Early-stage Clear Cell Carcinoma Research Articles

Prognosis and adjuvant chemotherapy for patients with malignant peritoneal cytology in early-stage non-endometrioid endometrial cancer

ObjectiveTo investigate the influence of malignant peritoneal cytology (MPC) on the prognosis of early-stage patients with endometrial clear cell carcinoma(CCC) and serous carcinoma(SC), and the value of chemotherapy in their treatment. MethodsA retrospective observational cohort study was conducted by querying the National Cancer Institute's Surveillance, Epidemiology, and End Results Program from 2010 to 2019. Women with early-stage CCC and SC with available peritoneal cytology results were enrolled. Propensity score matching(PSM) and propensity score inverse probability of treatment weighting (IPTW) was used to balance the measured covariates in each sub-cohort. ResultsA total of 3,616 eligible patients were included, and 368 patients had MPC (10.2%). Women with MPC were more likely to receive postoperative chemotherapy (OR 2.033; 95%CI 1.589–2.602). In PSM model, MPC had worse overall survival(OS) and cancer-specific survival (CSS) (All,p < 0.001). The 5-year OS rates were 56.5% for women with MPC and 74.4% for those with negative peritoneal cytology, and the 5-year CSS rates were 60.8% versus 80.0%(All, p < 0.0001). In the subgroup analyses, MPC was associated with decreased OS and CSS in serous, clear cell histology group, and stage IA cases(All,p < 0.001), but not for stage IB or stage II disease. In multivariate analysis, chemotherapy improved the prognosis of patients with MPC(OS:p = 0.005; CSS:p = 0.010). Additionally, in stage IA subgroup, chemotherapy improved survival outcomes in patients with MPC(OS:P = 0.025; CSS:P = 0.038), in NPC patients, however, chemotherapy was a good prognostic factor for OS (P = 0.001) but not for CSS(P = 0.300). ConclusionMPC was a prognostic factor for decreased survival in early-stage endometrial CCC and SC, and those with MPC could further benefit from chemotherapy.

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.

Systematic Lymphadenectomy and Oncological Outcomes of Women With Apparent Early-Stage Clear Cell Carcinoma of the Endometrium: A Multi-Institutional Cohort Study

ObjectiveThe survival value of systematic lymphadenectomy for endometrial cancer is ambiguous and controversial. The current study aimed to evaluate the long-term survival role of combined pelvic and para-aortic lymphadenectomy in patients with presumed early-stage clear cell carcinoma of the endometrium.MethodsPatients in three Chinese teaching hospitals who presented between 2012 and 2017 with apparent early-stage clear cell carcinoma of the endometrium and underwent surgical staging were selected. Patients who did and did not undergo systematic lymphadenectomy were identified and clinicopathological characteristics were compared. Disease-free survival and overall survival were evaluated following the generation of the Kaplan-Meier curves and the comparison using the log-rank test. A Cox proportional hazards model was employed to control for confounders.ResultsA total of 244 patients underwent systematic lymphadenectomy and 89 did not receive lymph node dissection. The demographic and baseline data were comparable between the two groups. The rate of disease-free survival at 5 years was 64.10% in patients who underwent systematic lymphadenectomy and 45.05% in patients who did not undergo lymphadenectomy. Patients who underwent systematic lymphadenectomy had better disease-free survival than those who did not receive lymphadenectomy (HR, 0.54. 95% CI, 0.38-0.76. P=0.000). The rate of 5-year overall survival was 68.87% in the lymphadenectomy group and 53.33% in patients who did not undergo systematic lymphadenectomy. Systematic lymphadenectomy was also associated with improved 5-year overall survival for women with presumed early-stage clear cell carcinoma of the endometrium (HR, 0.58. 95% CI, 0.39-0.85. P=0.005). After adjusting for confounders, systematic lymphadenectomy was still independently associated with improved disease-free survival and overall survival.ConclusionPatients with apparent early-stage clear cell carcinoma of the endometrium who underwent systematic lymphadenectomy had better long-term survival than those who did not undergo systematic lymphadenectomy.

Sensitive New Assay System for Serum Wisteria floribunda Agglutinin-Reactive Ceruloplasmin That Distinguishes Ovarian Clear Cell Carcinoma from Endometrioma.

Wisteria floribunda agglutinin (WFA)-reactive ceruloplasmin (CP) is a candidate marker for ovarian clear cell carcinoma (CCC) reported in our previous paper. Herein, a new measurement system was developed to investigate its potential as a serum marker for CCC. Site-specific glycome analysis using liquid chromatography/mass spectrometry showed that WFA-CP from CCC binds to WFA via the GalNAcβ1,4GlcNAc (LDN) structure. We used mutant recombinant WFA (rWFA), which has a high specificity to the LDN structure, instead of native WFA, to increase the specificity of the serum sample measurement. To improve the sensitivity, we used a surface plasmon field-enhanced fluorescence spectroscopy immunoassay system, which is approximately 100 times more sensitive than the conventional sandwich enzyme-linked immunosorbent assay system. With these two improvements, the specificity and sensitivity of the serum rWFA-CP measurement were dramatically improved, clearly distinguishing CCC from endometrioma, from which CCC originates. This rWFA-CP assay can be used clinically for the serodiagnosis of early-stage CCC, which is difficult to detect with existing serum markers.

Prevalence of lymph node metastasis and role of lymphadenectomy for apparent early-stage ovarian clear cell carcinoma

Objectives: Determine the incidence of lymph node (LN) metastasis and impact of lymphadenectomy (LND) on the survival of patients with apparent early stage clear cell carcinoma (OCCC). Methods: Patients with apparent early stage OCCC and no history of another tumor diagnosed between 2004 and 2015 who underwent surgery were drawn from the National Cancer Database. Performance of LND and incidence of LN metastasis was assessed from pathology report. Five-year overall survival (OS) was calculated after generation of Kaplan-Meier curves and OS was compared with the log-rank test. A Cox multivariate model was constructed to control for confounders. Results: Among 4589 patients with apparent early stage clear cell ovarian carcinoma, 80.9% underwent LND. Median number of LN removed was 13. Higher rates of LND were noted in academic centers (86.2% vs 76.8%, p Conclusions: Complete staging of patients with apparent early stage OCCC with LND may be associated with better survival. Prognosis of patients with lymph node metastasis is poor.

Comprehensive Serum Glycopeptide Spectra Analysis (CSGSA): A Potential New Tool for Early Detection of Ovarian Cancer.

Objectives: To conduct a comprehensive glycopeptide spectra analysis of serum between cancer and non-cancer patients to identify early biomarkers of epithelial ovarian cancer (EOC). Methods: Approximately 30,000 glycopeptide peaks were detected from the digested serum glycoproteins of 39 EOC patients (23 early-stage, 16 advanced-stage) and 45 non-cancer patients (27 leiomyoma and ovarian cyst cases, 18 endometrioma cases) by liquid chromatography mass spectrometry (LC–MS). The differential glycopeptide peak spectra were analyzed to distinguish between cancer and non-cancer groups by employing multivariate analysis including principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and heat maps. Results: Examined spectral peaks were filtered down to 2281 serum quantitative glycopeptide signatures for differentiation between ovarian cancer and controls using multivariate analysis. The OPLS-DA model using cross-validation parameters R2 and Q2 and score plots of the serum samples significantly differentiated the EOC group from the non-cancer control group. In addition, women with early-stage clear cell carcinoma and endometriomas were clearly distinguished from each other by OPLS-DA as well as by PCA and heat maps. Conclusions: Our study demonstrates the potential of comprehensive serum glycoprotein analysis as a useful tool for ovarian cancer detection.

Early-stage Uterine Pure and Mixed Clear Cell Carcinoma: Outcomes and Recurrence With and Without Adjuvant Therapy.

Clear cell carcinoma (CCC) of the uterus is a rare but aggressive histology for which the role of adjuvant therapy for stage I-II disease is unclear. Our study investigated outcomes and patterns of failure in these patients. We found 64 cases of CCC, including 26 of pure CCC, 22 mixed with endometrioid adenocarcinoma, and 16 mixed with uterine papillary serous carcinoma. Adjuvant treatment was given to 55%. Median follow-up was 51.9 months. By Kaplan-Meier estimate, 5-year vaginal recurrence-free survival (RFS) was 91.3%, pelvic RFS was 92.6%, distant metastasis RFS was 81.6%, disease-free survival was 79.6%, and overall survival was 79.7%. Median time to recurrence was 20.7 months (range, 2 to 40.5 mo). Patients treated adjuvantly had higher proportion of stage II disease (40% vs. 6.9% observed, P=0.0031) and 20% (7/35) recurred. There were no significant differences in outcomes by histologic subtypes but numerically more recurrences with uterine papillary serous involvement. By univariate analysis, higher stage, presence of lymphovascular invasion, and lack of lymph node dissection were predictive of worse overall survival. Age 65 years and above was predictive of worse cancer-specific survival. Of 12 who progressed, only 1 was salvaged and 11 died of disease. Of progressors, 10 had documented distant metastasis. Median time from recurrence to death was 4.5 months (range, 0.2 to 21.2 mo). Given aggressive and often unsalvageable nature of recurrence, consideration of adjuvant treatment (including chemotherapy and radiation) is warranted for early-stage CCC, particularly for stage II or those with poor prognostic factors.

Survival Impact of Adjuvant Paclitaxel and Carboplatin for Early-Stage Ovarian Clear-Cell Carcinoma with Complete Surgical Staging

Objectives: The aim of this study was to estimate the survival impact of adjuvant paclitaxel and carboplatin (TC) compared to cisplatin (CDDP)-based chemotherapies for early-stage ovarian clear-cell carcinoma (CCC). Methods: Clinicopathologic information on 99 stage I–II CCC patients was obtained between 1987 and 2005. All patients underwent complete surgical staging including systemic lymphadenectomy, followed by TC or various CDDP-based regimens. In the present study, only CCC patients with no residual tumor were enrolled. Results: The median age was 53 years and ranged from 30 to 69 years. Fifty-three (53.5%) patients received TC and 46 (46.5%) patients underwent various CDDP-based chemotherapies after initial surgery. Five-year progression-free survival (PFS) rates of TC and various CDDP groups were 66.5 and 75.8%, respectively (n.s., p = 0.933). In addition, 5-year overall survival (OS) rates of TC and various CDDP groups were 82.4 and 82.3%, respectively (n.s., p = 0.583). In multivariate analyses of OS and PFS, the regimen of chemotherapywas not a significant prognostic factor (OS, p = 0.502; PFS, p = 0.977. Conclusions: In our current examination of the long-term survival of early-stage CCC patients, we did not identify a superiority of TC over various CDDP-based regimens as frontline adjuvant chemotherapy.

Impact of Adjuvant External-Beam Radiation Therapy in Early-Stage Uterine Papillary Serous and Clear Cell Carcinoma

Adjuvant radiation therapy (RT) in early-stage high- to intermediate-risk endometrioid adenocarcinoma is well established and has been shown to improve locoregional control. Its role in the management of early-stage clear cell carcinoma and uterine papillary serous carcinoma (UPSC) remains controversial. Using the Surveillance Epidemiology and End Results database, we identified women with American Joint Committee on Cancer Stage Sixth Edition. Stage IA-IIB clear cell carcinoma or UPSC who underwent hysterectomy with or without adjuvant RT between 1988 and 2003. We used Kaplan-Meier and Cox regression analysis to compare overall survival (OS) for all patients. We identified 1,333 women of whom 451 had clear cell carcinoma and 882 had UPSC. Of those patients, 775 underwent surgery alone and 558 received adjuvant RT as well. For Stages I-IIB disease, the median OS with surgery alone was 106 months, vs. 151 months with adjuvant RT (p = 0.006). On subgroup analysis, we saw the benefit from adjuvant RT only in Stage IB-C patients. For Stage IB disease, patients undergoing surgery alone had a median OS of 117 months, vs. median survival not reached with the addition of RT (p = 0.006). For Stage IC disease, surgery alone had a median OS of 35 months vs. 120 months with RT (p = 0.001). Although the apparent benefit of RT diminished when measured via multivariate analysis, the impact of RT on survival did show a trend toward significance (hazard ration 0.808, confidence interval 95% 0.651-1.002, p = 0.052) In FIGO Stage IB-C papillary serous and clear cell uterine carcinoma, adjuvant RT seems to play an important role in improving survival.

Glypican-3 expression predicts poor clinical outcome of patients with early-stage clear cell carcinoma of the ovary

BackgroundGlypican-3 (GPC3), a membrane-bound heparan sulphate proteoglycan, may play a role in promoting cancer cell growth and differentiation. Recent studies reported that GPC3 is overexpressed in clear cell carcinoma (CCC)...

Vascular Endothelial Growth Factor Is a Promising Therapeutic Target for the Treatment of Clear Cell Carcinoma of the Ovary

This study examines the role of vascular endothelial growth factor (VEGF) as a therapeutic target in clear cell carcinoma (CCC) of the ovary, which has been regarded as a chemoresistant histologic subtype. Immunohistochemical analysis using tissue microarrays of 98 primary ovarian cancers revealed that VEGF was strongly expressed both in early-stage and advanced-stage CCC of the ovary. In early-stage CCCs, patients who had tumors with high levels of VEGF had significantly shorter survival than those with low levels of VEGF. In vitro experiments revealed that VEGF expression was significantly higher in cisplatin-refractory human CCC cells (RMG1-CR and KOC7C-CR), compared with the respective parental cells (RMG1 and KOC7C) in the presence of cisplatin. In vivo treatment with bevacizumab markedly inhibited the growth of both parental CCC cell-derived (RMG1 and KOC7C) and cisplatin-refractory CCC cell-derived (RMG1-CR and KOC7C-CR) tumors as a result of inhibition of tumor angiogenesis. The results of the current study indicate that VEGF is frequently expressed and can be a promising therapeutic target in the management of CCC. Bevacizumab may be efficacious not only as a first-line treatment but also as a second-line treatment of recurrent disease in patients previously treated with cisplatin.

The Impact of Complete Surgical Staging Upon Survival in Early-Stage Ovarian Clear Cell Carcinoma

Pure-type clear cell carcinoma (CCC) has been recognized as a distinct subtype of ovarian cancer, showing resistance to conventional platinum-based chemotherapy and resulting in poor prognosis. The aim of the study was to evaluate the effects of complete surgical staging procedures for early-stage CCC patients in a retrospective multi-institutional analysis. During the period 1992 to 2002, a total of 199 patients with pT1 M0 CCC were identified. Survival analysis was estimated by Kaplan-Meier methods, and prognostic factors were evaluated using a Cox regression model. Among pT1 M0 tumors, retroperitoneal lymph node status was negative in 125 cases (pN0, 63%), positive in 10 cases (pN1, 5%), and unknown in 64 cases (pNx, 32%). Progression-free survival of pN1 was significantly worse than that of pN0 (P < 0.05), whereas there was no significant difference between pN1 and pNx. There was no significant difference of overall survival (OS) among the 3 groups. Multivariate analysis revealed that peritoneal cytology status was the only independent prognostic factor for progression-free survival (P = 0.04), but completion of surgical staging procedures was not a prognostic factor. There was no significant prognostic factor for OS. Our study implied that complete surgical staging enabled us to distinguish a high-risk group of recurrence in pT1 M0 CCC; however, the procedure could not improve OS. Although the study was a limited retrospective study, the impact of peritoneal cytology status was more important than complete surgical staging procedure in CCC patients. More effective treatment modality was warranted, especially for CCC cases positive for malignant peritoneal cytology.

Early Pathologic Stage Clear Cell Carcinoma and Uterine Papillary Serous Carcinoma of the Endometrium

Clear cell carcinoma (CCC) and uterine papillary serous carcinoma (UPSC) are aggressive variants of endometrial carcinoma that may coexist or share some clinicopathologic features suggesting a similar biologic spectrum and the need for a common therapeutic approach. Twenty-nine cases of pathologic FIGO stage I and II CCC and 47 cases of FIGO stage I and II UPSC seen and treated at Yale-New Haven Hospital were reviewed, and the survival rates with regard to various pathological parameters were compared. Both groups of patients had similar clinical profiles with respect to presentation, age, weight, and medical problems. The 5-year survival for pathologic stage I patients with CCC was 72% and for those with UPSC 44%. The 5-year survival for pathologic stage II patients with CCC was 59% and for those with UPSC 32%. Analysis of survival showed that the depth of myometrial invasion, the presence of vascular space invasion, and the admixture of endometrioid features did not influence survival in either group of patients. In CCC, survival was also not influenced by the predominant histologic pattern, i.e., papillary versus nonpapillary. The results of this study suggest that early stage CCC and UPSC have similar clinicopathologic profiles, suggesting the need for aggressive approaches including a staging laparotomy and possibly similar therapy. However, the stage I CCC patients had a significantly better survival than the stage I UPSC patients.