Jessica N Mcalpine

University of British Columbia | UBC · Department of Obstetrics and Gynaecology

Aims: The significance of subclonal expression of p53 (abrupt transition from wild-type to mutant-pattern staining) is not well understood, and the arbitrary diagnostic cut-off of 10% between NSMP and p53abn molecular subtypes of endometrial carcinoma (EC) has not been critically assessed. Our aim was to characterise subclonal p53 and discrepant p...

Purpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10-20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas (EC) including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, tho...

Objectives: Despite recommendations for integrating molecular classification of endometrial cancers (EC) into pathology reporting and clinical management, uptake is inconsistent. To assign ProMisE subtype, all molecular components must be available (POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)) and often these are...

TPS5632 Background: Molecular classification of EC provides an opportunity to personalize treatment for patients with early disease based on prognosis. We hypothesize that de-escalated adjuvant treatment in patients with early-stage POLE-mutated ( POLEmut) or p53wt/NSMP (p53 wildtype/no specific molecular profile) EC is feasible and associated with...

Endometrial cancer (EC) has four molecular subtypes with strong prognostic value and therapeutic implications. The most common subtype (NSMP; No Specific Molecular Profile) is assigned after exclusion of the defining features of the other three molecular subtypes and includes patients with heterogeneous clinical outcomes. In this study, we employed...

Purpose: Detection of 11 pathogenic variants in the POLE gene in endometrial cancer (EC) is critically important to identify women with a good prognosis and reduce overtreatment. Currently, POLE status is determined by DNA sequencing, which can be expensive, relatively time-consuming, and unavailable in hospitals without specialized equipment and...

Objectives: Molecular classification of endometrial carcinoma (EC) is now recommended by the WHO, ESGO/ESTRO/ESP and NCCN guidelines. The pragmatic molecular classification tool, ProMisE, identifies four molecular subtypes based on next generation sequencing (NGS) for the detection of somatic pathogenic POLE mutations, and immunohistochemistry for...

Endometrial carcinoma (EC) is the most common gynecologic cancer in North America. A clinically molecular classifier called ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) was developed based on the TCGA classification. p53abn EC is the most aggressive of the four ProMisE prognostic molecular subtypes, responsible for 50-70% of...

In clinical practice, many diagnosis tasks rely on the identification of cells in histopathology images. While supervised machine learning techniques require labels, providing manual cell annotations is time-consuming due to the large number of cells. In this paper, we propose a self-supervised framework (VOLTA) for cell representation learning in...

Abnormal p53 (p53abn) immunohistochemical (IHC) staining patterns can be found in vulvar squamous cell carcinoma (VSCC) and differentiated vulvar intraepithelial neoplasia (dVIN). They can also be found in the adjacent skin that shows morphology that falls short of the traditional diagnostic threshold for dVIN. Vulvectomy specimens containing human...

Molecular classification provides an objective, reproducible framework for categorization of endometrial cancers (ECs), informing prognosis and selection of therapy. Currently, the uptake of molecular classification, integration in to EC management algorithms, and enrollment in molecular subtype-specific clinical trials lags behind what it could be...

There is emerging evidence that vulvar squamous cell carcinoma (VSCC) can be prognostically subclassified into 3 groups based on human papillomavirus (HPV) and p53 status: HPV-associated (HPV+), HPV-independent/p53 wild-type (HPV-/p53wt), or HPV-independent/p53 abnormal (HPV-/p53abn). Our goal was to assess the feasibility of separating VSCC and it...

Endometrial carcinoma (EC) can be divided into 4 prognostic molecular subtypes, and no specific molecular profile (NSMP) type is the most commonly occurring type (∼50%). Although described as having an intermediate to favorable prognosis, this subtype encompasses pathologically and molecularly diverse tumors. We aimed to identify factors associated...

Multipath artifacts present in double clad fiber-based OCT systems may provide cancer-sensitive image biomarkers. Preliminary work finds that analysis of these artifacts can distinguish between ex vivo fallopian tube specimens with and without cancerous lesions.

Objectives Shallow whole genome sequencing (sWGS) has been successfully used to derive copy number (CN) signatures in high grade serous ovarian cancer (HGSOC), recognizing two signatures associated with homologous recombination deficiencies (HRD). p53abn ECs share genomic features with HGSOC, supporting application of this platform to stratify this...

Objectives Despite recommendations for the integration of molecular classification in endometrial cancers (EC) into pathology reporting and clinical management, uptake is inconsistent. To assign ProMisE subtype, all molecular components must be available (POLE mutation status, MMR and p53 immunohistochemistry (IHC)) and often components are perform...

Objectives Optimal management of stage IA p53abn and/or high-grade non-endometrioid endometrial cancer(EC) without myometrial invasion is unclear, classified as intermediate risk in new 2020 ESGO-ESTRO-ESP guidelines. Current practice varies from surgery alone to adjuvant vault brachytherapy (VB)±chemotherapy. Our aim was to assess the risk of dise...

Objectives p53abn endometrial cancer (EC) is associated with a high risk of recurrence. Molecular classification of EC cohorts has shown that ~5% of low-grade endometrioid EC (EEC) are p53abn. There is debate whether these are misclassified glandular variants of serous EC, and whether the risk of recurrence justifies adjuvant therapy. Here, we aim...

Objectives EC management has been plagued by poor interobserver reproducibility of histomorphologic features for a long time. More recently integration of TCGA-inspired molecular classification into pathology reporting and treatment guidelines was recommended. It was the aim to investigate the impact of adding molecular classification to a patient...

Objectives Carcinosarcoma is a high-grade endometrial carcinoma (EC) that consists of a carcinomatous component juxtaposed with a malignant metaplastic stromal component. Our aim was to assess the molecular subtype(s) of carcinosarcomas in a population-based cohort. Methods We assessed IHC and NGS data on all cases diagnosed as carcinosarcoma and...

We assessed the landscape of diagnostic pathology practice and how molecular classification could potentially impact management of patients with endometrial cancer by collecting patient samples, clinicopathologic data, and patient outcomes from EC patients diagnosed in 2016 at 10 Canadian tertiary cancer centers and 19 community hospitals. ProMisE...

A cogent and comprehensive pathologic report is essential for optimal patient management, cancer staging, and prognostication. This article details the International Collaboration on Cancer Reporting (ICCR) process and the development of the vulval carcinoma reporting data set. It describes the "core" and "noncore" elements to be included in pathol...

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 Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) using p53 and mismatch repai...

How cell-to-cell copy number alterations that underpin genomic instability1 in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer2, remains understudied. Here, by applying scaled single-cell whole-genome sequencing3 to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-de...

Objective Vulvar squamous cell carcinoma and in situ lesions can be stratified by human papillomavirus (HPV) and TP53 status into prognostic risk groups using p16 and p53 immunohistochemistry. We assessed the significance of vulvar squamous cell carcinoma resection margin positivity for either differentiated vulvar intra-epithelial neoplasia (dVIN)...

Objectives: Molecular classification of endometrial cancer (EC) has been shown to have a strong prognostic value. Recent data support the predictive implications of molecular subtype assignment. Using combined EC cohorts that have undergone molecular classification, our objective was to assess the response to adjuvant therapy based on ESMO 2016 ris...

Abstract Endometrial carcinoma (EC) is the most common gynecological malignancy and fibroblast growth factor receptor 2 (FGFR2) is a frequently dysregulated receptor tyrosine kinase. FGFR2b and FGFR2c are the two main splice isoforms of FGFR2 and are normally localized in epithelial and mesenchymal cells, respectively. Previously, we demonstrated t...

(Abstracted from Gynecol Oncol 2022;165:376–384) Endometrial cancer (EC) continues to increase in incidence and mortality globally and represents the most common gynecologic cancer in North America. Approximately 22% of patients with stage 1 EC have extrauterine disease, most commonly in pelvic and/or para-aortic lymph nodes.

Objectives: Vulvar squamous cell carcinoma is subclassified into three prognostically relevant groups: (i) human papillomavirus (HPV) associated, (ii) HPV independent p53 abnormal (mutant pattern), and (iii) HPV independent p53 wild type. Immunohistochemistry for p16 and p53 serve as surrogates for HPV viral integration and TP53 mutational status....

Lay summary Endometrial carcinoma (EC) classification and risk stratification have undergone a global transformation in the last decade, shifting from a reliance on poorly reproducible histomorphological parameters such as grade and histotype, toward a molecular classification that is consistent and biologically informative. Molecular classificatio...

5594 Background: Molecular subtyping of endometrial cancer (EC), unlike histopathological evaluation, offers an objective and reproducible classification system that has strong prognostic value and therapeutic implications. The Proactive Molecular risk classifier for Endometrial cancer (ProMisE) was developed by our team as a pragmatic, cost-effect...

5542 Background: Detection of cancer with improved discrimination compared to current blood tests could be achieved using an approach that assesses extracellular vesicles (EVs). This approach should have high sensitivity (se) because of EVs abundance in blood and high specificity (sp) by assaying EVs with multiple cancer-related protein and glycosy...

Primary carcinomas of the vagina are uncommon and currently detailed recommendations for the reporting of resection specimens of these neoplasms are not widely available. The International Collaboration on Cancer Reporting (ICCR) is developing standardized, evidence-based reporting data sets for multiple cancer sites. We describe the development of...

Background: The role of lymph node assessment/dissection (LND) in endometrial cancer (EC) has been debated for decades, with significant practice variation between centers. Molecular classification of EC provides prognostic information and can be accurately performed on preoperative endometrial biopsies. We assessed the association between molecul...

Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1 -mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vi...

Objectives: The aims of this article were to describe 2 patients with a pathological diagnosis of differentiated exophytic vulvar intraepithelial lesion and to summarize the literature regarding this relatively new diagnosis. Materials and methods: The existing literature was searched on December 1, 2021, using the MEDLINE database (1966-2021),...

Endometrial cancer is the most common gynaecological cancer in high income countries and its incidence is rising globally. Although an ageing population and fewer benign hysterectomies have contributed to this trend, the growing prevalence of obesity is the major underlying cause. Obesity poses challenges for diagnosis and treatment and more resear...

Background: Opportunistic salpingectomy (OS) is the removal of fallopian tubes during hysterectomy for benign indications or instead of tubal ligation, for the purpose of preventing ovarian cancer. We determined rates of OS at the time of hysterectomy and tubal sterilization and examined how they changed over the study period. Methods: Using dat...

Objectives We measured the variation in practice across all aspects of endometrial cancer (EC) management and assessed the potential impact of implementation of molecular classification. Methods Centers from across Canada provided representative tumor samples and clinical data, including preoperative workup, operative management, hereditary cancer...

Importance: Opportunistic salpingectomy (OS), which is the removal of fallopian tubes during hysterectomy or instead of tubal ligation without removal of ovaries, is recommended to prevent ovarian cancer, particularly serous ovarian cancer. However, the effectiveness of OS is still undetermined. Objective: To examine observed vs expected rates o...

Background To drive translational medicine, modern day biobanks need to integrate with other sources of data (clinical, genomics) to support novel data-intensive research. Currently, vast amounts of research and clinical data remain in silos, held and managed by individual researchers, operating under different standards and governance structures;...

Objectives Molecular classification of endometrial cancer (EC) has important prognostic and therapeutic implications. p53abn EC represent the most aggressive molecular subtype, and recent data has shown a survival benefit from chemotherapy and targeted therapies. We describe the clinicopathologic diversity in presentation and outcomes of p53abn ECs...

Objectives Vulvar squamous cell carcinomas (VSCCs) can be stratified by HPV and TP53 mutation status to prognostically significant risk groups using p16 and p53 IHC. Treatment guidelines do not address optimal management of high molecular risk (TP53 mutated) pre-invasive neoplasia found at resection margins. Herein, we used p53 IHC to evaluate marg...

Objectives The World Health Organization (WHO) endorsed molecular classification of endometrial carcinoma (EC) to be incorporated in routine diagnostic workup, by evaluating p53 and mismatch repair (MMR) protein immunohistochemistry (IHC), as well as pathogenic mutations in the gene encoding DNA polymerase epsilon (POLE). The latter is currently th...

Objectives Increasing incidence and morbidity of endometrial cancer (EC) has resulted in high systemic cost burdens associated with management. Molecular classification is now being integrated into routine pathologic reporting, providing objective biologically-relevant data to direct care. We assessed the cost implications of this integration in a...

Objectives Molecular classification identifies >50% of endometrial cancers (ECs) as having ‘no specific molecular profile/NSMP’; without mismatch repair deficiency, p53 IHC abnormalities, or pathogenic POLE mutations. Clinical presentation and outcomes within NSMP ECs are diverse and optimal treatment unclear with new ESMO/ESTRO/ESP guidelines unch...

Introduction/Background* Tumor cell dissemination is associated with a less favorable outcome in breast cancer patients. In contrast, only limited clinical significance was yet reported for other gynecologic malignancies. We have previously reported disseminated tumor cells (DTC) not to be associated with established risk factors, L1CAM immunoreact...

Introduction/Background* Endometrial carcinoma patient care was based on histopathologic examination for many years. However, conventional pathologic features are known to suffer from high inter-observer variability and may be irreproducible in many cases. TCGA-derived molecular classification was shown to provide clinically meaningful data and was...

Introduction/Background* The TransPORTEC Consortium was established in 2013 by the PIs and translational science representatives of the PORTEC-3 trial groups from the Netherlands, United Kingdom, Australia, Canada and France. Purpose of the collaboration is to improve treatment of endometrial cancer (EC) patients. Here, we evaluate our experience w...

Introduction/Background* Vulvar squamous cell carcinoma (VSCC) is subclassified into three prognostically relevant groups: i) HPV-Associated (HPV-A), ii) HPV-Independent TP53 mutated (HPV-I p53abn), and iii) HPV-Independent TP53 wild type (HPV-I p53wt). Immunohistochemistry (IHC) for p16 and p53 are used as surrogate markers for HPV viral integrati...

Introduction/Background* The role of lymph node (LN) assessment in endometrial cancer (EC) has been a subject of debate for decades, with significant variation in use between centres. Molecular classification of EC provides objective, prognostic information and be performed on diagnostic endometrial biopsy specimens. The Proactive Molecular Risk Cl...

Background To drive translational medicine, modern day biobanks need to integrate with other sources of data (clinical, genomics) to support novel data-intensive research. Currently, vast amounts of research and clinical data remain in silos, held and managed by individual researchers, operating under different standards and governance structures;...

Following the discovery of the four molecular subtypes of endometrial cancer (EC) by The Cancer Genome Atlas (TCGA) in 2013, subsequent studies used surrogate markers to develop and validate a clinically relevant EC classification tool to recapitulate TCGA subtypes. Molecular classification combines focused sequencing ( POLE) and immunohistochemist...

Background: Endometrial cancers (ECs) with somatic mutations in DNA polymerase epsilon (POLE) are characterized by unfavorable pathological features, which prompt adjuvant treatment. Paradoxically, women with POLE-mutated EC have outstanding clinical outcomes, and this raises concerns of overtreatment. The authors investigated whether favorable ou...

Over the past decade, our understanding of endometrial cancer has changed dramatically from the two-tiered clinicopathologic classification system of type I and type II endometrial cancer through to the four distinct molecular subtypes identified by The Cancer Genome Atlas (TCGA) in 2013. In both systems there is a small subset of endometrial cance...

p>While endometrial cancer (EC) has an overall good prognosis, some patients do poorly and there is room for refinement within current classification systems. Using the TCGA prognostic grouping of EC, our group developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), which reliably and reproducibly stratifies ECs into fou...

As we move forward with integration of molecular classification into clinical care the assessment of additional clinicopathological and molecular features in the context of molecular subtype will enable us to further refine prognosis. In addition, molecular classification can enable stratification of clinical cohorts that have been often thought of...

Background there is no consensus on the cut-off for positivity of estrogen receptor (ER) and progesterone receptor (PR) in endometrial cancer (EC). Therefore we determined the cut-off value for ER and PR with the strongest prognostic impact on outcome. Methods immunohistochemical expression of ER and PR was scored as a percentage of positive EC ce...

Background: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian...

Introduction Patients with high-grade endometrial carcinoma (HGEC) are more likely to present with metastatic disease and require multimodal treatment. Appropriate workup of patients preoperatively can direct optimal order of treatment. International guidelines to guide care are non-proscriptive and inconsistent. We were interested in addressing pr...

Objectives In preparation for provincial implementation of ProMisE molecular classification, two KT objectives were identified: 1) build awareness of ProMisE with first line knowledge users (KUs); and 2) elucidate barriers and facilitators to KUs use of ProMisE. Methods KUs were defined as pathologists, and clinicians (general practitioners, gynec...

Objectives We wished to assess the potential impact of directing EC management based on molecular classification, and the projected cost implications of molecular subtype-directed care. Methods Surgical staging, treatment, surveillance, and hereditary cancer program(HCP) referrals were assessed for all ECs managed in a single calendar year (2016)...

Dedifferentiated endometrial carcinoma (DDEC) is a rare but highly aggressive type of endometrial cancer, in which an undifferentiated carcinoma arises from a low-grade endometrioid endometrial carcinoma. The low-grade component is often eclipsed, likely due to an outgrowth of the undifferentiated component, and the tumor may appear as a pure undif...

Mesonephric carcinomas (ME) and female adnexal tumours of probable Wolffian origin (FATWO) are derived from embryologic remnants of Wolffian/mesonephric ducts. Mesonephric-like carcinomas (MLC) show identical morphology to ME of the cervix, but occur in the uterus and ovary without convincing mesonephric remnants. ME, MLC and FATWO are challenging...

Objectives Molecular classification of endometrial carcinoma (EC) enables consistent classification of tumours and provides valuable prognostic and predictive information. Herein we describe molecular subtype distribution and histomorphologic correlates in recently diagnosed (2016) ECs from across Canada. Methods Molecular classification was perfo...

Human papillomavirus (HPV)-independent vulvar squamous cell carcinoma (VSCC) is an aggressive clinical entity. Current diagnostic guidelines for premalignant lesions are ambiguous, and their molecular profile and progression events are still unclear. We selected 75 samples, from 40 patients, including 33 VSCC, 8 verrucous carcinomas (VC), 13 differ...

Purpose: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared to other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a "one-size-fits-all" approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical...

Endometrial carcinoma, the most common gynaecological cancer, develops from endometrial epithelium which is composed of secretory and ciliated cells. Pathologic classification is unreliable and there is a need for prognostic tools. We used single cell sequencing to study organoid model systems derived from normal endometrial endometrium to discover...

Endometrial cancer (EC) is the fifth most common cancer in women worldwide. Global estimates show rising incidence rates in both developed and developing countries. Most women are diagnosed postmenopausal, but 14-25% of patients are premenopausal and 5% are under 40 years of age. Established risk factors include age and hyperestrogenic status assoc...

Endometrial epithelium gives rise to both endometrial and ovarian cancers (of clear-cell and endometrioid subtypes), the latter arising from ectopic endometrium (endometriosis). Endometrial epithelium comprises mainly secretory cells, with a minor ciliated cell population. Due to their scarcity, little is known about the biology or function of endo...

Objective: Endometrioid ovarian carcinoma (ENOC) is associated with a generally more favorable prognosis compared to other ovarian carcinoma histotypes. Nonetheless, patients are still treated with a “one size fits all” approach. While tumor staging offers some stratification, the development of personalized treatment concepts remains elusive. Our...

Purpose: The two most common molecular subtypes of endometrial cancers (EC), mismatch repair deficient (MMRd) and p53 wildtype (p53wt) comprise the majority of ECs and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of fibroblast growth factor receptor 2 (FGFR2) from FGFR2b to FGFR2c (norma...

Background: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal/ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of ind...

Purpose: Many rare ovarian cancer subtypes such as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) have poor prognosis due to their aggressive nature and resistance to standard platinum and taxane based chemotherapy. The development of effective therapeutics has been hindered by the rarity of such tumors. We sought to identify targe...

Objectives This review examines how response rates to progestin treatment of low-grade endometrial cancer can be improved. In addition to providing a brief overview of the pathogenesis of low-grade endometrial cancer, we discuss limitations in the current classification of endometrial cancer and how stratification may be refined using molecular mar...

Objectives Mismatch repair deficiency is observed in 25%–30% of all endometrial cancers. This can be detected by the absence of mismatch repair protein staining on immunohistochemistry, and is used as a screen for Lynch syndrome. Only 10% of women with mismatch repair deficiency have Lynch syndrome, but mismatch repair deficiency may still have pro...