The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women with FIGO Stage II Uterine Endometrioid Carcinoma

Purpose/Objective(s): To explore the prognostic significance of the depth of cervical stromal invasion (CSI) on survival endpoints in women with FIGO stage II uterine endometrioid adenocarcinoma. Materials/Methods: A total of 117 patients were included in this retrospective review. Between 1990 and 2021, all patients with FIGO stage II endometrial cancer (EC) underwent hysterectomy and oophorectomy at our institution, with or without lymph node dissection. Patients with synchronous ovarian or breast cancer, as well as those who had undergone adjuvant systemic chemotherapy for EC, were excluded from the study. Pathologic slides were retrieved for these patients and were reviewed by a gynecologic pathologist to determine stromal thickness and the depth of CSI. The depth of CSI was then measured as a percentage of invasion (% CSI) and used in the analysis as a continuous or dichotomous variable (\u3c 50% vs \u3e = 50%). Patients\u27 demographics, pathologic, and treatment characteristics were analyzed using univariate and multivariate analysis to calculate recurrence-free (RFS) and disease-specific (DSS) rates. Results: The median age for the study cohort was 65 years (range, 34–96), and the median follow-up was 131 months (range, 9–334). A total of 90 patients (77%) had lymph node dissection, with a median of 8 examined lymph nodes (range 0-18). Adjuvant radiation therapy (RT) with pelvic or vaginal cuff HDR brachytherapy, or a combination of the two, was completed in 92 patients (79 percent). The median % CSI was 27% (range, 1-100) with 68% of patients having ≥ 50% CSI. While there was a trend for a worse 5-year RFS and DSS for women with ≥ 50% CSI (69% vs. 83%, p = 0.093) and (78% vs. 91%, p = 0.034), respectively, the depth of CSI was not statistically significant as an independent predictor of 5-year RFS, DSS, or OS. The depth of CSI was not associated with a difference in the recurrence pattern (vaginal cuff, pelvic, paraaortic, or distant). In multivariate analysis, FIGO grade was the only predictor of 5-year OS. FIGO grade and the presence of lympho-vascular space invasion (LVSI) were independent predictors of 5-year RFS and DSS. Conclusion: Deep cervical stromal invasion does not appear to be an independent predictive factor for survival endpoints in women with stage II uterine endometroid cancer, according to our findings. The presence of LVSI and tumor grade were both independent predictors of recurrence-free and disease-specific survival. Pooled data analysis may be needed to validate our study findings

Divergent Metabolic Effects of Metformin Merge to Enhance Eicosapentaenoic Acid Metabolism and Inhibit Ovarian Cancer In Vivo

Metformin is being actively repurposed for the treatment of gynecologic malignancies including ovarian cancer. We investigated if metformin induces analogous metabolic changes across ovarian cancer cells. Functional metabolic analysis showed metformin caused an immediate and sustained decrease in oxygen consumption while increasing glycolysis across A2780, C200, and SKOV3ip cell lines. Untargeted metabolomics showed metformin to have differential effects on glycolysis and TCA cycle metabolites, while consistent increased fatty acid oxidation intermediates were observed across the three cell lines. Metabolite set enrichment analysis showed alpha-linolenic/linoleic acid metabolism as being most upregulated. Downstream mediators of the alpha-linolenic/linoleic acid metabolism, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were abundant in all three cell lines. EPA was more effective in inhibiting SKOV3 and CaOV3 xenografts, which correlated with inhibition of inflammatory markers and indicated a role for EPA-derived specialized pro-resolving mediators such as Resolvin E1. Thus, modulation of the metabolism of omega-3 fatty acids and their anti-inflammatory signaling molecules appears to be one of the common mechanisms of metformin\u27s antitumor activity. The distinct metabolic signature of the tumors may indicate metformin response and aid the preclinical and clinical interpretation of metformin therapy in ovarian and other cancers

Genomic Characterization of Pleural Solitary Fibrous Tumours

Pleural solitary fibrous tumours (pSFTs) are uncommon soft tissue tumours of the pleura. that may recur and contribute to the patients’ demise. We analyzed a group of benign and malignant pSFTs for copy number alterations and for common mutations in oncogenes and tumour-suppressor genes. Malignant SFTs demonstrated more copy number alterations, especially 8q (c-myc) gain, 10q (include PTEN) loss, and 13q (Rb1) loss. Mutations were rare in this limited study.MAS

Gastric varices from metastatic ovarian cancer with splenic involvement

Left-sided portal hypertension (LSPH), also known as splenoportal hypertension, is a rare but life-threatening cause of upper gastrointestinal bleeding. LSPH often occurs in non-cirrhotic patients as a consequence of splenic vein obstruction. We present a case of isolated gastric varices due to mass effect on the splenic vein and likely tumor thrombus due to metastatic ovarian cancer

Prognostic significance of depth and pattern of cervical stromal invasion in type 1 endometrial carcinoma

Background: The prognostic significance of cervical stromal invasion (CSI) by endometrial carcinoma is well established, and patients with this form of invasion are offered similar adjuvant therapy. It is not clear whether characteristics of this form of invasion have prognostic implications. We aim in this study to investigate the prognostic significance of depth and pattern of cervical stromal invasion in patients with type 1 endometrial carcinoma. Design: This is a retrospective study of patients with type 1, FIGO stage 2 endometrial cancer, who were treated at our institution between 1991 and 2019. After IRB approval, we assessed microscopic depth of CSI (measured as distance from cervical surface to deepest point of invasion within cervical stroma), cervical stromal thickness, and pattern of invasion (based on endocervical adenocarcinoma previously described patterns A, B, and C). Clinical data were collected from the medical records. Descriptive analysis and Cox regression models were produced. Results: Material and data were available on 50 patients. Median age at diagnosis was 65(41-91) years, of which 30 patients had FIGO grade 1, 23 showed \u3c50% myometrial invasion, 11 had angioinvasion, 40 had underwent lymph node dissection, and 42 received adjuvant radiation. Median depth of CSI was 3.5(0.5-20.0) mm, with median percentage invasion to cervical stromal thickness of 33.3(6.7-100)%. CSI to \u3e2/3 of cervical stroma was found in 8 (16%) of patients, and was associated with worse overall survival (OS) in univariable analysis (HR, 0.22; 95% CI, 0.06-0.75), and after controlling for age, race, grade, depth of myometrial invasion, angioinvasion, peritoneal washings, and adjuvant radiotherapy (HR, 0.08; 95% CI, 0.01-0.53). CSI of 5.0 mm or more, found in 16(32%) patients, was associated with tendency towards worse OS (HR, 3.1; 95% CI, 0.96 - 10.2), while CSI of 50% cervical stroma or more (n=17, 34%) or patterns of invasion were not associated with different OS on univariable analysis. Recurrence was present in 5(10%) of patients, significantly higher in those with \u3e1/3 CSI (LH, 7.1; 0=0.008). (Figure presented) Conclusions: A small subset of type 1, FIGO stage 2 endometrial cancers shows extension to more than 2/3 of cervical stroma and exhibits worse overall survival. Subcategorization of stage 2 and therapy tailoring may be indicated in these patients. Further studies are needed

Significance of non16/non18 high-risk HPV in women with negative or atypical concomitant cervical cytology

Background: Human papilloma virus (HPV) testing on cervical samples is being introduced as a standalone screening test. Clinical algorithm focuses on management of patients with the most common HPV types, 16 and 18. We aim in this study to examine the clinical significance of finding other high-risk HPV types on cervical samples that are cytologically negative or show only atypical squamous cells of unknown significance (ASC-US). Design: We retrospectively analysed patients who underwent cervical cytology and HPV co-testing at our institution in 2013. HPV testing was conducted using FDA-approved Cobas HPV Test (Roche Diagnostics), classifying HPV into HPV16, HPV18, and pooled non16/non18 HPV (types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). Cases with no previous abnormal cytology or HPV were included, and were classified based on HPV test into negative, non16/non18 HPV, and HPV16/18. Results of subsequent pathology are recorded, specifically high grade squamous intraepithelial lesion (HSIL) or carcinoma, categorized in this study under HSIL. Descriptive analysis and Pearson Chi-square test were conducted. Results: A total of 4075 cases were analyzed, with mean age of 43yrs (17-95). These include 2166(53%) negative and 1637(40%) ASC-US cytology. Overall, non16/non18 HPV was detected in 309(8%) cases, and HPV16/18 in 105(3%) cases. Among patients with negative cytology, non16/non18 HPV and HPV16/18 were found in 64(3%) and 17(0.8%) cases, respectively. The risk of HSIL development in cases with non16/non18 HPV is not different from that of HPV16/18(p=0.6), but is higher than that of HPV negative cases(p\u3c0.0001). These findings are similar in patients older than 29yrs. Among patients with ASC-US cytology, non16/non18 HPV was detected in 158(10%) cases while HPV16/18 in 56(3%) cases. The risk of HSIL in cases with non16/non18 HPV is higher than that of negative HPV cases(p\u3c0.0001) but lower than that of HPV16/18(p=0.036). In patients older than 29yrs, HSIL development risk is not different between non16/non18 HPV and HPV16/18(p=0.37), but is higher than that of HPV negative cases (p\u3c0.0001). Conclusions: For patients who developed HSIL after proceeding negative cytology, or in those \u3e29yrs with ASC-US cytology, the prevalence of non16/non18 HPV is not different from HPV16/HPV18. This study argues against stratification of high-risk HPV into different types (HPV16/18 vs non16/non18 HPV)

Prognostic significance of lymph node metastasis patterns in endometrial cancer.

Background: The clinical significance of the size and extracapsular extension (ECE) of lymph node (LN) metastasis is not clear. With the advent of sentinel LN biopsies in endometrial cancer, prognostic significance of lymph node metastasis pattern is critical and may guide further management. Design: This is a retrospective study of patients with endometrial cancer metastatic to regional LN, who underwent treatment at our institution between 1986 and 2007. After IRB approval, we assessed histologic dimension of largest LN metastasis, and presence of ECE. LN metastases are classified as macrometastases (when =\u3e 2mm) and micrometastasis (when \u3c2mm). Clinical data were collected from the medical records. Descriptive analysis and Cox regression models were produced. Results: 126 cases fit our inclusion criteria. Mean age at diagnosis was 65yrs (37-85). Of those, 65 (52%) were considered type 1. LN metastasis was classified as macrometastasis in 92 (73%) cases, including 42 (46%) type 1 cancers. ECE was identified in 33 (26%) cases, including 11 (30%) type 1 cancers. Within the entire sample, LN macrometastasis was significantly associated with recurrence (HR, 3.3; p=0.02), but not overall survival (HR, 1.27; p=0.5). This effect is not significant when adjusting for histologic type, and adjuvant treatment received (HR, 0.78; p=0.519). ECE was associated with worse overall survival and recurrence free survival, within the entire sample (HR, 2.5; p=0.003 and HR, 3.5; p\u3c0.001, respectively) and within type 1 endometrial cancers (HR, 5.4; p=0.001, and HR, 7.23; p\u3c0.001, respectively) but not within type 2 endometrial cancers, where ECE was more common (HR, 1.28; p=0.515). After adjusting to tumor type and adjuvant treatment received, ECE is still associated with worse overall and recurrence-free survival (HR, 2.65; p=0.003 and HR, 4.41; p\u3c0.001, respectively). Conclusions: As the size of lymph node metastasis does not significantly influence survival, lymph node micrometastasis should be carefully searched for within the surgical specimens. This, in addition to the adverse outcome related to ECE, extensive pathologic lymph node sampling, using protocols that detect \u3c0.2 cm metastasis and preserve perinodal fat, may be implemented. Routine reporting of ECE is also recommended. (Figure Presented)

Comparison of methanol fixation versus cryopreservation of the placenta for metabolomics analysis

Methods for collection of placental tissue at room temperature for metabolic profiling are described. Specimens were excised from the maternal side of the placenta and immediately flash frozen or fixed and stored for 1, 6, 12, 24, or 48 h in 80% methanol. Untargeted metabolic profiling was performed on both the methanol-fixed tissue and the methanol extract. Data were analyzed using Gaussian generalized estimating equations, two sample t-tests with false discovery rate (FDR) corrections, and principal components analysis. Methanol-fixed tissue samples and methanol extracts had a similar number of metabolites (p = 0.45, p = 0.21 in positive vs. negative ion mode). In positive ion mode, when compared to flash frozen tissue, both the methanol extract and methanol-fixed tissue (6 h) had a higher number of metabolites detected (146 additional metabolites, p(FDR) = 0.020; 149 additional metabolites, p(FDR) = 0.017; respectively), but these associations were not found in negative ion mode (all p(FDR) ≥ 0.05). Principle components analysis demonstrated separation of the metabolite features in the methanol extract, but similarity between methanol-fixed tissue and flash frozen tissue. These results show that placental tissue samples collected in 80% methanol at room temperature can yield similar metabolic data to flash frozen specimens

The Prognostic Significance of the Depth of Cervical Stromal Invasion in Women With FIGO Stage II Uterine Endometrioid Carcinoma

OBJECTIVE: The objective of this study was to investigate the prognostic significance of the depth of cervical stromal invasion (CSI) in women with FIGO stage II uterine endometrioid adenocarcinoma (EC). METHODS: Our database of women with EC was quired for patients with stage II EC. Pathologic slides were retrieved and reviewed by gynecologic pathologists to determine cervical stromal thickness and depth of CSI as a percentage of stromal thickness (%CSI). Kaplan-Meier, univariate, and multivariate analyses were used to compare recurrence-free, disease-specific (DSS), and overall survival (OS) between women who had\u3c50% versus ≥50% CSI. Univariate and multivariate analyses were used to assess other prognostic variables associated with survival endpoints. RESULTS: A total of 117 patients were included in our study who had hysterectomy between 1/1990 and 8/2021. Seventy-nine patients (68%) with \u3c50% and 38 (32w%) with ≥50% CSI. After a median follow-up of 131 months, 5-year DSS was significantly worse for women with ≥50% CSI (78% vs. 91%; P=0.04). However, %CSI was not an independent predictor for any of the studied survival endpoints. Independent predictors of worse 5-year recurrence-free survival and DSS included FIGO grade 3 tumors (P=0.02) and the presence of lymphovascular space invasion (P=0.03). Grade 3 tumors were the only independent predictor of worse 5-year OS (P=0.02). CONCLUSIONS: Our results suggest that deep CSI is not an independent prognostic factor for survival endpoints in women with stage II uterine endometroid adenocarcinoma. The lack of independent prognostic significance of the depth CSI needs to be validated in a multi-institutional analysis