demonstrated a left ovarian tumor 4 cm in diameter. Serum hormone assays revealed a follicle-stimulating hormone level of 4.8 mIU/ml, luteinizing hormone (LH) of 35.8 mIU/ml, estradiol of 24 pg/ml, progesterone of 1.6 ng/ml, and testosterone of 40 ng/dl. A left salpingo-oophorectomy was performed. The tumor was diagnosed as an adult-type GCT stage IIb (FIGO [International Federation of Obstetricians and Gynecologists], 1988). Spontaneous menstruation occurred soon after the surgery. Serum levels of LH also decreased to normal levels and showed cyclic changes during the menstrual cycle. Subsequently, the patient conceived and delivered a healthy female baby. The tumor recurred in the pelvis 50 months after the initial conservative surgery, with elevated serum LH levels of 36.0 mIU/ml and amenorrhea. The patient was treated by hysterectomy, right salpingo-oophorectomy, omentectomy, paraaortic and pelvic lymphadenectomy, and low anterior resection of the recto-sigmoid colon. Her hormone levels progressed to the postmenopausal state after this surgery. Although LH elevation in patients with GCT is rare and its mechanism is unknown, monitoring of serum LH may provide an additional tumor marker after conservative surgery in such patients.

Histone deacetylase inhibitors (HDACIs) can inhibit proliferation, induce cell cycle arrest and stimulate apoptosis of cancer cells. Our purpose was to investigate the antiproliferative effects of a novel HDACI, apicidin, on the Ishikawa endometrial cancer cell line, the SK-OV-3 ovarian cancer cell line and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of apicidin, and the effects on cell growth, cell cycle, apoptosis and related measurements were investigated. MTT assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of apicidin, although normal endometrial epithelial cells were viable after the treatment with the same doses of apicidin that induced the growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to apicidin decreased the proportion of cells in S-phase and increased the proportion in G0/G1 and/or G2/M phases of the cell cycle. Induction of apoptosis was confirmed by Annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with the altered expression of p21WAF1, p27KIP1, p16, cyclin A, and E-cadherin. Furthermore, apicidin treatment of these cell lines increased acetylation of H3 and H4 histone tails. These results suggest that apicidin exhibits the antiproliferative effects through selective induction of genes related to cell growth, malignant phenotype, and apoptosis. The findings raise the possibility that apicidin may prove particularly effective in the treatment of endometrial and ovarian cancers.

Objective: Histone deacetylase inhibitors (HDACIs) can inhibit cell proliferation, induce cell cycle arrest, and stimulate apoptosis of cancer cells., Methods: We investigated the effects of a novel synthesized HDACI, M344, on Ishikawa endometrial cancer cell line, SK-OV-3 ovarian cancer cell line, and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of M344, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated., Results: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of M344, although normal endometrial epithelial cells were viable after the treatment with the same doses of M344 that induced growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to M344 decreased the proportion of cells in the S-phase and increased the proportion in the G0/G1 phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, M344 treatment of these cell lines increased acetylation of H3 and H4 histone tails., Conclusions: These results raise the possibility that M344 may prove particularly effective in the treatment of endometrial cancers and ovarian cancers.

The leiomyoma of the ovary is a very rare form of ovarian neoplasia, while its uterine localization is very common. A 72-year-old woman was admitted for pelvic examination. Transvaginal ultrasonography and magnetic resonance imaging (MRI) revealed a pelvic mass (8 cm x 7 cm). At laparotomy, total hysterectomy and bilateral salpingo-oophorectomy were performed and histologic examination revealed a leiomyoma arising primarily in the ovary.

Histone deacetylase inhibitors (HDACIs) can inhibit cell proliferation, induce cell cycle arrest, and stimulate the apoptosis of cancer cells. We investigated the effects of a novel HDACI, Scriptaid, on the Ishikawa endometrial cancer cell line, SK-OV-3 ovarian cancer cell line, and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of Scriptaid, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of Scriptaid, although normal endometrial epithelial cells were viable after treatment with the same doses of Scriptaid that induced the growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to Scriptaid decreased the proportion of cells in the S phase and increased the proportion in the G0/G1 and/or G2/M phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with the altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, Scriptaid treatment of these cell lines increased acetylation of H3 and H4 histone tails. These results raise the possibility that Scriptaid may prove particularly effective in the treatment of endometrial and ovarian cancers.

Objectives: We investigated the effect of a novel synthesized histone deacetylase inhibitor (HDACI), CBHA, on three endometrial cancer cell lines, two ovarian cancer cell lines, and normal human endometrial epithelial cells., Methods: Endometrial and ovarian cancer cells were treated with various concentrations of CBHA, and its effect on cell growth, cell cycle, apoptosis, and related measurements was investigated., Results: The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that all endometrial and ovarian cancer cell lines were sensitive to the growth-inhibitory effect of CBHA, although normal endometrial epithelial cells were viable after treatment with the same doses of CBHA that induced growth inhibition in endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to CBHA decreased the proportion of cells in the S-phase and increased the proportion in the G(0)/G(1) phases of the cell cycle. Induction of apoptosis was confirmed by annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with altered expression of genes related to cell growth, malignant phenotype, and apoptosis. Furthermore, CBHA treatment of these cell lines increased acetylation of H3 and H4 histone tails., Conclusions: These results raise the possibility that CBHA may prove particularly effective in the treatment of endometrial and ovarian cancers., (Copyright 2006 S. Karger AG, Basel.)

Elf-1 is a member of the Ets transcription factor family that regulates the genes involved in cellular growth and differentiation. Enhanced expression of Elf-1 has been reported in prostate cancer, breast cancer, and osteosarcoma. The aim of this study was to elucidate the involvement of Elf-1 in ovarian carcinogenesis. We analyzed serial frozen tissue sections from 26 patients with epithelial ovarian carcinoma and 10 patients with benign cystadenoma of ovary for Elf-1 protein expression, using fluorescent immunohistochemistry. We analyzed the relationship between the percentages of Elf-1-stained cells and patient characteristics, including histological classification, clinical stage, histological grade, clinical outcome, and survival rate. Elf-1 was weakly detected in some benign cystadenomas (0-5.5%). There was, however, abundant Elf-1 immunoreactivity in the nucleus of the ovarian carcinoma cells along with a little cytoplasmic staining. Scoring on the basis of the percentage of nuclear-positive cells indicated that nuclear Elf-1 expression was significantly associated with PCNA-labeling index (p=0.04), clinical stage (p<0.01), histological grade (p<0.01), and clinical outcome (p=0.02). However, there was no relationship between Elf-1 expression and histological classification. Survival data were available for all patients and demonstrated that Elf-1 expression was significantly associated with poor prognosis (p<0.01). Our results demonstrate that Elf-1 expression in ovarian carcinoma correlates with the malignant potential of this tumor.

Recurrent ovarian cancer after front-line chemotherapy is incurable. In most institutions, chemotherapy is continued as salvage therapy after primary chemotherapy failure and despite the fact that long-term survival and complete responses are infrequent. Radiation therapy for patients with recurrent ovarian cancer has often been done with palliative intent. A patient with ovarian clear cell adenocarcinoma received irradiation with palliative intent to the whole pelvis after chemotherapy (paclitaxel, carboplatin, and irinotecan) produced no effect. Although she developed a rectovaginal fistula due to cancer invasion during radiation therapy. One year and half after the therapy, she is still alive with no evidence of disease. In an effort to maximize salvage potential and quality of life while minimizing toxicity, selected patients with ovarian cancer should be treated with radiation therapy directed to residual or recurrent sites.

Ca(2+)/calmodulin-dependent protein kinase IV (CaMKIV) is a multifunctional protein kinase expressed abundantly in the central nervous system. Because changes in intracellular Ca(2+) concentrations affect progression through the mitotic cell cycle, enhanced expression of CaMKIV has been reported in small cell lung carcinoma and hepatocellular carcinoma. To elucidate the involvement of CaMKIV in epithelial ovarian carcinogenesis, we analyzed serial frozen sections for CaMKIV protein expression in 26 patients with ovarian epithelial carcinoma and ten patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of CaMKIV-stained cells and the patient's characteristics, including histological classification, clinical stage, histological grade, and clinical outcome. In the benign ovarian cystadenoma, CaMKIV was detected in none of the cases examined. Most of the CaMKIV proteins were found in the nucleus of epithelial ovarian cancer tissue. CaMKIV expression was significantly associated with clinical stage (P<0.01), histological grade (P<0.01), and clinical outcome (P<0.01). Survival data were available for all patients, and univariate Cox regression analysis showed that CaMKIV expression was significantly associated with poor prognosis (P<0.05). Our results demonstrate that CaMKIV expression in epithelial ovarian cancer correlates with the malignant potential of this tumor.

Survivin is a new member of the inhibitor of apoptosis family of anti-apoptotic proteins. It has been reported that survivin is expressed during fetal development and in cancer tissues. Because suppression of apoptosis is important for carcinogenesis and tumor growth, we investigated the expression of survivin in human endometrial carcinomas. We analyzed serial frozen sections for survivin protein expression in 26 patients with ovarian epithelial carcinoma and 10 patients with benign cystadenoma of the ovary by fluorescent immunohistochemistry. We analyzed the relationship between the percentages of survivin-stained cells and the characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. Survivin was weakly detected in some benign ovarian cystadenomas (0-12.1%). There was, however, abundant survivin immunoreactivity in the nucleus and/or cytoplasm of the epithelial ovarian carcinoma cells. Scoring on the basis of the percentage of positive cells indicated that survivin expression was significantly associated with PCNA-labeling index, clinical stage, histological grade, clinical outcome, and survival rate (p<0.01, respectively). We conclude that the survivin protein is a defining diagnostic marker for epithelial ovarian carcinomas that may also yield prognostic information.

c-Ets1 controls the expression of some genes involved in extracellular matrix remodeling. To elucidate the involvement of c-Ets1 in epithelial ovarian carcinogenesis, we investigated the role of the proto-oncogene c-ets1 in the regulation of physiological processes such as cell proliferation, differentiation, and tumor invasion. Using fluorescent immunohistochemistry, we analyzed serial frozen sections for c-Ets1 protein expression in 26 patients with ovarian epithelial carcinoma, 10 patients with benign cystadenoma of the ovary, and 10 premenopausal patients with normal ovaries. We analyzed the relationship between the percentage of c-Ets1 stained cells in a patient and characteristics of the patient including histological classification, clinical stage, histological grade, and clinical outcome. c-Ets1 was not detected in any cases of benign ovarian cystadenoma. Most of the c-Ets1 proteins were found in the cytoplasm and some in the nucleus of epithelial ovarian cancer tissues. Moreover, c-Ets1 was strongly expressed in the head portion of papillary cancer tissues that had invaded the stroma. c-Ets1 expression was significantly associated with clinical stage (p<0.01), histological grade (p<0.01), and clinical outcome (p<0.01). Survival data were available for all patients and univariate Cox regression analysis showed that c-Ets1 expression was significantly associated with a poor prognosis (p<0.05). Our results demonstrate that c-Ets1 expression in epithelial ovarian cancer correlates to the malignant potential of the tumor.

Polo-like kinase (PLK), a cell cycle-regulated, cyclin-independent serine/threonine protein kinase, has been shown in recent reports to play a critical role during tumorigenesis. To investigate whether PLK plays a general role as a tumor marker of ovarian cancers, we examined the expression of PLK protein in ovarian cancers, and analyzed the relationship between PLK protein expression and histological grade. Immunohistochemically, the majority of PLK was found in the cytoplasm (around the nucleus), and a portion was found in the nucleus of ovarian cancer glands and also in the fluid secreted from these glands. PLK was expressed at the basement membrane of cancer glands and partly expressed in the head portion of papillary cancer tissues. A significant correlation was found between percentages of PLK-positive cells and histological grade of ovarian cancer (P<0.001). However, the expression of proliferating cell nuclear antigen, Ki-67, and cyclin B1 was independent of PLK expression. Taken together, these findings suggest that PLK expression may reflect the degree of malignancy rather than the degree of proliferation in ovarian cancer. Thus, in addition to being of diagnostic value, PLK activity in ovarian tumors may be modulated by chemotherapeutic agents or gene therapy to therapeutic effect.

A case of mucin-producing adenocarcinoma arising from a mature cystic teratoma of the right ovary is reported in a 67-year-old multiparous Japanese woman. The patient underwent total hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and adjuvant chemotherapy containing cisplatin, Adriamycin, and cyclophosphamide with the diagnosis of ovarian cancer, probable stage Ic. Treatment was successful even though the tumor extended through the cyst wall.

Objective: To investigate whether intraoperative rupture of epithelial ovarian cancer. influences the prognosis., Methods: Between 1984 and 1994, 46 patients with stage Ia and Ic epithelial ovarian cancer were treated at Oita Medical University Hospital. Of 46 patients, 20 had stage Ia tumors, 16 stage Ic secondary to capsular invasion-serosal disease or positive ascites or washings (stage Ic-ascites), and 10 stage Ic secondary to intraoperative rupture (Ic-rupture). Survival analysis was performed to compare the three groups of patients., Results: The ages (mean +/- SD) of patients with stage Ia, Ic-ascites and Ic-rupture at the first diagnosis were 40.1 +/- 17.0, 47.6 +/- 13.4 and 52.8 +/- 15.7, respectively. The age of the stage Ia group tended to be lower than those of the Ic-ascites and Ic-rupture groups. At operation, ovarian tumors of all patients in the Ic-rupture group were firmly adhered to surrounding organs, had markedly thin weak cyst walls and were easily ruptured during operation. Fourteen of 20 patients in the Ia group (70%), 5 of 16 patients in the Ic-ascites group (31.3%) and 3 of 10 patients in the Ic-rupture group (30%) showed signs of mucinous cystadenocarcinoma. The incidence of mucinous cystadenocarcinoma in Ia group was significantly lower than in the Ic-ascites (p < 0.025, chi 2-test) and Ic-rupture (p < 0.05, chi 2-test) groups. The Kaplan-Meier survival plot for stage Ia, Ic-ascites and Ic-rupture patients revealed a probability of 5-year survival of 100%, 87.5% and 63.5%, respectively. The probability of 5-year survival in the Ic-rupture group tended to be lower than that in other groups., Conclusions: The results of our study suggest that intraoperative rupture of a malignant ovarian cystic tumor may worsen the prognosis of patients with the FIGO stage I epithelial ovarian cancer.

A 10-year retrospective review of epithelial carcinoma of the ovary was performed about 95 patients which were diagnosed and treated at the Oita Medical University Hospital. The patients' ages at the first diagnosis ranged from 15 to 85 years with a mean of 51.6 years. Twenty-two of 95 patients (23.2%) were below the age of 40. Most patients analysed in this study complained of lower abdominal pain, lower abdominal mass, and/or lower abdominal fullness. Sixteen of 22 patients under the age of 40 (72.7%) and 27 of 73 patients over the age of 40 (37.0%) were diagnosed as having mucinous cystadenocarcinoma. The incidence of mucinous cystadenocarcinoma below the age of 40 was significantly higher than that over the age of 40 (p < 0.005, chi 2-test). Eleven patients below the age of 40 had FIGO stage Ia grade 1 disease and 2 of these patients were pregnant. The incidence of stage Ia disease under the age of 40 was significantly higher than that over the age of 40 (p < 0.005, chi 2-test). Both pregnant patients and 5 other patients with stage Ia disease were treated with only unilateral salpingo-oophorectomy. All patient with stage Ia disease had no evidence of recurrence within 5 years. This suggests that conservative surgery may be considered as the treatment for the FIGO stage Ia grade 1 ovarian cancer.

The distribution of argyrophil cells in epithelial ovarian tumors was studied in 127 cases. The results showed that not only mucinous tumors and endometrioid tumors contained argyrophil cells, but also some serous tumors expressed argyrophilia. 31% of serous tumors including 40% of serous adenocarcinomas contained variable numbers of argyrophil cells. Argyrophilia has been demonstrated in mucinous tumors, endometrioid tumors and Brenner tumors before. However, this is the first time the presence of argyrophilia in serous tumors has been noticed. Moreover, the argyrophil cells in 5 serous carcinomas showed reactivity with Neuroendocrine (chromogranin A) antibody but not with serotonin. The expression pattern of argyrophilia in the serous tumors was different from that of the mucinous tumors; in the former, argyrophil granules appeared in apical portions or throughout the cytoplasm of single or clustered cells. In addition, the argyrophilia in some serous tumors and endometrioid tumors decreased after diastase digestion. Ultrastructurally, no typical neurosecretory granule was found in the argyrophilic serous tumors. The findings in this study suggest that argyrophilia could be quite frequently found in ovarian epithelial tumors and in itself is not a very specific differential characteristic of carcinoid tumors. The argyrophilia found in a variety of epithelial ovarian tumors might lend additional support to the histogenesis and close relationship between the common epithelial tumors of the ovary.

The distribution of S-100 protein in 135 ovarian tumors, of which 127 were epithelial, was investigated using the immunoperoxidase method. S-100 protein has been demonstrated previously in tumors of various origins. The present study further revealed its characteristic distribution in common epithelial tumors of the ovary. S-100 protein was present in 69% of serous tumors (benign, 50%; borderline, 100%; malignant, 71%), as well as in the serous elements of serous & mucinous mixed tumors (30%). S-100 protein was also demonstrated in 25% of clear cell carcinomas and 29% of endometrioid carcinomas. Interestingly, none of the mucinous tumors were positive for S-100 protein. In addition, the expression of S-100 protein by epithelial ovarian tumors was compared with that of CA 125 and carcinoembryonic antigen (CEA). The distribution of S-100 protein was similar to that of CA 125, since both antigens were frequently present in serous tumors, although their expression patterns were different. On the other hand, S-100 protein-positive cases were almost negative for CEA or vice versa. Our observations indicate that demonstration of S-100 protein in common epithelial tumors of the ovary and comparison of S-100 protein distribution with that of CA 125 and CEA may further clarify the characteristics of common epithelial tumors of the ovary.