Restoration of ARID1A Protein in ARID1A-deficient Clear Cell Carcinoma of the Ovary Attenuates Reactivity to Cytotoxic T Lymphocytes.

BACKGROUND/AIM: Clear cell carcinoma is a prevalent histological type of ovarian cancer in East Asia, particularly in Japan, known for its resistance to chemotherapeutic agents and poor prognosis. ARID1A gene mutations, commonly found in ovarian clear cell carcinoma (OCCC), contribute to its pathogenesis. Recent data revealed that the ARID1A mutation is related to better outcomes of cancer immunotherapy. Thus, this study aimed to investigate the immunotherapy treatment susceptibility of OCCC bearing ARID1A mutations. MATERIALS AND METHODS: Expression of ARID1A was analyzed using western blotting in ovarian cancer cell lines. OCCC cell lines JHOC-9 and RMG-V were engineered to overexpress NY-ESO-1, HLA-A*02:01, and ARID1A. Sensitivity to chemotherapy and T cell receptor-transduced T (TCR-T) cells specific for NY-ESO-1 was assessed in ARID1A-restored cells compared to ARID1A-deficient wild-type cells. RESULTS: JHOC-9 cells and RMG-V cells showed no expression of ARID1A protein. Overexpression of ARID1A in JHOC-9 and RMG-V cells did not impact sensitivity to gemcitabine. While ARID1A overexpression decreased sensitivity to cisplatin in RMG-V cells, it had no such effect in JHOC-9 cells. ARID1A overexpression reduced the reactivity of NY-ESO-1-specific TCR-T cells, as observed by the IFNγ ESLIPOT assay. CONCLUSION: Cancer immunotherapy is an effective approach to target ARID1A-deficient clear cell carcinoma of the ovary.

Genome-wide DNA methylation in relation to ARID1A deficiency in ovarian clear cell carcinoma.

BACKGROUND: The poor chemo-response and high DNA methylation of ovarian clear cell carcinoma (OCCC) have attracted extensive attentions. Recently, we revealed the mutational landscape of the human kinome and additional cancer-related genes and found deleterious mutations in ARID1A, a component of the SWI/SNF chromatin-remodeling complex, in 46% of OCCC patients. The present study aims to comprehensively investigate whether ARID1A loss and genome-wide DNA methylation are co-regulated in OCCC and identify putative therapeutic targets epigenetically regulated by ARID1A. METHODS: DNA methylation of ARID1Amt/ko and ARID1Awt OCCC tumors and cell lines were analyzed by Infinium MethylationEPIC BeadChip. The clustering of OCCC tumors in relation to clinical and mutational status of tumors were analyzed by hierarchical clustering analysis of genome-wide methylation. GEO expression profiles were used to identify differentially methylated (DM) genes and their expression level in ARID1Amt/ko vs ARID1Awt OCCCs. Combining three pre-ranked GSEAs, pathways and leading-edge genes epigenetically regulated by ARID1A were revealed. The leading-edge genes that passed the in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines were regarded as candidate genes and finally verified by bisulfite sequencing and RT-qPCR. RESULTS: Hierarchical clustering analysis of genome-wide methylation showed two clusters of OCCC tumors. Tumor stage, ARID1A/PIK3CA mutations and TP53 mutations were significantly different between the two clusters. ARID1A mutations in OCCC did not cause global DNA methylation changes but were related to DM promoter or gene-body CpG islands of 2004 genes. Three pre-ranked GSEAs collectively revealed the significant enrichment of EZH2- and H3K27me3-related gene-sets by the ARID1A-related DM genes. 13 Leading-edge DM genes extracted from the enriched gene-sets passed the expression-based in-silico validation and showed consistent ARID1A-related methylation change in tumors and cell lines. Bisulfite sequencing and RT-qPCR analysis showed promoter hypermethylation and lower expression of IRX1, TMEM101 and TRIP6 in ARID1Amt compared to ARID1Awt OCCC cells, which was reversed by 5-aza-2'-deoxycytidine treatment. CONCLUSIONS: Our study shows that ARID1A loss is related to the differential methylation of a number of genes in OCCC. ARID1A-dependent DM genes have been identified as key genes of many cancer-related pathways that may provide new candidates for OCCC targeted treatment.

Exploration and prognostic analysis of two types of high-risk ovarian cancers: clear cell vs. serous carcinoma: a population-based study.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) is a rare pathological histotype in ovarian cancer, while the survival rate of advanced OCCC (Stage III-IV) is substantially lower than that of the advanced serous ovarian cancer (OSC), which is the most common histotype. The goal of this study was to identify high-risk OCCC by comparing OSC and OCCC, with investigating potential risk and prognosis markers. METHODS: Patients diagnosed with ovarian cancer from 2009 to 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) Program. Logistic and Cox regression models were used to identify risk and prognostic factors in high-risk OCCC patients. Cancer-specific survival (CSS) and overall survival (OS) were assessed using Kaplan-Meier curves. Furthermore, Cox analysis was employed to build a nomogram model. The performance evaluation results were displayed using the C-index, calibration plots, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Immunohistochemically approach was used to identify the expression of the novel target (GPC3). RESULTS: In the Cox analysis for advanced OCCC, age (45-65 years), tumor numbers (total number of in situ/malignant tumors for patient), T3-stage, bilateral tumors, and liver metastases could be defined as prognostic variables. Nomogram showed good predictive power and clinical practicality. Compared with OSC, liver metastases had a stronger impact on the prognosis of patients with OCCC. T3-stage, positive distant lymph nodes metastases, and lung metastases were risk factors for developing liver metastases. Chemotherapy was an independent prognostic factor for patient with advanced OCCC, but had no effect on CSS in patients with liver metastases (p = 0.0656), while surgery was significantly related with better CSS in these patients (p < 0.0001) (p = 0.0041). GPC3 expression was detected in all tissue sections, and GPC3 staining was predominantly found in the cytoplasm and membranes. CONCLUSION: Advanced OCCC and OCCC with liver metastases are two types of high-risk OCCC. The constructed nomogram exhibited a satisfactory survival prediction for patients with advanced OCCC. GPC3 immunohistochemistry is expected to accumulate preclinical evidence to support the inclusion of GPC3 in OCCC targeted therapy.

Exceptional Response to Trastuzumab Deruxtecan in a Patient With Recurrent Ovarian Clear Cell Carcinoma With Human Epidermal Growth Factor Receptor 2 Expression.

Case report of a HER2-expressed ovarian clear cell carcinoma with exceptional response to trastuzumab deruxtecan.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay.

BACKGROUND: Ovarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti-PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC. METHODS AND RESULTS: The retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion. CONCLUSIONS: In conclusion, anti-PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

A Curious Case of Clear Cell Morphology in a Patient with Lung Cancer: Diagnostic Challenges.

An 82-year-old woman with COPD presented to the emergency department with cough, increasing sputum production, wheezing, and worsening shortness of breath for two weeks. On imaging studies, the patient was found to have a right upper lobe spiculated nodule and an endobronchial lesion with near total occlusion of the right lower lobe bronchus with sub-segmental atelectasis. Bronchoscopy with EBUS-TBNA of subcarinal and right hilar lymph nodes revealed lung cancer with clear cell phenotype. Given the predominance of clear cell morphology, the diagnosis of metastatic renal or ovarian cancer was entertained. However, there was no evidence of renal or ovarian lesions on the PET-CT scan, ruling out the possibility. Salivary gland type lung cancer (STLC), which is responsible for less than 1% of all lung cancer cases in adults, was also considered. The two distinct STLCs that may have similar morphologic appearances are hyalinizing clear cell carcinoma (HCCC) and mucoepidermoid carcinoma (MEC). The other type of tumour in the lung that demonstrates a clear cell phenotype is perivascular epithelioid cell neoplasms or PEComa, which are mesenchymal in origin. Immunohistochemical staining was strongly positive for p63, CK5/6, CK7, CK-LMW, and negative for TTF-1, Napsin A, p16, and CK20. Additional staining, including HMB-45, S-100, and mucicarmine, were also negative. Next-generation sequencing for the salivary gland fusion panel, including EWSR1-ATF1 fusion and EWSR1 gene rearrangement for HCCC and MAML2 gene rearrangements for MEC, was negative. She was diagnosed with non-small cell lung cancer favouring squamous cell carcinoma with clear cell phenotype, a rare entity.

Global Incidence of Ovarian Cancer According to Histologic Subtype: A Population-Based Cancer Registry Study.

PURPOSE: Ovarian cancer can be categorized into distinct histologic subtypes with varying identifiable risk factors, molecular composition, clinical features, and treatment. The global incidence of ovarian cancer subtypes remains limited, especially in low- and middle-income countries (LMICs) without high-quality cancer registry systems. MATERIALS AND METHODS: We used data from population-based cancer registries of the Cancer Incidence in Five Continents project to calculate the proportions of serous, mucinous, endometrioid, clear cell, and other histologic subtypes of ovarian cancer. Proportions were applied to the estimated numbers of patients with ovarian cancer from Global Cancer Observatory 2020. Age-standardized incidence rates were calculated. RESULTS: Globally, an estimated 133,818 new patients of serous cancer, 35,712 new patients of mucinous cancer, 29,319 new patients of endometrioid cancer, and 17,894 new patients of clear cell cancer were identified in 2020. The distribution of ovarian cancer histologic subtypes exhibited regional variation. Eastern Europe had the highest rate of serous and mucinous carcinomas, whereas Northern Africa and Eastern Asia had the highest burden of endometrioid and clear cell carcinomas, respectively. CONCLUSION: This study provides a global incidence landscape of histologic subtypes of ovarian cancer, particularly in LMICs lacking comprehensive registry systems. Our analysis offers valuable insights into disease burden and guidance for tailored strategies for prevention of ovarian cancer.

Establishment of a human ovarian clear cell carcinoma cell line mutant in PIK3CB but not PIK3CA.

A human ovarian clear cell carcinoma cell line was established from a 46-year-old Japanese woman. That line, designated MTC-22, has proliferated continuously for over 6 months in conventional RPMI 1640 medium supplemented with 10% foetal bovine serum and has been passaged over 50 times. MTC-22 doubling-time is ~ 18 h, which is much shorter than most ovarian clear cell carcinoma lines reported to date. Morphologically, MTC-22 cells exhibit polygonal shapes and proliferate to form a monolayer in a jigsaw puzzle-like arrangement without contact inhibition. Ultrastructurally, cells exhibit numerous intracytoplasmic glycogen granules and well-developed mitochondria. G-band karyotype analysis indicated that cells have a complex karyotype close to tetraploid. We observed that the expression pattern of a series of ovarian carcinoma-related molecules in MTC-22 cells was identical to that seen in the patient's tumour tissue. Notably, MTC-22 cells, and the patient's carcinoma tissue, expressed low-sulphated keratan sulphate recognised by R-10G and 294-1B1 monoclonal antibodies, a hallmark of non-mucinous ovarian carcinoma, and particularly of clear cell ovarian carcinoma. Moreover, characteristic point mutations-one in ARID1A, which encodes the AT-rich interaction domain containing protein 1A, and the other in PIK3CB, which encodes the catalytic subunit of phosphoinositide 3-kinase-were seen in the patient's tumour tissue and retained in MTC-22 cells. Collectively, these findings indicate that MTC-22 cells could serve as a valuable tool for investigating the pathophysiology of ovarian clear cell carcinoma, particularly that harbouring PIK3CB mutations, and for developing and validating new diagnostic and therapeutic approaches to this life-threatening malignancy.

Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a gynecological cancer with a dismal prognosis; however, the mechanism underlying OCCC chemoresistance is not well understood. To explore the intracellular networks associated with the chemoresistance, we analyze surgical specimens by performing integrative analyses that combine single-cell analyses and spatial transcriptomics. We find that a chemoresistant OCCC subpopulation with elevated HIF activity localizes mainly in areas populated by cancer-associated fibroblasts (CAFs) with a myofibroblastic phenotype, which is corroborated by quantitative immunostaining. CAF-enhanced chemoresistance and HIF-1α induction are recapitulated in co-culture assays, which show that cancer-derived platelet-derived growth factor (PDGF) contributes to the chemoresistance and HIF-1α induction via PDGF receptor signaling in CAFs. Ripretinib is identified as an effective receptor tyrosine kinase inhibitor against CAF survival. In the co-culture system and xenograft tumors, ripretinib prevents CAF survival and suppresses OCCC proliferation in the presence of carboplatin, indicating that combination of conventional chemotherapy and CAF-targeted agents is effective against OCCC.

Case of metastatic clear cell odontogenic carcinoma with response to chemoimmunotherapy.

Our patient initially presented with 6 months of left jaw pain and gingival bleeding, leading to the discovery of a radiolucent left maxillary mass on dental evaluation. A biopsy confirmed clear cell odontogenic carcinoma, and the patient was treated with definitive surgery and radiation for localised disease. Unfortunately, the patient was found to have pulmonary metastases 3 months after initial management and was subsequently treated with a combination of cytotoxic chemotherapy and immunotherapy with a partial response. To our knowledge, this is the first case demonstrating the successful use of chemoimmunotherapy in metastatic clear cell odontogenic carcinoma.

Novel Ultrastructural Insights into the Clear-Cell Carcinoma of the Pancreas: A Case Report.

Pancreatic cancer, most frequently as ductal adenocarcinoma (PDAC), is the third leading cause of cancer death. Clear-cell primary adenocarcinoma of the pancreas (CCCP) is a rare, aggressive, still poorly characterized subtype of PDAC. We report here a case of a 65-year-old male presenting with pancreatic neoplasia. A histochemical examination of the tumor showed large cells with clear and abundant intracytoplasmic vacuoles. The clear-cell foamy appearance was not related to the hyperproduction of mucins. Ultrastructural characterization with transmission electron microscopy revealed the massive presence of mitochondria in the clear-cell cytoplasm. The mitochondria showed disordered cristae and various degrees of loss of structural integrity. Immunohistochemistry staining for NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2 (NDUFA4L2) proved specifically negative for the clear-cell tumor. Our ultrastructural and molecular data indicate that the clear-cell nature in CCCP is linked to the accumulation of disrupted mitochondria. We propose that this may impact on the origin and progression of this PDAC subtype.

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016.

INTRODUCTION: Early reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. METHODS: This single arm, two-stage, phase 2 trial included those with measurable disease and 1-3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). RESULTS: Between September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44-89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5-51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9-9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. CONCLUSIONS: Pembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.

Application of interpretable machine learning algorithms to predict distant metastasis in ovarian clear cell carcinoma.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) represents a subtype of ovarian epithelial carcinoma (OEC) known for its limited responsiveness to chemotherapy, and the onset of distant metastasis significantly impacts patient prognoses. This study aimed to identify potential risk factors contributing to the occurrence of distant metastasis in OCCC. METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed with OCCC between 2004 and 2015. The most influential factors were selected through the application of Gaussian Naive Bayes (GNB) and Adaboost machine learning algorithms, employing a Venn test for further refinement. Subsequently, six machine learning (ML) techniques, namely XGBoost, LightGBM, Random Forest (RF), Adaptive Boosting (Adaboost), Support Vector Machine (SVM), and Multilayer Perceptron (MLP), were employed to construct predictive models for distant metastasis. Shapley Additive Interpretation (SHAP) analysis facilitated a visual interpretation for individual patient. Model validity was assessed using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and the area under the receiver operating characteristic curve (AUC). RESULTS: In the realm of predicting distant metastasis, the Random Forest (RF) model outperformed the other five machine learning algorithms. The RF model demonstrated accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and AUC (95% CI) values of 0.792 (0.762-0.823), 0.904 (0.835-0.973), 0.759 (0.731-0.787), 0.221 (0.186-0.256), 0.974 (0.967-0.982), 0.353 (0.306-0.399), and 0.834 (0.696-0.967), respectively, surpassing the performance of other models. Additionally, the calibration curve's Brier Score (95%) for the RF model reached the minimum value of 0.06256 (0.05753-0.06759). SHAP analysis provided independent explanations, reaffirming the critical clinical factors associated with the risk of metastasis in OCCC patients. CONCLUSIONS: This study successfully established a precise predictive model for OCCC patient metastasis using machine learning techniques, offering valuable support to clinicians in making informed clinical decisions.

Magnetic resonance imaging-based radiomics analysis of the differential diagnosis of ovarian clear cell carcinoma and endometrioid carcinoma: a retrospective study.

PURPOSE: To retrospectively evaluate the diagnostic potential of magnetic resonance imaging (MRI)-based features and radiomics analysis (RA)-based features for discriminating ovarian clear cell carcinoma (CCC) from endometrioid carcinoma (EC). MATERIALS AND METHODS: Thirty-five patients with 40 ECs and 42 patients with 43 CCCs who underwent pretherapeutic MRI examinations between 2011 and 2022 were enrolled. MRI-based features of the two groups were compared. RA-based features were extracted from the whole tumor volume on T2-weighted images (T2WI), contrast-enhanced T1-weighted images (cT1WI), and apparent diffusion coefficient (ADC) maps. The least absolute shrinkage and selection operator (LASSO) regression with tenfold cross-validation method was performed to select features. Logistic regression analysis was conducted to construct the discriminating models. Receiver operating characteristic curve (ROC) analyses were performed to predict CCC. RESULTS: Four features with the highest absolute value of the LASSO algorithm were selected for the MRI-based, RA-based, and combined models: the ADC value, absence of thickening of the uterine endometrium, absence of peritoneal dissemination, and growth pattern of the solid component for the MRI-based model; Gray-Level Run Length Matrix (GLRLM) Long Run Low Gray-Level Emphasis (LRLGLE) on T2WI, spherical disproportion and Gray-Level Size Zone Matrix (GLSZM), Large Zone High Gray-Level Emphasis (LZHGE) on cT1WI, and GLSZM Normalized Gray-Level Nonuniformity (NGLN) on ADC map for the RA-based model; and the ADC value, spherical disproportion and GLSZM_LZHGE on cT1WI, and GLSZM_NGLN on ADC map for the combined model. Area under the ROC curves of those models were 0.895, 0.910, and 0.956. The diagnostic performance of the combined model was significantly superior (p = 0.02) to that of the MRI-based model. No significant differences were observed between the combined and RA-based models. CONCLUSION: Conventional MRI-based analysis can effectively distinguish CCC from EC. The combination of RA-based features with MRI-based features may assist in differentiating between the two diseases.

Histologic Subtypes in Endometriosis-Associated Ovarian Cancer and Ovarian Cancer Arising in Endometriosis: A Systematic Review and Meta-Analysis.

The definition of the association between ovarian cancer and endometriosis was first reported by Sampson in 1925. He identified the following criteria: (a) clear evidence of endometriosis in proximity to the tumour, (b) exclusion of a metastatic tumour to the ovary, (c) presence of tissue resembling endometrial stroma surrounding epithelial glands. The naming of these cancers is "endometriosis-associated ovarian cancer" (EAOC). Scott proposed an additional stringent criterion: evidence of histological transition from endometriosis to cancer is to define "ovarian cancer arising in endometriosis" (OCAE). The aim of this systematic review is to analyse the distribution of different ovarian cancer histotypes in EAOC and OCAE to understand their similarities and differences. A total of 31 studies were included. Four studies added data for both EAOC and OCAE. Twenty-three studies were selected for EAOC, with a total of 800 patients, and 12 studies were selected for OCAE, with a total of 375 patients. The results show no significant differences in the distribution of histotypes in the two populations analysed. Clear cell carcinoma (CCC) and endometrioid carcinoma (EC) were the most common subtypes and were less frequent in EAOC compared to OCAE; the odd ratios were 0.58 (0.26-1.29) and 0.65 (0.33-1.26) respectively, although the difference was not statistically significant. The other histotypes were present in small proportions. This analysis shows that the histological profiles of EAOC and OCAE are similar, suggesting a similar aetiopathological mechanism, which requires further research to investigate whether EAOC and OCAE may be in the same way but at different points of the process to malignancy or have different pathways of progression to malignancy.

Endometriosis-associated ovarian cancer: a different clinical entity.

OBJECTIVE: To compare survival outcomes and patterns of recurrence between endometriosis-associated ovarian cancer patients and non-endometriosis-associated ovarian cancer patients. METHODS: This retrospective study included data of consecutive patients with endometrioid or clear cell ovarian cancer treated at the Fondazione IRCCS Istituto Nazionale dei Tumori di Milano between January 2010 and June 2021. Patients were assigned to one of two groups according to the absence or presence of endometriosis together with ovarian cancer at final histological examination. Survival outcomes were assessed using Kaplan-Meier and Cox hazard models. Proportions in recurrence rate and pattern of recurrence were evaluated using the Fisher exact test. RESULTS: Overall, 83 women were included in the endometriosis-associated ovarian cancer group and 144 in the non-endometriosis-associated ovarian cancer group, respectively. Patients included in the non- endometriosis-associated ovarian cancer group had a shorter disease-free survival than those in the endometriosis-associated ovarian cancer group (23.4 (range 2.0-168.9) vs 60.9 (range 4.0-287.8) months; p<0.001). Univariable and multivariable analyses showed that the association with endometriosis, previous hormonal treatment, early stage at presentation, and endometrioid histology were related to better disease-free survival in the entire study population. Similarly, patients in the non-endometriosis-associated ovarian cancer group had a shorter median (range) overall survival than those in the endometriosis-associated ovarian cancer group (54.4 (range 0.7-190.6) vs 77.6 (range 4.5-317.8) months; p<0.001). Univariable and multivariable analyses showed that younger age at diagnosis, association with endometriosis, and early stage at presentation were related to better overall survival. The recurrence rate was higher in the non-endometriosis-associated ovarian cancer group (63/144 women, 43.8%) than in the endometriosis-associated ovarian cancer group (17/83 women, 20.5%; p<0.001). CONCLUSIONS: Endometriosis-associated ovarian cancer patients had significantly longer disease-free survival and overall survival than non-endometriosis-associated ovarian cancer patients, while the recurrence rate was higher in non-endometriosis-associated ovarian cancer patients.

Cervical clear cell carcinoma: Case report and literature review.

RATIONALE: Clear cell carcinoma (CCC) is a highly invasive malignant tumor. CCCs of the female reproductive system occur mostly in the endometrium and ovaries and rarely in the cervix. So, it is difficult to diagnose cervical clear cell carcinoma (CCAC) on imaging. This report helps to further deepen our understanding of CCAC. PATIENT CONCERNS: A 39-year-old female patient presented with vaginal discharge with no obvious cause, elevated levels of carcinoembryonic antigen (CEA), CA125, CA153, and squamous cell carcinoma antigen (SCC), and underwent ultrasonography (US) CT and MRI examination in our hospital, which showed a mass in the cervix of the uterus, considered of cervical squamous carcinoma. DIAGNOSES: The cervix biopsy guided by vaginoscope biopsy and immunohistochemistry confirmed CCAC, combined Magnetic Resonance Imaging examination, CCAC with pelvic lymph node metastasis was considered. INTERVENTIONS AND OUTCOMES: The patient refused further treatment and was discharged from hospital. LESSONS: CCAC exhibited no specific symptoms, and is slightly different from cervical squamous carcinoma in image features, mainly relying on immunohistochemistry for diagnosis. The reported case raised awareness of CCAC.

The malignant transformation of endometriosis: Is there a left lateral predisposition of ovarian clear cell and endometrioid carcinomas?

INTRODUCTION: Endometriosis affects 10% of women of reproductive age. There is evidence for a left lateral predisposition of endometriotic lesions and a 1.9-fold greater risk of ovarian cancer in endometriosis. The aim of this study is to determine whether a left lateral predisposition of ovarian clear-cell carcinoma (CCC) and endometrioid carcinoma (EC) exists. MATERIALS AND METHODS: A retrospective cohort study of all EC and CCC patients in Northern Ireland between March-2011 and June-2018. ANOVA was used to analyse preoperative prediction of stage, chi-squared (χ2) was used to compare left- and right-sided masses. Survival was estimated using Kaplan-Meier and log-rank test. A p-value <0.05 was considered significant. RESULTS: 158 patients were identified (95 EC, 55 CCC, 8 mixed). Mean age was 57.65 years with 69% presenting at stage 1. The mean CA125 was 559 U/mL (p = 0.850) and mean abdominal mass size was 14.12 cm (p = 0.732). The most common presenting symptom was an abdominal mass (37%). Despite 67% of patients having endometriosis on final pathology, only 8.9% had a known history pre-operatively. 51% of tumours were located on the left (p = 0.036). For unilateral tumours this was significant for EC (P = 0.002) but not for CCC (P = 0.555). The 1-, 3- and 5-year overall survival for all types/stages was 85%, 78% and 71% respectively. CONCLUSION: While CCC and EC are associated with endometriosis, only EC exhibits a left lateral predisposition. There is no association between preoperative CA125 or abdominal mass size and stage of disease.

Differentiation of ovarian serous carcinoma from ovarian clear cell carcinoma using a 10-gene signature selected by comprehensive gene expression analysis.

AIM: Ovarian serous carcinoma (OSC) and ovarian clear cell carcinoma (OCCC) are two major histological types of epithelial ovarian carcinoma (EOC), each with different biological features and clinical behaviors. Although immunostaining is commonly used for differential diagnosis between OSC and OCCC, correct identification of EOC with mixed-type histology is sometimes a diagnostic challenge. The aim of the present study was to explore candidate genes as potential diagnostic biomarkers that distinguish OSC from OCCC. METHODS: A total of 57 surgical specimens were obtained from EOC patients who had previously undergone primary debulking surgery. Total RNAs were extracted from fresh-frozen tissues of EOC patients, and were used for comprehensive gene expression analysis using DNA microarray technology. RESULTS: Ten candidate genes, FXYD2, TMEM101, GABARAPL1, ARG2, GLRX, RBPMS, GDF15, PPP1R3B, TOB1, and GSTM3 were up-regulated in OCCC compared to OSC. All EOC patients were divided into two groups according to hierarchical clustering using a 10-gene signature. CONCLUSION: Our data suggest that the 10 candidate genes would be an excellent marker for distinguishing OSC from OCCC. Furthermore, the molecular signatures of the 10 genes may enlighten us on the differences in carcinogenesis, and provide a theoretical basis for OCCC's resistance to chemotherapy in the future.