Practice guidelines for BRCA1/2 tumour testing in ovarian cancer.

The purpose of this document is to provide pre-analytical, analytical and post-analytical considerations and recommendations to Canadian clinical laboratories developing, validating and offering next-generation sequencing (NGS)-based BRCA1 and BRCA2 (BRCA1/2) tumour testing in ovarian cancers. This document was drafted by the members of the Canadian College of Medical Geneticists (CCMG) somatic BRCA Ad Hoc Working Group, and representatives from the Canadian Association of Pathologists. The document was circulated to the CCMG members for comment. Following incorporation of feedback, this document has been approved by the CCMG board of directors. The CCMG is a Canadian organisation responsible for certifying medical geneticists and clinical laboratory geneticists, and for establishing professional and ethical standards for clinical genetics services in Canada. The current CCMG Practice Guidelines were developed as a resource for clinical laboratories in Canada; however, they are not inclusive of all information laboratories should consider in the validation and use of NGS for BRCA1/2 tumour testing in ovarian cancers.

Variability in endometrial carcinoma pathology practice: opportunities for improvement with molecular classification.

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 molecular subtype (POLEmut, MMRd, p53abn, No Specific Molecular Profile (NSMP)) was assigned retrospectively. 1357 patients were fully evaluable including 85 POLEmut (6.3%), 380 MMRd (28.0%), 643 NSMP (47.4%), and 249 p53abn ECs (18.3%). Immunohistochemistry (IHC) for MMR proteins was undertaken at the time of primary diagnosis in 2016 in only 42% of the cohort (570/1357; range 3.5-95.4%/center). p53 IHC had only been performed in 21.1% of the cohort (286/1357; range 10.1-41.9%/center). Thus, based on the retrospective molecular subtype assignment, 54.7% (208/380) of MMRd EC had not been tested with MMR IHC (or MSI) and 48.2% (120/249) of p53abn ECs were not tested with p53 IHC in 2016. Molecular subtype diversity within histotypes was profound; most serous carcinomas were p53abn (91.4%), but only 129/249 (51.8%) p53abn EC were serous. Low-grade (Gr1-2) endometrioid carcinomas were mostly NSMP (589/954, 61.7%) but included all molecular subtypes, including p53abn (19/954, 2.0%). Molecular subtype was significantly associated with clinical outcomes (p < 0.001) even in patients with stage I disease (OS p = 0.006, DSS p < 0.001, PFS p < 0.001). Assessment of national pathologic practice in 2016 shows highly variable use of MMR and p53 IHC and demonstrates significant opportunities to improve and standardize biomarker reporting. Inconsistent, non-reflexive IHC resulted in missed opportunities for Hereditary Cancer Program referral and Lynch Syndrome diagnosis, and missed potential therapeutic implications (e.g., chemotherapy in p53abn EC, immune blockade for MMRd EC). Routine integration of molecular subtyping into practice can improve the consistency of EC pathology assessment and classification.

Variation in practice in endometrial cancer and potential for improved care and equity through molecular classification.

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 program (HCP) referrals, adjuvant therapy, surveillance and outcomes, for all EC patients diagnosed in 2016. Tumors were classified into the four ProMisE molecular subtypes. RESULTS: A total of 1336 fully evaluable EC patients were identified from 10 tertiary cancer centers (TC; n = 1022) and 19 community centers (CC; n = 314). Variation of surgical practice across TCs was profound (14-100%) for lymphadenectomy (LND) (mean 57% Gr1/2, 82% Gr3) and omental sampling (20% Gr1/2, 79% Gr3). Preoperative CT scans were inconsistently obtained (mean 32% Gr1/2, 51% Gr3) and use of adjuvant chemo or chemoRT in high risk EC ranged from 0-55% and 64-100%, respectively. Molecular subtyping was performed retrospectively and identified 6% POLEmut, 28% MMRd, 48% NSMP and 18% p53abn ECs, and was significantly associated with survival. Within patients retrospectively diagnosed with MMRd EC only 22% had been referred to HCP. Of patients with p53abn EC, LND and omental sampling was not performed in 21% and 23% respectively, and 41% received no chemotherapy. Comparison of management in 2016 with current 2020 ESGO/ESTRO/ESP guidelines identified at least 26 and 95 patients that would have been directed to less or more adjuvant therapy, respectively (10% of cohort). CONCLUSION: Molecular classification has the potential to mitigate the profound variation in practice demonstrated in current EC care, enabling reproducible risk assessment, guiding treatment and reducing health care disparities.

Brief family history questionnaire to screen for Lynch syndrome in women with newly diagnosed non-serous, non-mucinous ovarian cancers.

OBJECTIVES: While ovarian cancer is the third most common Lynch syndrome-associated cancer in women, there is no established screening strategy to identify Lynch syndrome in this population. The objective of this study was to assess whether the 4-item brief Family History Questionnaire can be used as a screening tool to identify women with ovarian cancer at risk of Lynch syndrome. METHODS: In this prospective cohort study, participants with newly diagnosed non-serous, non-mucinous ovarian cancer completed the brief Family History Questionnaire, extended Family History Questionnaire, and had tumors assessed with immunohistochemistry for mismatch repair proteins, MLH1 methylation, and microsatellite instability testing. All underwent universal germline testing for Lynch syndrome. Performance characteristics were compared between the brief Family History Questionnaire, extended Family History Questionnaire, immunohistochemistry±MLH1 methylation, and microsatellite instability testing. RESULTS: Of 215 participants, 169 (79%) were evaluable with both the brief Family History Questionnaire and germline mutation status; 12 of these 169 were confirmed to have Lynch syndrome (7%). 10 of 12 patients (83%) with Lynch syndrome were correctly identified by the brief Family History Questionnaire, compared with 6 of 11 (55%) by the extended Family History Questionnaire, 11 of 13 (85%) by immunohistochemistry±MLH1 methylation, and 9 of 11 (82%) by microsatellite instability testing. The sensitivity, specificity, positive predictive values, and negative predictive values of the brief Family History Questionnaire were 83%, 65%, 15%, and 98%, respectively. A combined approach with immunohistochemistry and the brief Family History Questionnaire correctly identified all 12 patients with Lynch syndrome. The brief Family History Questionnaire was more sensitive than the extended Family History Questionnaire and took <10 min for each patient to complete. CONCLUSIONS: The brief Family History Questionnaire alone or combined with immunohistochemistry may serve as an adequate screening strategy, especially in centers without access to universal tumor testing.

Maximizing cancer prevention through genetic navigation for Lynch syndrome detection in women with newly diagnosed endometrial and nonserous/nonmucinous epithelial ovarian cancer.

BACKGROUND: Despite recommendations for reflex immunohistochemistry (IHC) for mismatch repair (MMR) proteins to identify Lynch syndrome (LS), the uptake of genetic assessment by those who meet referral criteria is low. The authors implemented a comprehensive genetic navigation program to increase the uptake of genetic testing for LS in patients with endometrial cancer (EC) or nonserous/nonmucinous ovarian cancer (OC). METHODS: Participants with newly diagnosed EC or OC were prospectively recruited from 3 cancer centers in Ontario, Canada. Family history questionnaires were used to assess LS-specific family history. Reflex IHC for MMR proteins was performed with the inclusion of clinical directives in pathology reports. A trained genetic navigator initiated a genetic referral on behalf of the treating physician and facilitated genetic referrals to the closest genetics center. RESULTS: A total of 841 participants (642 with EC, 172 with OC, and 27 with synchronous EC/OC) consented to the study; 194 (23%) were MMR-deficient by IHC. Overall, 170 women (20%) were eligible for a genetic assessment for LS: 35 on the basis of their family history alone, 24 on the basis of their family history and IHC, 82 on the basis of IHC alone, and 29 on the basis of clinical discretion. After adjustments for participants who died (n = 6), 149 of 164 patients (91%) completed a genetic assessment, and 111 were offered and completed genetic testing. Thirty-four women (4.0% of the total cohort and 30.6% of those with genetic testing) were diagnosed with LS: 5 with mutL homolog 1 (MLH1), 9 with mutS homolog 2 (MSH2), 15 with mutS homolog 6 (MSH6), and 5 with PMS2. CONCLUSIONS: The introduction of a navigated genetic program resulted in a high rate of genetic assessment (>90%) in patients with gynecologic cancer at risk for LS.

Understanding the clinical implication of mismatch repair deficiency in endometrioid endometrial cancer through a prospective study.

OBJECTIVES: Findings on impact of mismatch repair deficiency (MMRd) on patient outcomes in endometrial cancer (EC) have been inconsistent to date. The objective of this study was to compare the oncologic outcomes and recurrence patterns between MMRd and MMR-intact (MMRi) endometrioid EC (EEC). METHODS: Between 2015 and 2018, we prospectively recruited 492 EEC cases from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR protein expression by immunohistochemistry (IHC). Clinicopathological, survival and recurrence patterns were compared between MMRd and MMRi cases. RESULTS: Of 492 EEC, 348 were MMRi (71%) and 144 were MMRd (29%) with median follow-up of 16.8 months (0-69.6). MMRd tumors tended to be grade 2 or 3 (56% vs. 29%, p < 0.001), with propensity for lymphovascular space invasion (28% vs. 18%, p = 0.024), lymph node involvement (7% vs. 5%, p < 0.001) and received more adjuvant treatment (46% vs. 33%, p = 0.027). This group also had significantly lower 3-year recurrence-free survival (78% vs. 90%, p = 0.014) although there was no difference in OS (p = 0.603). MMRd cases were more likely to recur in retroperitoneal lymph nodes (p = 0.045). Upon subgroup analysis, MLH1 methylated tumors had the worst prognostic features and survival outcomes. CONCLUSIONS: MLH1 methylated EECs exhibit more aggressive features compared to other MMRd and MMRi EECs. This may indicate an inherent difference in tumor biology, suggesting the importance of individualized management based on EC molecular phenotype.

Performance characteristics of screening strategies to identify Lynch syndrome in women with ovarian cancer.

BACKGROUND: For women with ovarian cancer (OC), the optimal screening strategy to identify Lynch syndrome (LS) has not been determined. In the current study, the authors compared the performance characteristics of various strategies combining mismatch repair (MMR) immunohistochemistry (IHC), microsatellite instability testing (MSI), and family history for the detection of LS. METHODS: Women with nonserous and/or nonmucinous ovarian cancer were recruited prospectively from 3 cancer centers in Ontario, Canada. All underwent germline testing for LS and completed a family history assessment. Tumors were assessed using MMR IHC and MSI. The sensitivity, specificity, and positive and negative predictive values of screening strategies were compared with the gold standard of a germline result. RESULTS: Of 215 women, germline data were available for 189 (88%); 13 women (7%) had pathogenic germline variants with 7 women with mutS homolog 6 (MSH6); 3 women with mutL homolog 1 (MLH1); 2 women with PMS1 homolog 2, mismatch repair system component (PMS2); and 1 woman with mutS homolog 2 (MSH2). A total of 28 women had MMR-deficient tumors (13%); of these, 11 had pathogenic variants (39%). Sequential IHC (with MLH1 promoter methylation analysis on MLH1-deficient tumors) followed by MSI for nonmethylated and/or MMR-intact patients was the most sensitive (92.3%; 95% confidence interval, 64%-99.8%) and specific (97.7%; 95% confidence interval, 94.2%-99.4%) approach, missing 1 case of LS. IHC with MLH1 promoter methylation analysis missed 2 patients of LS. Family history was found to have the lowest sensitivity at 55%. CONCLUSIONS: Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be most sensitive. However, IHC with MLH1 promoter methylation analysis also performed well and is likely more cost-effective and efficient in the clinical setting. The pretest probability of LS is high in patients with MMR deficiency and warrants universal screening for LS.

Low-grade serous carcinoma (LGSC): A Canadian multicenter review of practice patterns and patient outcomes.

OBJECTIVE: Patients with advanced low-grade serous carcinoma (LGSC) have poor long-term survival rates. As a rare histotype, there are uncertainties regarding the use of current therapies. Thus, we studied practice patterns and treatment outcomes as part of a national initiative to better understand and improve the care of women with advanced LGSC. METHODS: This retrospective cohort study was conducted in 5 Canadian referral institutions from 2000 to 2016. Data collection and pathology reporting were standardized. Outcome measures included overall survival (OS), progression-free survival (PFS), progression-free intervals (PFI), and time to next treatment (TTNT). Cox regression analysis was used to evaluate the effects of clinical and pathologic factors on outcomes and prognosis. RESULTS: There were 134 patients (stage II-IV) with a median follow-up of 32.4 months (range 1.6-228). Four primary treatments were compared across institutions: 1) surgery followed by chemotherapy (56%), 2) neoadjuvant chemotherapy (NACT) followed by surgery (27%), 3) surgery alone (9%), and 4) surgery followed by anti-hormone therapy (4%). Primary platinum/paclitaxel chemotherapy was used in 81%. Patients treated with NACT had worse PFS. Multivariable Cox regression analysis identified lesser residual disease, younger age, and primary peritoneal origin as variables significantly associated with better OS/PFS (p < 0.03). One institution had significantly better PFS than the others (p = 0.025), but this finding could be related to a higher frequency of primary peritoneal LGSC. PFI and TTNT intervals in patients with relapsed disease were not significantly different after the first relapse irrespective of treatment type. CONCLUSIONS: There are notable differences in practice patterns across Canada. This underscores the need for ongoing strategies to measure, evaluate and achieve optimal patient outcomes for women with advanced LGSC.

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers.

OBJECTIVES: For synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests. METHODS: 30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing. RESULTS: Of 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium. CONCLUSIONS: There was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

Cervical Adenocarcinoma: A Comparison of the Reproducibility of the World Health Organization 2003 and 2014 Classifications.

OBJECTIVE: The aim of the study was to compare the reproducibility of malignant glandular tumors of the uterine cervix classified per World Health Organization (WHO) 2003 and 2014. MATERIALS AND METHODS: Two pathologists reviewed 228 cases composed of adenocarcinoma in situ and 22 adenocarcinoma histotypes and selected 405 representative hematoxylin and eosin slides, which were digitally scanned. Six other pathologists (3 gynecological and 3 anatomical) independently reviewed and classified the images per both WHO classifications. One year later, they classified a random sample of 25 cases. Inter- (inter-OR) and intra-observer (intra-OR) reproducibility of the 6 pathologists and separately for gynecological compared with anatomical pathologists was tested using κ statistics. RESULTS: Both classifications were collapsed into 6 categories as benign, adenocarcinoma in situ, and mucinous, endometrioid, rare, and adenosquamous-miscellaneous carcinomas. WHO 2014 had an additional category: endocervical adenocarcinoma, usual type. Inter-observer κ values were more reliable than the intra-OR results based on 95% CIs. The average inter-OR κ values with both classifications were moderate between the 6 pathologists and between the 3 anatomical pathologists. In contrast, they were substantial between the 3 gynecological pathologists. With both classifications, the average intra-OR κ values of the 6 pathologists and both pathologist groups trended toward substantial. CONCLUSIONS: Reproducibility among 6 pathologists is unaffected by changes in the WHO 2014 classification and averages moderate between different and trends toward substantial between the same pathologist. Reproducibility between different pathologists can improve to substantial when they have expertise in gynecological pathology.

Further insights into long-term trends in relative survival of vulvar cancer patients: a population-based study.

OBJECTIVE: The main objective of this article was to investigate the trends in relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States during the periods of 2004 to 2011 and to examine how these trends are associated with the stage of tumor at diagnosis. METHODS: We identified patients with primary invasive squamous cell vulvar cancer and recorded tumor stage in the Surveillance, Epidemiology, and End Results cancer registry database. Women younger than 40 years were excluded because of small number of patients in this age group. A flexible parametric model was used to estimate 1- and 2-year relative survival ratios and excess mortality rate. RESULTS: In total, 4647 women were identified with invasive squamous cell vulvar cancer and known tumor stage in the data set. One- and two-year relative survival ratios increased over time for women with tumors staged I to III but it decreased for women with tumor staged IV. The excess mortality rate was much larger for stage IV compared to the other stages. CONCLUSIONS: Trends in relative survival ratio for invasive vulvar cancer patients have opposite directions depending on the stage of tumor. The mechanism of such behavior is not fully known and yet to be examined in future studies. However, this finding highlights the importance of early detection of preinvasive and early stage disease.

Ease and comfort of cervical and vaginal sampling for Chlamydia trachomatis and Trichomonas vaginalis with a new Aptima specimen collection and transportation kit.

Use of a new collection kit for vaginal and cervical sampling was reported as easy by the majority of 692 women and not uncomfortable (by 87.4% of those ≥ 25 years old and 78.8% of those <25 years old). By Aptima testing, patient- and physician-collected samples agreed strongly for Chlamydia trachomatis (99.6% to 99.3%; κ = 0.93 to 0.89) and T. vaginalis (99.6% to 98.9%; κ = 0.97 to 0.78).

Evaluation of a new APTIMA specimen collection and transportation kit for high-risk human papillomavirus E6/E7 messenger RNA in cervical and vaginal samples.

BACKGROUND: An APTIMA specimen collection and transportation (SCT) kit was developed by Hologic/Gen-Probe. OBJECTIVES: To compare cervical SCT samples to PreservCyt and SurePath samples and self-collected vaginal samples to physician-collected vaginal and cervical SCT samples. To determine ease and comfort of self-collection with the kit. STUDY DESIGN: Each woman (n = 580) self-collected a vaginal SCT, then filled out a questionnaire (n = 563) to determine ease and comfort of self-collection. Colposcopy physicians collected a vaginal SCT and cervical PreservCyt, SCT, and SurePath samples. Samples were tested by APTIMA HPV (AHPV) assay. RESULTS: Agreement between testing of cervical SCT and PreservCyt was 91.1% (κ = 0.82), and that of SurePath samples was 86.7% (κ = 0.72). Agreement of self-collected vaginal SCT to physician-collected SCT was 84.7% (κ = 0.68), and that of self-collected vaginal to cervical SCT was 82.0% (κ = 0.63). For 30 patients with CIN2+, AHPV testing of cervical SCT was 100% sensitive and 59.8% specific compared with PreservCyt (96.6% and 66.2%) and SurePath (93.3% and 70.9%). Vaginal SCT sensitivity was 86.7% for self-collection and 80.0% for physician collection. Most patients found that vaginal self-collection was easy, 5.3% reported some difficulty, and 87.6% expressed no discomfort. CONCLUSIONS: Cervical samples collected with the new SCT kit compared well to traditional liquid-based samples tested by AHPV. Although there was good agreement between self-collected and physician-collected samples with the SCT, in a limited number of 30 women, vaginal sampling identified fewer with CIN2+ precancerous cervical lesions than cervical SCT sampling. Comfort, ease of use, and detection of high-risk HPV demonstrated that the kit could be used for cervical and vaginal sampling.

Trends in incidence and survival of women with invasive vulvar cancer in the United States and Canada: a population-based study.

AIM: The aim of this study is to estimate trends in incidence and relative survival in women diagnosed with invasive squamous cell vulvar cancer in the United States (U.S.) and Canada over the periods of 1973-2010 for U.S. and 1992-2008 for Canada. METHODS: We identified patients with primary invasive squamous cell vulvar cancers in the Surveillance, Epidemiology, and End Results cancer registry database and the Canadian Cancer Registry dataset. Women younger than 40 years were excluded because of the small number of patients in this age group. A flexible parametric model was used to estimate two- and five-year relative survival ratios and excess mortality rate. RESULTS: In total 15,041 patients diagnosed with invasive squamous cell vulvar cancer were included in this analysis. The incidence rate of vulvar cancer increased in both U.S. and Canada. Two- and five-year relative survival ratios decreased over time for both countries, particularly for patients 80 years and over. CONCLUSIONS: The incidence rate of invasive vulvar cancer continued to increase in U.S. and Canada while its two- and five-year relative survival ratios gradually decreased for all age groups over the last few decades. Also, excess mortality rate reaches to its peak after about 6 months from diagnosis and then starts to decline. This is the first report that examine relative survival ratio for vulvar cancer in Canada and U.S. and serves as a basis for future similar studies.

Do deeper sections increase the frequency of detection of serous tubal intraepithelial carcinoma (STIC) in the "sectioning and extensively examining the FIMbriated end" (SEE-FIM) protocol?

Studies have suggested serous tubal intraepithelial carcinoma (STIC) of the fallopian tube to be a putative precursor to ovarian and peritoneal serous carcinoma. It has been recommended that resected fallopian tube specimens should be rigorously examined for STIC, especially in women at high risk of serous carcinoma, such as those with BRCA mutations or with a strong family history. The SEE-FIM protocol allows for the greatest surface area of the tube to be histologically assessed. There have been suggestions that multiple deeper sections should be examined if the initial hematoxylin and eosin (H&E) sections are negative; however, whether this identifies more cases of STIC has not rigorously examined. We examined deeper sections from 56 cases of pelvic carcinoma in which the initial H&E sections of the fallopian tubes were negative for STIC. All initial and deeper sections underwent consensus review by panel of experts in gynecologic pathology. These cases are part of a larger study in which we had examined 300 consecutive bilateral salpingectomies using the SEE-FIM protocol and a single-H&E section per block and had identified 68 cases of pelvic serous carcinoma, of which 12 were associated with STIC. We calculated the sensitivity of a single-H&E section to detect STIC, as compared with examination of multiple deeper sections, and reevaluated the clinicopathologic data of the parent study in light of the additional cases of STIC. In the 56 cases initially negative for STIC, 4 cases of STIC were identified after examination of multiple deeper sections of the fallopian tubes. The single-H&E section SEE-FIM approach therefore detected only 75% (95% confidence interval, 51%-90%) of STIC that was present. Three of these new cases were associated with primary ovarian serous carcinoma and 1 with primary peritoneal serous carcinoma. All 3 new cases associated with ovarian carcinoma were noted in women without neoadjuvant chemotherapy. In considering the data from the parent study, we calculated a statistically significant lower incidence of STIC in women with ovarian serous carcinoma who received neoadjuvant chemotherapy as compared with those who did not (P=0.042). Our study demonstrated that additional cases of STIC can be detected if deeper sections are examined. These additional cases also highlighted a statistically significant difference in the incidence of STIC associated with ovarian serous carcinoma who received neoadjuvant chemotherapy relative to those who did not. Consideration to this should be given in future studies of the prevalence of STIC and to routine examination of salpingectomy specimens from women at high risk for pelvic serous carcinoma.

Characterization of androgenetic/biparental mosaic/chimeric conceptions, including those with a molar component: morphology, p57 immnohistochemistry, molecular genotyping, and risk of persistent gestational trophoblastic disease.

Recent studies have demonstrated the value of ancillary techniques, including p57 immunohistochemistry and short tandem repeat genotyping, for distinguishing hydatidiform moles (HM) from nonmolar specimens and for subtyping HMs as complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM). With rare exceptions, CHMs are p57-negative and androgenetic diploid; partial hydatidiform moles are p57-positive and diandric triploid; and nonmolar specimens are p57-positive and biparental diploid. Androgenetic/biparental mosaic/chimeric conceptions can have morphologic features that overlap with HMs but are genetically distinct. This study characterizes 11 androgenetic/biparental mosaic/chimeric conceptions identified in a series of 473 products of conception specimens subjected to p57 immunohistochemistry and short tandem repeat genotyping. Fluorescence in situ hybridization was performed on 10 to assess ploidy. All cases were characterized by hydropically enlarged, variably sized and shaped villi. In 5 cases, the villi lacked trophoblastic hyperplasia, whereas in 6 there was a focal to extensive villous component with trophoblastic hyperplasia and features of CHM. The villi lacking trophoblastic hyperplasia were characterized by discordant p57 expression within individual villi (p57-positive cytotrophoblast and p57-negative stromal cells), whereas the villous components having trophoblastic hyperplasia were uniformly p57-negative in both cell types. Short tandem repeat genotyping of at least 2 villous areas in each case demonstrated an excess of paternal alleles in all regions, with variable paternal:maternal allele ratios (usually >2:1); pure androgenetic diploidy was identified in those cases with a sufficiently sized villous component having trophoblastic hyperplasia and features of CHM. Fluorescence in situ hybridization demonstrated uniform diploidy in 7 cases, including 4 of 5 tested cases with trophoblastic hyperplasia and 3 of 5 cases without trophoblastic hyperplasia. Two cases without trophoblastic hyperplasia had uniformly diploid villous stromal cells but 1 had triploid and 1 had tetraploid cytotrophoblast; 1 case with trophoblastic hyperplasia had uniformly diploid villous stromal cells but a mixture of diploid, triploid, and tetraploid cytotrophoblast. In 3 cases with a CHM component, persistent gestational trophoblastic disease developed. These results indicate that androgenetic/biparental mosaic/chimeric conceptions are most often an admixture of androgenetic diploid (p57-negative) and biparental diploid (p57-positive) cell lines but some have localized hyperdiploid components. Recognition of their distinctive p57 expression patterns and genotyping results can prevent misclassification as typical CHMs, PHMs, or nonmolar specimens. The presence of androgenetic cell lines, particularly in those with a purely androgenetic CHM component, warrants follow-up because of some risk of persistent gestational trophoblastic disease.

Intraoperative pathology consultation: error, cause and impact.

BACKGROUND: Correlation of intraoperative frozen section diagnosis with final diagnosis can be an important component of an institution's quality assurance process. METHODS: We performed a quality assurance review of 1207 frozen section diagnoses from 812 surgical cases performed in the Hamilton Regional Laboratory Medicine Programme during a 6-month period in 2007. We reviewed the frozen section and permanent slides from all potentially discordant cases using a multiheaded microscope to arrive at a consensus pertaining to the type and reason for error. We reviewed the clinical record to determine whether there had been a potential adverse impact on immediate clinical management. RESULTS: Frozen sections were most commonly requested for head and neck, nervous system and female genital tract specimens. Twenty-eight frozen sections (3%) were deferred. We identified 24 discordant diagnoses involving 3% of cases and 2% of specimens. The organ systems showing the greatest frequency of discordance relative to the total number from that system were the nervous system, head and neck, and the lungs. Of the errors identified, most occurred owing to diagnostic misinterpretation, followed by problems related to tissue sampling. There was a potential adverse impact on immediate clinical management in 14 cases. CONCLUSION: Our results add to the Canadian data on the correlation between frozen sections and permanent sections; we note comparability to the concordance rates reported in the literature.

CONTEXTE: La corrélation entre le diagnostic fondé sur une analyse peropératoire des coupes congelées et le diagnostic final pourrait être un élément important du processus d'assurance qualité dans les établissements de santé. MÉTHODES: À des fins d'examen de l'assurance qualité, le Programme régional de médecine de laboratoire d'Hamilton a procédé à une revue de 1207 diagnostics fondés sur l'analyse de coupes congelées prélevées lors de 812 interventions chirurgicales au cours d'une période de 6 mois en 2007. Nous avons analysé les coupes congelées et les spécimens fixés pour tous les cas potentiellement discordants à l'aide d'un microscope multitête, dans la recherche d'un consensus quant au type d'erreur et à la raison de celle-ci. Nous avons passé en revue les dossiers cliniques pour mesurer, le cas échéant, un quelconque impact négatif sur la prise en charge clinique immédiate. RÉSULTANTS: Les coupes congelées ont le plus souvent été demandées pour des spécimens de tissu de la tête et du cou, du système nerveux et des voies génitales féminines. Vingt-huit coupes congelées (3 %) ont été écartées. Nous avons relevé 24 diagnostics discordants concernant 3 % des cas et 2 % des spécimens. Les systèmes et organes pour lesquels la fréquence de la discordance a été la plus élevée par rapport au nombre total de spécimens du même type, ont été le système nerveux, la tête et le cou et les poumons. Parmi les erreurs relevées, la plupart ont été attribuables à une mauvaise interprétation diagnostique, suivie de problèmes relatifs au prélèvement tissulaire. Dans 14 cas, l'erreur a pu exercer un impact négatif sur la prise en charge clinique immédiate. CONCLUSIONS: Nos résultats viennent étayer les données canadiennes sur la corrélation entre les coupes congelées et les lames adhérentes; nous notons que nos taux de concordance sont comparables à ceux qui sont cités dans la littérature.

Five-year trends in mortality indices among gynecological cancer patients in Canada.

OBJECTIVE: To estimate and compare the five-year trends in excess mortality rate, net probability of death, and crude probability of death for patients diagnosed with epithelial invasive gynecological cancers in Canada. We compared these trends among ovarian, uterine, and cervical cancers. METHODS: A flexible parametric model was used to estimate the three mortality indices for gynecological cancers. We incorporated age group, type of cancer, and year of diagnosis in the model to estimate these indices over a five-year period after diagnosis. RESULTS: In total, 39,681 women who were diagnosed with epithelial invasive gynecological cancers were included in this analysis with a mean age of 57.9 (SD=15.1) years at diagnosis. Approximately 30% of patients were younger than 50 years old at diagnosis and 45% were between 50 and 69 years old. Ovarian cancer had the worst prognosis among the gynecological cancers based on all three mortality indices. CONCLUSIONS: The three mortality indices provide a clear insight in understanding the elements of mortality in population-based cancer studies where the underlying cause of death is not correctly identified, the accuracy of death certificates varies overtime and among countries, and death tends to be a multi-factorial event.

Frequency of serous tubal intraepithelial carcinoma in various gynecologic malignancies: a study of 300 consecutive cases.

Serous tubal intraepithelial carcinoma (STIC) has been implicated in the pathogenesis of pelvic serous carcinoma. We hypothesized that, if this is the case, the frequency of STIC should be substantially lower in endometrial serous carcinomas, in nonserous gynecologic malignancies, and in benign gynecologic neoplasms than in ovarian or peritoneal serous carcinomas. From 2007 to 2009 the fallopian tubes of 342 consecutive gynecologic cases were entirely submitted for histology using the Sectioning and Extensively Examining the FIMbriated end protocol. This study included 300 of these cases (277 TAH-BSO, 23 BSO) after exclusion. The hematoxylin and eosin-stained slides from the fallopian tubes were independently reviewed by 2 gynecologic pathologists who were blinded to all other findings; disagreements were resolved by a third pathologist. Among 46 cases of ovarian malignancies, STIC was identified in 6 (18.8%) of 32 cases of serous carcinoma, but not in any other subtype. Similarly, STIC coexisted in 4 (14.3%) of 28 cases of endometrial serous carcinoma; however, no STIC was identified in any of the 74 cases of nonserous endometrial malignancies. STIC was identified in 2 (28.6%) of 7 cases of peritoneal serous carcinoma. No STIC was identified among 15 nongynecologic malignancies, 90 cases of benign conditions, and 27 cases of other conditions including 4 cases of cervical adenocarcinoma in situ and high-grade cervical intraepithelial lesions, 8 cases of endometrial atypical complex hyperplasias, and 15 cases of ovarian borderline tumors. In conclusion, the fallopian tube may be the origin of some pelvic serous carcinomas. Other possibilities that may explain the origin of pelvic high-grade serous carcinoma are discussed. Given that STIC coexisted with 14% of endometrial serous carcinomas, a more unifying theory may be that gynecologic serous carcinomas and STIC are multifocal lesions.