TCGA molecular groups of endometrial cancer: Pooled data about prognosis

Background: After The Cancer Genome Atlas (TCGA) findings, four novel prognostic groups may direct the management of endometrial cancer (EC): POLE-mutated/ultramutated (POLEmt), microsatellite-instable/hypermutated (MSI), copy-number-low/p53-wild-type (p53wt), and copy-number-high/p53-mutated (p53mt). However, data about prognosis in each group are different across the studies, and definitive pooled estimates are lacking after validation series. Such data may be crucial in directing clinical study design and establishing the optimal tailored management of patients. Aim: To provide pooled estimates of hazard ratio (HR) for overall survival (OS), disease-specific survival (DSS), progression-free survival (PFS) in each prognostic group. Materials and 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 each TCGA EC group. Both univariable and multivariable HR analysis was performed for OS, DSS and PFS in each group, using p53wt as reference group. Results: Six studies with 2818 patients were included. Regarding OS, pooled HRs were 3.179 and 1.986 for p53mt group, 1.522 and 1.192 for MSI group, and 0.589 and 0.795 for POLEmt group at univariable and multivariable analyses, respectively. Regarding DSS, pooled HR were 5.052 and 2.133 for p53mt group, 1.965 and 1.068 for MSI group, and 0.552 and 0.325 for POLEmt group at univariable and multivariable analyses, respectively. Regarding PFS, pooled HR were 3.512 and 1.833 for p53mt group, 1.354 and 0.817 for MSI group, and 0.287 and 0.217 for POLEmt group at univariable and multivariable analyses, respectively. Conclusions: Prognosis of p53mt group is consistently the worst one and is further worsened by unfavorable clinicopathological factors. Prognosis of MSI group overlaps with p53wt group but is worsened by unfavorable clinicopathological factors. Prognosis of POLEmt group is the best one and does not seem to be significantly affected by clinicopathological factors

PTEN as a predictive marker of response to conservative treatment in endometrial hyperplasia and early endometrial cancer. A systematic review and meta-analysis

OBJECTIVE: Several markers have been studied to predict the responsiveness of endometrial hyperplasia (EH) and early endometrial cancer (EEC) to progestin therapy. PTEN has played a major role in this field, although its predictive significance is still undefined. We aimed to assess if loss of PTEN expression on pre-treatment endometrial specimen may be a predictive markers of response to progestins in EH and EEC. STUDY DESIGN: MEDLINE, EMBASE, Web of Sciences, Scopus, ClinicalTrial.gov, OVID and Cochrane Library were searched for relevant articles from the inception to May 2018. All studies assessing PTEN expression as predictive marker in EH and EEC treated with progestin were included. Relative risk (RR) for therapy failure was calculated with 95% confidence interval (CI) and a significant p-value<0.05, with a subgroup analysis based on the histologic category (EEC or EH) and the administration route of progestin (oral or intrauterine). RESULTS: Seven cohort studies assessing 376 patients were included. PTEN loss was not significantly associated with the outcome of therapy in the overall analysis (RR = 1.24, 95% CI, 0.88-1.76, p = 0.21), in + the subgroups of EEC (RR = 0.89, 0.32-2.49, p = 0.83), EH (RR = 1.30, 0.90-1.87 p = 0.16), oral progestin (RR = 1.25 0.88-1.79, p = 0.22) and intrauterine device (RR = 1.02, 0.36-2.87, p = 0.97). CONCLUSION: PTEN seems not to be useful as predictive marker of response to the conservative treatment of EH and EC, regardless of the administration route (oral or intrauterine) of progestins. We advise future researcher not to further assess PTEN as a stand-alone predictive marker

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

Prognostic factors in Krukenberg tumor

BACKGROUND: Krukenberg tumor (KT) is a rare secondary ovarian tumor. Little is known about clinicopathologic factors affecting prognosis in KT. OBJECTIVE: To assess the prognostic value of clinicopathologic factors in KT through a systematic review and meta-analysis. METHODS: Electronic databases were searched from their inception to February 2019 for studies assessing the association of clinicopathologic factors with overall survival in KT. Pooled hazard ratio (HR) was calculated for each factor; a p value < 0.05 was considered significant. RESULTS: Twenty-three studies with 1743 patients were included. A decreased overall survival was significantly associated with peritoneal involvement (HR 1.944; p = 0.003), ascites (HR 2.055; p = 0.034), synchronous presentation (HR 1.679; p = 0.034) and increased serum CEA levels (HR 1.380; p = 0.010), but not with age > 50 (HR 0.946; p = 0.743), menopausal status (HR 1.565; p = 0.204), gastric origin (HR 1.600; p = 0.201), size > 5 cm (HR 1.292; p = 0.119), size > 10 cm (HR 0.925; p = 0.714), bilateral ovarian involvement (HR 1.113; p = 0.347), non-peritoneal extaovarian metastases (HR 1.648; p = 0.237), liver metastases (HR 1.118, p = 0.555), predominant signet ring cell morphology (HR 1.322; p = 0.208) and levels of CA125 (HR 0.933; p = 0.828) and CA19.9 (HR 0.996; p = 0.992). CONCLUSION: Peritoneal involvement, synchronous presentation, ascites and increased serum CEA levels appear as unfavorable prognostic factors in KT and might affect the patient management

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