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Background: Current preoperative imaging is insufficient to predict survival and tumor recurrence in endometrial cancer (EC), necessitating invasive procedures for risk stratification., Purpose: To establish a multiparametric MRI radiomics model for predicting disease-free survival (DFS) and high-risk histopathologic features in EC., Methods: This retrospective study included 71 patients with histopathology-proven EC and preoperative MRI over a 10-year period. Clinicopathology data were extracted from health records. Manual MRI segmentation was performed on T2-weighted (T2W), apparent diffusion coefficient (ADC) maps and dynamic contrast-enhanced T1-weighted images (DCE T1WI). Radiomic feature (RF) extraction was performed with PyRadiomics. Associations between RF and histopathologic features were assessed using logistic regression. Associations between DFS and RF or clinicopathologic features were assessed using the Cox proportional hazards model. All RF with univariate analysis p-value < 0.2 were included in elastic net analysis to build radiomic signatures., Results: The 3-year DFS rate was 68% (95% CI = 57%-80%). There were no significant clinicopathologic predictors for DFS, whilst the radiomics signature was a strong predictor of DFS (p<0.001, HR 3.62, 95% CI 1.94, 6.75). From 107 RF extracted, significant predictive elastic net radiomic signatures were established for deep myometrial invasion (p=0.0097, OR 4.81, 95% CI 1.46, 15.79), hysterectomy grade (p=0.002, OR 5.12, 95% CI 1.82, 14.45), hysterectomy histology (p=0.0061, OR 18.25, 95% CI 2.29,145.24) and lymphovascular space invasion (p<0.001, OR 5.45, 95% CI 2.07, 14.36)., Conclusion: Multiparametric MRI radiomics has the potential to create a non-invasive a priori approach to predicting DFS and high-risk histopathologic features in EC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Renton, Fakhriyehasl, Weiss, Milosevic, Laframboise, Rouzbahman, Han and Jhaveri.)

Background: The objective of this study is to assess the correlation between the pre-operative CA125 Elimination rate constant K(KELIM) score and the intraoperative chemo-response score (CRS) in patients with advanced high grade serous ovarian cancer(HGSC) treated with neoadjuvant chemotherapy(NACT)., Methods: This is a retrospective cohort study of patients with Stage III-IV HGSC treated with NACT from March 2010 to December 2019 at Princess Margaret Cancer Center, Toronto, Canada. KELIM scores were calculated based on the tool devised by You et al. available online. CRS was assessed using an established 3-tier scoring system. An association analysis was performed to determine if the KELIM score assessed during NACT can predict CRS score at the time of interval cytoreductive surgery(ICS)., Results: 172 patients were included in this analysis. Patients with CRS 1-2 had a lower median Platinum Free Interval(PFI) (9.24 vs 13.64 months, p = 0.005), lower median progression free survival(PFS) (14.99 vs 20.29 months, p = 0.003) and lower 5-year overall survival(OS) (63.8% vs 69.7%, p = 0.54) compared to patients with CRS3. Among patients with CRS 1-2(n = 115), 68.7% had KELIM <1, while 56.2% of patients with CRS3 had KELIM ≥1(56.2%), p = 0.0017, suggesting a correlation between the KELIM and CRS scores. Furthermore, patients with KELIM ≥1 and CRS3 had significantly higher PFS compared to other groups(median PFS 28.27 months vs 17.66 months for KELIM ≥1/CRS 1/2; 17.13 months for KELIM <1/CRS 3; and 14.53 months for KELIM <1/CRS 1-2, p = 0.003)., Conclusion: The biochemical KELIM score correlated with the surgical pathologic CRS score and may predict pathological response to chemotherapy. This information can be utilized to tailor and personalize treatment in patients with advanced ovarian malignancy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The three-tier (A vs. B vs. C) pattern-based (Silva) classification system is a strong and fairly reproducible predictor of the risk of lymph node involvement and recurrence of human papillomavirus (HPV)-associated endocervical adenocarcinoma (EA). Recently, a binary pattern-based classification system has been proposed which incorporates the Silva pattern and lymphovascular invasion (LVI) to assign tumors as "low risk" or "high risk" and this may have superior prognostic significance compared with the three-tier system as well as current International Federation of Gynecology and Obstetrics (FIGO) staging of cervix-confined disease. The interobserver reproducibility of this binary system, however, is unknown. Representative slides from 59 HPV-associated EAs (1-3 slides/case) were independently reviewed by 5 gynecologic pathologists who participated in an online training module before the study. In the first review, a pattern was assigned using the three-tier system. On the second review, a "low risk" or "high risk" designation was assigned and the presence or absence of LVI was specifically documented. Interobserver agreement was assessed using Fleiss' kappa. The binary system showed improved interobserver agreement (kappa=0.634) compared with the three-tier system (kappa=0.564), with a higher proportion of cases having agreement between at least 4/5 reviewers (86% vs. 73%). Nineteen and 8 cases showed improved and worse interobserver agreement using the binary system, respectively; the remainder showed no change. 3/5 reviewers showed no intraobserver discrepancy while the remaining 2 did in a small subset of cases (n=2 and 4, respectively). In this study, a binary pattern-based classification system showed improved interobserver agreement compared with the traditional three-tier system., Competing Interests: A.H. reports advisory/teaching work for Merck. The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mucinous ovarian carcinoma is an uncommon malignancy characterized by resistance to chemotherapy and poor survival in the metastatic setting. HER2 amplification is a frequent late event in carcinogenesis, yet the incidence of HER2-low in mucinous ovarian carcinoma is unknown. Further, the optimal method for determining overexpression in these tumors is not established. We sought to assess the ASCO/CAP and ToGA trial scoring methods for HER2 IHC with correlation to FISH, p53, and mismatch repair protein status and to determine the incidence of HER2-low in mucinous ovarian carcinoma. A total of 29 tumors from 23 patients were included. Immunohistochemistry for HER2, p53, MLH1, PMS2, MSH2, and MSH6 was performed. Scoring was performed according to the ASCO/CAP and ToGA trial criteria. HER2 FISH was performed and scored according to the ASCO/CAP criteria. The proportion of HER2-low, defined as 1+ or 2+ staining with negative FISH, was determined. Using ASCO/CAP, 26% demonstrated 3+ while 35% demonstrated 2+ staining. Using ToGA, 30% demonstrated 3+ while 57% demonstrated 2+ staining. By FISH, 26% were positive for HER2 amplification. Both systems captured all FISH-positive cases; the use of ASCO/CAP resulted in fewer equivocal and false-positive cases. Among HER2-negative cases, 88% were HER2-low. Aberrant p53 expression was detected in 55% of cases; mismatch repair deficiency was not identified in any cases. ASCO/CAP guidelines are accurate and resource-effective in determining HER2 overexpression in mucinous ovarian carcinoma. HER2-low is common in these tumors; further studies to determine the role of HER2-targeted therapy including antibody-drug conjugates are indicated., Competing Interests: A.M. declares honoraria from AstraZeneca, Clovis, GSK, and PharmaMar. S.L. declares consulting fees from AstraZeneca, GSK, Roche, Merck, Eisai, Novocure, and Shattuck Labs. S.L. is the principal investigator or co-investigator of different clinical trials with agents from AstraZeneca, Merck, Roche, GSK, Regeneron, Repare Therapeutics, and Clovis. A.C.S. declares honoraria from Pfizer and personal financial interest in Bionano Genomics. The remaining authors declare no conflict of interest., (Copyright © 2024 by the International Society of Gynecological Pathologists.)

Low-grade endometrial stromal sarcoma (LGESS) represents a morphologically and genetically heterogenous mesenchymal neoplasm. Previous work has shown that approximately half of LGESS are characterized by JAZF1::SUZ12 gene fusions, while a smaller proportion involves rearrangement of other genes. However, a subset of cases has no known genetic abnormalities. To better characterize the genomic landscape of LGESS, we interrogated a cohort with targeted RNA sequencing (RNA-Seq). Cases previously diagnosed as low-grade endometrial stromal neoplasia (n=51) were identified and re-reviewed for morphology and subjected to RNA-Seq, of which 47 were successfully sequenced. The median patient age was 49 years (range: 19 to 85). The most commonly detected fusions were JAZF1::SUZ12 (n=26, 55%) and BRD8::PHF1 (n=3, 6%). In addition to the usual/typical LGESS morphology, some JAZF1::SUZ12 fusion tumors showed other morphologies, including fibrous, smooth muscle, sex-cord differentiation, and myxoid change. Novel translocations were identified in 2 cases: MEAF6::PTGR2 and HCFC1::PHF1 . Ten tumors (21%) had no identifiable fusion, despite a similar morphology and immunophenotype to fusion-positive cases. This suggests that a subset of cases may be attributable to fusion products among genes that are not covered by the assay, or perhaps altogether different molecular mechanisms. In all, these findings confirm that RNA-Seq is a potentially useful ancillary test in the diagnosis of endometrial stromal neoplasms and highlight their diverse morphology., Competing Interests: Conflicts of Interest and Source of Funding: Funding of this study was, in part, provided by the Martin E. Blackstein research fund and the Panov 2 Research Program. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Ovarian carcinoma is characterized by heterogeneity at the molecular, cellular and anatomical levels, both spatially and temporally. This heterogeneity affects response to surgery and/or systemic therapy, and also facilitates inherent and acquired drug resistance. As a consequence, this tumour type is often aggressive and frequently lethal. Ovarian carcinoma is not a single disease entity and comprises various subtypes, each with distinct complex molecular landscapes that change during progression and therapy. The interactions of cancer and stromal cells within the tumour microenvironment further affects disease evolution and response to therapy. In past decades, researchers have characterized the cellular, molecular, microenvironmental and immunological heterogeneity of ovarian carcinoma. Traditional treatment approaches have considered ovarian carcinoma as a single entity. This landscape is slowly changing with the increasing appreciation of heterogeneity and the recognition that delivering ineffective therapies can delay the development of effective personalized approaches as well as potentially change the molecular and cellular characteristics of the tumour, which might lead to additional resistance to subsequent therapy. In this Review we discuss the heterogeneity of ovarian carcinoma, outline the current treatment landscape for this malignancy and highlight potentially effective therapeutic strategies in development., (© 2023. Springer Nature Limited.)

Objectives: The study aimed to define the accuracy of intraoperative frozen section (FS) for the detection of metastases in sentinel lymph node biopsy (SLNB) and describe the pattern of lymph node (LN) spread and relation to molecular classifiers in patients with high-grade endometrial cancer (EC)., Methods: We performed a secondary outcome of clinicopathologic data from the Sentinel Lymph Node Biopsy versus Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging (SENTOR) prospective cohort study evaluating SLNB in patients with clinical stage I high-grade EC (ClinicalTrials.gov ID: NCT01886066). The primary outcome was the sensitivity of FS of the sentinel lymph node (SLN) specimen, compared to a standardized ultrastaging protocol. Secondary outcomes included the pattern and characteristics of LN spread., Results: There were 126 patients with high-grade EC with a median age of 66 years (range:44-86) and a median Body Mass Index (BMI) of 26.9 kg/m 2 (range:17.6-49.3). FS was performed on surgical specimens from 212 hemipelves; SLNs were identified in 202 specimens (95.7%) and fatty tissue alone was identified in 10 specimens (4.7%). Of the 202 hemipelves in which SLNs were identified, 24 were positive for metastatic disease on final pathology. Initial FS correctly identified only 12, yielding a sensitivity of 50% (12/24, 95% CI 29.6-70.4) and a negative predictive value of 94% (178/190, 95% CI 89-96.5). A total of 24 patients (19%) had LN metastases: 16 (13%) had isolated pelvic metastases, 7 (6%) had both pelvic and para-aortic metastases and 1 (0.8%) had an isolated para-aortic metastasis., Conclusions: Intraoperative FS of SLNs in high-grade EC patients has poor sensitivity. Since isolated para-aortic metastases are rare, para-aortic lymphadenectomy may be omitted in patients in which SLNs were successfully mapped to the pelvis., Competing Interests: Declaration of Competing Interest None of the authors have any relevant conflicts of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT., Patients and Methods: A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic., Results: Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%-34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%-33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09)., Conclusions: Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233., (©2022 American Association for Cancer Research.)

The distinction between low-grade and high-grade endometrial stromal sarcomas (LGESS, HGESS) is increasingly defined by genetics. Recently, variant genomic alterations involving BCOR or BCORL1 have been reported in endometrial stromal sarcoma (ESS), although it remains unclear whether these justify a diagnosis of LGESS or HGESS. In this study, we describe clinicopathologic and molecular features of ESS with such alterations to help clarify their classification in the spectrum of ESS. We collected a cohort of 13 ESS harboring variant alteration involving BCOR (6 with internal tandem duplication, 1 with EP300::BCOR fusion, 1 with BCOR::LPP fusion) and BCORL1 ( 4 with JAZF1::BCORL1 fusion, 1 with EPC1::BCORL1 fusion). The median patient age at primary diagnosis was 51 years (range: 18 to 70 y). Median tumor size at primary diagnosis was 9.3 cm (range: 4.5 to 21 cm), and extrauterine disease spread (stage IIIB-C) was present in 27%. The tumors were composed of round to spindled cells with cellularity and cytologic atypia ranging from mild to marked and a median mitotic count of 18/10 HPFs (range: 2 to 85/10 HPFs). At least focally myopermeative growth was noted in 8/8 assessable cases. Of 12 patients with follow-up data (median: 25 mo), 4 patients died of disease and 3 were alive with recurrent disease. Unsupervised hierarchical clustering of DNA methylation data together with a large cohort of uterine mesenchymal tumors that included YWHAE::NUTM2 and Z C3H7B::BCOR HGESS and molecularly confirmed LGESS revealed a common methylation signature for all ESS with variant BCOR and BCORL1 alterations and HGESS with YWHAE::NUTM2 and ZC3H7B::BCOR gene fusion. Copy number analysis revealed amplifications of CDK4 and MDM2 , as well as homozygous deletions of CDKN2A/B and NF1 in a subset of tumors. Our results indicate that ESS with BCOR internal tandem duplication and variant BCOR and BCORL1 rearrangements clinically and molecularly resemble conventional HGESS., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the German Cancer Aid (Grant: 70112499) and the Krebs- und Scharlachforschung Mannheim (F.K.F.K.). F.K.F.K. is funded by the Physician Scientist-Program of Heidelberg University. A.v.D. is recipient of an Illumina research grant. For the remaining authors none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Chromosomal translocations frequently promote carcinogenesis by producing gain-of-function fusion proteins. Recent studies have identified highly recurrent chromosomal translocations in patients with endometrial stromal sarcomas (ESSs) and ossifying fibromyxoid tumors (OFMTs), leading to an in-frame fusion of PHF1 (PCL1) to six different subunits of the NuA4/TIP60 complex. While NuA4/TIP60 is a coactivator that acetylates chromatin and loads the H2A.Z histone variant, PHF1 is part of the Polycomb repressive complex 2 (PRC2) linked to transcriptional repression of key developmental genes through methylation of histone H3 on lysine 27. In this study, we characterize the fusion protein produced by the EPC1 - PHF1 translocation. The chimeric protein assembles a megacomplex harboring both NuA4/TIP60 and PRC2 activities and leads to mislocalization of chromatin marks in the genome, in particular over an entire topologically associating domain including part of the HOXD cluster. This is linked to aberrant gene expression-most notably increased expression of PRC2 target genes. Furthermore, we show that JAZF1-implicated with a PRC2 component in the most frequent translocation in ESSs, JAZF1-SUZ12 -is a potent transcription activator that physically associates with NuA4/TIP60, its fusion creating outcomes similar to those of EPC1-PHF1 Importantly, the specific increased expression of PRC2 targets/ HOX genes was also confirmed with ESS patient samples. Altogether, these results indicate that most chromosomal translocations linked to these sarcomas use the same molecular oncogenic mechanism through a physical merge of NuA4/TIP60 and PRC2 complexes, leading to mislocalization of histone marks and aberrant Polycomb target gene expression., (© 2022 Sudarshan et al.; Published by Cold Spring Harbor Laboratory Press.)

Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis., (© 2021. The Author(s).)

Objective: Compare recurrence-free survival (RFS) and morbidity between radical hysterectomy (RH) and simple hysterectomy (SH) for clinically diagnosed stage II endometrial cancer., Methods: A multicentre, retrospective study, from 2000 to 2015, involving patients with endometrial cancer with cervical involvement preoperatively and stromal invasion on final pathology. Wilcoxon rank-sum test, Fisher exact test, Kaplan-Meier survival functions, and Cox proportional hazards models were used for analysis., Results: Ninety of 1613 patients had clinical stage II endometrial cancer; 57 underwent RH and 33 underwent SH, with no difference in adjuvant treatment or morbidity. About half of patients (51%) had pathologic stage III-IV disease. Mean follow-up was 3.3 and 3.8 years for SH and RH, respectively. Thirty-three percent of patients with RH and SH experienced a recurrence. Most recurrences were distant: 90% with SH and 79% with RH. There was no difference in RFS between groups (2-year: SH 65% vs. RH 75%; 5-year: SH 54% vs. RH 63%; P = 0.72). Controlling for stage, adjuvant treatment, and margin status, RH was not associated with RFS (HR 0.62; 95% CI 0.28-1.35). Among 44 patients with pathologic stage II disease, 7 had a recurrence (4 SH and 3 RH); 6 of 7 had distant recurrences., Conclusions: Fifty-one percent of patients with clinical stage II endometrial cancer had advanced disease on final pathology, highlighting the importance of surgical staging. RH was not associated with RFS or reduced morbidity. Most recurrences were distant. Although RH could be performed to achieve negative surgical margins, SH may be sufficient for central, small tumours given the high risk of advanced disease and distant recurrence. Research efforts should further elucidate the ideal management of these patients., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective: Ovarian clear cell carcinoma has unique clinical and molecular features compared with other epithelial ovarian cancer histologies. Our objective was to describe the incidence of second primary malignancy in patients with ovarian clear cell carcinoma., Methods: Retrospective cohort study of patients with ovarian clear cell carcinoma at two tertiary academic centers in Toronto, Canada between May 1995 and June 2017. Demographic, histopathologic, treatment, and survival details were obtained from chart review and a provincial cancer registry. We excluded patients with histologies other than pure ovarian clear cell carcinoma (such as mixed clear cell histology), and those who did not have their post-operative follow-up at these institutions., Results: Of 209 patients with ovarian clear cell carcinoma, 54 patients developed a second primary malignancy (25.8%), of whom six developed two second primary malignancies. Second primary malignancies included: breast (13), skin (9), gastrointestinal tract (9), other gynecologic malignancies (8), thyroid (6), lymphoma (3), head and neck (4), urologic (4), and lung (4). Eighteen second primary malignancies occurred before the index ovarian clear cell carcinoma, 35 after ovarian clear cell carcinoma, and 7 were diagnosed concurrently. Two patients with second primary malignancies were diagnosed with Lynch syndrome. Smoking and radiation therapy were associated with an increased risk of second primary malignancy on multivariable analysis (OR 3.69, 95% CI 1.54 to 9.07, p=0.004; OR 4.39, 95% CI 1.88 to 10.6, p=0.0008, respectively). However, for patients developing second primary malignancies after ovarian clear cell carcinoma, radiation therapy was not found to be a significant risk factor (p=0.17). There was no significant difference in progression-free survival (p=0.85) or overall survival (p=0.38) between those with second primary malignancy and those without., Conclusion: Patients with ovarian clear cell carcinoma are at increased risk of second primary malignancies, most frequently non-Lynch related. A subset of patients with ovarian clear cell carcinoma may harbor mutations rendering them susceptible to second primary malignancies. Our results may have implications for counseling and consideration for second primary malignancy screening., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Whether sentinel lymph node biopsy (SLNB) can replace lymphadenectomy for surgical staging in patients with high-grade endometrial cancer (EC) is unclear., Objective: To examine the diagnostic accuracy of, performance characteristics of, and morbidity associated with SLNB using indocyanine green in patients with intermediate- and high-grade EC., Design, Setting, and Participants: In this prospective, multicenter cohort study (Sentinel Lymph Node Biopsy vs Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging [SENTOR] study), accrual occurred from July 1, 2015, to June 30, 2019, with early stoppage because of prespecified accuracy criteria. The study included patients with clinical stage I grade 2 endometrioid or high-grade EC scheduled to undergo laparoscopic or robotic hysterectomy with an intent to complete staging at 3 designated cancer centers in Toronto, Ontario, Canada., Exposures: All patients underwent SLNB followed by lymphadenectomy as the reference standard. Patients with grade 2 endometrioid EC underwent pelvic lymphadenectomy (PLND) alone, and patients with high-grade EC underwent PLND and para-aortic lymphadenectomy (PALND)., Main Outcomes and Measures: The primary outcome was sensitivity of the SLNB algorithm. Secondary outcomes were additional measures of diagnostic accuracy, sentinel lymph node detection rates, and adverse events., Results: The study enrolled 156 patients (median age, 65.5 years; range, 40-86 years; median body mass index [calculated as weight in kilograms divided by height in meters squared], 27.5; range, 17.6-49.3), including 126 with high-grade EC. All patients underwent SLNB and PLND, and 101 patients (80%) with high-grade EC also underwent PALND. Sentinel lymph node detection rates were 97.4% per patient (95% CI, 93.6%-99.3%), 87.5% per hemipelvis (95% CI, 83.3%-91.0%), and 77.6% bilaterally (95% CI, 70.2%-83.8%). Of 27 patients (17%) with nodal metastases, 26 patients were correctly identified by the SLNB algorithm, yielding a sensitivity of 96% (95% CI, 81%-100%), a false-negative rate of 4% (95% CI, 0%-19%), and a negative predictive value of 99% (95% CI, 96%-100%). Only 1 patient (0.6%) was misclassified by the SLNB algorithm. Seven of 27 patients with node-positive cancer (26%) were identified outside traditional PLND boundaries or required immunohistochemistry for diagnosis., Conclusions and Relevance: In this prospective cohort study, SLNB had acceptable diagnostic accuracy for patients with high-grade EC at increased risk of nodal metastases and improved the detection of node-positive cases compared with lymphadenectomy. The findings suggest that SLNB is a viable option for the surgical staging of EC.

The aim of this study was to determine the prevalence of somatic and germline pathogenic variants (PVs) in high-grade serous cancer (HGSC) and to demonstrate the technical feasibility and effectiveness of a large-scale, population-based tumor testing program. It involved a retrospective review of genetic test results in 600 consecutive HGSC tumor samples and a subsequent comparison of germline and tumor results in a subset of 200 individuals. Tumor testing was successful in 95% of samples (570/600) with at least one BRCA1/2 PV identified in 16% (93/570) of cases. Among the 200 paired cases, BRCA1/2 PVs were detected in 38 tumors (19%); 58% were somatic (22/38); and 42% were germline (16/38). There was 100% concordance between germline and tumor test results. This is the largest series of BRCA1/2 testing in HGSC (tumor-only and paired cohorts), reported to date, and our data show that an effectively designed and validated population-based tumor testing program can be used to determine both treatment eligibility and hereditary cancer risk., (© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Competing Interests: Competing interests: AMO is on the steering committee of GlaxoSmithKline, AstraZeneca, Clovis, Tesaro and Merck (uncompensated), and is PI on clinical trials for AstraZeneca, GlaxoSmithKline, and Clovis.

Background: The uterus is one of the most dynamic organs in the human body, and this dynamic homeostasis is supported by endometrial stem/progenitor cells (ES/PCs), which are heterogeneous in their phenotype and degree of differentiation. ES/PCs are generally localized in the endometrial stroma, the site of origin for adenosarcoma and endometrial stromal sarcoma (ESS). Subsets of ESSs and adenosarcomas harbor SUZ12 or DICER1 gene alterations, two genes with roles in embryonic stem cell biology. However, the possible contribution of ES/PCs to tumorigenesis is unexplored., Method: We examined the expression of eleven ES/PC markers, along with three proteins expressed in the mature endometrial stroma (ER, PR and CD10) in 60 uterine tumors (24 low-, 11 high-grade ESS, 25 adenosarcomas). Protein expression profiles were assessed by unsupervised hierarchical clustering. miRNA expression profiles were examined in a subset of adenosarcoma with/without DICER1 mutations, using the NanoString platform., Results: ES/PC markers were variably expressed, and the tumors exhibited limited immunophenotypic resemblance to different ES/PCs. Within the ESSs, the ES/PC marker clustering pattern was prognostic for both overall and disease-free survival. Comparing adenosarcomas and ESSs, most high-grade ESSs clustered with one another, while low-grade ESSs and adenosarcomas tended to cluster with one another. Among the adenosarcomas, the miRNA expression profiles were varied with respect to the DICER1 mutation status, with pathway analysis pointing to dysregulated signal transduction and stem cell biology., Conclusions: ESSs and adenosarcomas exhibit varying immunophenotypic resemblance to ES/PCs. These expression profiles have prognostic implications and may be genetically driven., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Gastric-type endocervical adenocarcinoma (GAS) is a recently described, uncommon, and aggressive tumor with distinct morphologic features and HPV-independent etiology. Data on GAS in liquid-based cytology (LBC) Papanicolaou (Pap) test preparations from a North American patient population are scant. We systematically assessed the cytomorphologic characteristics of GAS in LBC from patients in Ontario and examined if glandular cell nuclear area could represent a readily assessable feature which may aid in GAS detection., Study Design: Pap test slides preceding the diagnosis of GAS were retrieved locally or requested from outside laboratories. A structured review of 15 cytomorphologic features was performed using the available LBC Pap test slides of GAS and a set of usual-type endocervical adenocarcinomas (UEA). Morphometry of the glandular cell nuclear area was performed, and normalized values were compared to UEA and benign endocervical cells., Results: At least 1 Pap test (5 ThinPrep®, 11 SurePath®, and 1 direct smear) was available for 14 patients. Original LBC Pap test diagnoses were negative for intraepithelial lesion or malignancy (NILM) (7), adenocarcinoma/carcinoma (6), atypical glandular cells (2), and adenocarcinoma in situ (1). Review detected abnormal glandular cells in 6/7 NILM cases. Honeycomb-like sheets, nuclear enlargement, and microvesicular cytoplasm were the single most common architectural, nuclear, and cytoplasmic features, respectively. Microvesicular cytoplasm (100 vs. 17%), honeycomb-like sheets (87 vs. 8%), prominent nucleoli (93 vs. 25%), and anisonucleosis (93 vs. 50%) were most discriminatory for GAS versus UEA, respectively. Yellow mucin, intranuclear cytoplasmic pseudoinclusions, and goblet/Paneth-like cells were uncommon, but unique for GAS. Glandular cell nuclear area normalized to neutrophils was found to be significantly increased in GAS compared to benign endocervical cells., Conclusions: GAS is under-recognized and may mimic reactive endocervical cells. Awareness of the tumor type and its cytomorphology is critical for early detection. Identification of glandular cells with uniform nuclear enlargement in conjunction with any of the other cytologic features may help avoid false-negative Pap results. Neutrophils may serve as convenient size reference and visual aid., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Competing Interests: Competing interests: None declared.

Embryonal rhabdomyosarcomas (ERMS) account for 2-3% of cancers in pediatric and adolescent populations. They are rarer in adults. We and others have reported that ERMS arising in the uterine cervix may harbor mutations in the gene encoding the microRNA biogenesis enzyme, DICER1, but a large series of cases has not been published. In the uterus, distinguishing ERMS from adenosarcoma can be very challenging, even for expert pathologists, and DICER1 alterations have been identified in a variable subset of uterine adenosarcomas. We hypothesized that DICER1 genetic testing may be useful in distinguishing between ERMS and adenosarcoma. We conducted a central pathology review-based study of 64 tumors initially thought to be uterine ERMS or adenosarcoma; 19 neoplasms had a consensus diagnosis of ERMS, 27 of adenosarcoma and for 18, no consensus diagnosis was reached. The median age at diagnosis was 30 years (range 2.5-69) for ERMS, 57.5 years (range 27-82) for adenosarcoma, and 65.5 years (range 32-86) for no consensus cases. In our series, the DICER1 mutation prevalence differed between the three groups: DICER1 alterations were present in 18/19 (95%) ERMS, 7/27 (26%) adenosarcomas (p < 0.001), and 4/18 (22%) no consensus cases. A germline alteration was present in 6/12 ERMS patients tested versus 0/6 adenosarcoma patients. Thus, although DICER1 mutations are near ubiquitous in uterine ERMS and are significantly less common in uterine adenosarcoma, DICER1 testing is only of value in distinguishing between the two neoplasms when a DICER1 mutation is absent, as this is helpful in excluding ERMS. On review of the clinical and radiological features of the single DICER1 wild-type cervical ERMS, this was thought most likely to be of vaginal origin. Given the significant prevalence of DICER1 germline pathogenic variants in uterine ERMS, all patients with this diagnosis should be referred to a genetics service.

Gastric-type endocervical adenocarcinoma is an uncommon aggressive type of endocervical adenocarcinoma that is not associated with human papillomavirus (HPV). At present, this tumor is classified under the spectrum of mucinous carcinoma of the uterine cervix. The clinical stage of gastric-type endocervical adenocarcinoma at the time of diagnosis is usually more advanced compared to the HPV-associated endocervical adenocarcinoma. Widespread dissemination to unusual sites, such as omentum, peritoneum, and distant organs, can be present. Owing to its rare incidence, diagnostic dilemmas, and aggressive behavior, clinical management can be challenging. In this study, we aimed to elucidate the molecular characteristics of these tumors by using next-generation sequencing (NGS) to assess 161 unique cancer-driver genes for single-nucleotide and copy-number variations, gene fusions, and insertions/deletions within gastric-type endocervical adenocarcinoma tumors. In total, 92 variants were detected across the 14 samples tested (7 variants on average per tumor). TP53 was the most recurrently mutated gene followed by MSH6, CDKN2A/B, POLE, SLX4, ARID1A, STK11, BRCA2, and MSH2. Abnormal p53 expression was observed in nine cases by immunohistochemistry, of which TP53 variants were present in four cases. MDM2 gene amplification in 12q15 (69202190-69233452) locus was seen in two cases that express normal p53 levels by immunohistochemistry. Four cases had STK11 null (frameshift/nonsense) variants, three of which were previously reported in Peutz-Jeghers syndrome. Overall, genes that are implicated in DNA damage, repair, cell cycle, Fanconi anemia pathway, and the PI3K-AKT signaling pathways were found to be mutated. Of note, genes known to have acquired and/or inherited variants in endometrial tumors were enriched within our cohort. In conclusion, our study shows the genetic heterogeneity of gastric-type endocervical adenocarcinoma with some potentially actionable molecular alterations, which highlights the importance of further molecular characterization for better identification of this rare entity, and hence better clinical management.

Objective: The objective of this study was to determine the outcomes of patients with unresectable endometrial cancer managed with definitive or neoadjuvant radiation (RT) and/or chemotherapy., Materials and Methods: Patients with unresectable stages II to IVA endometrial cancer who were treated with curative intent between January 2000 and March 2018 were identified. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate logistic regression analysis was performed to identify factors associated with receipt of surgery. Multivariate Cox regression analysis was performed to identify factors associated with OS and DFS., Results: Of the 59 patients identified, the median age was 63 years (range: 37 to 88 y) and histology was endometrioid in 59%. Median follow-up was 2.2 years (range: 0.3 to 9.8 y). Seventeen patients (29%) received neoadjuvant chemotherapy, 28 (47%) neoadjuvant radiation, and 14 (24%) definitive RT; 39 (66%) underwent surgery. Patients who received surgery had higher 3-year OS and DFS than those who did not (84% vs. 41%; P<0.001 and 56% vs. 11%; P<0.001, respectively). Factors associated with higher odds of surgical resection included younger age, endometrioid histology, and earlier stage. Younger age, endometrioid histology, and surgical resection were significantly associated with higher OS. Surgical resection was also associated with higher DFS., Conclusions: Surgical resection following RT and/or chemotherapy for locally advanced, unresectable endometrial cancer is associated with higher DFS and OS and more likely to be achieved in endometrioid subtypes.

Endometrial cancer is the most common gynecologic malignancy in North America and the incidence is rising worldwide. Treatment consists of surgery with or without adjuvant therapy depending on lymph node involvement as determined by lymphadenectomy. Lymphadenectomy is a morbid procedure, which has not been shown to have a therapeutic benefit in many patients, and thus a new method to diagnose lymph node metastases is required. To test novel imaging agents, a reliable model of endometrial cancer with retroperitoneal lymph node metastases is needed. The VX2 endometrial cancer model has been described frequently in the literature; however, significant variation exists with respect to the method of model establishment. Furthermore, no studies have reported on the use of cultured VX2 cells to create this model as only cells propagated in vivo have been previously used. Herein, we present a standardized surgical method and post-operative monitoring method for the establishment of the VX2 endometrial cancer model and report on the first use of cultured VX2 cells to create this model.

Objective: This study sought to evaluate the clinicopathologic features, surgical management, and survival of patients over 12 years at two academic centres., Methods: Patients diagnosed with vulvar or vaginal melanoma between 2002 and 2014 were identified through pathology databases. Clinical and pathologic data were extracted from the medical records. The Kaplan-Meier method was used to calculate recurrence-free survival and overall survival (OS), and univariate analyses using a Cox proportional hazard model were used to detect covariates related to survival., Results: Patients with vulvar melanoma were more likely to undergo surgical excision (84.0% vs. 55.6%, P = 0.0243) and were more likely to achieve negative margins (70.0% vs. 16.7%, P < 0.0001). Forty-eight percent of patients with vulvar melanoma had a lymph node evaluation; sentinel node biopsies were performed in 32%. Actuarial median OS for vulvar melanoma was 45 months compared with 10.48 months for vaginal melanoma. A subset of 10 patients with vulvar melanoma who survived longer than 60 months was identified. Eight significant predictors of OS were demonstrated for vulvar melanomas: clinical stage, maximum tumour size, tumour thickness, lymphovascular space invasion status, clinically enlarged lymph nodes, sentinel lymph nodes, lymph node status, and radiation treatment. Patients with positive or indeterminate margin status demonstrated a higher risk of recurrence than did patients with negative margins (hazard ratio 2.60; 95% CI 1.14-5.90)., Conclusion: Surgical excision with adequate margins is the mainstay of primary management when feasible. Lymph node evaluation, including sentinel nodes, may be considered in selected patients. Vulvar and vaginal sites differ markedly with respect to pathology, initial management, and survival, and they should be evaluated separately., (Copyright © 2018 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objective : To investigate Porphysome fluorescence image-guided resection (PYRO-FGR) for detection of uterine tumour, metastatic lymph nodes and abdominal metastases in a model of endometrial cancer. Methods : White New Zealand rabbits were inoculated with VX2 cells via intra-myometrial injection. At 30 days, Porphysomes were administered intravenously. At 24 h the abdomen was imaged and fluorescent tissue identified (PYRO-FGR). After complete resection of fluorescent tissue, fluorescence-negative lymph nodes and peritoneal biopsies were removed. Histopathology including ultra-staging and analysis by a pathologist was used to detect tumour. Fluorescence signal to background ratio (SBR) was calculated and VX2 (+) tissue compared to VX2 (-) tissue. Biodistribution was calculated and Porphysome accumulation in fluorescent VX2 (+) tissue compared to fluorescent VX2 (-) and non-fluorescent VX2 (-) tissue. Results : Of 17 VX2 models, 10 received 4 mg/kg of Porphysomes and 7 received 1 mg/kg. Seventeen tumours (UT), 81 lymph nodes (LN) and 54 abdominal metastases (AM) were fluorescence-positive and resected. Of these, 17 UT, 60 LN and 45 AM were VX2 (+), while 16 LN and 5 AM were VX2 (-). Nine specimens were excluded from analysis. Thirty-one LN and 53 peritoneal biopsies were fluorescence-negative and resected. Of these, all LN and 51/53 biopsies were VX2 (-) with only 2 false-negative biopsies. Sensitivity and specificity of PYRO-FGR for VX2 (+) tissue was 98.4% / 80.0% overall, 100% / 100% for UT, 100% / 66.0 % for LN and 95.7% / 91.4% for AM. Increased SBR and biodistribution was observed in VX2 (+) tissue vs. VX2 (-) tissue. Conclusions : Porphysomes are a highly sensitive imaging agent for intra-operative detection and resection of uterine tumour, metastatic lymph nodes and abdominal metastases., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

In recent times, there has been a growing tendency to treat advanced gynaecological malignancies with neoadjuvant chemotherapy (NACT), with the goal of reducing tumour volume and enhancing operability resulting in optimal cytoreduction. This approach is used in particular for patients with advanced high-grade serous carcinoma of the ovary, fallopian tube or peritoneum. Pathology plays a crucial role in the management of these patients, both before and after NACT. Prior to initiation of NACT, a biopsy should be performed, usually of the omental cake, to confirm that a malignancy is present, to identify the site of origin of the tumour and to type and grade the tumour. Histopathologists must be aware of the resultant morphological effects of NACT when examining specimens following interval cytoreduction surgery. Tumour typing and grading, and even the identification of residual neoplasia, are particular challenges. Immunohistochemistry, when used judiciously, can be a useful adjunct in certain scenarios. A pathological assessment of the response to chemotherapy, and the pathological stage should be provided in the pathology report, as these may inform prognosis and subsequent management. We present a comprehensive overview of the relevant clinical and pathological aspects pertaining to NACT for gynaecological malignancies for the practicing surgical pathologist., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To elucidate potential markers of endometriosis and endometriosis-associated endometrioid and clear cell ovarian carcinomas using mass spectrometry-based proteomics. Methods: A total of 21 fresh, frozen tissues from patients diagnosed with clear cell carcinoma, endometrioid carcinoma, endometriosis and benign endometrium were subjected to an in-depth liquid chromatography-tandem mass spectrometry analysis on the Q-Exactive Plus. Protein identification and quantification were performed using MaxQuant, while downstream analyses were performed using Perseus and various bioinformatics databases. Results: Approximately 9000 proteins were identified in total, representing the first in-depth proteomic investigation of endometriosis and its associated cancers. This proteomic data was shown to be biologically sound, with minimal variation within patient cohorts and recapitulation of known markers. While moderate concordance with genomic data was observed, it was shown that such data are limited in their abilities to represent tumours on the protein level and to distinguish tumours from their benign precursors. Conclusions: The proteomic data suggests that distinct markers may differentiate endometrioid and clear cell carcinoma from endometriosis. These markers may be indicators of pathobiology but will need to be further investigated. Ultimately, this dataset may serve as a basis to unravel the underlying biology of the endometrioid and clear cell cancers with respect to their endometriotic origins., Competing Interests: No competing interests were disclosed.

Inflammatory myofibroblastic tumors of the uterus are rare, and although most have a favorable prognosis, a small subset exhibit extrauterine disease, recur, or cause death. In this study, we evaluated the morphology and immunoprofile of 13 uterine inflammatory myofibroblastic tumors, including four with aggressive behavior. ALK rearrangements were detected by fluorescence in situ hybridization and fusion partners by anchored multiplex assay. Patients ranged from 8 to 63 (mean 39) years and tumors from 2.5 to 20 (mean 7.4) cm. Myxoid, compact, and hyalinized patterns were noted in 13, 12, and 2 tumors, ranging from 1 to 100%, 5 to 99%, and 0 to 5%, respectively. Nuclear atypia was mild in six (46%), moderate in five (38%), and severe in two (15%), with ganglion-like cells in two tumors. Mitoses ranged from 0 to 24 (mean 5) per 10 high-power fields. Inflammation was mild in five (38%), moderate in three (23%), and marked in five (38%), consisting of a lymphoplasmacytic infiltrate that was lymphocyte-predominant in six (46%). Lymphovascular invasion was noted in two (15%) and necrosis in eight (62%). All but one tumor were ALK-positive by immunohistochemistry, with granular cytoplasmic staining in nine (82%). ALK rearrangements (tested in 10) were detected in eight and was absent in one. The remaining tumor showed an isolated green 5' ALK signal. Fusion partners were identified in 10 (77%) and included THBS1 (n=3), IGFBP5 (n=2), DES (n=2), SEC31 (n=1), TPM3 (n=1), and TIMP3 (n=1). Size ≥8 cm was predictive of aggressive behavior (P<0.01), with increased mitoses (≥7 per 10 high-power fields), lymphovascular invasion, and compact-predominance approaching statistical significance. These data show that inflammatory myofibroblastic tumors of the uterus are morphologically heterogenous with frequent ALK expression and a variety of ALK fusion partners. Recognition of this rare mesenchymal neoplasm is crucial as those with aggressive behavior can potentially be treated with tyrosine kinase inhibitors.

Objective: Sentinel lymph node (SLN) biopsy is becoming a reasonable alternative to pelvic lymphadenectomy in early-stage cervical cancer. It is therefore imperative that centres without prior experience are able to successfully implement the procedure. The objectives of the current study were to (1) describe the process of implementing an SLN biopsy program with a novel peer mentorship component and (2) assess post-program quality improvement metrics, including SLN detection rate (DR) and diagnostic parameters., Methods: An institutional SLN biopsy protocol was developed collaboratively by gynaecologic oncology, nuclear medicine, and pathology departments at University Health Network, Toronto, Ontario. All decisions were based on the best evidence available. Newly diagnosed, early-stage cervical cancer patients undergoing primary surgery were then recruited prospectively for SLN biopsy with combined technique, followed by pelvic lymphadenectomy to evaluate key quality indicators, including SLN DR, sensitivity, and negative predictive value. Surgeons with previous SLN biopsy experience mentored surgeons unfamiliar with the technique. Interim analyses and multidisciplinary rounds were regularly carried out to identify failures of technique or protocol., Results: Thirty-nine patients (median age 42) were enrolled in the study between August 2010 and February 2014. The median number of SLNs and total pelvic lymph nodes removed per patient were 3 and 19, respectively. SLN DRs were 92% per patient (36/39), 88.5% per hemipelvis (69/78), and 85% bilaterally (33/39). SLN biopsy correctly identified seven of eight hemipelvises with nodal metastases, yielding a sensitivity of 88% (95% CI 0.47 to 1.00) and a false negative rate of 12% (95% CI 0 to 0.53). Surgeons undergoing peer mentorship (n = 3) performed as effectively (DR 100%) as surgeons (n = 2) with prior experience (DR 85%)., Conclusions: This study provides a model upon which other centres can adopt and validate cervical SLN biopsy. High SLN DRs and accurate identification of lymph node metastases can be achieved by focusing on multidisciplinary collaboration, knowledge translation with creation of evidence-based protocols, peer mentorship, and ongoing quality control., (Copyright © 2017 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Sharing of personal health information is subject to multiple constraints, which may dissuade some organizations from sharing their data. Summarized deidentified data, such as that derived from k-means cluster analysis, is subject to far fewer privacy-related constraints. In this paper, we examine the extent to which analysis of clustered patient types can match predictions made by analyzing the entire dataset at once. After reviewing relevant literature, and explaining how data are summarized in each cluster of similar patients, we compare the results of predicting death, and length of stay (LOS) in the ICU 1 ICU: Intensive care unit.

Objectives: Stratified mucin-producing intraepithelial lesion (SMILE) is an uncommon premalignant lesion of the uterine cervix. A detailed examination of preinvasive SMILE cases including a comparison of the cytologic features with usual-type adenocarcinoma in situ (AIS) and human papillomavirus (HPV) genotyping was performed., Study Design: Excisions and preceding Papanicolaou (Pap) tests were retrieved from the files of 2 tertiary care centers. Histologic review estimated the lesional SMILE proportion. Pap tests were reviewed and assessed for architectural, cellular and background features. Cobas® HPV test was performed., Results: 13 cases were identified. Mean/median patient age was 35/33 years (range 23-51 years). Concurrent high-grade squamous intraepithelial lesion was found in 10/13 (77%) and AIS in 8/13 (62%) cases. In 6 cases, SMILE was dominant (≥50%) and represented in 5/6 corresponding Pap tests. Cytology interpretations differed more often in the SMILE-dominant group (p < 0.05). SMILE and AIS had overlapping features. Feathering and prominent nucleoli were absent in SMILE. HPV DNA was detected in all 12 cases tested. HPV 18 was most common (7/12). Excisions with positive/suspicious margins were reported in 5/6 SMILE-dominant versus 3/7 nondominant cases., Conclusion: SMILE is best considered as an AIS variant for cytologic, etiologic and management purposes. Cytologic features overlap with AIS, but are more subtle and easily missed. HPV testing may play a role in facilitating SMILE detection., (© 2016 S. Karger AG, Basel.)