Benign Endometriotic Cysts Research Articles

YAP1 Suppression by ZDHHC7 Is Associated with Ferroptosis Resistance and Poor Prognosis in Ovarian Clear Cell Carcinoma.

Ovarian clear cell carcinoma (OCCC), which has unique clinical characteristics, arises from benign endometriotic cysts, forming an oxidative stress environment because of excess iron accumulation, and exhibits poor prognosis, particularly in advanced stages owing to resistance to conventional therapeutics. Ferroptosis is an iron-dependent form of programmed cell death induced by lipid peroxidation and controlled by Hippo signaling. We hypothesized that overcoming ferroptosis resistance is an attractive strategy because OCCC acquires oxidative stress resistance during its development and exhibits chemoresistant features indicative of ferroptosis resistance. This study aimed to determine whether OCCC is resistant to ferroptosis and clarify the mechanism underlying resistance. Unlike ovarian high-grade serous carcinoma cells, OCCC cells were exposed to oxidative stress. However, OCCC cells remained unaffected by lipid peroxidation. Cell viability assays revealed that OCCC cells exhibited resistance to the ferroptosis inducer erastin. Moreover, Samroc analysis showed that the Hippo signaling pathway was enriched in OCCC cell lines and clinical samples. Furthermore, patients with low expression of nuclear yes-associated protein 1 (YAP1) exhibited a significantly poor prognosis of OCCC. Moreover, YAP1 activation enhanced ferroptosis in OCCC cell lines. Furthermore, suppression of zinc finger DHHC-type palmitoyltransferase 7 (ZDHHC7) enhanced ferroptosis by activating YAP1 in OCCC cell lines. Mouse xenograft models demonstrated that ZDHHC7 inhibition suppressed tumor growth via YAP1 activation by erastin treatment. In conclusion, YAP1 activation regulated by ZDHHC7 enhanced ferroptosis in OCCC. Thus, overcoming ferroptosis resistance is a potential therapeutic strategy for OCCC.

Tissue factor pathway inhibitor II as a specific biomarker for pre-operative prediction of clear-cell carcinoma of the ovary.

e18077 Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinomas (CCC) from borderline ovarian tumors (BD) and non-CCC epithelial ovarian cancers (EOC). We examined the prediction performances of TFPI2, including high specificity, for preoperative diagnosis of CCC in multi-center settings. Methods: We collected serum samples obtained preoperatively from patients with ovarian masses who needed surgical treatment to confirm pathological diagnoses in five hospitals in Japan. The diagnostic powers of serum levels of TFPI2 (cutoff value 270 pg/mL) and CA125 (cutoff value 35 U/mL) to discriminate CCC from BD, non-CCC-EOC, and benign lesions were compared. Results: A total of 351 patients (77 ovarian benign lesions, 65 BD and 209 EOC including 69 CCC) were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean±SD, 508.2±812.0 pg/mL) than in patients with benign lesions (154.7±46.5), BD (181±95.5) and non-CCC EOC (265.4±289.1). TFPI2 had a high diagnostic specificity to CCC (sensitivity and specificity: 43.5% and 79.5%, respectively). The sensitivity of TFPI2 was improved to 71.1% when combined with CA125, and it was increased in Stage II–IV CCC (66.7%) compared with Stage I CCC (33.3%). In patients with benign endometriotic cysts (BEM), no patient was positive for TFPI2 but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating Stage II–IV CCC from BD and non-CCC EOC patients (AUC 0.815 for TFPI2 versus 0.505 for CA125) or from BEM (AUC 0.957 for TFPI2 versus 0.748 for CA125). Conclusions: High specificity of TFPI2 for the preoperative detection of CCC was re-verified with the defined cutoff level of TFPI2 in practice. TFPI2 and CA125 may have a substantial contribution to the precise prediction of intractable CCC. [Table: see text]

Comparison of endometriotic cysts and ovarian cancer in association with endometriotic cysts

ObjectiveThe aim of this study was to clarify the clinical, laboratory, and imaging findings of ovarian cancer in association with endometriotic cysts by detailed comparison of the findings of benign and malignant tumors. Methods and materialsThis was a retrospective study of 138 women who had an operation for ovarian tumors at the Department of Obstetrics and Gynecology of Kochi Health Sciences Center between September 1, 2011, and July 30, 2015. The ovarian tumors were divided into two groups: the benign group (endometriotic cysts) and the malignant group (ovarian cancer in association with endometriotic cysts). ResultsOf the 138 patients, 28 had malignant disease, and 110 had benign endometriotic cysts. Patients in the malignant group were significantly older than patients in the benign group. The mean maximum tumor diameter was also significantly larger for the malignant tumors. Unilocular-solid and multilocular-solid type tumors were present in 25.0% and 75.0% of malignant tumors, and in 9.1% and 19.1% of benign tumors, respectively. The mean maximum solid component diameter and height were significantly larger in the malignant tumors than in the benign tumors. The solid components were present on the abdominal side of the cyst wall in 12.5% of benign tumors and in 51.9% of malignant tumors. ConclusionIn elderly patients, the presence of large solid components in large endometriotic cysts, especially the abdominal side of the cyst wall, might suggest malignancy. Micro abstractThe aim of this study was to clarify the findings of ovarian cancer in association with endometriotic cysts by detailed comparison of the findings of benign and malignant tumors. The presence of solid components in large endometriotic cysts, especially the abdominal side of the cyst wall, might suggest malignancy.

FDG PET/CT Pitfalls in Gynecologic and Genitourinary Oncologic Imaging.

The role of whole-body positron emission tomography (PET)/computed tomography (CT) with fluorodeoxyglucose ( FDG fluorodeoxyglucose ) is now established in the assessment of many gynecologic and genitourinary malignant tumors. FDG fluorodeoxyglucose PET/CT has been widely adopted for staging assessments in patients with suspected advanced disease, in cases of suspected disease recurrence, and for determining prognosis in a number of malignancies. A number of pitfalls are commonly encountered when reviewing FDG fluorodeoxyglucose PET/CT scans in gynecologic and genitourinary cases; these pitfalls can be classified into those that yield potential false-positive or false-negative results. Potential false positives include physiologic uptake of FDG fluorodeoxyglucose by the endometrium and ovaries in premenopausal patients, physiologic renal excretion of FDG fluorodeoxyglucose into the ureters and the urinary bladder, and increased FDG fluorodeoxyglucose activity in benign conditions such as uterine fibroids, pelvic inflammatory disease, and benign endometriotic cysts. Potential false negatives include low-level FDG fluorodeoxyglucose uptake by necrotic, mucinous, cystic, or low-grade tumors and the masking of serosal and peritoneal disease by adjacent physiologic bowel or bladder activity. In addition, there are inherent technical limitations-such as motion artifact (from respiratory motion and bowel peristalsis) and the limited spatial resolution of PET-that may limit the assessment of small-volume malignant disease. Knowledge of the key imaging features of physiologic and nonphysiologic FDG fluorodeoxyglucose uptake, in addition to understanding the principles of adequate patient preparation and PET scanning protocols, is important for accurate interpretation of gynecologic and genitourinary oncologic FDG fluorodeoxyglucose PET/CT studies. ©RSNA, 2017.

Cyst fluid hemoglobin species in endometriosis and its malignant transformation: The role of metallobiology.

The aim of the present study was to assess the relative concentrations of hemoglobin (Hb) species in endometriosis as a possible indicator of malignancy. Electronic absorption spectroscopy was employed to quantify the Hb species present in the cyst fluid collected from 8 patients with endometriosis-associated ovarian cancer (EAOC), and compared with those present in the cyst fluid of 35 patients with benign endometriotic cysts. The 620/580 nm ratio in the electronic absorption spectrum, which was used as a surrogate indicator of the methemoglobin (metHb)/(oxyhemoglobin+metHb) ratio, was measured in each cyst fluid by ultraviolet/visible grating spectrophotometric microplate reader. The optimal cutoff value was defined according to the analysis of receiver operating characteristic (ROC) curve. The sensitivity and specificity of detection were calculated on the basis of the cutoff value to differentiate EAOC from endometriosis. The 620/580 nm ratio of cyst fluid in EAOC patients was much lower than that measured in women with benign cysts (0.389±0.266 vs. 0.666±0.188, P=0.021). ROC curve analysis performed using 0.35 as the optimal cutoff value indicated that the 620/580 nm ratio had a sensitivity, specificity, positive predictive value (PPV) and negative predictive value of 62.5, 100.0, 100.0 and 92.1%, respectively, in the diagnosis of EAOC. In conclusion, metHb is one of the most abundant Hb species in benign cysts, and the absorption 620/580 nm ratio of cyst fluid exhibits high specificity and PPV as a surveillance test for the early detection of malignant transformation of endometriosis. Thus, metallobiology highlights diverse features involved in Hb homeostasis and the pathogenesis of malignant transformation of endometriosis.

Novel MRI technique to distinguish malignant transformation from benign endometriotic cysts

Novel MRI technique to distinguish malignant transformation from benign endometriotic cysts

FDG-PET/CT pitfalls in gynecological and genitourinary oncological imaging

The role of whole-body positron emission tomography(PET)/ computed tomography (CT) with fluorodeoxyglucose (FDG) is now established in the assessment of many gynecologic and genitourinary malignant tumors. FDG PET/CT has been widely adopted for staging assessments in patients with suspected advanced disease, in cases of suspected disease recurrence, and for determining prognosis in a number of malignancies. A number of pitfalls are commonly encountered when reviewing FDG PET/CT scans in gynecologic and genitourinary cases; these pitfalls can be classified into those that yield potential false- positive or false- negative results. Potential false positives include physiologic uptake of FDG by the endometrium and ovaries in premenopausal patients, physiologic renal excretion of FDG into the ureters and the urinary bladder, and increased FDG activity in benign conditions such as uterine fibroids, pelvic inflammatory disease, and benign endometriotic cysts. Potential false negatives include low-level FDG uptake by necrotic, mucinous, cystic, or low-grade tumors and the masking of serosal and peritoneal disease by adjacent physiologic bowel or bladder activity. In addition, there are inherent technical limitations- such as motion artifact (from respiratory motion and bowel peristalsis) and the limited spatial resolution of PET-that may limit the assessment of small-volume malignant disease. Knowledge of the key imaging features of physiologic and nonphysiologic FDG uptake, in addition to understanding the principles of adequate patient preparation and PET scanning protocols, is important for accurate interpretation of gynecologic and genitourinary oncologic FDG PET/CT studies. (C) RSNA, 2017 center dot radiographics. rsna. org

Cyst fluid iron-related compounds as useful markers to distinguish malignant transformation from benign endometriotic cysts

The purpose of this study was to investigate cyst fluid levels of total iron, heme iron and free iron in benign endometriotic cysts and endometriosis-associated ovarian cancer (EAOC) and to demonstrate the significance of these biomarkers in differential diagnosis between EAOC and endometriotic cysts. Cyst fluid samples were obtained from eleven patients with EAOC and thirty-six women with benign endometriotic cysts at the time of surgery. The median (± SD) total iron levels for endometriotic cysts and EAOC cysts were 244.4 ± 204.9 mg/L and 14.2 ± 36.6 mg/L, respectively. EAOC patients had much lower levels of iron-related compounds compared with endometriotic cyst samples (p< 0.001). When the total iron results were analyzed using the receiver operating characteristics (ROC) curve method, the optimum diagnostic cut-off point was 64.8 mg/L, sensitivity was 90.9%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 97.3%. Patient demographic characteristics such as tumor size, age at operation, parity and menopause were not correlated with cyst fluid iron levels. We conclude for the first time that iron-related compounds are important biomarkers that can predict malignant transformation with high sensitivity and specificity for women with endometriosis.

The ARID1A pathway in ovarian clear cell and endometrioid carcinoma, contiguous endometriosis, and benign endometriosis

ObjectiveTo assess ARID1A-encoded protein (BAF250a) and phosphorylated AKT (pAKT) expression, apoptosis, and the DNA damage response pathway in endometrioid and clear cell ovarian cancers (endometriosis-associated ovarian cancers [EAOCs]), and benign endometriotic ovarian cysts. MethodsIn a retrospective study, tissue samples were reviewed from patients who had undergone surgery for EAOC or endometriotic ovarian cysts at a center in Montreal, QC, Canada, between 2000 and 2012. A tissue microarray including cases of endometrioid carcinoma, clear cell carcinoma, contiguous endometriosis (i.e. apparently benign endometriosis near the EAOC), and benign endometriotic ovarian cysts, was analyzed for the expression of various proteins. ResultsLoss of BAF250a expression was seen in 13 (22%) of 59 endometrioid cancers, 17 (47%) of 36 clear cell cases, 8 (44%) of 18 contiguous endometriosis cases, and 3 (8%) of 66 benign endometriotic ovarian cysts. In tissues showing loss of BAF250a, expression of pAKT, γH2AX, BIM, and BAX was higher in EAOC and contiguous endometriosis than in benign endometriosis (P<0.05), whereas expression of pATM, pCHK2, and Bcl2 was low. All proteins except for Bcl2 showed low expression in benign endometriosis. ConclusionLoss of ARID1A-encoded protein seems to be an early event in EOAC, along with pAKT activation, alteration of γH2AX, and concomitant activation of the apoptosis pathway.

Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma

BackgroundThis study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA).Materials and methodsThe promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis.ResultsFrequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts. The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed.ConclusionsMethylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway.

Transmembrane Estrogen Receptor GPR30 is More Frequently Expressed in Malignant Than Benign Ovarian Endometriotic Cysts and Correlates With MMP-9 Expression

Molecular studies supporting the idea of malignant transformation of endometriosis are sparse and not well substantiated. The aims of this study were to detect expression levels of the novel estrogen-responsive receptor G protein-coupled estrogen receptor 1 GPER, also termed GPR30, and to determine its correlation with matrix metalloproteinase-9 (MMP-9) in benign and malignant ovarian endometriotic cysts and to explore the significance of GPR30. Immunohistochemical staining with the streptavidin-peroxidase method was conducted to determine the expression of GPR30 and MMP-9 in 24 cases of endometriosis-associated ovarian carcinoma (EAOC) and 32 specimens of ovarian endometriosis without malignant transformation. Reverse transcriptase polymerase chain reaction was performed to determine messenger RNA expression of GPR30 and MMP-9 in benign and malignant ovarian endometriotic cysts. We also investigated their associations with known clinic pathological parameters and the interrelationship between the expressions of the 2 proteins. The positive staining ratio of GPR30 was 95.8% (23/24) in EAOC cases, and the HScore was 268; whereas the positive ratio was 25% (8/32) in benign endometriotic cysts, and the Hscore was 95. Matrix metalloproteinase-9 was expressed in all 24 EAOC cases and 87.5% (28/32) of the benign samples, and the Hscores were 280 and 260, respectively (P > 0.05). The receptor GPR30 was significantly higher in EAOCs than in benign endometriotic cysts (P < 0.05). The expression of GPR30 messenger RNA was also significantly higher in malignant ovarian endometriotic cysts than in the benign group. The receptor GPR30 was positively related to tumor size, tumor stage, and lymph node metastasis. A positive relationship between GPR30 and MMP-9 was found (P = 0.002). The results suggest that the abnormal expression of GPR30 may be involved in malignant transformation, invasion, and metastasis of EAOCs. Testing of GPR30 expression levels may present both diagnostic and therapeutic options for the treatment of ovarian malignancies.

Promoter methylation of sFRP5 in patients with ovarian clear cell adenocarcinoma

Specific tumour suppressor genes with promoter methylation in ovarian clear cell adenocarcinoma (OCCA) can be one important epigenetic mark distinguishing OCCA from ovarian serous adenocarcinoma (OSA), benign endometriotic cysts and normal ovarian epitheliums. Five OCCA cell lines, 63 cancer tissues (48 OCCA and 15 OSA), 10 benign endometriotic cysts and five normal ovarian epitheliums were analysed by methylation-specific PCR using pooled DNAs to determine the methylation status of the promoter of the target genes, including genes for secreted frizzled-related proteins (sFRP1 to 5), adenomatous polyposis coli (APC), retinoblastoma protein 1 (Rb1), breast cancer 1 gene (BRCA1), p14(ARF), p15(INK4b), p16(INK4a) and survivin. Methylation frequencies of identified targets were further analysed with individual DNA samples. The sFRP5 promoter was significantly methylated in all OCCA cell lines, with 64.6% in OCCA tissues compared with 13.3% in OSA, and 0% in benign endometriotic cysts and normal ovarian epitheliums (P < 0.0001). With a median follow-up of 44 months, the expected 5-year overall survival (OS) for patients with methylated sFRP5 promoter were significantly worse than for those with unmethylated sFRP5 (52% vs. 88%, P = 0.03). After adjusting for age, stage, and residual disease after primary surgery, patients with unmethylated sFRP5 promoter had an independent good prognostic factor in OS (P = 0.017). The high percentage of promoter methylation in the sFRP5 gene in OCCA indicates its importance in the development of OCCA and is a potential useful marker for prognoses and target for treatment of OCCA.

Site of origin of epithelial ovarian cancer: the endometriosis connection.

To investigate the left- and right-sided distribution of ovarian malignant surface epithelial tumours, data were collected on 209 women undergoing first-line surgery for Stage I and II disease. Considering the unilateral cancers, the observed proportion of left-sided lesions was 35/54 (65%) in the endometrioid, 20/45 (44%) in the serous, 19/35 (54%) in the clear cell, 13/29 (45%) in the mucinous, 2/8 (25%) in the mixed, and 2/5 (40%) in the undifferentiated histological type group. The proportion of left-sided unilateral endometrioid cancers was significantly different from the expected 50% (chi2(1), 4.74, P = 0.03) and very similar to that previously observed for benign endometriotic cysts, constituting further evidence in favour of a possible development of endometrioid cancers from the latter lesions.