Investigator
University Health Network
Biomarkers in High-Grade Serous Ovarian Cancer: Context Is Everything
Summary The Oxford Classic Epithelial-to-Mesenchymal Transition (OxC-EMT) score identifies a high-risk subgroup of patients with high-grade serous carcinoma with inferior survival. This commentary discusses the evaluation of high-grade serous carcinoma biomarkers in context and the important steps in transition from a prognostic to a validated predictive biomarker to inform clinical utility. See related article by Rai et al., p. 188
Endometrial Carcinoma Molecular Classification and Barriers to Implementation, Possible Solutions, and the Implications for Ongoing Clinical Trials
Molecular classification of endometrial carcinoma provides important prognostic and predictive information and ongoing clinical trials are investigating different treatment paradigms and therapy de-escalation. Despite its benefits, there is variability in the application of molecular classification worldwide, including in Canada. A digital survey was distributed to gynaecologic pathologists in 13 Canadian academic pathology departments, and areas of homogeneity and variability in practice for endometrial carcinoma molecular classification were identified. Perceived barriers to universal application included resource restrictions and ambiguity of management implications. Focused research, knowledge translation, and guideline development will aid in more consistent implementation/application.
Cytologic features of gynecologic germ cell tumors and carcinomas exhibiting germ cell tumor differentiation
AbstractBackgroundIn this study, the authors sought to describe the cytologic features of primary gynecologic germ cell tumors and carcinomas exhibiting germ cell differentiation because little information currently exists.MethodsAn institutional database search was performed to identify histologically confirmed gynecologic germ cell tumors and carcinomas with germ cell tumor differentiation. Available cytologic material was reviewed by three observers, and morphologic features were recorded in addition to patient age at original diagnosis, primary tumor site, site(s) from which the examined cytologic material was obtained, and the type of examined cytologic preparations.ResultsIn total, 15 cytologic specimens from 12 women (aged 19–82 years) were identified and included touch preparations of core biopsies from various sites (n = 6), fine‐needle biopsies (n = 2), pelvic washings (n = 1), ascitic fluids (n = 4), pelvic cyst fluid (n = 1), and endometrial aspirate (n = 1). Of the 12 patients, seven had primary gynecologic germ cell tumors, four had gynecologic (ovarian and endometrial) tumors exhibiting somatic yolk sac tumor‐like differentiation, and the remaining patient had an intestinal‐type adenocarcinoma arising within an ovarian teratoma. There was morphologic overlap among many of the cases, although cytoplasmic vacuolation/granular cytoplasm was seen in 75% of primary yolk sac tumors or carcinomas with yolk sac tumor differentiation, and dense/squamoid cytoplasm was seen in 100% of teratomatous elements that were sampled.ConclusionsGerm cell tumors and somatic neoplasms exhibiting germ cell tumor differentiation occurring in adult women share some cytologic features and may be difficult to distinguish from one another, although some tumor types showed characteristic cytomorphologic findings.
Moderately differentiated Sertoli–Leydig cell tumour: a hormone-secreting neoplasm associated with DICER1 syndrome
Presence and extent of lymphovascular invasion in surgical stage I squamous cell carcinoma of the cervix: a comprehensive, international, multicentre, retrospective clinicopathological study
The aim of this study was to determine whether the presence and extent of lymphovascular invasion (LVI) is prognostic in surgical stage I cervical squamous cell carcinoma (SCC). All available tumour slides and/or paraffin blocks from 426 patients with stage I cervical SCC treated surgically with curative intent were collected from 18 institutions and retrospectively analysed. Presence and extent of LVI (focal <5 spaces, extensive ≥5 spaces) were assessed on scanning magnification in large haematoxylin and eosin slide sets in 366 cases. Progression-free survival (PFS) was calculated as the time from surgery to first progression or death or last follow-up, whichever occurred first. Overall survival (OS) was defined as the time from surgery to death or last follow-up. Clinicopathological and statistical analyses were performed on 97 patients with the International Federation of Gynecology and Obstetrics (FIGO) 2018 stage IA and 329 patients with stage IB SCC of the cervix. LVI, both focal and extensive, was more frequent in stage IB than in stage IA (p<0.001). Patients with stage IB carcinomas with extensive LVI had worse PFS [hazard ratio (HR) 2.86; 95% confidence interval (CI) 1.49, 5.49; p=0.005] and OS (HR 2.88; 95% CI 1.38, 6.02; p=0.012) than those with focal or no LVI. In stage IA, in contrast, the presence and extent of LVI did not associate with PFS (p=0.926) or OS. Extensive LVI was not statistically correlated with PFS and OS in substages IA1, IA2 or IB2. PFS (HR 3.7; 95% CI 1.61, 8.46; p<0.001) and OS (HR 4.18; 95% CI 1.58, 11.04; p=0.002) in stage IB1, and PFS (HR 7.78; 95% CI 0.87, 69.82; p=0.039) in stage IB3 were diminished in the presence of extensive LVI. In conclusion, in patients with FIGO stage I cervical SCC, the presence and extent of LVI has prognostic significance in stage IB carcinoma, and quantifying LVI is recommended.
Preclinical Combination Targeting VEGF and PI3K in a Rare, Aggressive Mixed Endometrial Carcinoma: An Applied Case Report
Abstract We report a rare case of a young patient (VENUS 167) initially diagnosed with grade 1 endometrioid endometrial cancer, which, following endocrine treatment, presented with mixed aggressive carcinoma with three distinct histologic patterns: grade 1 endometrioid, large cell neuroendocrine, and undifferentiated carcinoma. The surgical specimen at the time of disease progression was used to establish OPTO.85, a patient-derived organoid (PDO), followed by a corresponding organoid-derived xenograft (ODX). Multi-omic analyses confirmed that OPTO.85 accurately reflected the patient’s tumor characteristics. Whole-exome sequencing analysis identified oncogenic alterations in PIK3CA, ARID1A, and CTNNB1. Further RNA sequencing and assay for transposase-accessible chromatin using sequencing analyses revealed enrichment in VEGF and Wnt signaling pathways, suggesting therapeutic vulnerabilities. A high-throughput drug screen was conducted using ApexBio-approved and epigenetic drug libraries, along with kinase inhibitor and tool compound libraries developed at the Ontario Institute of Cancer Research. The OPTO.85 PDO exhibited sensitivity to PI3K inhibitors and responsiveness to VEGF inhibition. Cediranib demonstrated synergy with BKM120, significantly reducing organoid growth. This combination also showed in vivo efficacy in the ODX model, in which dual inhibitors significantly suppressed tumor growth compared with single compounds. This case exemplifies the impact of genomic profiling and patient-derived models in identifying actionable molecular changes in rare cancers with limited therapeutic options and poor prognosis. It highlights that high-throughput sequencing for individual patient tumors and generation of patient-derived models are feasible in endometrial cancer. This preclinical model may assist clinical decision and personalized therapy requiring validation in prospective studies. Significance: This study characterizes a rare aggressive mixed endometrial carcinoma that developed after hormonal therapy. Patient-derived organoid and xenograft models revealed actionable targets in the VEGF and PI3K pathways. Combined cediranib and BKM120 treatment showed synergistic antitumor effects in vitro and in vivo. These findings highlight the potential of integrating molecular profiling and drug testing to guide personalized therapies in rare and recurrent endometrial cancers.
