Integration of Molecular Data in the Prognostic Stratification and Management of Endometrial Carcinoma

In the last years, the TCGA-based molecular classifier have been progressively integrated in the management of endometrial carcinoma. While molecular assays are increasingly available across pathology laboratories, the additional costs will expectedly be compensated by a reduction in overtreatments and a prevention of recurrences. The additional time might be shortened by assessing molecular markers on biopsy specimens. Retrospective data suggest that the molecular classifier will have a major impact of on the risk stratification, with many patients having their risk class down- or upstaged based on POLE mutations or p53 abnormalities, respectively. However, there are still several issues to be resolved, such as the prognostic value of the TCGA classifier in each FIGO stage, or the type of adjuvant treatment most suitable for each molecular group. Other issues regard the prognostic stratification of the mismatch repair-deficient and “no specific molecular profile” groups, which currently follows the same criteria; however, the former seems to be prognostically consistent regardless of FIGO grade and histotype, whereas the latter appears highly heterogeneous. Numerous clinical, histological, immunohistochemical and molecular markers have been proposed to refine the TCGA classification, but their prognostic value is still undefined. Hopefully, prospective data collected in the next years will help resolving these issues

Impact of endometrial carcinoma histotype on the prognostic value of the TCGA molecular subgroups

Background: The Cancer Genome Atlas (TCGA) identified four prognostic subgroups of endometrial carcinoma: copy-number-low/p53-wild-type (p53wt), POLE-mutated/ultramutated (POLEmt), microsatellite-instability/hypermutated (MSI), and copy-number-high/p53-mutated (p53mt). However, it is still unclear if they may be integrated with the current histopathological prognostic factors, such as histotype. Objective: To assess the impact of histotype on the prognostic value of the TCGA molecular subgroups of endometrial carcinoma. Methods: A systematic review and meta-analysis was performed by searching 7 electronic databases from their inception to April 2019 for studies assessing prognosis in all TCGA subgroups of endometrial carcinoma. Pooled hazard ratio (HR) for overall survival (OS) was calculated in two different groups (“all-histotypes” and “endometrioid”), using p53wt subgroup as reference standard; HR for non-endometrioid histotypes was calculated indirectly. Disease-specific survival and progression-free survival were assessed as additional analyses. Results: Six studies with 2818 patients were included. In the p53mt subgroup, pooled HRs for OS were 4.322 (all-histotypes), 2.505 (endometrioid), and 4.937 (non-endometrioid). In the MSI subgroup, pooled HRs were 1.965 (all-histotypes), 1.287 (endometrioid), and 6.361 (non-endometrioid). In the POLEmt subgroup, pooled HRs were 0.763 (all-histotypes), 0.481 (endometrioid), and 2.634 (non-endometrioid). Results of additional analyses were consistent for all subgroups except for non-endometrioid POLEmt carcinomas. Conclusion: Histotype of endometrial carcinoma shows a crucial prognostic value independently of the TCGA molecular subgroup, with non-endometrioid carcinomas having a worse prognosis in each TCGA subgroup. Histotype should be integrated with molecular characterization for the risk stratification of patients in the future

Significant risk of occult cancer in complex non-atypical endometrial hyperplasia

BACKGROUND: In the 2014 WHO classification of endometrial hyperplasia (EH), complex EH is lumped together with simple EH in the benign category of non-atypical EH. OBJECTIVE: To assess the risk of coexistent cancer in complex EH and simple EH without atypia, through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to January 2019 for relevant articles. RESULTS: Twelve studies assessing a total of 804 non-atypical EH were included. The risk of coexistent cancer was significantly higher in complex EH (12.4%) than in simple EH (2%), with an OR of 6.03 (p = 0.0002). CONCLUSION: Even in the absence of cytologic atypia, complex EH is associated with a significant risk of coexistent cancer. Further studies are necessary to investigate the need for a revision in the WHO classification

Diabetes Mellitus Is Associated with Occult Cancer in Endometrial Hyperplasia

In the management of women diagnosed with endometrial hyperplasia (EH), it is crucial to determine the risk of coexistent cancer. Diabetes mellitus has been recently suggested as a significant risk factor. However, results in this regard are conflicting. Our aim was to assess the association between diabetes mellitus and coexistent cancer in women diagnosed with endometrial hyperplasia. A systematic review and meta-analysis was performed by searching electronic databases from their inception to October 2018 for studies assessing the presence of coexistent cancer after a preoperative diagnosis of endometrial hyperplasia in women stratified for diabetes mellitus. Odds ratio was calculated with 95% confidence interval; a p value <0.05 was considered significant. Twelve retrospective studies with 1579 EH were included. Diabetes mellitus showed significant association with the presence of cancer coexistent with endometrial hyperplasia (OR = 1.96; 95% CI, 1.07-3.60; p = 0.03). Heterogeneity among studies was moderate (I2 = 55%). Funnel plot showed asymmetric distribution of OR values, with the large and accurate studies showing results stronger than small and less accurate one; this finding should exclude a publication bias. In women diagnosed with endometrial hyperplasia, diabetes mellitus is a risk factor for coexistent cancer, and thus may be included in a predictive algorithm for the risk stratification. In women conservatively treated, glycemic control may be required to prevent the risk of progression. Further studies are necessary to confirm the clinical significance of diabetes mellitus in this field

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 &lt;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 &lt; 0.001). Similar results were found for UCS vs SC (HR = 1.53; P &lt; 0.001) and UCS vs CCC (HR = 1.60; P &lt; 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

Use of negative pressure wound therapy systems after radical vulvectomy for advanced vulvar cancer

A retrospective cohort study was performed to evaluate the efficacy of negative pressure wound therapy in improving vulvectomy healing. Women who underwent radical vulvectomy with complete inguinofemoral lymphadenectomy for advanced vulvar cancer were divided into two groups according to immediate postoperative care: patients treated with negative pressure wound therapy using the device applied on the site of the wound (including vulva and inguinal region), and patients receiving conventional care. 18 patients were included in the study. 7 (38.9%) women were treated with negative pressure wound therapy immediately after the surgery and were included in the intervention group, and 11 (61.1%) patients were included in the control group. Women who received negative pressure wound therapy had significantly lower length of stay in the hospital (14.2 ± 4.7 versus 17.1 ± 6.1 days, mean difference −6.90 days, 95% confidence interval −11.91 to −1.89), and significantly lower length for wound healing (−31.90 days, 95% confidence interval −43.48 to −20.32). In conclusion, the utilization of the negative wound pressure therapy may contribute to reduce hospitalization after radical vulvectomy for vulvar cancer. Large and well-designed randomized trials with cost effectiveness analyses are needed to confirm these findings

Clinical characteristics of patients with endometrial cancer and adenomyosis

open11noA better endometrial cancer (EC) prognosis in patients with coexistent adenomyosis has been reported. Unfortunately, it is still unclear if this better prognosis is related to a more favorable clinical profile of adenomyosis patients. We aimed to evaluate differences in the clinical profiles of EC patients with and without adenomyosis. A systematic review and meta-analysis was performed by searching seven electronics databases for all studies that allowed extraction of data about clinical characteristics in EC patients with and without adenomyosis. Clinical characteristics assessed were: age, Body Mass Index (BMI), premenopausal status, and nulliparity. Mean difference in mean ± standard deviation (SD) or odds ratio (OR) for clinical characteristics between EC patients with and without adenomyosis were calculated for each included study and as a pooled estimate, and graphically reported on forest plots with a 95% confidence interval (CI). The Z test was used for assessing the overall effect by considering a p value &lt; 0.05 as significant. Overall, eight studies with 5681 patients were included in the qualitative analysis, and seven studies with 4366 patients in the quantitative analysis. Pooled mean difference in mean ± SD between EC women with and without adenomyosis was −1.19 (95% CI: −3.18 to 0.80; p = 0.24) for age, and 0.23 (95% CI: −0.62 to 1.07; p = 0.60) for BMI. When compared to EC women without adenomyosis, EC women with adenomyosis showed a pooled OR of 1.53 (95% CI: 0.92 to 2.54; p = 0.10) for premenopausal status, and of 0.60 (95% CI: 0.41 to 0.87; p = 0.007) for nulliparity. In conclusion, there are not significant differences in clinical characteristics between EC patients with and without adenomyosis, with the exception for nulliparity. Clinical features seem to not underlie the better EC prognosis of patients with adenomyosis compared to patients without adenomyosis.openCasadio P.; Raffone A.; Maletta M.; Travaglino A.; Raimondo D.; Raimondo I.; Santoro A.; Paradisi R.; Zannoni G.F.; Mollo A.; Seracchioli R.Casadio P.; Raffone A.; Maletta M.; Travaglino A.; Raimondo D.; Raimondo I.; Santoro A.; Paradisi R.; Zannoni G.F.; Mollo A.; Seracchioli R

Diagnostic accuracy of MRI in the differential diagnosis between uterine leiomyomas and sarcomas: A systematic review and meta-analysis

Background: Differential diagnosis between uterine leiomyomas and sarcomas is challenging. Magnetic resonance imaging (MRI) represents the second-line diagnostic method after ultrasound for the assessment of uterine masses. Objectives: To assess the accuracy of MRI in the differential diagnosis between uterine leiomyomas and sarcomas. Search Strategy: A systematic review and meta-analysis was performed searching five electronic databases from their inception to June 2023. Selection Criteria: All peer-reviewed observational or randomized clinical trials that reported an unbiased postoperative histologic diagnosis of uterine leiomyoma or uterine sarcoma, which also comprehended a preoperative MRI evaluation of the uterine mass. Data Collection and Analysis: Sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio, and area under the curve on summary receiver operating characteristic of MRI in differentiating uterine leiomyomas and sarcomas were calculated as individual and pooled estimates, with 95% confidence intervals (CI). Results: Eight studies with 2495 women (2253 with uterine leiomyomas and 179 with uterine sarcomas), were included. MRI showed pooled sensitivity of 0.90 (95% CI 0.84–0.94), specificity of 0.96 (95% CI 0.96–0.97), positive likelihood ratio of 13.55 (95% CI 6.20–29.61), negative likelihood ratio of 0.08 (95% CI 0.02–0.32), diagnostic odds ratio of 175.13 (95% CI 46.53–659.09), and area under the curve of 0.9759. Conclusions: MRI has a high diagnostic accuracy in the differential diagnosis between uterine leiomyomas and sarcomas

Fractional Microablative CO2 Laser-Related Histological Changes on Vulvar Tissue in Patients With Genitourinary Syndrome of Menopause

Background and Objectives: Fractional CO2 laser has been proposed as an effective treatment for the genitourinary syndrome of menopause (GSM). However, the effects of laser treatment on vulvar tissue have never been assessed. We aimed to assess histological changes related to fractional CO2 laser in vulvar tissue from GSM patients. Study Design/Materials and Methods: A single-center observational prospective cohort study was performed enrolling all GSM patients from July 2017 to October 2018. Patients underwent three outpatient vulvovaginal applications of fractional CO2 laser and vulvar biopsy before and after treatment. Rates of histological changes in vulvar tissue, the difference in means of Vulva Health Index (VuHI), Vaginal Health Index (VHI), Visual Analogue Scale scores for GSM symptoms, and procedure-related pain, and rate of patient's overall satisfaction with treatment were assessed. Univariate comparisons between continuous variables were performed by using the paired t-test (α error = 0.05). Results: Of 20 enrolled patients, 18 underwent all laser applications, and 15 underwent both vulvar biopsies. 93.3% of patients showed remodeling of vulvar connective tissue; 80% showed improvement in vulvar epithelium trophism and 86.7% showed neovascularization. Differences in means between before and after treatment were significant for VuHI, VHI, and all GSM symptoms. Means ± standard deviation of the degree of pain at each laser application were 4.4 ± 0.9, 3.7 ± 1.6, and 2.9 ± 1.9. The rate of overall satisfaction with the treatment was 72.2%. Conclusions: Fractional CO2 laser leads to a restoration of the normal architecture of vulvar tissue, with significant improvement in GSM-related signs and symptoms, and overall satisfaction with the treatment in most GSM patients. Lasers Surg. Med. © 2020 Wiley Periodicals LLC

Corded and hyalinized endometrioid carcinoma: Summary of clinical, histological, immunohistochemical and molecular data

Corded and hyalinized endometrioid carcinoma (CHEC) represents a potential pitfall for pathologists. This study aimed to provide a complete overview of all clinicopathological and molecular features of CHEC. Electronic databases were searched for all published series of CHEC. Clinical, histological, immunohistochemical and molecular data about CHEC were extracted and pooled. Six studies with 62 patients were identified; mean age was 49.8 years (range 19–83). Most cases showed FIGO stage I (68%), low grade (87.5%), and a favorable outcome (78.4%), with “no specific molecular profile” (NSMP). A subset of cases showed high-grade features (12.5%), p53 abnormalities (11.1%) or mismatch repair (MMR) deficiency (20%) and occurred at an older age (mean age&gt;60 years). Common features of CHEC were: superficial localization of the corded component (88.6%), squamous/morular differentiation (82.5%), nuclear β-catenin accumulation (92%), partial/total loss of CKAE1/AE3 (88.9%), estrogen receptor (95.7%) and e-cadherin (100%), stromal changes such as myxoid (38.5%), osteoid (24%) and chondroid (4.5%), CTNNB1 mutations (57.9%), and POLE-wild-type (100%); 24.4% of cases showed lymphovascular space invasion. A minority of cases (16.2%) showed poor outcome despite a low-grade, NSMP phenotype; the molecular basis for the aggressiveness of these cases is still undefined. Further studies are necessary in this field