Examining the Diagnostic Yield of Tumour Testing and Qualifying Germline Concordance for Hereditary Cancer Variants in Patients with High-Grade Serous Carcinoma.

Despite advances in treatment, prognosis for most patients with high-grade serous carcinoma (HGSC) remains poor. Genomic alterations in the homologous recombination (HR) pathway are used for cancer risk assessment and render tumours sensitive to platinum-based chemotherapy and poly (ADP-ribose) polymerase inhibitors (PARPi), which can be associated with more favourable outcomes. In addition to patients with tumours containing BRCA1 or BRCA2 pathologic variants, there is emerging evidence that patients with tumours harbouring pathologic variants in other HR genes may also benefit from PARPi therapy. The objective of this study is to assess the feasibility of primary-tumour testing by examining the concordance of variant detection between germline and tumour-variant status using a custom hereditary cancer gene panel (HCP). From April 2019 to November 2020, HCP variant testing was performed on 146 HGSC formalin-fixed, paraffin-embedded tissue samples using next-generation sequencing. Of those, 78 patients also underwent HCP germline testing using blood samples. A pathogenic variant was detected in 41.1% (60/146) of tumours tested, with 68.3% (41/60) having either a BRCA1 or BRCA2 variant (n = 36), or BRCA1/2 plus a second variant (n = 5), and 31.2% (19/60) carrying a pathogenic variant in another HCP gene. The overall variant rate among the paired germline and tumour samples was 43.6% (34/78), with the remaining 56% (44/78) having no pathogenic variant detected in the germline or tumour. The overall BRCA1/2 variant rate for paired samples was 33.3% (26/78), with germline variants detected in 11.5% (9/78). A non-BRCA1/2 germline variant in another HCP gene was detected in 9.0% (7/78). All germline variants were detected in the tumour, demonstrating 100% concordance. These data provide evidence supporting the feasibility of primary-tumour testing for detecting germline and somatic variants in HCP genes in patients with HGSC, which can be used to guide clinical decision-making, and may provide opportunity for improving patient triage and clinical genetic referral practices.

p53 immunohistochemistry in endometrial cancer: clinical and molecular correlates in the PORTEC-3 trial.

Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).

Insufficient and Scant Endometrial Samples: Determining Clinicopathologic Outcomes and Consistency in Reporting.

There are no widely accepted pathologic criteria for reporting endometrial samples with limited tissue and no consensus on the clinical follow-up of patients with these samples. Our study compares clinicopathologic outcomes and determines reporting consistency for these samples. This was done in 3 parts: (1) retrospective chart review of all patients with reported insufficient or scant endometrial samples from 2010 to 2013 at our center to determine repeat sampling and final pathologic diagnosis; (2) survey of gynecologists about their practice for managing patients with these samples; (3) blind review of 99 cases of previously reported scant or insufficient samples in which 4 reviewers separately reassigned cases as scant, insufficient, or diagnostic. Agreement was determined across reviewers. For part (1): 1149 patients had insufficient (49%) or scant (51%) samples with no significant difference in repeat biopsy rate (33% vs. 31%; P=0.33). Final diagnosis of uterine malignancy was higher in patients with a previous insufficient sample than with scant (19% and 9%, respectively), but this was not statistically significant. For part (2): among gynecologists surveyed, 4 of 5 reported managing patients with insufficient or scant samples similarly. For part (3): complete consensus across raters occurred in 57% of cases (Fleiss κ, 0.4891). Similar repeat biopsy rates between scant and insufficient samples suggest that our clinicians choose similar management for both terminologies. As such, distinction between insufficient and scant samples may not be necessary in pathologic reporting. Given the malignancy outcomes, both groups merit repeat sampling in the appropriate context.

Performance measures related to colposcopy for canadian cervical cancer screening programs: identifying areas for improvement.

OBJECTIVE: To describe performance measures related to colposcopic examinations in Canadian cervical cancer screening programs; specifically, time to colposcopy, histological investigation rate, and agreement between cytology and histology. METHODS: As part of a national report on the performance of cervical cancer screening, aggregate provincial cervical cancer screening data provided by provinces to the Pan-Canadian Cervical Screening Network were used to evaluate colposcopy program performance measures for women 20 to 69 years of age who had a Pap test in 2009 and 2010. RESULTS: A total of 37 523 women had a high-grade or more severe Pap test result. The proportion of women who had a colposcopy ≤ 90 days after their Pap test ranged from 30.9% to 51.5%. Fewer women 60 to 69 years of age had a colposcopy than women in younger age groups. The proportion of women who had a high-grade or more severe Pap test result and colposcopy who had a biopsy within 12 months ranged from 82.1% to 96.5%. The proportion of biopsy results that agreed with the Pap test result ranged from 59.5% to 82.1%. CONCLUSION: The time from having a high-grade Pap test result to undergoing colposcopy must be reduced to lower the risk of adverse outcomes and the stress associated with delayed follow-up. The agreement between screening cytology and histology meets the national target of ≥ 65%. Although six of 13 provinces and territories provided data for colposcopy-related performance measures, more information is needed to assess colposcopy services accurately at the national level.

Objectif : Décrire les mesures de rendement associées aux examens colposcopiques au sein des programmes canadiens de dépistage du cancer du col utérin (plus particulièrement : le délai avant le recours à la colposcopie, le taux d'exploration histologique et le taux de concordance des résultats cytologiques et histologiques). Méthodes : Dans le cadre d'un rapport national sur le rendement du dépistage du cancer du col utérin, les données agrégées provinciales sur ce dépistage qu'ont fournies les provinces à l'Initiative pancanadienne sur le dépistage du cancer du col de l'utérus ont été utilisées pour évaluer les mesures du rendement des programmes de colposcopie chez les femmes de 20 à 69 ans qui avaient subi un test de Pap en 2009 et en 2010. Résultats : En tout, 37 523 femmes avaient obtenu des résultats de test de Pap indiquant la présence d'une anomalie de haut grade histologique ou d'une anomalie plus grave. La proportion des femmes qui ont subi une colposcopie ≤ 90 jours à la suite de leur test de Pap se situait entre 30,9 % et 51,5 %. Moins de femmes du groupe d'âge des 60 à 69 ans ont subi une colposcopie, par comparaison avec les femmes des groupes d'âge plus jeunes. La proportion des femmes qui avaient obtenu des résultats de test de Pap indiquant la présence d'une anomalie de haut grade histologique ou d'une anomalie plus grave, qui ont subi une colposcopie et qui ont subi une biopsie dans un délai de 12 mois se situait entre 82,1 % et 96,5 %. La proportion des résultats de biopsie qui concordaient avec les résultats de test de Pap se situait entre 59,5 % et 82,1 %. Conclusion : Le délai entre l'obtention de résultats de test de Pap indiquant la présence d'une anomalie de haut grade histologique et la tenue d'une colposcopie se doit d'être réduit pour que l'on puisse abaisser le risque d'issues indésirables et le stress qui sont associés au report du suivi. Le taux de concordance des résultats cytologiques et histologiques atteint la cible nationale de ≥ 65 %. Bien que six des 13 provinces et territoires aient fourni des données sur les mesures de rendement associées à la colposcopie, plus de renseignements s'avèrent requis pour que l'on puisse évaluer avec précision les services de colposcopie au niveau national.

A validation study of the FocalPoint GS imaging system for gynecologic cytology screening.

BACKGROUND: Studies of the performance of the automated FocalPoint Guided Screening (FPGS) imaging system in gynecologic cytology screening relative to manual screening have yielded conflicting results. In view of this uncertainty, a validation study of the FPGS was conducted before its potential adoption in 2 large laboratories in Ontario. METHODS: After an intense period of laboratory training, a cohort of 10,233 current and seeded abnormal slides were classified initially by FPGS. Manual screening and reclassification blinded to the FPGS results were then performed. Any adequacy and/or cytodiagnostic discrepancy between the 2 screening methods subsequently was resolved through a consensus process (truth). The performance of each method's adequacy and cytodiagnosis vis-a-vis the truth was established. The sensitivity and specificity of each method at 4 cytodiagnostic thresholds (atypical squamous cells of undetermined significance or worse [ASC-US+], low-grade squamous intraepithelial lesion or worse [LSIL+], high-grade squamous intraepithelial lesion or worse [HSIL+], and carcinoma) were compared. The false-negative rate for each cytodiagnosis was determined. RESULTS: The performance of FPGS in detecting carcinoma, HSIL+, and LSIL+ was no different from the performance of manual screening, but the false-negative rates for LSIL and ASC-US were higher with FPGS than with manual screening. CONCLUSIONS: The results from this validation study in the authors' laboratory environment provided no evidence that FPGS has diagnostic performance that differs from manual screening in detecting LSIL+, HSIL+, or carcinoma.

HPV testing in primary cervical screening: a systematic review and meta-analysis.

OBJECTIVE: Previous findings from cross-sectional studies have shown human papillomavirus (HPV) testing to be more sensitive than cytology testing for primary cervical screening. This systematic review aims to assess whether the increase in baseline detection with HPV testing corresponds to lower rates in subsequent screening rounds. METHODS: We searched Medline, EMBASE, and the Cochrane Library for randomized controlled trials (published from 2005 to 2010) comparing HPV-based and cytology-based cervical screening. Primary outcomes of interest were relative rates of higher grade cervical intraepithelial neoplasia and invasive cervical cancer. Secondary outcomes included test performance characteristics and colposcopy referral rates. Results were pooled where possible using a random effects model. RESULTS: Seven randomized trials were identified. Across studies, HPV testing was more accurate than conventional cytology and detected significantly more CIN3+ in the first screening round (Mantel-Haenszel [M-H] risk ratio 1.67; 95% CI 1.27 to 2.19) and significantly less in the second screening round (M-H RR 0.49; 95% CI 0.37 to 0.66). There were no differences in pooled rates of CIN2+ (M-H RR 1.19; 95% CI 0.94 to 1.50) and CIN3+ (M-H RR 1.09; 95% CI 0.84 to 1.42), but there was a higher pooled rate of CIN2 (M-H RR 1.37; 95% CI 1.12 to 1.68) over two screening rounds. A trend towards lower rates of invasive cervical cancer was observed. CONCLUSION: Organized screening programs in higher resource settings should consider adopting HPV testing as the primary screening test for women 30 or 35 years of age and older. Further research is needed to determine optimal screening strategies for younger women.

Cervical screening: a guideline for clinical practice in Ontario.

OBJECTIVE: To develop guidelines to inform the Ontario Cervical Screening Program's invitations to women in the target population, provide evidence-based clinical practice guidance for practitioners, and inform policy decisions. METHODS: A systematic review was conducted of relevant websites, the Medline and EMBASE databases (2005 to November 2010), and the Cochrane Library (2005 to 2010). No guidelines or systematic reviews were located that addressed the topics of interest. The evidence base consisted of seven randomized controlled trials, three case-control studies, one cohort study, and one review article. A methodologist performed data identification and extraction. Review of the data and quality assessment was carried out by the authors, who have expertise in methodology, gynaecologic oncology, pathology, and family medicine. The systematic review methods and resulting recommendations were reviewed by an internal panel with clinical, methodological, and oncology expertise. External review was provided by Ontario clinicians and other experts. CONCLUSIONS: The guideline development process led to recommendations for the optimal primary cervical screening method, screening interval, and age of screening cessation for Ontario women in the target population. There was insufficient evidence to provide a recommendation for age of initiation of cervical screening with HPV testing. The creation of an organized screening program in the province will allow the implementation of evidence-based recommendations. We provide interim recommendations for cervical screening until HPV testing has been funded.

Prognostic value of microsatellite instability (MSI) and PTEN expression in women with endometrial cancer: results from studies of the NCIC Clinical Trials Group (NCIC CTG).

AIM: The impact of PTEN status and microsatellite instability (MSI) on the prognosis of women with endometrial cancer is controversial. The aim of this study was to investigate MSI and PTEN expression in two patient populations using data from NCIC CTG studies. METHODS: Archival paraffin embedded tumour from women with endometrial cancer enrolled in NCIC CTG studies: EN5 (stage I/II) and IND 126, 148 and 160 (advanced/recurrent disease) were examined for MSI using BAT25/26 and for PTEN expression using immunohistochemistry. PTEN and MSI status were correlated with clinicopathologic variables and survival using data from NCIC CTG trial databases. RESULTS: PTEN and MSI results were available from 128 and 163 patients, respectively. MSI+ tumours were more common in women enrolled in EN5 compared to the IND studies (p=0.01). PTEN negative tumours were associated with improved survival in both univariate (hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.32-0.94; p=0.03) and multivariate (adjusted HR 0.54, 95% CI 0.30-0.96; p=0.03) analyses in women enrolled in IND studies. Microsatellite stable tumours were associated with an improved prognosis in univariate (HR 0.18, 95% CI 0.06-0.51; p<0.0001) and multivariate (adjusted HR 0.16, 95% CI 0.05-0.5; p<0.0001) analyses in women enrolled in EN5. There was no significant correlation between MSI and PTEN status. CONCLUSIONS: PTEN negative tumours in women with advanced disease are associated with improved survival. MSI+ tumours are more common in early stage disease and in this group of women are associated with a worse prognosis.

The optimum organization for the delivery of colposcopy service in Ontario: a systematic review.

OBJECTIVE: To determine the optimum organization for colposcopy service delivery in Ontario, Canada. METHODS: A multidisciplinary expert panel was convened to develop a systematic review to inform organizational guidelines. MEDLINE, EMBASE, CINAHL, HealthSTAR, and the Cochrane Library databases were searched from 1996 to February 2006 for articles that reported guidance or outcomes relating to improved outcomes in colposcopy training, qualifications, accreditation, maintenance of competency, the delivery of colposcopy, reducing default from colposcopy clinics, and/or strategies to improve patient satisfaction or comfort. In addition, an environmental scan identified unpublished documents related to the delivery of colposcopy services. RESULTS: Sixteen guidance documents related to the delivery of colposcopy services were identified; 5 from the published literature and 11 from the environmental scan. These documents were used by the panel to inform the systematic review and companion guidelines. CONCLUSIONS: Overall, the Ontario Colposcopy Guidelines Development Group believes that the benefits associated with the implementation of colposcopy recommendations in Ontario will result in greater organization of care and improved patient outcomes. In addition, the group anticipates that these recommendations will provide useful guidance to regional planning authorities, hospital administrators, and Cancer Care Ontario, as well as colposcopists and other practitioners, in the planning of integrated regional and provincial cancer screening services.

Comparison of ThinPrep and conventional smears in salivary gland fine-needle aspiration biopsies.

BACKGROUND: ThinPrep (TP) cytology for evaluation of nongynecological specimens is being increasingly used. There are few studies comparing TP with conventional smears (CS) in salivary gland (SG) fine-needle aspiration biopsies (FNAB). This study compares diagnostic accuracy and morphology of TP and CS in SG FNABs. METHODS: The authors retrospectively reviewed 98 satisfactory SG FNABs with both TP and CS. All cases had surgical resection. CS and TP slides were assessed for multiple morphological parameters, as well as the ability to make the diagnosis. Chi-square analysis was performed to compare CS and TP. RESULTS: An accurate diagnosis was rendered more commonly with CS compared with TP (57% versus 42%; P = .032), whereas the unsatisfactory rate was greater with TP compared with CS (19% versus 9%; P = .041). The error (4%) and indeterminate (35%) rates for TP were similar to CS. The diagnostic yield was greater for cellular cases, which were more frequent with CS compared with TP, than for cases of low cellularity; the diagnostic yield of cellular TP cases and cellular CS cases was similar. Artifacts (crush, air drying, obscuring blood) were more frequent (12%, 13%, and 27% versus 2%, 0%, and 1%; P

Decreasing incidence of cervical adenocarcinoma in Ontario: is this related to improved endocervical Pap test sampling?

In many developed countries, the incidence of cervical cancer has decreased. These reductions have been specific to squamous cell carcinoma (SCC) and have not included adenocarcinoma (AC). Incidence of AC has increased steadily over the last 20 years. The intent of this article is to examine trends in cervical adenocarcinoma incidence in Ontario over a 20-year period in relation to screening practices. All cases of cervical cancer between 1981 and 2002 were extracted from the Ontario Cancer Registry (a population-based, provincial-wide database). Age-standardized incidence rates were calculated overall, by broad age groups and by morphological type (SCC and AC). Time trends were assessed using JoinPoint methodology. In Ontario, opportunistic cervical cancer screening has been accompanied by significantly decreased rates of SCC since at least 1981. Conversely, the incidence of AC rose by 3.1% per year (95% CI: 1.6%, 4.6%) between 1981 and 1995, and subsequently declined by 4.0% per year (95% CI: -7.4%, -0.5%). From the mid- to late-1990s, instructions were distributed to clinicians, reinforcing the importance of dual specimen collection (i.e., using both spatula and endocervical brush). At the same time, laboratories routinely provided physicians with kits that included both spatula and brush. The subsequent decline in AC incidence may be due, in part, to improved specimen collection. As well, the decline may be partly due to increased awareness of AC precursors among cytopathologists and clinicians, and/or improvements in laboratory training and quality assurance.

Improving quality of care for patients undergoing arterial embolization for uterine fibroids: case report and review.

BACKGROUND: Uterine artery embolization (UAE) is an effective and accepted management option for symptomatic uterine fibroids. This case report presents a complication following UAE and is followed by a review outlining the need to monitor quality of care for women who undergo this procedure. CASE: A 37-year-old woman presented with fever and general malaise refractory to medical treatment 16 days after UAE was performed to treat a symptomatic fibroid. At hysterectomy, 20 days after UAE, a 10 cm necrotic and infected submucosal fibroid with cervicitis was identified. CONCLUSION: Complications of UAE for treatment of fibroids will be minimized if patients are selected appropriately, if the procedure is performed correctly, and if outcomes, efficacy, and complication rates are monitored.

Report of the 2003 pan-Canadian forum on cervical cancer prevention and control.

OBJECTIVE: To develop evidence-based consensus recommendations on the delivery of cervical cancer screening, human papillomavirus (HPV) education, HPV testing, and the optimal tool for cervical cytology within the Canadian health system. PARTICIPANTS: Leading up to a forum held in Ottawa on November 21 and 22, 2003, 254 registrants reviewed position papers through a Web-based discussion group. Experts in program management, clinical practice, epidemiology, public health, economics, and women's health, representing 48 organizations, then participated in the 2-day forum to develop consensus recommendations. EVIDENCE: Writing groups prepared position papers on optimal methods for cervical cytology; education concerning HPV; HPV testing in primary screening; HPV testing as a triage tool in cytopathology; and delivery mechanisms for cervical screening. Systematic reviews were the primary source of evidence supplemented by literature searches. CONSENSUS PROCESS: Feedback from Web-based discussions was incorporated into consecutive drafts of position papers. At the forum, recommendations and supporting evidence were presented, further debated in small-group sessions, and discussed in a plenary session. Despite divergent professional mandates and opinions, consensus was achieved on 15 recommendations across all areas. Final recommendations were posted to the Web for further input and circulated for written consensus by participants. CONCLUSIONS: The recommendations cover the use of new evidence and technologies in cervical cancer prevention in Canada and provide a framework for provision of HPV education, planning the implementation of new cervical screening technologies in Canada, the development of evaluation plans, and new research areas.

Results of the implementation of liquid-based cytology-SurePath in the Ontario screening program.

BACKGROUND: The objective of the current study was to evaluate the adequacy and detection rates of SurePath after its implementation in Ontario. METHODS: The detection and adequacy rates of the SurePath liquid-based cytology system (SP-LBC) were calculated for manually reviewed slides of the year 2002. The adequacy and detection rates from this study group were compared with a historical conventional smear (CS) group from the same laboratories during the same period of the previous year. RESULTS: The SP-LBC study group consisted of 352,680 specimens with cytodiagnoses and the CS group included 378,990 specimens. The unsatisfactory rate for SP-LBC (0.24%) was less than that of the CS group (0.58%). The detection rate of atypical squamous cells (ASC+) by the SP-LBC group (4.69%) was greater than that of the CS group (3.81%), as was the detection rate of low-grade squamous intraepithelial lesions (LSIL+; 2.13% vs. 1.50% in the CS group). There was only a trend toward increased detection of high-grade squamous intraepithelial lesions (HSIL+) in the SP-LBC group (0.34%) relative to the CS group (0.31%), because the detection rate for carcinoma by SP-LBC declined. CONCLUSIONS: The implementation of SP-LBC has been followed by better specimen adequacy and detection rates for ASC+, LSIL+, and a trend of increased detection of HSIL+ relative to CS practice. To determine sensitivity rates, a histopathologic database for cervical carcinoma and precancer needs to be established.