Uterine Serous Carcinoma Research Articles

XCT inhibitor sulfasalazine depletes paclitaxel-resistant tumor cells through ferroptosis in uterine serous carcinoma.

Glutathione (GSH) is a primary antioxidant that protects cells against reactive oxygen species (ROS), and high levels of GSH promote cancer cell survival and resistance to chemotherapy. The glutamine transporter xCT is essential for the intracellular synthesis of GSH, whereby xCT determines the intracellular redox balance. However, whether xCT inhibition can overcome GSH-mediated resistance to chemotherapeutic agents in uterine serous carcinoma (USC) remains unclear. Thus, the present study investigated the effect of the xCT inhibitor, sulfasalazine (SAS) on cytotoxicity in paclitaxel-sensitive and -resistant USC cell lines. The molecular mechanism by which SAS induces ferroptotic cell death in paclitaxel-resistant cells was assessed. The results of the cytotoxicity assay demonstrated that SAS was more cytotoxic in paclitaxel-resistant cells compared with in -sensitive cells; however, paclitaxel cytotoxicity was not enhanced in either of the USC cell lines. Immunoblotting analysis and the cell death assays performed using ferroptosis inhibitors indicated that SAS-mediated cell death was induced through ferroptosis, and not apoptosis, in paclitaxel-resistant cells. Furthermore, ROS production was increased in paclitaxel-resistant but not in -sensitive cells, even at low SAS concentration, and JNK was activated, which is a downstream target in the Ras signaling pathway. Knockdown of JNK reversed the inhibitory effect of SAS on cell proliferation and cell death. The synthetic lethal interaction between ROS accumulation and Ras effector JNK activation may be critical for enhancing the sensitivity to ferroptotic cell death mediated by xCT inhibitor, SAS. Taken together, the results of the present study suggest that xCT inhibition may be an effective treatment for patients with recurrent paclitaxel-resistant USC.

Hormone Receptor Expression and Prognosis of Uterine Papillary Serous Carcinoma: Redefining the Threshold for Positivity

Objectives: Uterine papillary serous carcinoma (UPSC) is an aggressive endometrial cancer (EC) that has classically been characterized by both p53 mutations and lack of estrogen receptor (ER). However, ER expression is increasingly being recognized in UPSC. The clinical interpretation of ER in EC is drawn from the breast literature, with “positive” being defined as ≥1% of tumor nuclei staining, and there is inconsistency between studies regarding its relationship to long-term oncology outcomes. The objective of this work was to assess recurrence-free survival and EC-related death in UPSC according to ER and progesterone receptor (PR) expression, comparing definitional cutoffs of 1% and 10% for positivity.

Clinicopathologic and molecular genetic comparison of primary uterine serous adenocarcinomas from African American and Caucasian women.

e19092 Background: The study aimed to identify whether there were racial disparities in the clinicopathologic features and genetic mutation characteristics between African American (AA) and Caucasian women with uterine serous carcinoma. Methods: Clinicopathologic features, molecular genetic data of patients with uterine serous carcinoma were obtained from The Cancer Genome Atlas (TCGA), including age of diagnosis, body mass index (BMI), tumor grade, FIGO stage, myometrial invasion, lymph node involvement, overall survival and progression free survival. MLH1, MSH2, MSH6, PMS2, BRCA1, BRCA2, CHEK2, TP53 mutations were involved. A statistical analysis of these parameters was performed for AA and Caucasian women. Results: 44 AA and 97 Caucasian patients with uterine serous carcinoma were analyzed. There were no PMS2 and BRCA2mutations in tumors of African American patients. Compared to Caucasian patients, tumors from AA patients had no statistically significant differences in Lynch syndrome related genes ( MSH2, MSH6, PMS2) (4.5% versus 14.3%, p = 0.149) and HR pathway genes ( BRCA1, BRCA2, CHEK2) (9.1% versus 19.6%, p = 0.09). Tumors from AA patients had no statistically significant differences in alterations of the TP53 gene (79.5% versus 71.3%, p = 0.312). There were no statistically significant differences between the two groups regarding age at diagnosis, BMI, tumor histology, tumor grade, lymph node involvement, myometrial invasion, FIGO stage, overall survival or progression-free survival between the two groups ( p > 0.05). Conclusions: This study identified no statistically significant differences in clinicopathologic features and genetic mutations in AA and Caucasian women with uterine serous carcinomas. Especially, there were no differences in survival identified between two groups. Much larger database may be necessary to be analyzed in future. [Table: see text]

A phase II trial of the Wee1 inhibitor adavosertib (AZD1775) in recurrent uterine serous carcinoma.

6009 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial carcinoma characterized by TP53 mutations ( > 90%), often concomitantly with oncogenic mutations or amplifications that can increase replication stress. As such, USC may therefore be uniquely sensitive to further interference of cell cycle regulation by Wee1 inhibition. This two-stage single arm Phase 2 study was conducted to assess the activity of the Wee1 inhibitor adavosertib as monotherapy in recurrent USC. Methods: Women with recurrent USC (defined as non-carcinosarcoma uterine cancers with any serous component) were eligible. Patients (pts) were required to have had at least one prior platinum-based chemotherapy regimen; those with known MSI-H/MMRd disease were required to have received prior PD1/PDL1 therapy or to be ineligible for such therapy. There was no upper limit on the number of prior lines pts could have received. All pts were required to have RECIST measurable disease. Pts received adavosertib 300mg daily on days 1 through 5 and 8 through 12 of a 21-day cycle. Coprimary endpoints were objective response and progression-free survival at 6 months (PFS6). Results: Between OCT-11-2018 and SEP-30-2019, 35 pts enrolled on study. Median follow-up is 4.6 months. The median number of prior lines was 3 (range 1-8). 34 pts were considered evaluable for response. In these pts, 9 confirmed and 1 unconfirmed responses were observed, for an ORR of 29.4% (95% CI 15.1-47.5%). The PFS at 6 months was 58.7% (95% CI: 39.5-73.7%). The median PFS is 6.1 months and the median duration of response is 9.0 months. Frequently observed Grade 3 or higher related adverse events included neutropenia (32.3%), anemia (20.6%), and fatigue (23.5%). Immunohistochemistry and targeted next-generation sequencing were performed to investigate potential biomarkers of response. Conclusions: Adavosertib monotherapy demonstrates promising clinical activity in women with USC. The observed monotherapy activity is higher than in other diseases, and additional exploration of the biology of Wee1 inhibition in USC is needed. Further studies of adavosertib in this patient population are planned. Clinical trial information: NCT03668340.

Human epidermal growth factor 2 (HER2) in early stage uterine serous carcinoma: A multi-institutional cohort.

6084 Background: Uterine serous carcinoma (USC) is a rare and aggressive malignancy, accounting for 40% of all endometrial cancer deaths. Human Epidermal Growth Factor Receptor 2 (HER2) has emerged as an important prognostic and therapeutic target in USC. Given recent randomized trial results, HER2-directed therapy is now recommended in advanced-stage or recurrent, HER2-positive disease. The significance of tumoral HER2 expression in early-stage disease has not yet been established. Methods: In this IRB-approved, retrospective, multi-institutional cohort, women diagnosed with stage I USC from 2000-2018 were identified. Patient demographic, treatment, and survival data were collected. Immunohistochemistry (IHC) was performed for HER2 and scored 0-3+. Equivocal IHC results (2+) were further tested with in-situ hybridization (ISH) per the 2007 ASCO-CAP HER2 breast cancer guidelines. HER2 overexpression (“positive”) was defined as 3+ IHC or ISH positive. Kaplan-Meier analyses and Cox-proportional hazards were used to compare survival between the cohorts. Results: In total, 173 patients with stage I USC were tested for HER2; 25% were HER2-positive, 77.4% had stage IA and 22.6% had stage IB disease. Adequate clinical follow up was available for 168 patients. There were no significant differences in age, race/ethnicity, body mass index, surgical management, sub-stage, tumor size, adjuvant therapy, or follow-up duration between the HER2-positive and negative cohorts. On univarite analysis, presence of lymph-vascular space invasion was correlated with HER2-positive tumors (p=0.003). After a median follow-up of 50 months, there were 41 (24.4%) recurrences. Significantly more recurrences were observed in the HER2-positive cohort (47.6% vs. 16.7%, p<0.001). HER2 overexpression was also associated with poorer progression-free (PFS) and overall survival (OS) (p<0.001 and p=0.012). After adjusting for prognostic factors including sub-stage and adjuvant treatment, those with HER2-positive tumors experienced inferior PFS (aHR 3.67, 95%CI 1.92-6.98; p<0.001) and OS (aHR 2.03, 95%CI 1.03-4.01; p=0.042) compared to HER2-negative tumors. Conclusions: Uterine serous carcinoma is a poor prognostic tumor, even in patients with early-stage disease. Given its significant association with worse survival outcomes, tumoral HER2 overexpression appears to be a prognostic biomarker in women with stage I disease. These data provide rationale for clinical trials with HER2-directed therapy in early-stage uterine serous carcinoma.

Clinicopathologic analysis of MMR gene mutations and uterine adenocarcinomas: An updated population-based study.

e18100 Background: Endometrial carcinoma frequently harbors genetic alterations in genes encoding mismatch repair (MMR) enzymes, a finding which has important implications for adjuvant therapy. The aim of this study is to determine an optimal screening strategy to detect MMR mutations for each histologic subtype of endometrial carcinoma (EC). Methods: We performed a comparative analysis of the demographic, clinical, pathologic, and molecular data, including MLH1, MLH3, PMS1, PMS2, MSH2, MSH3, MSH6, and EPCAM, for 562 patients from The Cancer Genome Atlas database (TCGA), stratified by tumor histologic subtype. Results: Molecular data was available for 562 patients, of which 162 (28.8%) had tumors that were positive for MMR mutations. We did not separate somatic and germline mutation. Of these tumors, the penetrate rate of FIGO grade 3 endometrioid endometrial carcinoma (EEC G3) (84/184, 45.7%) was significantly higher than the one of uterine serous carcinoma (USC) (35/156, 22.4%) ( p < 0.001), grade 2 (EEC G2) (26/129, 20.2%) ( p < 0.001), and grade 1 (EEC G1) (17/93, 18.3%) ( p < 0.001). Of EEC G3 tumors, patients with MMR gene mutations were significantly older ( p = 0.024) or had lower BMI's than MMR mutation noncarriers ( p = 0.028). Of 562 endometrial carcinomas, alterations in MSH2 (n = 55), MSH6 (n = 54), MSH3 (n = 50) were the most frequent mutations. There were no differences in overall survival and progression-free interval between MMR mutation carriers and nonmutation carriers (p > 0.05) except that PFI with MMR gene mutation was higher than with MMR proficiency in EEC G3 ( p = 0.014). Conclusions: EEC G3 harbored the most MMR mutations among EC. EEC G3 and USC could be more considered to screen MMR mutation due to more MMR mutations occurred in EEC G3 and USC than did among EEC G2 and EEC G1. Besides MLH1, MSH2, MSH6, PMS2 and EPCAM mutation , MLH3, MSH3, PMS1 mutation could be screened in patients with newly diagnosed endometrial carcinoma. [Table: see text]

Fallopian tube abnormalities in uterine serous carcinoma

ObjectiveUterine serous carcinoma (USC) is presumed to arise from endometrial intra-epithelial carcinoma (EIC), whereas tubo-ovarian high-grade serous carcinomas have similar precursor lesions in the Fallopian tube, i.e. serous tubal intra-epithelial carcinoma (STIC). The presence of Fallopian tube abnormalities and their clonal relationship to the concurrent USC was investigated. MethodsIn this multicenter study, all patients treated for USC between 1992 and 2017 were retrospectively identified. Histopathological diagnosis of USC, EIC and STIC was revised by an expert pathologist. Additionally, all Fallopian tube sections were immunohistochemically stained (p53 and Ki-67). Fallopian tube abnormalities were classified as either p53 signature, serous tubal intra-epithelial lesion (STIL) or STIC. The USCs and Fallopian tube abnormalities were analyzed by targeted next-generation sequencing. ResultsIn 168 included patients, Fallopian tube abnormalities were found in 27.4% (46/168): p53-signatures in 17.9% (30/168), STILs in 3.0% (5/168) and STICs in 6.5% (11/168). In subgroup analysis, STICs were found in 9.5% (11/115) of patients with at least one section of the fimbriated end embedded. Next-generation sequencing showed identical TP53-mutations in the STIC and corresponding USC. ConclusionsIn conclusion, the presence of Fallopian tube abnormalities was shown in a high percentage of patients with USC, representing either true precursor lesions or metastasized disease.

Immunotherapy Associated Vaginal Mucositis [31H

INTRODUCTION: Immune checkpoint inhibitors (ICPi), has revolutionized our approach to treating solid tumors, including gynecologic malignancies. Compared to standard chemotherapy, the adverse events associated with immunotherapies, are often mild and localized. While a rash is most commonly reported side effect of ICPi therapy, there have been few cases of mucositis caused by ICPi therapy, and no documented case of an ICPi therapy causing vaginal mucositis. METHODS: This is a presentation of a 67-year-old woman with a history of stage I metastatic uterine serous carcinoma who was initially treated with a hysterectomy, bilateral salpingo-oophorectomy, and lymphadenectomy. The patient had reoccurrence despite adjuvant radiation and chemotherapy and was enrolled in a phase 2 clinical trial with Cabozantinib and Nivolumab. Nine days after administration of IV Nivolumab during the second cycle, she reported onset of severe, non-radiating perineal pain. Pelvic examination revealed multiple, deep, erythematous ulcerations and necrosis around the periurethral area, consistent with grade 3 mucositis. The treatment was discontinued and she was started on prednisone therapy. Re-examination in 1 month showed decreased fibrinous material indicating that mucositis had improved. CONCLUSION: As immunotherapy is becoming more widely used in gynecologic malignancies, providers need to be aware of rare complications associated with these therapies. Such toxicities should be correctly identified and treated appropriately and expediently. Most patients will continue to benefit from administered immunotherapy and can be restarted once the toxicities are alleviated. To our knowledge, this is a first reported case of vaginal mucositis associated with Nivolumab therapy in a patient with gynecologic malignancy.

Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report

A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.

Pathogenesis and Clinical Management of Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer that has not been well characterized. It accounts for less than 10% of all endometrial cancers and 80% of endometrial cancer–related deaths. Currently, staging surgery together with chemotherapy or radiotherapy, especially vaginal cuff brachytherapy, is the main treatment strategy for USC. Whole-exome sequencing combined with preclinical and clinical studies are verifying a series of effective and clinically accessible inhibitors targeting frequently altered genes, such as HER2 and PI3K3CA, in varying USC patient populations. Some progress has also been made in the immunotherapy field. The PD-1/PD-L1 pathway has been found to be activated in many USC patients, and clinical trials of PD-1 inhibitors in USC are underway. This review updates the progress of research regarding the molecular pathogenesis and putative clinical management of USC.

Uterin seröz karsinom ve uterin berrak hücreli karsinom tanısı alan hastalarda klinikopatolojik özelliklerin ve sağ kalım sonuçlarının karşılaştırılması

AbstractAim: We aimed to compare the clinicopathological characteristics and survivals between uterine serous carcinoma (USC) and uterine clear cell carcinoma (UCCC).Materials and Methods: The study population consists of women who were diagnosed with USC and UCCC according to the final pathology reports. Demographic, clinicopathological and survival data were collected and analyzed.Results: A total of 69 patients with USC and 36 patients with UCCC were included in the final analysis. Patients in the USC group tend to have more advanced stage disease compared to the patients in the UCCC group and this was statistically significant between the groups (61.1% vs 36.2%, respectively; p=0.015). Patients with USC were more likely to have omental metastasis (17/69 vs 2/36, p=0.016) and positive peritoneal cytology (25/69 vs 5/36, p=0.016). In the multivariate analysis, only positive peritoneal cytology remained as an independent prognostic factor for decreased disease free survival (DFS) for the entire cohort (HR 5.07, 95% CI 2.07-12.42; p<0.001). Only positive peritoneal cytology was an independent prognostic factor for decreased overall survival (OS) for the entire cohort (HR 3.50, 95% CI 1.31-9.33; p=0.012) in the multivariate analysis.Conclusion: We concluded that positive peritoneal cytology was an independent prognostic factor for both DFS and OS in patients with USC and UCCC in the current study. Because of the high rate of omental metastasis in the USC group, we also suggest performing an omentectomy as a part of the comprehensive surgical staging surgery.

The correlation between the expression of LncRNA-OVAAL and the recurrence and prognosis of uterine papillary serous carcinoma after operation

Objective To investigate the relationship between long non-coding ovarian adenocarcinoma amplified RNA (LncRNA-OVAAL) and tumor recurrence and prognosis in uterine papillary serous carcinoma (UPSC). Methods From May 2012 to November 2016, 32 patients with UPSC in our hospital were selected as observation group, and 30 patients with other benign diseases were selected as control group. Real-time polymerase chain reaction (PCR) was used to detect the expression of LncRNA-OVAAL in the enrolled patients. The receiver operating characteristic (ROC) curve was used to analyze the cutoff value of LncRNA-OVAAL. The relationship between LncRNA-OVAAL expression and clinicopathological features was analyzed. The cumulative survival rate was calculated and survival analysis was performed. The Cox risk regression model was used to analyze the single-factor and multi-factor analysis of prognosis and overall survival rate. Results The expression of LncRNA-OVAAL in patients with UPSC was elevated, which was related to age, vascular invasion, menopause, recurrence and preoperative serum human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125) (P<0.05). High expression of LncRNA-OVAAL was a risk factor for postoperative recurrence and overall survival in patients with UPSC (P<0.05). Conclusions The high expression of LncRNA-OVAAL has a certain evaluation value for predicting postoperative recurrence and prognosis in patients with UPSC. Key words: RNA, long noncoding; Uterine papillary serous carcinoma; Neoplasm recurrence; Prognosis

A 73-gene proliferative transcriptomic signature predicts uterine serous carcinoma patient survival and response to primary therapy

ObjectivesTo develop a transcriptomic signature capable of predicting overall survival (OS) for uterine serous carcinoma (USC). MethodsRNAseq data for 58 USC patients were obtained from TCGA. Expression of 73 candidate genes was measured for 67 Augusta University (AU) samples using NanoString technology. ResultsAnalysis of the TCGA RNAseq data identified 73 genes that individually predict prognosis for USC patients and an elastic net model with all 73 genes (USC73) distinguishes a good OS group with low USC73 score from a poor OS group with high USC73 score (5-year OS = 83.3% and 13.3% respectively, HR = 40.1; p = 3 × 10−8). This finding was validated in the independent AU cohort (HR = 4.3; p = 0.0004). The poor prognosis group with high USC73 score consists of 37.9% and 32.8% of patients in the TCGA and AU cohort respectively. USC73 score and pathologic stage independently contribute to OS and together provide the best prognostic value. Early stage, low USC73 patients have the best prognosis (5-year OS = 85.1% in the combined dataset), while advanced stage, high USC73 patients have the worst prognosis (5-year OS = 6.4%, HR = 30.5, p = 1.2 × 10−12). Consistent with the observed poor survival, primary cell cultures from high USC73 patients had higher proliferation rate and cell cycle progression; and high USC73 patients had lower rates of complete response to standard therapy. ConclusionsThe USC73 transcriptomic signature and stage independently predict OS of USC patients and the best prediction is achieved using USC73 and stage. USC73 may also serve as a therapeutic biomarker to guide patient care.

Targeting human epidermal growth factor receptor 2 (HER2) in gynecologic malignancies.

The purpose of this review is to describe the role of the human epidermal growth factor receptor 2 (HER2) as a biomarker and potential target in gynecologic malignancies and to describe contemporary updates in the use of anti-HER2 treatments for these cancers. Approximately 25-30% of all patients with uterine serous carcinoma overexpress tumoral HER2. The anti-HER2 antibody trastuzumab represents an effective, targeted therapy with significant efficacy in the treatment of HER2-positive breast and gastric cancer. Recently, trastuzumab efficacy has also been demonstrated in a randomized controlled trial of women with advanced or recurrent uterine serous carcinoma. Additionally, trastuzumab may be effective in women with HER2-positive uterine carcinosarcoma. The role of anti-HER2 therapy is unclear in women with other gynecologic malignancies but is being evaluated. HER2 amplification/overexpression is an effective therapeutic target in select gynecologic malignancies, and especially in the rare endometrial cancer subtype, uterine serous carcinoma. As anti-HER2-targeted therapies become increasingly available, more treatment options may become available for women with HER2-positive disease.

Adjuvant chemotherapy in endometrial cancer.

The role of adjuvant chemotherapy (CT) is controversial in endometrial carcinoma (EC). Surgery alone is usually curative for women who are at a low risk of disease recurrence. The treatment of EC following surgical staging is based on the risk of relapse, which is defined by the cancer stage at diagnosis, histology of the tumor and other prognostic factors such as grade differentiation, the presence of substantial lymphovascular invasion (LVSI), or depth of myometrial invasion (MI). External beam radiotherapy (EBRT) and/or vaginal brachytherapy (VBT) improved local control and are used as adjuvant treatment for early-stage disease. The role of adjuvant CT is controversial in early-stage EC, and there is no uniform approach to the treatment of women with stage III EC or early-staged non-endometrioid EC. Available evidence did not support the indication of adjuvant CT in stage I-II endometroid EC. In those cases at higher risk of relapse, defined as grade 3 tumors with substantial (no focal) LVSI, specifically with deep MI or cervical involvement, could be considered. Adjuvant CT should be administered to stage III EC patients. When RT is indicated (extensive lymph node involvement or deep MI), sequential treatment with RT or "sandwich" regimen may be considered rather than concurrent CRT. The patients with stage IA MI or IB USC may be offered adjuvant CT alone or in combination with VBT, whereas in stage II uterine serous carcinoma patients adding EBRT may be reasonable. Management approach for patients with stage IA without MI USC who underwent a comprehensive surgery remains controversial, and surveillance alone or CT plus VBT is an appropriate option. Early-stage clear-cell carcinoma patients might not benefit for adjuvant CT, but stage III patients might benefit from the combination of CT and EBRT. Stage I-III uterine carcinosarcoma patients might be offered adjuvant CT followed by RT or as a "sandwich" régimen.

Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Promotes Uterine Serous Cancer Cell Proliferation and Cell Cycle Progression.

Uterine serous carcinoma (USC) is the most aggressive form of endometrial cancer, with poor survival rates and high recurrence risk. Therefore, the purpose of this study was to identify therapeutic targets that could aid in the management of USC. By analyzing endometrial cancer samples from The Cancer Genome Atlas (TCGA), we found Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) to be highly expressed in USC and to correlate with poorer overall survival. UCHL1 silencing reduced cell proliferation in vitro and in vivo, cyclin B1 protein levels and cell cycle progression. Further studies showed that UCHL1 interacts with cyclin B1 and increases cyclin B1 protein stability by deubiquitination. Treatment of USC-bearing mice with the UCHL1-specific inhibitor reduced tumor growth and improved overall survival. Our findings suggest that cyclin B1 is a novel target of UCHL1 and targeting UCHL1 is a potential therapeutic strategy for USC.

The role of vaginal brachytherapy in stage I endometrial serous cancer: a systematic review.

PurposeSerous adenocarcinoma (uterine serous carcinoma – USC) is a rare and aggressive histologic subtype of endometrial cancer, with a high-rate of recurrence and poor prognosis. The adjuvant treatment for stage I patients is unclear. The purpose of this study was to evaluate the outcomes of stage I USC treated exclusively with chemotherapy plus vaginal brachytherapy (VBT).Material and methodsA systematic research using PubMed, Scopus, and Cochrane library was conducted to identify full articles evaluating the efficacy of VBT in patients with stage I USC. A search in ClinicalTrials.gov was performed in order to detect ongoing or recently completed trials, and in PROSPERO for searching ongoing or recently completed systematic reviews.ResultsAll studies were retrospective and 364 of evaluated patients were found. The average local control was 97.5% (range, 91-100%), the disease free-survival was 88% (range, 82-94%), the overall survival was 93% (range, 72-100%), the specific cancer survival was 89.4% (range, 84.8-94%), and the G3-G4 toxicity was 0-8%.ConclusionsThese data support the concept that in adequately selected patients, VBT alone may be a suitable radiotherapy technique in women with stage I USC who underwent surgical staging and received adjuvant chemotherapy.

Role of Immunohistochemistry to Distinguish Grade 3 Endometrioid Carcinoma and Uterine Serous Carcinoma.

The categorization of endometrial carcinomas into endometrioid and serous categories has prognostic implications but many-a-times, it is difficult to categorize based solely on morphology. The present study was conducted to determine an appropriate immunohistochemical panel to distinguish grade 3 endometrioid carcinoma from serous carcinoma. This study was a retrospective and a prospective study including 63 cases of endometrial carcinoma diagnosed on morphology as either grade 3 endometrioid (n=29) or serous endometrial carcinomas (n=34). Immunohistochemistry (IHC) was performed using tissue microarrays for 8 immunomarkers on 60 cases. The mean age of presentation was not significantly different for both types of carcinomas and the most common presentation was postmenopausal bleeding (93% of the total cases, P=0.66). Obesity (P=0.038), lymph nodal involvement (P=0.044), and stage at presentation (P=0.042) were found to be significantly different among the 2 types of carcinomas. Estrogen and progesterone receptor (ER, PR) positivity was more common (47.6% and 28.2%, respectively) in endometrioid carcinomas as compared with serous. Mutation type (diffuse or null) p53 staining was a powerful predictor of serous carcinomas. IMP3 and p16 were found to be positive in most cases of serous carcinoma (64.1% and 79.5%, respectively). Vimentin and β-catenin were found to be of limited utility. On the basis of IHC, 21 cases could be categorized as grade 3 endometrioid carcinomas and 39 as type 2 carcinomas (serous and clear cell carcinoma). The most appropriate IHC panel to differentiate endometrioid and serous endometrial carcinomas includes ER, PR, IMP3, p53, and p16.

Stage III uterine serous carcinoma: modern trends in multimodality treatment

ObjectiveTo examine outcomes in a modern treatment era for stage III uterine serous carcinoma (USC).MethodsFifty women were retrospectively identified as 2009 International Federation of Gynecology and Obstetrics stage III USC patients who received radiotherapy (RT) at our institution between 1/2003–5/2018. The patients were divided into 2 cohorts: 20 in the early era (2003–2010) and 30 in the modern era (2011–2018). Patient characteristics were compared using χ2 tests for categorical variables and t-tests for continuous variables. Recurrence free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards.ResultsThe modern era differed from the early era in the increased use of volume-directed external beam RT (EBRT) as opposed to vaginal brachytherapy (VB) alone (33.3% vs 5.0%, p=0.048), minimally invasive surgery (56.7% vs. 25%, p=0.027), sentinel node sampling (26.7% vs. 0%, p=0.012), computed tomography imaging in the perioperative period (63.3% vs. 30%, p=0.044), and human epidermal growth factor receptor 2/neu testing (96.7% vs. 55%, p=0.001). Median follow-up for early and modern eras was 37.27 and 33.23 months, respectively. The early vs. modern 3-year RFS was 33% and 64% (p=0.039), respectively, while the 3-year OS was 55% and 90% (p=0.034). Regional nodal recurrence more common among the patients who received VB only (p=0.048).ConclusionModern era treatment was associated with improved RFS and OS in patients with stage III USC. Regional nodal recurrences were significantly reduced in patients who received EBRT.

Survival implication of lymphadenectomy in patients surgically treated for apparent early-stage uterine serous carcinoma.

ObjectiveUterine serous carcinoma (USC) is a rare highly aggressive disease. In the present study, we aimed to investigate the survival implication of the systematic lymphadenectomy in patients who underwent surgery for apparent early-stage USC.MethodsConsecutive patients with apparent early-stage USC surgically treated at six Italian referral cancer centers were analyzed. A comparison was made between patients who underwent retroperitoneal staging including at least pelvic lymphadenectomy “LND” vs. those who underwent hysterectomy alone “NO-LND”. Baseline, surgical and oncological outcomes were analyzed. Kaplan- Meier curves were calculated for disease-free survival (DFS) and disease-specific survival (DSS). Associations were evaluated with Cox proportional hazard regression and summarized using hazard ratio (HR).ResultsOne hundred forty patients were analyzed, 106 LND and 34 NO-LND. NO-LND group (compared to LND group) included older patients (median age, 73 vs.67 years) and with higher comorbidities (median Charlson Comorbidity Index, 6 vs. 5) (p<0.001). No differences in terms of recurrence rate (LND vs. NO-LND, 33.1% vs. 41.4%; p=0.240) were observed. At Cox regression analysis lymphadenectomy did not significantly influence DFS (HR=0.59; 95% confidence interval [CI]=0.32–1.08; p=0.09), and DSS (HR=0.14; 95% CI=0.02–1.21; multivariable analysis p=0.07). Positive node was independently associated with worse DFS (HR=6.22; 95% CI=3.08–12.60; p<0.001) and DSS (HR=5.51; 95% CI=2.31–13.10; p<0.001), while adjuvant chemotherapy was associated with improved DFS (HR=0.38; 95% CI=0.17–0.86; p=0.02) and age was independently associated with worse DSS (HR=1.07; 95% CI=1.02–1.13; p<0.001).ConclusionsAlthough lymphadenectomy did not show survival benefits in patients who underwent surgery for apparent early-stage USC, the presence of lymph node metastasis was the main adverse prognostic factors, supporting the prognostic role of the retroperitoneal staging also in this histological subtype.