Presence Of Lymphovascular Space Invasion Research Articles

Prognostic and clinicopathological role of prognostic nutritional index (PNI) in endometrial cancer: A meta-analysis

BackgroundThe effect of prognostic nutritional index (PNI) on predicting prognosis of endometrial cancer (EC) patients has been widely analyzed, but no consistent findings are obtained. We therefore performed a meta-analysis for determining accurate role of PNI in predicting EC prognosis. MethodsWe comprehensively searched PubMed, Web of Science, Embase, Cochrane Library, and CNKI databases from inception till January 5, 2024. Correlation between PNI and survival outcomes in EC was evaluated by pooled hazard ratios (HRs) and 95 % confidence intervals (CIs). ResultsThere were altogether eight articles involving 3,164 patients enrolled into this meta-analysis. According to our pooled results, low PNI significantly predicted the dismal overall survival (OS) (HR = 1.72, 95%CI = 1.33–2.22, p < 0.001) and inferior progression-free survival (PFS)/disease-free survival (DFS)/recurrence-free survival (RFS) (HR = 2.49, 95%CI = 1.62–3.84, p < 0.001) for EC patients. Furthermore, as revealed by our pooled results, a decreased PNI was significantly connected to FIGO stage III-IV (OR = 2.06, 95%CI = 1.42–2.99, p < 0.001), tumor grade of G3 (OR = 1.68, 95%CI = 1.32–2.14, p < 0.001), presence of lymphovascular space invasion (LVSI) (OR = 1.72, 95%CI = 1.14–2.61, p = 0.010), and presence of myometrial invasion (MMI) (OR = 2.04, 95%CI = 1.51–2.77, p < 0.001) in EC. ConclusionAccording to our meta-analysis results, the decreased PNI is markedly related to poor OS and inferior PFS/DFS/RFS of EC patients. Additionally, decreased PNI was indicative of features implying tumor progression and development in EC.

Pattern of LRR in Endometrial Cancer and Identification of Predictive Factors

Background: Tailored adjuvant treatment is key to managing endometrial cancer effectively. Understanding prognostic factors of loco-regional failure and the impact of adjuvant treatment can help in treatment de-escalation without compromising survival outcomes. The aim of this study was to assess the pattern of failure in endometrial cancer patients and to determine predicting Loco-Regional Recurrence (LRR) factors. Patients and methods: Data were collected from 214 patients treated for endometrial cancer between 2005 and 2012 in Salah Azaiez Institute in Tunisia. All patients underwent upfront surgery followed by adjuvant brachytherapy with or without external beam radiation. The median follow-up period was 44 months. Univariate and multivariate analyses were performed to identify prognostic factors for LRR. Results: The 5-year overall survival rate was 78.1%, and the 5-year progression-free survival rate was 80.1%. LRR occurred in 25 patients (11.6%), with a median recurrence time of 29 months (range 4 months - 46 months). Pelvic relapse was the most common site, occurring in 10 patients. Vaginal relapses were observed in 9 patients, and retro-peritoneal relapses were observed in 6 cases. FIGO stage, tumor grade, histologic type, Lympho-Vascular Space Invasion (LVSI), and delays in adjuvant treatment were significant predictors of LRR. Conclusion: Identifying prognostic factors for LRR in endometrial cancer is crucial for optimizing adjuvant treatment strategies. Higher FIGO stages and the presence of LVSI were independent predictive factors for LRR. Tailored adjuvant treatment, taking these prognostic factors into account, is essential to improve patient outcomes and minimize unnecessary treatment-related toxicity.

New staging of endometrial carcinoma - FIGO 2023.

To review the changes in the new version of the FIGO 2023 staging system for endometrial cancer. The new FIGO 2023 endometrial cancer staging system provides key updates for the diagnosis and treatment of endometrial cancer. An important step in diagnosis is molecular classification, which allows more accurate risk stratification for recurrence and the identification of targeted therapies. The new staging system, based on the recommendations of the international societies ESGO, ESTRO and ESP, incorporates not only the description of the pathological and anatomical extent of the disease, but also the histopathological characteristics of the tumour, including the histological type and the presence of lymphovascular space invasion. In addition, the staging system uses molecular testing to classify endometrial cancers into four prognostic groups: POLEmut, MMRd, NSMP and p53abn. Each group has its own specific characteristics and prognosis. The most significant changes have occurred in stages I and II, in which the sub-staging better reflects the biological behaviour of the tumour. This update increases the accuracy of prognosis and improves individualized treatment options for patients with endometrial cancer. The updated FIGO staging of endometrial cancer for 2023 incorporates different histologic types, tumour features, and molecular classifications to better reflect the current improved understanding of the complex nature of several endometrial cancer types and their underlying bio logic behaviour. The aim of the new endometrial cancer staging system is to better define stages with similar prognosis, allowing for more precise indication of individualised adjuvant radiation or systemic treatment, including the use of immunotherapy.

Effect of time interval between surgery and the initiation of adjuvant therapy on the oncologic outcomes of early-stage endometrial cancer.

To identify the impact of time interval between surgery and initial adjuvant radiotherapy on oncologic outcomes in early-stage endometrial cancer. This retrospective cohort study included patients with stage I/II endometrial cancer who underwent surgical staging and adjuvant therapy at Songklanagarind Hospital from January 1, 2007, to December 31, 2017. Patients were categorized into two groups: TI <6 weeks and TI ≥6 weeks. The effects of TI and clinicopathological factors on recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox proportional-hazards regression. In total, 177 patients were enrolled, with 52% receiving adjuvant radiotherapy at <6 weeks (overall median TI 5.7 weeks). The recurrence and death rates were 13% and 10.2%, respectively. The median follow-up time was 46.6 months. The overall 3-year RFS and OS rates were 88.2% and 85.2%, respectively. The TI significantly affected the 3-year RFS (94.4% vs 81.2%; P = 0.008) and 3-year OS (95.5% vs 83.2%; P = 0.012) in patients with TI <6 and ≥6 weeks, respectively. In multivariate analysis, the depth of myometrial invasion (MI), presence of lymphovascular space invasion, and TI were independent prognostic factors for both RFS and OS. Delaying the TI (≥6 weeks) was significantly associated with a worse RFS (hazard ratio [HR] 3.70; 95% confidence interval [CI]: 1.34-10.22; P = 0.012) and an inferior OS (HR 3.80; 95% CI: 1.23-11.69; P = 0.02). A delay in the TI between surgery and the initiation of adjuvant radiotherapy of ≥6 weeks negatively affected the oncologic outcomes in early-stage endometrial cancer.

Impact of adjuvant treatment on survival in patients with 2023 FIGO stage IIC endometrial cancer: a retrospective analysis from two tertiary centers in Korea and Taiwan.

In early-stage endometrial cancer, aggressive histologic types (grade 3 endometrioid, serous, clear cell, carcinosarcomas, undifferentiated, mixed, and other unusual types) are associated with an increased risk of distant metastases and worse survival. However, the optimal adjuvant treatment for these patients remains controversial. The present study investigated the outcomes of different adjuvant treatments in patients with 2023 FIGO stage IIC endometrial cancer. We retrospectively identified patients with 2023 FIGO stage IIC endometrial cancer who underwent surgery followed by either adjuvant treatment or observation from 2000 to 2020 at two tertiary centers in Korea and Taiwan. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using Kaplan-Meier estimates and Cox proportional-hazards models. We also analyzed recurrence patterns after different adjuvant treatments. A total of 272 patients were identified; 204 received adjuvant treatment postoperatively, whereas 68 only underwent observation. Adjuvant treatment was not associated with improved RFS or OS. Non-endometrioid histologic types (p=0.003) and presence of lymphovascular space invasion (LVSI, p=0.002) were associated with worse RFS, whereas only non-endometrioid histologic types impacted OS (p=0.004). In subgroup analyses, adjuvant treatment improved OS in patients with LVSI (p=0.020) and in patients with both LVSI and grade 3 endometrioid histologic type (p=0.007). We found no difference in locoregional and distant recurrence between patients undergoing adjuvant treatment or observation. In this study, the addition of adjuvant treatment was associated with an OS benefit for patients with LVSI, especially those with grade 3 endometrioid tumors.

Real-World Data Assessing the Impact of Lymphovascular Space Invasion on the Diagnostic Performance of Sentinel Lymph Node Mapping in Endometrial Cancer.

SLN mapping has emerged as a standard of care in endometrial cancer due to its high sensitivity and significant reduction in morbidity. Although lymphovascular space invasion (LVSI) is a known risk factor for lymph node metastasis and recurrence, evidence on the reliability of SLN mapping in LVSI-positive patients is scarce. The aim of this study was to determine the impact of LVSI on the diagnostic performance of SLN mapping. This retrospective cohort study included patients with endometrial cancer who underwent primary surgical treatment at the Bern University Hospital, Switzerland, between 2012 and 2022. LVSI was present in 22% of patients and was significantly associated with lymph node metastasis (p < 0.001) and recurrence (p < 0.001). In node-negative patients with only SLN mapping performed, LVSI was an independent predictor of recurrence during multivariable Cox regression analysis (p = 0.036). The negative predictive value of SLN mapping was 91.5% and was significantly lower in tumors with LVSI (75.0%) compared to LVSI-negative tumors (95.6%, p = 0.004). The presence of LVSI was significantly associated with worse oncological outcomes. LVSI was an independent predictor of recurrence in node-negative patients with only SLN mapping performed. Furthermore, the negative predictive value of SLN mapping was significantly lower in LVSI-positive tumors.

Salvage Abdominoperineal Resection for Locally Recurrent or Persistent Anal Squamous Cell Carcinoma after Definitive Chemoradiation.

Initial treatment for patients with squamous cell carcinoma of the anal canal includes definitive chemoradiation. Salvage abdominoperineal resection (APR) is the treatment of choice for recurrent or persistent disease. Older studies suggest approximately 50% successful salvage of recurrent or persistent disease with APR. Risk factors for failure after salvage APR are incompletely characterized. Using a single institutional database, patients were identified who underwent salvage APR after definitive intensity-modulated radiotherapy-based chemoradiation between 2003 and 2022. Clinical and pathologic variables analyzed included age at APR, sex, race, HIV status, initial cT stage, initial cN stage, radiation dose, recurrent vs persistent disease, recurrent pT stage, recurrent pN stage, the presence of LVSI, PNI or <2mm surgical margins, and the use of either intraoperative radiation or another treatment modality in addition to APR. The log rank test was used to determine differences in time from APR to events (local recurrence, distant metastasis and death) based on clinical and pathologic variables. The Cox Proportional Hazard Model was used to perform multivariable analysis for all factors with a univariate P-value <0.1. Of 628 patients with anal squamous cell carcinoma, 50 (8.0%) were treated with abdominoperineal resection for locally recurrent (n = 29, 58%) or locally persistent (n = 21, 42%) disease. Median [interquartile range] follow up was 40.0 months [15.2-68.0 months] from APR. Median local recurrence-free survival was not reached; 1- and 2-year local recurrence-free survival was 81% (95% CI 72-92%) and 76% (64-89%). On multivariable analysis, pathologic T-stage of the recurrence (3.85 (1.07-13.9); P = .040), the presence of lymphovascular space invasion (9.1 (1.12-73.62); P = .038) and surgical margins <2mm (8.81 (2.11-36.73); P = .003) were all significantly associated with higher rates of local recurrence. Median distant metastasis-free survival was not reached; 1- and 2-year distant metastasis-free survival was 88% (81-98%) and 79% (67-92%). On multivariable analysis, only persistent (versus recurrent) local disease was significantly associated with higher rates of distant metastasis (1.23 (1.05-5.55) P = .043). Median overall survival was not reached; 1- and 2-year overall survival was 90% (81-98%) and 78% (65-90%). On multivariable analysis, only recurrent pT stage (T3/4 vs T1/2) was associated with higher rates of death (5.87 (1.02-33.65); P = .047). APR is a successful salvage modality for anal squamous cell carcinoma with recurrent or persistent disease after chemoradiation results. Patients with pT3/4 disease, lymphovascular space invasion, surgical margins <2 mm may be associated with higher re-recurrence rates and may benefit from more frequent monitoring or treatment escalation.

Prognostic Impact of Mismatch Repair Deficiency on Stage I-II Endometrioid Endometrial Cancer Treated with Adjuvant Radiation Therapy: A Multi-Institutional Analysis

To report the impact of mismatch repair (MMR) status on outcomes in patients with stage I-II endometrioid endometrial cancer (EEC). This is a multi-institutional retrospective cohort study across 11 institutions. Preliminary data from 7 centers is available for analysis. Patients with known MMR status and stage I-II EEC status post-surgical staging treated with adjuvant radiation therapy were included. Overall survival (OS) and recurrence-free survival (RFS) rates were estimated by the Kaplan-Meier method. Univariate and multivariate analyses were performed by Cox proportional hazard models for OS/RFS. Statistical analyses were conducted using statistical software. A total of 573 patients with median age at diagnosis of 65 years (Interquartile Range (IQR) 58-71) were eligible. Most patients were White (79%), had FIGO 2009 Stage I (89.7%) and FIGO grade 1-2 (74.7%). MMR deficiency (dMMR) was reported in 191 patients (33%) while 382 patients (67%) had preserved MMR (pMMR). External beam radiation therapy (EBRT) +/- vaginal brachytherapy (VBT) was delivered to 124 patients (21.6%) while 449 patients (78.4%) received VBT alone. After a median follow-up of 41 months ((IQR) 28-60 months), the estimated OS and RFS rates for the entire cohort were 95.1% and 85%, respectively. On univariate analysis, age >65 (p < 0.001), grade 3 (p < 0.001), presence of lymphovascular space invasion (LVSI) (p = 0.039) and deep myometrial invasion (p = 0.03) were associated with worse OS. The OS was inferior in the dMMR group, however, it did not reach significance (92% vs 96.1%, p = 0.06). On multivariate analysis, older age (p < 0.001) and grade 3 (p = 0.002) were the only predictors for worse OS. On univariate analysis for RFS, age >65 (p = 0.02), grade 3 (p = 0.018) and dMMR (72.9% vs 91%, p < 0.001) were associated with worse RFS. On multivariate analysis, age >65 (p = 0.015) and dMMR (p < 0.001) were significant predictors of worse RFS. Preliminary data from 7 out of 11 participating institutions showed that dMMR status leads to significantly decreased RFS in patients with early-stage EEC. While awaiting the results of NRG GYN020 and RAINBO prospective trials, this large study suggests that treatment intensification could be warranted in patients with dMMR early-stage EEC.

Endometrial cancer: predictors and oncological safety of tumor tissue manipulation.

The main goal of this study is to assess the impact of tumor manipulation on the presence of lympho-vascular space invasion and its influence on oncological results. We performed a retrospective multi-centric study amongst patients who had received primary surgical treatment for apparently early-stage endometrial cancer. A multivariate statistical analysis model was designed to assess the impact that tumor manipulation (with the use of uterine manipulator or preoperative hysteroscopy) has on lympho-vascular development (LVSI) in the final surgical specimen. A total of 2852 women from 15 centers were included and divided into two groups based on the lympho-vascular status in the final surgical specimen: 2265 (79.4%) had no LVSI and 587 (20.6%) presented LVSI. The use of uterine manipulator was associated with higher chances of lympho-vascular involvement regardless of the type used: Balloon manipulator (HR: 95% CI 4.64 (2.99-7.33); p < 0.001) and No-Balloon manipulator ([HR]: 95% CI 2.54 (1.66-3.96); p < 0.001). There is no evidence of an association between the use of preoperative hysteroscopy and higher chances of lympho-vascular involvement (HR: 95% CI 0.90 (0.68-1.19); p = 0.479). Whilst performing common gynecological procedures, iatrogenic distention and manipulation of the uterine cavity are produced. Our study suggests that the use of uterine manipulator increases the rate of LVSI and, therefore, leads to poorer oncological results. Conversely, preoperative hysteroscopy does not show higher rates of LVSI involvement in the final surgical specimen and can be safely used.

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

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). 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<50% versus ≥50% CSI. Univariate and multivariate analyses were used to assess other prognostic variables associated with survival endpoints. A total of 117 patients were included in our study who had hysterectomy between 1/1990 and 8/2021. Seventy-nine patients (68%) with <50% 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). 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.

Prediction of Deep Myometrial Infiltration, Clinical Risk Category, Histological Type, and Lymphovascular Space Invasion in Women with Endometrial Cancer Based on Clinical and T2-Weighted MRI Radiomic Features.

To predict deep myometrial infiltration (DMI), clinical risk category, histological type, and lymphovascular space invasion (LVSI) in women with endometrial cancer using machine learning classification methods based on clinical and image signatures from T2-weighted MR images. A training dataset containing 413 patients and an independent testing dataset consisting of 82 cases were employed in this retrospective study. Manual segmentation of the whole tumor volume on sagittal T2-weighted MRI was performed. Clinical and radiomic features were extracted to predict: (i) DMI of endometrial cancer patients, (ii) endometrial cancer clinical high-risk level, (iii) histological subtype of tumor, and (iv) presence of LVSI. A classification model with different automatically selected hyperparameter values was created. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve, F1 score, average recall, and average precision were calculated to evaluate different models. Based on the independent external testing dataset, the AUCs for DMI, high-risk endometrial cancer, endometrial histological type, and LVSI classification were 0.79, 0.82, 0.91, and 0.85, respectively. The corresponding 95% confidence intervals (CI) of the AUCs were [0.69, 0.89], [0.75, 0.91], [0.83, 0.97], and [0.77, 0.93], respectively. It is possible to classify endometrial cancer DMI, risk, histology type, and LVSI using different machine learning methods.

Prognostic Value of β-Catenin and L1CAM Expressions in Type I Endometrial Carcinoma.

The aim of this study is to evaluate the expression of β-catenin and L1CAM in the type I of Endometrial Carcinoma. This study was an analytical study with a cross-sectional design using 49 samples of type I Endometrial Carcinoma. Immunohistochemical method was used to evaluate the expression of β-catenin and L1CAM related to two significant prognostic parameters i.e., lymphovascular space invasion (LVSI) and metastases event of type I Endometrial Carcinoma samples. From all samples collected, based on the presence of LVSI, there were 17 cases (34.7%) with LVSI and 32 (65.3%) no LVSI. Among them, there were 13 cases that included lymph node or omental samples in type I Endometrial Carcinoma, 5 (38.5%) cases of metastasis, and 8 (61.5%) cases that did not metastasize. The statistical results showed that there was a significant correlation between β-catenin and L1CAM expressions examined from tumor cells with lymphovascular space invasion and the presence of metastases in the type I Endometrial Carcinoma (p <0.05). This study suggest that the positive expression of β-catenin together with L1CAM can participate in the development of tumor cells in type I Endometrial Carcinoma, in its ability to involve lymphovascular space invasion, and metastases to other sites. Our results indicate that both of β-catenin and L1CAM are prominent biomarkers for the prognosis of type I Endometrial Carcinoma.

Lymph Node Metastasis and Patterns of Recurrence in Vulvar Carcinoma: 10 Years' Single Center Experience.

Vulvar carcinoma is a relatively rare malignancy and there is a paucity of data, especially from India and other developing countries regarding the prognostic factors impacting recurrence and survival. A retrospective observational study was conducted in the Department of Gynecologic Oncology at a tertiary care, regional cancer institute, including all patients with carcinoma vulva who underwent surgery between 2009 and 2018. Demographic profile, surgical-pathological information, details of neo-adjuvant chemotherapy, adjuvant radiation and chemotherapy, and peri-operative complications were analyzed. Long-term follow-up data was gathered, with an evaluation of various prognostic factors impacting recurrence and overall survival outcome. Forty-five cases with mean age of 56.2years (range 29-82) were treated during the study period. Surgery was the initial treatment modality in 41 (91.1%) cases. Neo-adjuvant chemotherapy prior to surgery was given to four cases. After complete surgico-pathological staging, most patients had stage I disease (26 cases, 57.8%) and 22.2% had stage II disease. Owing to microscopic lymph node involvement, seven cases (15.6%) belonged to FIGO stage III disease. Two cases had stage IVA disease with fixed groin nodes. Adjuvant chemotherapy in the form of 5-fluoro uracil and cisplatin was administered to four out of the nine patients with nodal involvement. The remaining five were advised adjuvant groin radiation. At a median follow-up of 34months (range 2-114months), 12 cases (26.7%) experienced a recurrence and one case with stage IVA disease progressed during adjuvant chemotherapy. The 5-year overall survival was 76.6% and the 5-year disease-free survival was 69.6%. There were a total number of 10 deaths, of which seven were due to disease recurrence or progression and the remaining 30% of deaths were due to medical co-morbid conditions. Overall survival was negatively impacted by increasing age (age > 60years), number of positive nodes, presence of perinodal spread, and stage of the disease. Recurrence-free survival was significantly reduced in those with the presence of peri-nodal spread and lympho-vascular space invasion. The incidence of lymph node metastasis was found to be higher in patients with age > 60years, increasing tumor size, presence of lympho-vascular space invasion and the number of lymph nodes removed. In carcinoma vulva, treatment should be individualized with multidisciplinary cooperation. In our series, we found that the stage of disease, nodal positivity, and nodal positivity with extra-capsular spread were significant prognostic factors impacting survival on analysis. Lymph nodal positivity was associated with increasing tumour size, presence of lympho-vascular invasion, and patient age.

The risk of lymph node metastasis in the new FIGO 2018 stage IA cervical cancer with >7 mm diameter.

In the 2018 FIGO staging system, cervical cancers with ≤5 mm depth of invasion (DOI) and a diameter of >7 mm, first classified as stage IB, are classified as stage IA. In this group, it is unclear what the risk of lymph node metastasis (LNM) is. This retrospective cohort study aims to determine the incidence of LNM and to study the association between disease-related characteristics and LNM. Women diagnosed with FIGO 2009 IB cervical cancer, with ≤5 mm DOI and a diameter >7 mm, treated with a radical hysterectomy and pelvic lymphadenectomy between 1985 and 2020 were selected from the databases of the Amsterdam University Medical Center and the University Medical Center Groningen. The specimens of patients with LNM were revised by expert pathologists. The incidence of LNM was calculated. The associations between LNM and DOI, diameter, histological type, clinical visibility and lymphovascular space invasion (LVSI) were evaluated by calculating odds ratios using logistic regression. Of the 389 patients included, 10 had pathologically confirmed LNM (2.6%, 95% confidence interval=1.3%-4.5%). In case of LVSI, univariate analysis showed an increased risk of LNM (p=0.003 and p=0.012, respectively). No difference in LNM was found between lesions diagnosed by microscopy and clinically visible lesions. No LNM were found in patients without LVSI and a DOI of ≤3 mm. For patients with stage IA cervical cancer with a diameter >7 mm, we recommend considering a pelvic lymph node assessment in case of DOI >3 mm and/or presence of LVSI.

Can mismatch repair status be added to sentinel lymph node mapping algorithm in endometrioid endometrial cancer?

ObjectiveTo evaluate the relation between mismatch repair (MMR) status and the risk of lymph node metastasis in endometrial cancer, and whether this additional data can be incorporated to current SLN (sentinel lymph node) algorithm. MethodsWe included a series of 332 women that underwent SLN mapping ± systematic lymphadenectomy from January 2013 to December 2021. Protein expressions of MLH1, MSH2, MSH6, PMS2 were examined by immuno-histochemistry and considered MMRd (deficient) when at least one protein was not expressed. ResultsMMRd was noted in 20.8% of cases and correlated to grade 3 (p = 0.018) and presence of lymphovascular space invasion (p = 0.032). Moreover, MMRd was an independent risk factor for lymph node metastasis (OR 2.76, 95% CI 1.36–5.62). Notably, 21.7% (15/69) cases with MMRd had lymph node metastasis compared to 9.5% (25/263) of cases with MMRp (proficient) (p = 0.005). The overall and bilateral SLN detection rates were 91.9% and 75.9%, respectively. Of the 80 (24%) cases of non-bilateral SLN detection, 66.2% had low-grade tumors (G1/G2) and myometrial invasion <50%. Considering MMR status an independent prognostic factor for lymph node metastasis, a systematic lymphadenectomy (side specific or bilateral) would forgo in 53.7% (43/80) of cases with non-bilateral detection, representing 13% (43/332) of all endometroid tumors. ConclusionMMR status was independently related to lymph node metastasis in endometrioid EC. Moreover, MMR status may help to select patients that can forgo systematic lymphadenectomy in case of undetected SLN.

Correlation of PD-L1 immunohistochemical expression with microsatellite instability and p53 status in endometrial carcinoma.

Endometrial carcinoma (EC) is the most common gynaecological cancer worldwide. The Cancer Genome Atlas molecular grouping of a given case of EC could be assessed by POLE gene mutation, mismatch repair (MMR) 'to reflect microsatellite instability' and p53 status, which has proved to be of prognostic value. Programmed cell death receptor 1 (PD-1) and its ligand (PD-L1) are playing a progressively important role in tumour immunology and cancer treatment. To investigate PD-L1 immunohistochemical expression in EC in relation to MMR and p53 status. Associations between marker expression and different histopathological parameters were also investigated. This retrospective study was performed on archival biopsies of 170 cases of EC using a tissue microarray model. Immunohistochemical staining was applied using antibodies against PD-L1, MLH1, MSH2 and p53. The percentages of positivity were as follows: PD-L1, 19.6%; MLH1, 79.5%; MSH2, 78.5%; and p53 mutant, 13.8%. There was significant correlation between MLH1 expression and MSH2 expression (p=0.008). Tumour grade was significantly correlated with stage (p=0.005) and p53 mutant expression (p=0.008). Combined PD-L1 positivity and MMR deficiency showed significant correlation with the presence of lymphovascular space invasion (p=0.014). MSH2 negativity was significantly associated with poorer overall survival (p=0.014). A panel of immunohistochemical markers (PD-L1, MLH1, MSH2 and p53) could help to predict the prognosis and plan the treatment of patients with EC. MMR deficiency seems to be a good predictor for PD-L1 status, and therefore the response to potential PD-1/PD-L1 inhibitor therapy.

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

<h3>Purpose/Objective(s)</h3> 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. <h3>Materials/Methods</h3> 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 (< 50% vs > = 50%). Patients' demographics, pathologic, and treatment characteristics were analyzed using univariate and multivariate analysis to calculate recurrence-free (RFS) and disease-specific (DSS) rates. <h3>Results</h3> 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. <h3>Conclusion</h3> 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.

Racial Disparities in Patients with Stage IIIC Endometrial Cancer

<h3>Purpose/Objective(s)</h3> To report the impact of race on clinical outcomes in patients with stage IIIC endometrial carcinoma (EC). <h3>Materials/Methods</h3> A retrospective multi-institutional cohort study was conducted across 13 Northern American academic centers and included patients with stage IIIC endometrial carcinoma (EC) who received both chemotherapy and radiation in an adjuvant setting. Overall survival (OS) and recurrence-free survival (RFS) were calculated by Kaplan-Meier method. Univariable and multivariable analysis were performed by Cox proportional hazard models for RFS/OS. Propensity score matching was used to estimate the effect of race on survival outcomes. Statistical analyses were conducted using statistical software. <h3>Results</h3> A total of 90 Black and 568 non-Black patients (83%) were identified with a median age at diagnosis of 62 (Interquartile Range (IQR) 55-70). Median follow-up was 45.3 months (IQR 24-71 months). Black patients were significantly older (p<0.0001), had significantly more non-endometrioid histology (p<0.0001), grade 3 tumors (p<0.0001) and were more likely to have >1 positive paraaortic lymph nodes (PALN) compared to non-black patients. The presence of lymphovascular space invasion (LVSI), depth of myometrial involvement, number of total nodes involved, adnexal and cervical involvement and stage were not correlated with race (all p>0.1). As for treatment type, chemoradiotherapy sequencing approach was not correlated with race and no difference in number of chemotherapy cycles between Black and non-Black patients (p=0.32) was observed. Black patients were more often treated with external beam radiation therapy (EBRT) (43.3% and 24%, respectively) while a higher proportion of non-black patients received both EBRT and vaginal cuff brachytherapy (VBT) (65% vs. 38 %) (P<0.0001) despite similar cervical involvement. The 5-year estimated OS and RFS rates were 45% and 47% compared to 77% and 68% for Black patients vs. non-black patients, respectively (p<0.001). After propensity score matching, the 2 groups were well balanced for most of the covariates (age, histology, stage, grade, number of positive PALN, adnexal and cervical involvement) except for depth of myometrial invasion and radiation type. The estimated hazard ratios (HRs) of Black vs. non-Black patients were 1.613 (95% CI = (1.01, 2.575), p-value = 0.045) for OS and 1.487 (95% CI = (0.906, 2.440), p-value = 0.116) for RFS, indicating that Black patients have significantly worse OS. RFS differences did not reach statistical significance. <h3>Conclusion</h3> Compared to non-Black patients, Black patients have higher rates of non-endometrioid histology, grade 3 tumors and number of PALNs. After propensity score matching, Black patients had worse OS but no statistically significant difference in RFS. Racial disparities could be mitigated by better access to care, equitable inclusion on randomized trials, and identification of genomic/molecular differences to better tailor adjuvant treatment.

Trends in Use and Clinical Outcomes Associated with Post-Operative Radiation Therapy for HPV-Associated Oropharyngeal Squamous Cell Carcinomas

<h3>Purpose/Objective(s)</h3> Intermediate and high-risk features (IRFs/HRFs) for locoregional recurrence following initial surgery for oropharyngeal SCCs (OP-SCCs) were defined prior to the known association of HPV with OP-SCC. There are limited reports on practice patterns and outcomes associated with post-operative radiation therapy (RT) or chemoradiation (CRT). We aimed to address these questions with the National Cancer Database (NCDB). <h3>Materials/Methods</h3> The NCDB was queried for patients with HPV-associated OP-SCCs managed initially with surgery with IRFs or HRFs. IRFs were defined as T3/T4 disease, node positive disease, and the presence of lymphovascular space invasion (LVSI), and HRFs as positive margins and extranodal extension (ENE). Patients were stratified into groups if they received no adjuvant therapy, RT, or CRT. Patients treated with RT or C-RT were required to have documentation of receipt of 50-70 Gy. Kaplan-Meier analysis was utilized for comparison of overall survival (OS) between treatment arms followed by a Cox multivariate (MVA) proportional-hazards model and propensity score analyses performed using inverse probability treatment weighting (IPTW). <h3>Results</h3> We identified 6,301 patients; 1,319 patients had positive margins, 2,266 patients had ENE, and 3,074 patients had one or two HRFs. The median number of RFs was 2 (range: 1-5). Regarding treatment, 1,606, 2,407, and 2288 patients received no RT, RT, and CRT, respectively. The median RT dose was 60 Gy (range: 50-70 Gy). Median age was 58 years (range: 24-90) and the median Charlson-Deyo comorbidity score was 0 (range: 0-3). Among patients with IRFs, 8-year OS with no RT (84.3%) was significantly lower vs. RT (90.1%) or CRT (88.8%; <i>p</i> < 0.0001) with no difference with RT vs. CRT (<i>p</i> = 0.13). On Cox MVA, RT was associated with significantly improved OS vs. no RT (hazard ratio (HR) = 0.57 (95% CI: 42.7-75.2%); <i>p</i> < 0.0001) but not CRT (HR = 1.37 (95% CI: 0.97-1.93). On IPTW analyses, receipt of RT or CRT was associated with significantly improved OS on Cox MVA (HR = 0.72 (95% CI: 0.57-0.91; <i>p</i> = 0.006). Among patients with HRFs, 8-year OS with no RT (69.1%) was significantly lower vs. RT (79.3%) or CRT (82.1%; <i>p</i> < 0.001) with no difference with RT vs. CRT (<i>p</i> = 0.22). On sub-group analysis of patients with positive margins, 8-year OS was not significantly different between RT (80.5%) and CRT (81.2%; <i>p</i> = 0.72). On Cox MVA comparing RT to CRT, CRT was not associated with significantly improved OS (HR = 0.94 (95% CI: 0.74-1.18)) for patients with HRFs. On IPTW analyses, CRT was not associated with improved 8-year OS (81.8%) vs. RT (81.5%) for patients with HRFs or on Cox MVA (HR = 0.97 (95% CI: 0.76-1.24); <i>p</i> = 0.81)). <h3>Conclusion</h3> A significant proportion of HPV-associated OP-SCC patients with IRFs or HRFs did not receive RT, which was associated with inferior OS. CRT did not result in superior outcomes compared to RT for patients with HRFs. Traditional HRFs as indications for CRT require re-evaluation for HPV-associated OP-SCC patients in prospective studies.

Targeted Molecular Testing in Endometrial Carcinoma: Validation of a Clinically Driven Selective ProMisE Testing Protocol.

Incorporation of molecular classification into clinicopathologic assessment of endometrial carcinoma (EC) improves risk stratification. Four EC molecular subtypes, as identified by The Cancer Genome Atlas, can be diagnosed through a validated algorithm Pro active M olecular R is k Classifier for E ndometrial Cancer (ProMisE) using p53 and mismatch repair (MMR) protein immunohistochemistry (IHC), and DNA polymerase epsilon ( POLE) mutational testing. Cost and access are major barriers to universal testing, particularly POLE analysis. We assessed a selective ProMisE algorithm (ProMisE-S): p53 and MMR IHC on all EC's with POLE testing restricted to those with abnormal MMR or p53 IHC (to identify POLEmut EC with secondary abnormalities in MMR and/or p53) and those with high-grade or non-endometrioid morphology, stage >IA or presence of lymphovascular space invasion (so as to avoid testing on the lowest risk tumors). We retrospectively compared the known ProMisE molecular classification to ProMisE-S in 912 EC. We defined a group of "very low-risk" EC (G1/G2, endometrioid, MMR-proficient, p53 wild-type, stage IA, no lymphovascular space invasion) in whom POLE testing will not impact on patient care; using ProMisE-S, POLE testing would not be required in 55% of biopsies and 38% of all EC's, after evaluation of the hysterectomy specimen, in a population-based cohort. "Very low-risk" endometrioid EC with unknown POLE status showed excellent clinical outcomes. Fifteen of 166 (9%) of all p53abn EC showed G1/G2 endometrioid morphology, supporting the potential value of universal p53 IHC. The addition of molecular testing changed the risk category in 89/896 (10%) EC's. In routine practice, POLE testing could be further restricted to only those patients in whom this would alter adjuvant therapy recommendations.