Uterine Clear Cell Carcinoma Research Articles

Prognostic nomogram for predicting the overall survival rate of patients with uterine clear-cell carcinoma: Based on SEER database.

To evaluate the risk factors for uterine clear-cell carcinoma (UCCC) and construct nomograms predicting 1-, 3-, and 5-year overall survival rates of patients with UCCC. The demographic and clinical information of 1674 patients diagnosed with UCCC between 2004 and 2015, including age, race, marital status, tumor size, American Joint Committee on Cancer (AJCC) stage, and details of surgery and radiotherapy/chemotherapy, was collected from the Surveillance, Epidemiology, and End Results (SEER) database. After excluding patients with unknown AJCC stage, race, marital status, or lymph node information, 1469 patients remained. Risk factors were determined using univariate and multivariate analyses, and nomograms were developed to predict 1-, 3-, and 5-year overall survival of UCCC. Various indicators were used to evaluate the performance of the nomogram, such as the C-index, net classification improvement (NRI) and decision curve analysis (DCA). Age, log odds of positive lymph nodes, AJCC stage, surgery status, and chemotherapy status were independent risk factors for UCCC. The C-indexes of the training group and AJCC stage groups were 0.771 and 0.697, respectively. The results for the area under the receiver operating characteristics curve, NRI, and calibration curves indicated that the nomogram had good predictive ability. DCA revealed that the nomogram had greater clinical applicability than AJCC stage alone. Internal validation using the validation cohort also demonstrated that this nomogram had good predictive performance. A new nomogram comprising a combination of demographic and clinical characteristics provided better survival predictions than the AJCC staging system alone, which will facilitate prognostic assessments and clinical decision-making.

Abstract B002: ARID1A loss activates MAPK signaling via DUSP4 downregulation: a mechanistic insight in endometrial carcinoma

Abstract The intricate interplay between chromatin remodelers, transcriptional regulation, and downstream cellular processes is gradually unraveling. AT-rich interactive domain-containing protein 1A (ARID1A), a tumor suppressor and chromatin remodeler, is frequently mutated in endometrium-related malignancies including ovarian or uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). How ARID1A mutation alters downstream signaling is yet to be established. Based on the TCGA proteomics datasets, MAPK and ARID1A are negatively correlated in endometrial cancer. Yet, the underlying molecular mechanism of this association remains unclear. Using ARID1A-proficient and ARID1A-deficient isogenic human endometrial epithelial cells, we explored transcriptomic changes and discovered notable downregulation of a MAPK phosphatase, dual-specificity phosphatase 4 (DUSP4), in ARID1A-deficient cells. This expression pattern was further validated in additional pairs of isogenic cell lines, ES-2, MCF10a, and HCT116. Chromatin immunoprecipitation sequencing (ChIP-seq) was utilized to assess active and repressive transcription histone marks on global and 5’ transcriptional regulatory regions of DUSP4. ChIP-seq demonstrated decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 enhancer and promoter regions of ARID1A-deficient cells, suggesting ARID1A's role in modulating chromatin accessibility and gene expression. Furthermore, a positive correlation between ARID1A and DUSP4 expression was established using a Pax8-driven conditional knockout mouse cohort and in human endometroid carcinoma tissues. Moreover, an inverse expression correlation between ARID1A and the phosphatase substrates of DUSP4, including p-p38, p-JNK, and p-ERK in the MAPK signaling pathway, was observed in this genetically engineered murine model and in the TCGA datasets of human uterine carcinomas. Interestingly, ectopic DUSP4 expression decreased cell proliferation, and MAPK pathway targeting, specifically via ERK inhibitor Ulixertinib, significantly mitigated tumor growth in vivo. In conclusion, our findings suggest ARID1A modulates DUSP4 expression by remodeling the chromatin landscape which leads to an inhibitory effect on the MAPK pathway and suppresses tumor progression. ARID1A-DUSP4-MAPK axis offers a promising avenue for developing targeted therapies against ovarian or uterine CCC and EMCA. Citation Format: Jayaprakash Mandal, Zheng-Cheng Yu, Ie-Ming Shih, Tian-Li Wang. ARID1A loss activates MAPK signaling via DUSP4 downregulation: a mechanistic insight in endometrial carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr B002.

ARID1A loss activates MAPK signaling via DUSP4 downregulation

BackgroundARID1A, a tumor suppressor gene encoding BAF250, a protein participating in chromatin remodeling, is frequently mutated in endometrium-related malignancies, including ovarian or uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). However, how ARID1A mutations alter downstream signaling to promote tumor development is yet to be established.MethodsWe used RNA-sequencing (RNA-seq) to explore transcriptomic changes in isogenic human endometrial epithelial cells after deleting ARID1A. Chromatin immunoprecipitation sequencing (ChIP-seq) was employed to assess the active or repressive histone marks on DUSP4 promoter and regulatory regions. We validated our findings using genetically engineered murine endometroid carcinoma models, human endometroid carcinoma tissues, and in silico approaches.ResultsRNA-seq revealed the downregulation of the MAPK phosphatase dual-specificity phosphatase 4 (DUSP4) in ARID1A-deficient cells. ChIP-seq demonstrated decreased histone acetylation marks (H3K27Ac, H3K9Ac) on DUSP4 regulatory regions as one of the causes for DUSP4 downregulation in ARID1A-deficient cells. Ectopic DUSP4 expression decreased cell proliferation, and pharmacologically inhibiting the MAPK pathway significantly mitigated tumor formation in vivo.ConclusionsOur findings suggest that ARID1A protein transcriptionally modulates DUSP4 expression by remodeling chromatin, subsequently inactivating the MAPK pathway, leading to tumor suppression. The ARID1A-DUSP4-MAPK axis may be further considered for developing targeted therapies against ARID1A-mutated cancers.

Molecular landscape of ERBB2/HER2 gene amplification among patients with gynecologic malignancies; clinical implications and future directions

ObjectiveInvestigate the prevalence of ERBB2/HER2 gene amplification among patients with gynecologic malignancies. MethodsThe American Association of Cancer Research (AACR) Genomics Evidence of Neoplasia Information Exchange (GENIE) (version 13.1) database was accessed and patients with endometrial, ovarian, and cervical cancer were identified. Patients with available data on the presence of copy-number gene alterations were selected for further analysis. Incidence of ERBB2 amplification following stratification by tumor site and histology was evaluated. Data from the OncoKB database, as provided by cBioPortal, was utilized to determine presence of pathogenic genomic alterations. ResultsA total of 6961 patients who met the inclusion criteria were identified: 49.1% with ovarian cancer, 45.2% with endometrial cancer and 5.7% with cervical cancer respectively. Overall incidence of ERBB2 amplification was 3.8%. Highest incidence of ERBB2 amplification was observed among patients with mucinous ovarian (14.4%), uterine serous (13.2%), uterine clear cell (9.4%), and uterine carcinosarcoma (7.9%). ERBB2 amplification was rare among patients with TP53 wild-type endometrioid endometrial cancer (0.4%). High incidence of mutations in genes of the PI3K pathway was observed among patients with ERBB2 amplified tumors. ConclusionERBB2 amplification is frequently encountered among patients with uterine serous carcinoma, and mucinous ovarian carcinoma. In addition, a high incidence was also observed among those with uterine clear cell carcinoma, and uterine carcinosarcoma. For patients with endometrioid endometrial carcinoma, incidence of ERBB2 amplification is low, especially in the absence of TP53 mutations.

Comparison of clinical characteristics and prognosis in endometrial carcinoma with different pathological types: a retrospective population-based study

BackgroundEndometrial carcinoma (EC) is the second most common gynecological malignancy, and the differences between different pathological types are not entirely clear. Here, we retrospectively collected eligible EC patients to explore their differences regarding clinical characteristics and prognosis.MethodsFive hundred seventy EC patients from the First Affiliated Hospital of Zhengzhou University were included. Prognostic factors were measured using the univariate/multivariate Cox models. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary endpoints, respectively.ResultsIn total, 396 patients with uterine endometrioid carcinoma (UEC), 106 patients with uterine serous carcinoma (USC), 34 patients with uterine mixed carcinoma (UMC), and 34 patients with uterine clear cell carcinoma (UCCC) were included. Comparison of baseline characteristics revealed patients diagnosed with UEC were younger, had more early clinical stage, and had lower incidence of menopause and lymph node metastasis. Compared to UEC, other pathological EC obtained more unfavorable OS (UCCC: HR = 12.944, 95%CI = 4.231–39.599, P < 0.001; USC: HR = 5.958, 95%CI = 2.404–14.765, P < 0.001; UMC: HR = 1.777, 95%CI = 0.209–15.114, P = 0.599) and PFS (UCCC: HR = 8.696, 95%CI = 1.972–38.354, P = 0.004; USC: HR = 4.131, 95%CI = 1.243–13.729, P = 0.021; UMC: HR = 5.356, 95%CI = 0.935–30.692, P = 0.060). Compared with UEC patients, the OS of UCCC patients in stage I–II and USC patients in stage III–IV were significantly worse, while UMC patients in stage I–II favored poorer PFS. The OS of UCCC patients receiving no postoperative adjuvant therapy or chemotherapy alone were significantly worse.ConclusionsThe baseline characteristics of UEC and other rare EC types varied greatly, and the prognostic significance of different pathological types on EC patients depended on clinical tumor stages and therapeutic options.

P64-2 Durable response and adverse events in a patient with non-MSI-H uterine clear cell carcinoma on pembrolizumab/lenvatinib

P64-2 Durable response and adverse events in a patient with non-MSI-H uterine clear cell carcinoma on pembrolizumab/lenvatinib

Clinical, pathological, and comprehensive molecular analysis of the uterine clear cell carcinoma: a retrospective national study from TMRG and GINECO network

BackgroundUterine clear cell carcinomas (CCC) represent less than 5% of uterine cancers. Their biological characteristics and clinical management remain uncertain. A multicenter study to explore both clinical and molecular features of these rare tumors was conducted.MethodsThis multicenter retrospective national study was performed within the French TMRG (Rare Gynecologic Malignant Tumors) network. Clinical data and, when available, FFPE blocks were collected. Clinical features, treatments, and outcome (progression-free survival (PFS) and overall survival (OS)) were analyzed and correlated to the protein (tissue micro-array), RNA (Nanostring nCounter® technology), and DNA (array-Comparative Genomic hybridization and target-next generation sequencing) levels using the tumor samples available.ResultsSixty-eight patients with uterine CCC were enrolled, 61 from endometrial localization and 5 with cervix localization. Median age at diagnosis was 68.9 years old (range 19–89.7). Most tumors were diagnosed at an early stage (78% FIGO stage I–II). Hysterectomy (performed in 90%) and lymph node dissection (80%) were the most frequent surgical treatment. More than 70% of patients received external beam radiotherapy and 57% received brachytherapy. Nearly half (46%) of the patients received chemotherapy. After a median follow-up of 24.7 months, median PFS was 64.8 months (95 CI [5.3–124.4]) and median OS was 79.7 (IC95 [31.0–128.4]). Low hormone receptor expression (13% estrogen-receptor positive), frequent PI3K pathway alterations (58% PTEN loss, 50% PIK3CA mutations), and P53 abnormalities (41%) were observed. Mismatch repair deficiency was identified in 20%. P16 expression was associated with shorter PFS (HR = 5.88, 95 CI [1.56–25], p = 0.009). Transcriptomic analyzes revealed a specific transcriptomic profile notably with a high expression of immune response-associated genes in uterine CCC displaying a very good overall prognosis.ConclusionsUterine CCC reported to be potentially MSI high, hormone receptors negative, and sometimes TP53 mutated. However, some patients with immune response-associated features and better prognosis may be candidate to treatment de-escalation and immunotherapy.

A nomogram for predicting cancer-specific survival in patients with uterine clear cell carcinoma: a population-based study

Uterine clear cell carcinoma (UCCC) is a relatively rare endometrial cancer. There is limited information on its prognosis. This study aimed to develop a predictive model predicting the cancer-specific survival (CSS) of UCCC patients based on data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018. A total of 2329 patients initially diagnosed with UCCC were included in this study. Patients were randomized into training and validation cohorts (7:3). Multivariate Cox regression analysis identified that age, tumor size, SEER stage, surgery, number of lymph nodes detected, lymph node metastasis, radiotherapy and chemotherapy were independent prognostic factors for CSS. Based on these factors, a nomogram for predicting the prognosis of UCCC patients was constructed. The nomogram was validated using concordance index (C-index), calibration curves, and decision curve analyses (DCA). The C-index of the nomograms in the training and validation sets are 0.778 and 0.765, respectively. Calibration curves showed good consistency of CSS between actual observations and nomogram predictions, and DCA showed that the nomogram has great clinical utility. In conclusion, a prognostic nomogram was firstly established for predicting the CSS of UCCC patients, which can help clinicians make personalized prognostic predictions and provide accurate treatment recommendations.

Clinical utility of plasma ctDNA sequencing monitoring and tumor molecular profile exploration in endometrial carcinoma: A Caribbean prospective cohort from Martinique.

e17625 Background: A higher incidence of agressive endometrial cancer (EC) has been reported amongst the Martinican population. Indeed, there are respectively 25%, 12% and 3 % of high grade serous carcinoma, carcinosarcoma and clear cell uterine carcinoma, all with poor prognosis. Genomic stratification helps to improve the management of patients with EC. Indeed, localized EC molecular classification discriminated the benefit of adjuvant therapy according to molecular subgroups. However, collecting tissue samples in EC remains challenging. The aim of our study was to assess the clinical utility of ctDNA monitoring in EC and tumor tissue molecular profiling in high grade non endometrioid EC. Methods: We conducted a prospective monocentric study including high grade non endometrioid EC patients enrolled in the EndoNGS trial (NCT04932525). Each patient underwent molecular analysis to define the tumor molecular landscape. A comparative analysis “tumor-germline” including microsatellite instability and panel gene sequencing was then performed. ctDNA was profiled using dPCR and RT PCR. Results: From May 2020 to September 2021, 25 patients with high grade non endometriod EC were included. Median age at diagnosis was 72 years (60-88). FIGO stage at diagnosis was I, II, III and IV in 28%, 4%, 32% and 24% respectively. 10 patients out 25 received radiochemotherapy. Only 6 underwent exclusive radiotherapy and 13 received adjuvant platinum chemotherapy addjuvant to surgery. All tumor had MSS and none harbored a POLE mutation. 19 patients underwent molecular profiling according to a panel of 80 genes. The analysis identified 30 mutations: 22 pathogenic missenses, 3 nonsenses and 5 frameshift mutations. A TP53 mutation was observed in 89.5 % of cases. We identified 26% hotspot mutations. The other mutations are infrequent or not described in TGCA database. TP53 mutation analysis reported 15 missenses, one frameshift and one nonsense mutation. Moreover 88% of TP53 mutated tumors were affected by biallelic inactivation. In this population, variants in PIK3CA represent 26% compared to 42% reported from TGCA database and none PPP2R1A and FBXW7 mutations have been detected compared to 32% and 24% for PPP2R1A and FBXW7 respectively. ctDNA abondance was correlated to the stage. 10 patients had positive ctDNA at diagnosis (9 were stage III and 1 stage IV). In 3 patients, ctDNA became negative during therapy (radiochemotherapy). During course of disease, 15 relapsed, (with a median 12 month relapse free period) amongst which 10 had positive ctDNA. Conclusions: We reported for the first time the molecular profiling of aggressive EC in a homogenous carribbean cohort from Martinique. Overall, our analysis demonstrates that genomic profiling with a large panel of ctDNA in localized EC is reliable and feasible; ctDNA monitoring was associated to early relapse.

The role of adjuvant treatment for early-stage uterine clear cell carcinomas

BackgroundUterine clear cell carcinoma is a rare and aggressive subtype of endometrial carcinoma. Prospective clinical trials have not been feasible for this rare tumor, and data regarding the optimal adjuvant treatment regimen for early-stage uterine clear cell carcinomas is limited. Our study's objective was to determine if adjuvant chemotherapy or radiation therapy improves patients' outcomes in stage I and II uterine clear cell carcinoma. MethodsPatients with stage I and II uterine clear cell carcinoma were identified at a single institution. All cases were reviewed by a gynecologic pathologist. Both pure and mixed non-serous uterine clear cell carcinomas were included. Primary outcomes were recurrence free survival and overall survival. ResultsA total of 71 patients were identified including 39 (55%) pure and 32 (45%) mixed clear cell carcinoma. Most patients were FIGO stage IA (77.5%). Most patients (n = 58, 82%) received adjuvant therapy, including 43 (61%) receiving chemotherapy, 50 (70%) receiving radiation therapy, and 35 (49%) receiving both. Recurrence free survival was not significantly different among patients receiving no or <6 cycles of chemotherapy versus patients receiving 6 cycles of chemotherapy (p = 0.39). However, median OS was significantly different among patients receiving no or <6 cycles of chemotherapy versus 6 cycles of chemotherapy (p = 0.004). On univariable analysis, 6 cycles of chemotherapy was significantly associated with improved OS (HR 0.1, 95% CI 0.01–0.07). Presence of LVSI, mutated p53, number of pelvic and para-aortic lymph nodes assessed, adjuvant chemotherapy (any number of cycles), and >2 medical co-morbidities were not significant predictors of OS on univariable analysis. On multivariable analysis, 6 cycles of adjuvant chemotherapy remained a significant predictor of improved OS (HR 0.1, 95% CI 0.01–0.8). ConclusionsIn this study, administration of 6 cycles of chemotherapy appears to significantly improve OS. This finding suggests consideration of 6 cycles of adjuvant chemotherapy in patients with early-stage uterine clear cell carcinoma, however clinical trials are needed to confirm these findings.

Survival after laparoscopy versus laparotomy for apparent early-stage uterine clear cell carcinoma: Results of a large multicenter cohort study.

ObjectiveTo compare the long-term survival between laparoscopic surgery and open surgery in patients with apparent early-stage uterine clear cell carcinoma (UCCC).Patients and methods254 patients with apparent early-stage UCCC were reviewed. Comparisons were made between patients who underwent laparoscopic surgery versus those who underwent open surgery. Baseline data, clinicopathological data, and oncological outcomes were analyzed. 5-year disease-free survival (DFS) rate and 5-year overall survival (OS) rate were estimated and compared using the Kaplan-Meier method and the Log-rank test. The Cox proportional hazard regression model was employed to control the confounding factors.Results147 patients underwent laparoscopic surgery, and 107 patients were managed by open surgery. No differences in terms of recurrence rate (laparoscopy versus laparotomy: 10.9% versus 12.9%, P=0.842) and recurrence pattern were observed. For patients who underwent open surgery and patients who underwent laparoscopic surgery, the 5-year DFS rates and 5-year OS rate were 75.8% (95% CI: 65.8%-83.2%) and 69.1% (95% CI: 58.8%-77.4%), 66.0% (95% CI: 57.1%-73.5%) and 60.8% (95% CI: 52.0%-68.5%), respectively. The Cox proportional hazards regression model shown that for apparent early-stage UCCC, the approach of surgical staging was not an independent predictor for survival (laparoscopy versus laparotomy: for DFS, aHR=1.06, 95% CI=0.64-1.75, P=0.826; for OS, aHR=1.10, 95% CI=0.72-1.68, P=0.671).ConclusionFor apparent early-stage UCCC, in terms of oncological survival, laparoscopic surgery was as safe as open surgery.

The role of adjuvant treatment for early-stage uterine clear cell carcinoma (405)

<b>Objectives:</b> Uterine clear cell carcinoma (UCCC) is a rare histologic subtype of endometrial carcinoma (EC) that is associated with early metastasis, chemoresistance, and poor survival. Due to the aggressive behavior of UCCC and the inability to perform prospective clinical trials for this rare tumor type, adjuvant treatment choices for stage I and II UCCC are often made at the provider's discretion. Our objectives were to determine if adjuvant chemotherapy (CT), radiation therapy (RT), or both were associated with differences in recurrence-free survival (RFS) and overall survival (OS) in stage I and II UCCC confirmed by gynecologic pathology review. <b>Methods:</b> All patients with stage I and II UCCC between 2006 and 2019 were identified via a single institution pathology database. Electronic medical records were used for demographic and clinical- pathologic data. All cases were reviewed by a gynecologic pathologist. Cases of both pure UCCC and mixed non-serous UCCC were included due to prior evidence that mixed UCCC outcomes are driven by the clear cell (CC) component. RFS and OS were analyzed using Kaplan-Meier (KM) failure functions and a Cox proportional hazards (PH) model. <b>Results:</b> A cohort of 71 patients was identified, including 39 (55%) pure UCCC and 32 (45%) mixed UCCC. Most patients were FIGO stage IA (77.5%). Mixed UCCC tumors ranged from 2-90% CC. Among 32 patients with mixed UCCC, 30 (94%) had endometrioid/CC, and two (6%) had endometrioid, CC, and mucinous histology. Of 58 (82%) patients receiving adjuvant therapy, 43 (61%) received CT, 50 (70%) received RT, and 35 (49%) received both. Recurrences were rare, with one local, three regional, and three distant recurrences in the cohort. Deaths were also rare (<i>n</i>=9) and most likely to be cancer-related (<i>n</i>=4). The Median follow-up time was 1078 days. The 5-year RFS was 85% (95% CI: 70-93%) and 5-year OS was 88% (95% CI: 74-94%). 5-year RFS and OS among patients with and without RT were 88% (95% CI: 39-98%) versus 85% (95% CI: 71-93%) and 88% (95% CI: 62-97%) versus 87% (95% CI: 68-95%). 5-year RFS and OS among patients with and without CT were 82% (95% CI: 0.64-0.92) versus 94% (95% CI: 65-99%) and 90% (95% CI: 75-96%) versus 79% (95% CI: 32-95%). There was no difference in RFS among patients receiving no or less than six cycles of CT (<i>n</i>=38) versus patients who received six cycles (<i>n</i>=32) (HR: 0.5, 95% CI: 0.1-2.4). OS was significantly improved for patients who received six cycles of CT versus patients who received no or less than six cycles of CT (HR: 0.1, 95% CI: 0.01-0.7). On univariate analysis, receiving six cycles of CT was predictive of OS. No other variables were statistically significant; however, lymphovascular space invasion and >2 medical comorbid conditions were included in the Cox PH multivariable analysis given their clinical significance. Adjuvant CT remained a significant predictor of improved OS (HR: 0.1, 95% CI: 0.01-0.8) when controlling for these clinically significant factors. <b>Conclusions:</b> In this cohort, OS was significantly improved with six cycles of CT, and CT remained a significant predictor of OS on multivariable analysis. While additional studies are needed, our findings support a full course of adjuvant CT in patients with early-stage UCCC.

Oncological Safety of Laparoscopic Surgery for Women with Apparent Early-stage Uterine Clear Cell Carcinoma: A Multicenter Retrospective Cohort Study

To study the effect of different surgical approaches (laparoscopy and laparotomy) on the oncological outcomes of patients with apparent early-stage uterine clear cell carcinoma (UCCC). Retrospective cohort study. Four Chinese teaching hospitals. A total of 273 women with apparent early-stage UCCC. All included patients were surgically staged by laparoscopy or laparotomy. The eligible patients were divided into the laparotomy group and the laparoscopy group. Disease-free survival (DFS) and overall survival (OS) were evaluated by the Kaplan-Meier method and compared by the log-rank test. The Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the effect of surgical approach on DFS and OS. With a median follow-up of 31.0 months, the 3-year DFS rates were 68.82% and 64.27% in the laparotomy group and the laparoscopy group, respectively. The difference in DFS between the 2 groups was not statistically significant (HR, 1.06; 95% CI, 0.72-1.58; p=.758). In addition, the 3-year OS rate (72.76% vs 73.46%; HR, 1.06; 95% CI, 0.65-1.72; p=.823) was not different between the 2 groups. Furthermore, multivariable analysis showed that for patients with apparent early-stage UCCC, the approach of surgical staging was not an independent prognostic factor for OS (adjusted HR, 1.29; 95% CI, 0.78-2.12; p=.321) and DFS (adjusted HR, 1.11; 95% CI, 0.73-1.68; p=.621). For clinical early-stage clear cell carcinoma of the uterus, staging by laparoscopy is oncologically safe. This needs to be justified by further prospective studies.

Cervical cytology in the detection of uterine clear cell carcinoma: Diagnostic predictors from a case-control study.

Uterine clear cell adenocarcinoma (CCC) is a rare, aggressive malignancy with poor prognosis. The present study aimed to identify and describe its characteristic morphological features in cervical cytology. This was a 3-year retrospective case-control study. Cases included cervical samples of histopathologically proven endometrial and cervical CCC. Controls included cervical samples of histopathologically proven endometrial serous carcinoma (n=15), endometrioid adenocarcinoma (n=20), and endocervical adenocarcinoma (n=15). Twenty-eight cytomorphological features were evaluated; the strength of association was determined by odds ratio (OR) and Cramer's V, and the diagnostic accuracy of statistically significant features was assessed. Cases consisted of histopathologically proven 25 (34.7%) endometrial and 13 (18.0%) cervical CCC. Corresponding cervical samples were available for a total of 14 (36.8%) patients, of which 13 (92.8%) were positive for epithelial cell abnormality. On univariate analysis, three cytomorphological variables were significant predictors of uterine CCC: presence of dense cytoplasm (OR=88; V=0.72), deep nuclear membrane irregularities (OR=17.5; V=0.55), and coarse chromatin (OR=21.3; V=0.46). Dense cytoplasm had the highest positive predictive value (92%) and high specificity (97.8%), whereas coarse chromatin had the highest sensitivity (92.3%) and negative predictive value (96.7%). The presence of dense cytoplasm and deep nuclear membrane irregularities in the tumour cells were strong predictors, and coarse chromatin a moderate predictor, of uterine CCC compared to its close cytological mimics.

Metastasis of clear cell adenocarcinoma of the uterine corpus to the cerebellum

Brain metastases from clear cell uterine carcinoma are extremely rare and are associated with a poor prognosis. Case report. A case of metastasis to the cerebellum in a 55-year-old patient with uterine adenocarcinoma is presented. The diagnosis of uterine cancer T2N1M1, stage IV was established in 2016. Extirpation of the uterus, lymph node dissection, radiation and chemotherapy were performed. In 2018, the patient developed neurological symptoms. On MRI scan a tumor in the posterior cranial fossa was found. Without progression in other organs and the area of the primary focus. The tumor was resected. Histology: brain metastasis from clear cell uterine adenocarcinoma. Radiation and chemotherapy were performed. The patient’s neurological symptoms regressed. In the future, a complete response to the treatment was recorded. Discussion. Our case illustrates a rare metastasis from clear cell uterine adenocarcinoma. Brain metastases from uterine adenocarcinoma do not have a specific radiographic feature. Management of such patients should include a combined treatment, which can increase life expectancy. The life expectancy of our patient at the time of the control examination was 29 months.

Clinicopathological and survival analysis of 34 cases of uterine clear cell carcinoma

Objective: To analyze the clinicopathological features and prognostic factors of patients with uterine clear cell carcinoma (UCCC). Methods: UCCC patients who underwent surgery and complete follow-up at Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College between January 1, 2004 and December 31, 2014 were retrospectively reviewed. The Kaplan-Meier method and Cox regression analysis were used for survival analysis. Results: The study included 34 patients. Only 18 patients (52.9%) were diagnosed with UCCC preoperatively and 8 patients (23.5%) underwent UCCC standard comprehensive staging surgery. Among the 34 patients, stage ⅠA was 17 cases (50.0%), stage ⅠB was 1 case (2.9%), stage Ⅱ was 4 cases (11.8%), stage ⅢA was 2 cases (5.9%), stage ⅢB was 1 case (2.9%), stage ⅢC1 was 5 cases (14.7%) and stage ⅣB was 4 cases (11.8%). The median follow-up period was 72 months, 5-years disease-free survival (DFS) rate and overall survival (OS) rates for all patients were 79.1% and 81.3%, respectively. Univariate analysis result showed that preoperative CA125 level, range of lymphadenectomy, tumor stage and peritoneal cytology were significantly associated with DFS (P<0.05). Preoperative CA125 level, range of lymphadenectomy, tumor stage, peritoneal cytology and lymph vascular space invasion were significantly associated with OS (P<0.05). Multivariate analysis result showed that peritoneal cytology was the only independent prognostic factor for DFS, the relapse risk of peritoneal cytology positive patients was 11.47 folds higher than that of the negative patients (P=0.009). Tumor stage was the only independent prognostic factor for OS, the death risk of ⅣB stage patients was 25.29 folds higher than that of theⅠA stage (P=0.009). Conclusions: The preoperative pathological diagnosis of UCCC is difficult, which results in incomplete surgical staging. Peritoneal cytology and tumor stage are independent prognostic factors for DFS and OS of UCCC patients, which deserve much more attention in clinical practice.

Adjuvant vaginal interventional radiotherapy in early-stage non-endometrioid carcinoma of corpus uteri: a systematic review.

PurposeThis systematic review focused on rare histological types of corpus uteri malignancy, including uterine carcinosarcoma (UCS), uterine clear cell carcinoma (UCCC), and uterine papillary serous carcinoma (UPSC), and it is proposed to assist with clinical decision-making. Adjuvant treatment decisions must be made based on available evidences. We mainly investigated the role of vaginal interventional radiotherapy (VIRt) in UCS, UCCC, and UPSC managements.Material and methodsA systematic research using PubMed and Cochrane library was conducted to identify full articles evaluating the efficacy of VIRt in early-stage UPSC, UCCC, and UCS. A search in ClinicalTrials.gov was performed in order to detect ongoing or recently completed trials as well as in PROSPERO for ongoing or recently completed systematic reviews. Survival outcomes and toxicity rates were obtained.ResultsAll studies were retrospective. For UCS, the number of evaluated patients was 432. The 2- to 5-year average local control (LC) was 91% (range, 74.2-96%), disease-free survival (DFS) 88% (range, 82-94%), overall survival (OS) 79% (range, 53.8-84.3%), the average 5-year cancer-specific survival (CSS) was 70% (range, 70-94%), and G3-G4 toxicity was 0%. For UCCC, the number of investigated patients was 335 (UCCC – 124, mixed – 211), with an average 5-year LC of 100%, DFS of 83% (range, 82-90%), OS of 93% (range, 83-100%), and G3-G4 toxicity of 0%. For UPSC, the number of examined patients was 1,092 (UPSC – 866, mixed – 226). The average 5-year LC was 97% (range, 87.1-100%), DFS 84% (range, 74.7-95.6%), OS 93% (range, 71.9-100%), CSS 89% (range, 78.9-94%), and G3-G4 toxicity was 0%.ConclusionsThese data suggest that in adequately selected early-stage UPSC and UCCC patients, VIRt alone may be suitable in women who underwent surgical staging and received adjuvant chemotherapy. In early-stage UCS, a multidisciplinary therapeutic approach has to be planned, considering high-rate of pelvic and distant relapses.

The effect of surgical approach on the outcomes and prognosis of high-risk histologic endometrioid carcinomas.

High-risk histologic endometrioid carcinomas include poorly differentiated endometrial carcinoma (PDEC), uterine clear cell carcinoma (UCCC), uterine carcinosarcoma (UCS), and uterine papillary serous carcinomas (UPCS). The purpose of this study was to investigate and compare the effect of open surgery and minimally invasive surgery on the prognosis of patients with high-risk endometrial cancer tissue types. A retrospective analysis was conducted to investigate 57 UCS or UPCS, 53 UCCC, and 110 PDEC patients receiving initial treatment at the Department of Gynecology in Shaanxi Provincial Tumor hospital and the Affiliated Hospital of Medical College of Xi'an Jiaotong University between February 2010 and January 2015. Prognostic factors were determined using univariate/multivariate analysis, and survival rates were assessed using the Kaplan-Meier method. The Cox regression model was adopted to assess the independent prognostic factors. Two hundred and twenty patients who met the criteria were included in this study. At the end of follow-up period, 94 patients were still alive. Univariate analysis found that the survival time of the patients was related to staging, adjuvant therapy, and surgical approach. Multivariate analysis revealed that surgical approach, staging, pathology, and adjuvant therapy were independent prognostic factors. Minimally invasive surgery has a shorter survival time compared to open surgery in women with PDEC, UCCC, UCS, and UPCS. Multivariate analysis confirmed that staging, pathological type, surgical approach, and postoperative adjuvant therapy are independent risk factors for prognosis and affect the survival of women with PDEC, UCCC, UCS, and UPCS.

Combined anti-HER2 and hormonal treatment in a patient with HR+HER2+ clear-cell uterine carcinoma: A case report.

Clear-cell carcinoma (CCC) of the uterus is an aggressive disease. Current international guidelines on the treatment of uterine carcinomas predominantly cover cancer with endometrioid histology, and clinicians tend to use the same approach for patients with non-endometrioid histology due to the absence of separate guidelines for these rare tumor types. At present, molecular analysis enables the assessment of novel and non-standard treatment options based on the individual characteristics of a tumor. The present report presents a clinical case of successful treatment of a patient with clear cell uterine carcinoma with HER2 and ER expression. Non-toxic targeted treatment was used based on immunohistochemistry (IHC) data. The patient received anti-HER2 and hormonal treatment and demonstrated an excellent response. The follow-up period was 47 months and the patient remained stable during treatment without significant toxicity. Therefore, this approach demonstrated the potential for selecting highly-specific therapy for rare tumors, which lack distinct recommendations for their treatment.

Histomolecular features of high-grade endometrial cancers.

High-grade endometrial cancers (ECs) are an aggressive subset of ECs accounting for 70-80% of EC-related deaths. Currently, staging surgery, together with chemotherapy or radiotherapy, is the primary treatment strategy for these cancers. The widespread use of next-generation sequencing has led to a refined understanding of EC's genomics with important information for diagnosis and therapy for individual patients (precision medicine). However, advances in the genomics assessment of high-grade tumors have been slower due to their lower incidence than low-grade EC. This article will briefly introduce the current state of knowledge of the genomics of G3 endometrioid EC, serous uterine cancer, clear cell uterine carcinoma and uterine carcinosarcoma and discuss its implications for diagnosis and targeted therapy.