Ovarian Clear Cell Carcinoma: Genomic Characterization, Pathogenesis and Targeted Therapy.

Ovarian clear cell carcinomas (OCCCs) are a subtype of ovarian epithelial tumors that arise from the malignant transformation of endometriosis (EMs). These tumors have distinctive molecular features, high malignant potential, low sensitivity to conventional chemotherapy, and poor prognosis. The process and mechanism of malignant transformation from EMs to OCCCs remains elusive. Elucidation of the molecular pathogenesis and drug resistance mechanism of OCCCs is essential to guide the clinical management and basic research of this disease. This paper provides a comprehensive review of the mechanisms of malignant transformation, genomic characteristics, drug resistance and targeted therapy of OCCCs. The review aims to provide new insights for the clinical management of advanced OCCCs.

Clinical perspectives of rare ovarian tumors: clear cell ovarian cancer.

Ovarian clear cell carcinoma (OCCC) is a rare and distinct histological type of epithelial ovarian carcinoma in terms of its histopathological, clinical and genetic features. Patients with OCCC are younger and diagnosed at earlier stages than those with the most common histological type-high-grade serous carcinoma. Endometriosis is considered a direct precursor of OCCC. Based on preclinical data, the most frequent gene alternations in OCCC are mutations of AT-rich interaction domain 1A and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. The prognosis of patients with early-stage OCCC is favorable, whereas patients at an advanced stage or who have the recurrent disease have a dismal prognosis due to OCCC's resistance to standard platinum-based chemotherapy. Despite a lower rate of response due to its resistance to standard platinum-based chemotherapy, the treatment strategy for OCCC resembles that of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and adjuvant platinum-based chemotherapy. Alternative treatment strategies, including biological agents based on molecular characteristics specific to OCCC, are urgently needed. Furthermore, due to its rarity, well-designed collaborative international clinical trials are needed to improve oncologic outcomes and the quality of life in patients with OCCC.

Development and external validation of nomograms for predicting individual survival in patients with ovarian clear cell carcinoma.

PURPOSE: Ovarian clear cell carcinoma (OCCC) is a distinct and highly malignant subtype of ovarian cancer with high individual heterogeneity in survival that requires specific prognostic predictive tools. Thus, this study aimed to construct and validate nomograms for predicting individual survival in OCCC patients. METHODS: In total, 91 patients with OCCC who were diagnosed and treated at Renji Hospital between 2010 and 2020 were extracted as the training cohort, then 86 patients from the First Affiliated Hospital of USTC were used as the external validation cohort. Prognostic factors that affect survival were identified using least absolute shrinkage and selection operator regression. Nomograms of progression-free survival (PFS) and overall survival (OS) were then established with the Cox regression model and the performance was subsequently evaluated using the concordance index (C-index), calibration plots, decision curve analysis (DCA), and risk subgroup classification. RESULTS: Advanced tumor, ascites of >400 mL, lymph node-positive, CA199 of >142.3 IU/mL, and fibrinogen of >5.36 g/L were identified as risk factors for OS while advanced tumor, ascites of >400 mL, lymph node-positive, and fibrinogen of >5.36 g/L were risk factors for PFS. The C-indexes for the OS and PFS nomograms were 0.899 and 0.731 in the training cohort and 0.804 and 0.787 in the validation cohort, respectively. The calibration plots showed that nomograms could provide better consistency in predicting patient survival than the FIGO staging system. DCA also demonstrated that nomograms were more clinically beneficial than the FIGO staging system. Additionally, patients could be classified into two risk groups based on scores using nomograms, with significant survival differences. CONCLUSIONS: We developed nomograms that could more objectively and reliably predict the individual survival of patients with OCCC compared with the FIGO staging system. These tools might assist in clinical decision-making and management of patients with OCCC to improve their survival outcomes.

New therapies for clear cell ovarian carcinoma.

Ovarian clear cell carcinoma is a rare subtype of epithelial ovarian cancer with unique clinicopathological features. The most common genetic aberration observed is loss of function ARID1A mutations. Advanced and recurrent ovarian clear cell carcinoma is characterized by resistance to standard-of-care cytotoxic chemotherapy and a poor prognosis. Despite the distinct molecular features of ovarian clear cell carcinoma, current treatments for this subtype of epithelial ovarian cancer are based on clinical trials which predominantly recruited patients with high grade serous ovarian carcinoma. These factors have encouraged researchers to develop novel treatment strategies specifically for ovarian clear cell carcinoma which are currently being tested in the context of clinical trials. These new treatment strategies currently focus on three key areas: immune checkpoint blockade, targeting angiogenesis, and exploiting ARID1A synthetic lethal interactions. Rational combinations of these strategies are being assessed in clinical trials. Despite the progress made in identifying new treatments for ovarian clear cell carcinoma, predictive biomarkers to better define those patients likely to respond to new treatments remain to be elucidated. Additional future challenges which may be addressed through international collaboration include the need for randomized trials in a rare disease and establishing the relative sequencing of these novel treatments.

Clinical Features and Prognostic Factors of Cervical Clear Cell Adenocarcinoma: A Retrospective Analysis of 74 Cases from a Tertiary Hospital.

The retrospective study aimed to analyze the clinical characteristics, primary treatment, and prognosis of cervical clear cell adenocarcinoma in a tertiary referral center. The medical data of cervical clear cell adenocarcinoma patients treated in our institution between 1993 and 2020 were reviewed. Their clinical characteristics and information on treatment and follow-up were collected. Seventy-four cases were included. Six early-stage patients successfully preserved their fertility. Forty-five patients underwent a radical hysterectomy. Patients with pathological risk factors all received adjuvant treatment including chemotherapy, radiotherapy, and chemoradiation. Fifteen patients without risk factors underwent surveillance and five patients received adjuvant chemotherapy for poorly differentiated disease. Twenty cases had radiation for primary treatment. Six of them underwent surgery after chemoradiotherapy, and five had pathological residual disease, including three who had pathological risk factors. The median follow-up interval was 36 months, with a 3-year OS and PFS rate of 82.4% and 81.4%, respectively. No recurrence or death was observed in patients with fertility-sparing treatment. FIGO stage was prognostic factors of PFS (P = .001) and OS(P = .006) and lymph node status was that of PFS (P = .023). FIGO stage and lymph node status were prognostic factors for survival. Fertility-sparing treatment is a safe option for young patients in early stage. Early-stage patients without risk factors may benefit from postoperative surveillance. Occult tumor after chemoradiotherapy is common, and surgical resection is recommended when operable residual disease is detected.

Successful treatment of a patient with recurrent metastatic clear cell carcinoma of the uterine cervix.

Clear cell carcinoma (CCC) of the uterine cervix is a rare gynecologic cancer that accounts for 4-9% of adenocarcinoma of the uterine cervix. Two types of uterine cervical CCCs are known: A type that is associated with in utero exposure to diethylstilbestrol (DES) and idiopathic type that is unrelated to DES exposure. Due to its rare incidence, the clinical behavior and pathological characteristics of CCCs are not fully described and treatment recommendations are not standardized. Moreover, only a few cases are reported on the recurrent metastatic CCCs and the results of various treatment trials are inconsistent. We present a case of successfully treated idiopathic metastatic CCC of the uterine cervix that recurred after concurrent chemoradiotherapy.

Primary clear cell adenocarcinoma of female urinary tract: a case report and literature review.

BACKGROUND: Primary clear cell adenocarcinoma of the urethra is extremely rare, reported only in single case reports, and its histological origin is not clear. There is no standard treatment for CCAU at present, and surgery is still the main treatment for CCAU without distant metastasis. CASE PRESENTATION: A 67-year-old female complained of gross hematuria with frequent micturition and urgency. No urethral diverticulum was found by cystoscopy or MRI, and the mass grew around the urethra. Urethral and anterior pelvic viscera resection was performed. Clear cell adenocarcinoma was confirmed by immunohistochemistry after the operation, and no recurrence or metastasis was found after one year of follow-up. CONCLUSION: CCAU is very rare, and most cases originate from the urethral diverticulum and some may also originate from tissues around the urethra. For CCAU patients without distant metastasis, the main treatment is still surgery, and radiotherapy and chemotherapy can be performed for patients with distant metastasis. Gene detection may provide guidance for the precise chemotherapy of CCAU.

Uterine papillary serous and clear cell carcinomas: Comparison of characteristics and clinical outcomes.

INTRODUCTION: To assess the rate of disease control and survival after adjuvant treatment in patients with uterine papillary serous (PSC) and clear cell carcinoma (CCC) and compare the results between these two subtypes. METHODS: The medical charts of 199 patients with de novo uterine PSC or CCC who underwent radiotherapy (RT) following surgery between 2001 and 2019 in three radiation oncology departments were retrospectively evaluated. Adjuvant treatment was decided by a multidisciplinary tumor board. All patients were planned to undergo adjuvant 4-6 cycles of chemotherapy with external beam RT (EBRT) and/or vaginal brachytherapy (VBT). RESULTS: Median age was 63 years for all, 64 years for PSC, and 59 years for CCC, respectively. Complete surgical staging was applied in 98% of patients. Histopathologic subtype was PSC in 142 (71%) and pure CCC in 57 (29%) patients, respectively. FIGO stage was I in 107 (54%), II in 35 (18%), and III in 57 (28%) patients, respectively. Lympho-vascular space invasion and positive peritoneal cytology (PPC) were present in 42% and 10% of patients, respectively. All patients but 23 (12%) underwent adjuvant chemotherapy. Median follow-up was 49.5 months for all patients, 43.9 months for patients with PSC, and 90.4 months for patients with CCC, respectively. During follow-up, 20 (10%) patients developed pelvic recurrence (PR) and 37 (19%) developed distant metastasis (DM). PSC subtype increased the PR and DM rates, although the latter not statistically significant. The 5-year overall survival and disease-free survival rate was 73% and 69% for all patients, 71% and 66% for patients with PSC, and 77% and 75% for patients with CCC, respectively. The difference was more prominent in patients with stage ≥ IB disease. In multivariate analysis, advanced age and PPC significantly decreased all survival rates. CONCLUSION: PSC has a worse prognosis than CCC with regard to pelvic and distant recurrence with a trend for decreased survival rates. Therefore, a more aggressive therapy is needed for patients with uterine PSC, particularly in patients with stage ≥ IB disease.

Clear Cell Carcinoma (CCC) of the Cervix Is a Human Papillomavirus (HPV)-independent Tumor Associated With Poor Outcome: A Comprehensive Analysis of 58 Cases.

Cervical clear cell carcinoma (CCC) is a rare human papillomavirus-independent adenocarcinoma. While recent studies have focused on gastric-type endocervical adenocarcinoma (GTA), little is known about CCC. A total of 58 (CCCs) were collected from 14 international institutions and retrospectively analyzed using univariable and multivariable methods and compared with 36 gastric-type adenocarcinomas and 173 human papillomavirus-associated (HPVA) endocervical adenocarcinoma (ECA) regarding overall survival (OS) and recurrence-free survival (RFS). Most cases were FIGO stage I (72.4%), with Silva C pattern of invasion (77.6%), and the majority were treated with radical surgery (84.5%) and adjuvant therapy (55.2%). Lymphovascular invasion was present in 31%, while lymph node metastasis was seen in 24.1%; 10.3% were associated with abdominopelvic metastases at the time of diagnosis; 32.8% had recurrences, and 19% died of disease. We did not find statistically significant differences in OS and RFS between CCC and GTA at 5 and 10 years (P=0.313 and 0.508, respectively), but there were significant differences in both OS and RFS between CCC and HPVA ECA (P=0.003 and 0.032, respectively). Also, OS and RFS in stage I clear cell and GTA were similar (P=0.632 and 0.692, respectively). Multivariate analysis showed that OS is influenced by the presence of recurrence (P=0.009), while RFS is influenced by the FIGO stage (P=0.025). Cervical CCC has poorer outcomes than HPVA ECA and similar outcomes to human papillomavirus-independent GTA. Oncologic treatment significantly influences RFS in univariate analysis but is not an independent prognostic factor in multivariate analysis suggesting that alternative therapies should be investigated.

Fibrinogen/albumin ratio as a promising predictor of platinum response and survival in ovarian clear cell carcinoma.

BACKGROUND: This study aims to evaluate the role of the fibrinogen/albumin ratio (FAR) in predicting platinum resistance and survival outcomes of patients with ovarian clear cell carcinoma (OCCC). METHODS: Coagulation function and D-dimer, serum albumin, CA125 and HE4 levels were measured before surgery in OCCC patients undergoing initial surgery in our institution. FAR was calculated as fibrinogen/albumin level. The correlation between these indicators and clinicopathological features, platinum response, and survival outcomes was further analyzed. The Kaplan-Meier method and multivariable Cox regression model were used to assess the effects of FAR on progression-free survival (PFS) and overall survival (OS). RESULTS: Advanced stage patients accounted for 42.1% of the 114 participants. Optimal cytoreductive surgery was achieved in 105 patients, and the complete resection rate was 78.1%. FAR was associated with tumor stage, residual tumor and platinum response. A receiver operating characteristic curve for predicting platinum response showed that the optimal cutoff point of the FAR was 12%. The sensitivity was 73.3% and the specificity was 68.2%. In multivariate analysis, FAR ≥12% (HR = 4.963, P = 0.002) was an independent risk factor for platinum resistance. In addition, FAR and D-dimer proved to be independent negative factors for outcomes including both PFS and OS. The median follow-up time was 52 months. A high FAR (≥ 12%) showed a stronger correlation with poor OS and PFS in the subgroup analysis of advanced and completely resected patients. CONCLUSIONS: The FAR might be a potential preoperative biochemical marker for predicting treatment response and oncological outcomes in OCCC patients.

Clear cell carcinoma of the endometrium.

Clear cell endometrial carcinoma represents an uncommon and poorly understood entity. Data from molecular/genomic profiling highlighted the importance of various signatures in assessing the prognosis of endometrial cancer according to four classes of risk (POLE mutated, MMRd, NSMP, and p53 abnormal). Unfortunately, data specific to clear cell histological subtype endometrial cancer are lacking. More recently, data has emerged to suggest that most of the patients (more than 80%) with clear cell endometrial carcinoma are characterized by p53 abnormality or NSMP type. This classification has important therapeutic implications. Although it is an uncommon entity, clear cell endometrial cancer patients with POLE mutation seem characterized by a good prognosis. Chemotherapy is effective in patients with NSMP (especially in stage III and IV) and patients with p53 abnormal disease (all stages). While, preliminary data suggested that patients with MMRd are less likely to benefit from chemotherapy. The latter group appears to benefit much more from immune checkpoint inhibitors: recent data from clinical trials on pembrolizumab plus lenvatinib and nivolumab plus cabozantinib supported that immunotherapy plus tyrosine kinase inhibitors (TKI) would be the most appropriate treatment for recurrent non-endometrioid endometrial cancer (including clear cell carcinoma) after the failure of platinum-based chemotherapy. Moreover, ongoing clinical trials testing the anti-tumor activity of innovative products will clarify the better strategies for advanced/recurrent clear cell endometrial carcinoma. Further prospective evidence is urgently needed to better characterize clear cell endometrial carcinoma.

Uterine carcinosarcoma vs endometrial serous and clear cell carcinoma: A systematic review and meta-analysis of survival.

BACKGROUND: It is unclear whether uterine carcinosarcoma (UCS) is more aggressive than endometrial serous carcinoma (SC) and clear cell carcinoma (CCC). OBJECTIVES: To compare the prognosis of UCS to that of endometrial SC and CCC, through a systematic review and meta-analysis. METHODS: Four electronic databases were searched from January 2000 to October 2020. All studies assessing hazard ratio (HR) for death in UCS vs SC and/or CCC. HRs for death with 95% confidence interval were extracted and pooled by using a random-effect model. A significant P-value <0.05 was adopted. RESULTS: Six studies with 11 029 patients (4995 with UCS, 4634 with SC, 1346 with CCC and 54 with either SC or CCC) were included. UCS showed a significantly worse prognosis than SC/CCC both overall (HR = 1.51; P = 0.008) and at early stage (HR = 1.58; P < 0.001). Similar results were found for UCS vs SC (HR = 1.53; P < 0.001) and UCS vs CCC (HR = 1.60; P < 0.001). CONCLUSIONS: Compared to SC and CCC, UCS has a significantly worse prognosis, with a 1.5-1.6-fold increased risk of death. This might justify a more aggressive treatment for UCS compared to SC and CCC. Further studies are necessary to define the prognostic impact of different molecular subgroups.

A clearer view on ovarian clear cell carcinoma.

INTRODUCTION: Ovarian clear cell carcinoma (OCCC) is a less common subtype accounting for approximately 5% of all epithelial ovarian cancers (EOCs). Clinical experience and research findings confirm the remarkable differences in clinical behavior, molecular alterations and pathogenesis of OCCC. The diagnosis of OCCC is typically set at a younger age, and earlier stage and in a background of endometriosis. RESULTS: Molecularly, OCCCs rarely harbor BRCA1/BRCA2 mutations and have fewer copy number variants (CNVs). The most common molecular changes occur in the SWI/SNF chromatin remodeling complex genes, the PI3K/AKT signaling pathway and the receptor tyrosine kinase (RTK)/Ras signaling pathway.Five-year disease-specific survival of patients with OCCC is worse compared to high grade serous carcinomas (HGSOC). The current treatment options for OCCC are based on studies that included patients with predominantly HGSOC and only a minor proportion of cancers with clear cell histology. In order to improve outcomes for patients with OCCC, research should be specific for this subtype. DISCUSSION: As the available information about the specific characteristics of OCCC is increasing, especially at a molecular level, it should be possible to continuously improve the specific diagnostics and treatment. Since OCCC is so rare, it is essential to collect new evidence at an international level. To avoid extrapolation from EOC trials with possible erroneous conclusions, patients should always be encouraged to participate in specific histological trials and basket trials, while paying extra attention to OCCC-like subtypes.

Prognostic and Theranostic Biomarkers in Ovarian Clear Cell Carcinoma.

In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theranostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 samples of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theranostic biomarkers (ALK, BRAF V600E, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-yr ovarian cancer-specific survival of 33.3%, compared with 91.5% in the other stage I cases). Among theranostic targets, ERBB2 amplification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 amplification for inclusion in gynecological basket trials targeting this alteration.

Improved long-term survival of corpus cancer in Japan: A 40-year population-based analysis.

The incidence of uterine corpus cancer has been increasing globally due to increase in obesity. However, a detailed analysis of long-term epidemiological trends of corpus cancer in Japan, where obesity is relatively minimal, has not been conducted. In this retrospective, population-based study using the Osaka Cancer Registry, we analyzed 15 255 cases of corpus neoplasia registered between 1977 and 2016. We determined the age-standardized incidence, mortality, relative survival and conditional survival rates, and the treatment trends for corpus cancer over the last 40 years in Japan. The age-standardized incidence rate of corpus neoplasia increased sharply in 2000-2011 (APC = 9.9, 95% CI: 8.4-11.3), whereas the mortality rate trended to a much more modest increase (APC = 3.3, 95% CI: 2.7-3.8). Compared to 1977-2000, 10-year survival rates for post-2000 cases of localized and regional corpus cancers significantly improved (from 87.7% [95% CI: 85.8-89.4] to 94.2% [95% CI: 92.7-95.7] and from 47.5% [95% CI: 43.3-51.6] to 64.4% [95% CI: 61.0-67.6], respectively). This was largely associated with the significant increase in the percentage of localized and regional patients who received chemotherapy instead of radiation as an adjuvant therapy combined to surgery (P < .001 for both). We found that each histological type (endometrioid carcinoma, serous carcinoma, clear cell carcinoma and carcinosarcoma) has different characteristics of trend of age-standardized incidence rate, relative survival and distribution of extent of disease. In endometrioid carcinoma, the age-standardized incidence rate increased consistently after 1990, but the rate of increase was decreasing after 1997.

Proposing a molecular classification associated with hypercoagulation in ovarian clear cell carcinoma.

BACKGROUND: Although ovarian clear cell carcinoma (CCC) is associated with high incidence of thromboembolism, the clinicopathological and biological significance of hypercoagulable status in CCC remains unclear. MATERIALS AND METHODS: We retrospectively analyzed pretreatment D-dimer levels, thromboembolic status, and clinical outcome of 125 CCCs in the discovery set and 143 CCCs in two other independent validation sets. Next, we performed RNA sequencing of 93 CCCs and compared coagulation-related gene profiles with 2492 pan-cancer data. We investigated differences in molecular characteristics of CCC subclasses based on coagulation status. RESULTS: In the discovery dataset, D-dimer elevation above the normal range was significantly associated with shorter progression-free and overall survival, irrespective to thromboembolic status. Multivariate analysis identified D-dimer elevation and clinical stage as an independent prognostic factors. We confirmed the prognostic significance of D-dimer elevation in the validation sets. Tissue factor and IL6, which are considered key elements of cancer-induced hypercoagulation, were highly expressed in CCC than in other cancers regardless of D-dimer level. Higher activity of various oncogenic pathways was observed in CCC with compared to without D-dimer elevation. Moreover, hierarchical cluster analysis divided 57 CCCs with D-dimer elevation into immunologically hot and cold tumor subtypes. Hot tumors were characterized by enrichment of T-cell inflamed phenotype, inflammation, the epithelial-mesenchymal transition, and high serum levels of CRP, and cold tumors by enrichment of cell cycle and MYC pathways. CONCLUSIONS: CCC represents hypercoagulable disease and elevate D-dimer is a prognostic factor for decreased survival in CCC. D-dimer high CCC has distinct molecular characteristics into the inflammatory-driven pathway (hot tumor) and the immune-suppressive pathway (cold tumor). Treatment implication of our proposed molecular classification merits further investigation.

Clear cell carcinoma of the ovary: Epidemiology, pathological and biological features, treatment options and clinical outcomes.

Clear cell carcinoma of the ovary is a rare and distinct histotype of epithelial ovarian carcinomas. Women diagnosed with clear cell carcinomas are usually younger and diagnosed at earlier stages than those with the most common high-grade serous histology. Endometriosis is considered a main risk factor for the development of clear cell carcinoma of the ovary, and it can be considered a precursor of of this tumor, as it is identified in more than 50% of patients with clear cell carcinoma. Different molecular pathways and alterations heve been identified in ovarian clear cell carcinoma, including the most common mutations of AT-rich interaction domain 1A [ARID1A] and phosphatidylinositol-4,5-bisphosphate 3-kinase [PIK3] catalytic subunit alpha [PIK3CA]. The prognosis of patients at early stage is favorable, while patients with advanced or recurrent disease experience a poor oncologic outcomes. Despite a lower rate of responses due to an intrinsic chemoresistance, the treatment strategy for advanced disease resembles the treatment of high-grade serous carcinoma, which includes aggressive cytoreductive surgery and platinum-based chemotherapy. For this reason, the role of adjuvant chemotherapy in patients with stage I disease undergoing complete surgical staging is still under debate. Alternative treatments, including biological agents that target different pathways constitute the most promising treatment strategies, and well-designed, collaborative international trials should be designed in order to improve the oncologic outcomes and the quality of life of patients with this aggressive disease.

Genetic alterations and their therapeutic implications in epithelial ovarian cancer.

BACKGROUND: Genetic alterations for epithelial ovarian cancer are insufficiently characterized. Previous studies are limited regarding included histologies, gene numbers, copy number variant (CNV) detection, and interpretation of pathway alteration patterns of individual patients. METHODS: We sequenced 410 genes to analyze mutations and CNV of 82 ovarian carcinomas, including high-grade serous (n = 37), endometrioid (n = 22) and clear cell (n = 23) histologies. Eligibility for targeted therapy was determined for each patient by a pathway-based approach. The analysis covered DNA repair, receptor tyrosine kinase, PI3K/AKT/MTOR, RAS/MAPK, cell cycle, and hedgehog pathways, and included 14 drug targets. RESULTS: Postulated PARP, MTOR, and CDK4/6 inhibition sensitivity were most common. BRCA1/2 alterations, PTEN loss, and gain of PIK3CA and CCND1 were characteristic for high-grade serous carcinomas. Mutations of ARID1A, PIK3CA, and KRAS, and ERBB2 gain were enriched in the other histologies. PTEN mutations and high tumor mutational burden were characteristic for endometrioid carcinomas. Drug target downstream alterations impaired actionability in all histologies, and many alterations would not have been discovered by key gene mutational analysis. Individual patients often had more than one actionable drug target. CONCLUSIONS: Genetic alterations in ovarian carcinomas are complex and differ among histologies. Our results aid the personalization of therapy and biomarker analysis for clinical studies, and indicate a high potential for combinations of targeted therapies.

Clear Cell Adenocarcinoma in Men: A Series of 15 Cases.

Clear cell adenocarcinoma (CCA) is a rare tumor in the genitourinary tract with female predominance and few reports in men. We identified 15 cases of CCA in men evaluated at our institution. Five arose in the bladder, 7 in the prostate or prostatic urethra, 2 in the membranous urethra (1 multifocal in the prostatic and membranous urethra), 1 periprostatic (likely from an embryologic remnant), and 1 between rectum and bladder (likely in a prostatic utricle cyst). No cases showed associated Müllerian structures. One case showed separate foci of nephrogenic adenoma at diagnosis, and 1 case showed urothelial carcinoma in situ on a later follow-up biopsy. Four tumors extended into other organs (prostate to seminal vesicle and periprostatic soft tissue, periprostatic soft tissue to prostate, prostatic urethra to bladder and rectum, and prostate to bladder neck). One tumor showed extraprostatic extension alone. Four tumors metastasized to lymph nodes, with 3 also metastasizing to other sites (bladder, lung and adrenal, and right flank). Eleven patients underwent resection, including 3 transurethral resections. Seven underwent other treatments, including radiation (5 [1 for recurrence]), chemotherapy (3), hormonal therapy (3), immunotherapy with nivolumab (1), and targeted therapy with gefitinib (1). The mean follow-up was 35 months (range: 1 to 138 mo). At the last follow-up, 7 patients showed no evident disease and 3 were alive with disease. Four died with the cause of death unknown, with 2 cases having confirmed disease at the time of death and the remaining 2 dying less than a year after diagnosis. The mean time to death was 16 months (range: 6 to 39 mo). No follow-up was available on 1 patient. All patients who died in this series had CCA of the prostate or prostatic urethra. Pathologists need to be attuned to CCA occurring in males, given that the literature emphasizes its occurrence in females. In addition to established sites such as bladder and urethra, our series demonstrates that tumor may present in unusual adjacent sites, such as in periprostatic embryologic remnants or prostatic utricle.