Lynch Syndrome Screening of Women with Endometrial Cancer: Feasibility and Outcomes in a Community Program.

OBJECTIVE: Universal screening of endometrial cancer for underlying Lynch syndrome (LS) using DNA mismatch repair immunohistochemistry (MMR IHC) has been recommended. The objective of this study was to assess the feasibility and outcomes of using office endometrial samplings in a community LS screening program. METHODS: A community laboratory adopted Cancer Care Ontario's LS screening recommendations. All new endometrial cancers in women aged <70 years were screened for LS using MMR IHC and MLH1 promoter methylation testing cascade for MLH1/PMS2-deficient cases. This retrospective validation study analyzes the first year's results. RESULTS: Of 693 new endometrial cancers, 467 (67.4%) were eligible for LS screening. Both MMR IHC and MLH1 promoter methylation testing were conclusive in >98% of cases. MMR deficiency (MMRd), which includes LS screen-positive cases, was identified in 25.9% of patients (121/467). LS screen-positive tumours comprised 5.9% (27/467) of all cases. CONCLUSION: Endometrial samplings from community practice are suitable for pre-operative LS screening. This testing can identify MMRd endometrial cancers with significant prognostic implications. Approximately 1 in 20 Ontario women <70 years of age with endometrial cancer screen positive for LS. Pre-operative and/or operative assessment for co-existent colonic neoplasms needs to be considered in this high-risk group. In addition, these women should be referred to genetic counselling.

Assessment of Adult Women With Ovarian Masses and Treatment of Epithelial Ovarian Cancer: ASCO Resource-Stratified Guideline.

PURPOSE: To provide expert guidance to clinicians and policymakers in three resource-constrained settings on diagnosis and staging of adult women with ovarian masses and treatment of patients with epithelial ovarian (including fallopian tube and primary peritoneal) cancer. METHODS: A multidisciplinary, multinational ASCO Expert Panel reviewed existing guidelines, conducted a modified ADAPTE process, and conducted a formal consensus process with additional experts. RESULTS: Existing sets of guidelines from eight guideline developers were found and reviewed for resource-constrained settings; adapted recommendations from nine guidelines form the evidence base, informing two rounds of formal consensus; and all recommendations received ≥ 75% agreement. RECOMMENDATIONS: Evaluation of adult symptomatic women in all settings includes symptom assessment, family history, and ultrasound and cancer antigen 125 serum tumor marker levels where feasible. In limited and enhanced settings, additional imaging may be requested. Diagnosis, staging, and/or treatment involves surgery. Presurgical workup of every suspected ovarian cancer requires a metastatic workup. Only trained clinicians with logistical support should perform surgical staging; treatment requires histologic confirmation; surgical goal is staging disease and performing complete cytoreduction to no gross residual disease. In first-line therapy, platinum-based chemotherapy is recommended; in advanced stages, patients may receive neoadjuvant chemotherapy. After neoadjuvant chemotherapy, all patients should be evaluated for interval debulking surgery. Targeted therapy is not recommended in basic or limited settings. Specialized interventions are resource-dependent, for example, laparoscopy, fertility-sparing surgery, genetic testing, and targeted therapy. Multidisciplinary cancer care and palliative care should be offered.Additional information can be found at www.asco.org/resource-stratified-guidelines. It is ASCO's view that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

Androgenetic/Biparental Mosaic/Chimeric Conceptions With a Molar Component: A Diagnostic and Clinical Challenge.

Hydatidiform moles (HM) are gestational trophoblastic diseases which arise due to an imbalance in genetic material and which are morphologically characterized by enlarged and irregular chorionic villi and trophoblastic hyperplasia, among other features. The morphologic differential diagnosis for HM encompasses a number of entities including androgenetic/biparental mosaic/chimeric (ABMC) conceptions, an interesting duo of lesions with a nonmolar form (placental mesenchymal dysplasia) and a molar form (typically with a complete HM component). ABMC conceptions contain a mixture of 2 cell populations (1 androgenetic and 1 biparental) and arise as a result of mosaicism (mitotic error in a zygote) or chimerism (fusion of 2 zygotes). Because of their unique molecular underpinnings, these rare lesions show a number of findings including the presence of multiple villous populations, discordant p57 immunostaining, and mixed genotypes. ABMC conceptions are important to accurately diagnose as the molar form in particular carries a risk for persistent gestational trophoblastic diseases and thus requires appropriate treatment and follow-up. In this report, we provide detailed characterizations of 2 such cases of ABMC conceptions with a molar component. Both patients (ages 34 and 31) were in the first trimester of pregnancy and had ultrasound findings concerning for HM. Increased comprehension of the pathogenesis and morphology of ABMC conceptions, combined with ancillary techniques including p57 immunohistochemistry, fluorescence in situ hybridization, and molar genotyping, has allowed us to accurately and efficiently identify these lesions. However, a number of pitfalls exist which may lead to misdiagnosis.

Comparing endometrial receptivity array to histologic dating of the endometrium in women with a history of implantation failure.

For patients with recurrent implantation failure in IVF, histologic or transcriptomic testing of the endometrium during the mid-secretory phase is often considered. Histological dating of endometrial biopsies (Noyes criteria) can determine if endometrial morphology is consistent with the period of receptivity. Alternatively, endometrial tissue can be sent for a commercial Endometrial Receptivity Array (ERA) test which characterizes the gene expression of the endometrium using a panel of 238 genes that have been implicated in endometrial receptivity. This study aimed to compare the two tests to assess their concordance and to examine the ability of the ERA to successfully predict implantation and pregnancy in a subsequent personalized embryo transfer. A retrospective review was done of 97 patients with a history of implantation failure who underwent an ERA, 35 of whom had histologic dating on the same sample. ERA and histology were classified as 'concordant' when samples were receptive by both tests or non-receptive by both tests. The ERA result was then used to personalize the embryo transfer day, and pregnancy rates from the first subsequent frozen transfer cycle were analyzed. The results indicated that there is poor concordance between ERA and histological dating with only 40.0% agreement and a kappa (95%CI) = -0.18 (-0.50, 0.14). According to the ERA, 48.5% of biopsies were receptive, 47.4% were non-receptive and 2.01% were insufficient tissue for analysis. The clinical pregnancy rate in patients shown to be receptive by ERA was 26.7% and non-receptive was 22.5% following the subsequent personalized ET (p = 0.66). This study concludes that there is a high degree of discordance between histological dating of the endometrium and molecular analysis by ERA. There was no evidence of clinical benefit when embryo transfer was personalized according to ERA in patients with a history of implantation failure.

Synovial Sarcoma of the Female Genital Tract: A Protean Mimic of Müllerian Neoplasia.

Synovial sarcoma most commonly occurs in the extremities but has rarely been described in the female genital tract. In this series, we describe the clinical, morphologic, immunohistochemical, and molecular features of 7 cases of vulvovaginal synovial sarcoma (vulva, n=6; vagina, n=1). We emphasize their wide morphologic spectrum, which can overlap significantly with other more common tumors at these sites, as highlighted by 2 cases initially diagnosed as other entities (endometrioid carcinoma and malignant peripheral nerve sheath tumor). The average patient age was 41 (range: 23 to 62) years and tumor size ranged from 0.8 to 7 cm. Histologically, the tumors were biphasic (n=6) and monophasic (n=1). All cases were confirmed with fluorescence in situ hybridization or sequencing, and 5/5 cases were positive for the novel immunohistochemical markers SSX and SS18-SSX. In 3 cases with follow-up, 2 patients died of disease and 1 was alive with no evidence of disease. Previously described cases arising in the female genital tract are also reviewed. Vulvovaginal monophasic synovial sarcoma raises a broad differential diagnosis, including smooth muscle tumors, spindled carcinomas, and melanoma. Biphasic synovial sarcoma may mimic Müllerian carcinosarcoma, endometrioid carcinoma with spindled, corded, and hyalinized elements, and mesonephric-like adenocarcinoma. Awareness that synovial sarcoma can occur in the female genital tract with a wide variety of histologic appearances is critical for correctly diagnosing this rare entity. In particular, synovial sarcoma should be considered for any deeply situated "adenocarcinoma" in the vulva, with attention to subtle spindle cell differentiation.

Does Ki-67 Have a Role in the Diagnosis of Placental Molar Disease?

The use of p57 immunohistochemistry (IHC) can distinguish complete mole (CM) from partial mole (PM) and nonmolar abortus (NMA). Molecular genotyping (MG) is the gold standard method for the definitive diagnosis of PM and NMA. However, MG is expensive and not always available. Some data suggest Ki-67 IHC may be helpful in distinguishing NMAs from PMs and could be a substitute for MG. In this study, we examined the utility of p57 and Ki-67 IHC stains in the diagnosis of placental molar disease. The study cohort consisted of 60 cases of products of conception (20 CMs, 20 PMs, and 20 NMAs). All CM cases showed absent (<10%) p57 IHC in chorionic villi. All PM and NMA cases had been subjected to MG and showed diandric triploid or biparental inheritance, respectively. Ki-67 and p57 IHC staining was done on formalin-fixed paraffin-embedded sections from all 60 cases. Both IHC stains were interpreted blinded to the diagnosis. On rereview, we recorded the percentage of cells with nuclear p57 staining in villous cytotrophoblast and stromal cells. Ki-67 proliferative index (%) was determined by manual count of at least 500 villous cytotrophoblastic cells in areas with highest Ki-67 reactivity. Any intensity of nuclear staining was considered positive. The utility of p57 IHC is mainly to exclude or confirm CM. Although there is a significantly higher Ki-67 expression in CMs in comparison to PMs and NMAs, this did not add diagnostic utility. PMs tend to have higher Ki-67 expression than NMAs; however, the difference is not statistically significant. Our data suggest that the use of p57 and Ki-67 IHC cannot reliably distinguish PM from NMAs.

Guideline No. 390-Classification and Management of Endometrial Hyperplasia.

OBJECTIVE: The aim of this guideline is to aid primary care physicians and gynaecologists in the initial evaluation of women with suspected endometrial hyperplasia, to recommend the use of the 2014 World Health Organization classification for endometrial hyperplasia by all health care providers, and to guide the optimal treatment of women diagnosed with endometrial hyperplasia. INTENDED USERS: Physicians, including gynaecologists, obstetricians, family physicians, general surgeons, emergency medicine specialists; nurses, including registered nurses and nurse practitioners; medical trainees, including medical students, residents, and fellows; and all other health care providers. TARGET POPULATION: Adult women (18 years and older) presenting with suspected or confirmed endometrial hyperplasia. OPTIONS: The discussion relates to the medical therapy as well as surgical treatment options for women with and without atypical endometrial hyperplasia. EVIDENCE: For this guideline, relevant studies were searched in PubMed, Cochrane Wiley, and the Cochrane Systematic Reviews using the following terms, either alone or in combination, with the search limited to English language materials, human subjects, and published since 2000: (endometrial hyperplasia, endometrial intraepithelial neoplasia, endometrial sampling, endometrial curettage, diagnosis) AND (treatment, progestin therapy, surgery, LNG-IUS, aromatase inhibitors, metformin ), AND (obesity). The search was performed in April 2018. Relevant evidence was selected for inclusion in the following order: meta-analyses, systematic reviews, guidelines, randomized controlled trials, prospective cohort studies, observational studies, non-systematic reviews, case series, and reports. Additional significant articles were identified through cross-referencing the identified reviews. The total number of studies identified was 2152, and 82 studies were included in this review. VALIDATION METHODS: The content and recommendations were drafted and agreed upon by the authors. The Executive and Board of the Society of Gynecologic Oncology of Canada reviewed the content and submitted comments for consideration, and the Board of the Society of Obstetricians and Gynaecologists of Canada approved the final draft for publication. The quality of evidence was rated using the criteria described in the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology framework. The interpretation of strong and weak recommendations was also included. The Summary of Findings is available upon request. BENEFITS, HARMS, AND/OR COSTS: It is expected that this guideline will benefit women with endometrial hyperplasia. This should guide patient informed consent before both medical and surgical management of this condition. GUIDELINE UPDATE: Evidence will be reviewed 5 years after publication to decide whether all or part of the guideline should be updated. However, if important new evidence is published prior to the 5-year cycle, the review process may be accelerated for a more rapid update of some recommendations. SUMMARY STATEMENTS: RECOMMENDATIONS.

Trends in the US and Canadian Pathologist Workforces From 2007 to 2017.

Importance: The current state of the US pathologist workforce is uncertain, with deficits forecast over the next 2 decades. Objective: To examine the trends in the US pathology workforce from 2007 to 2017. Design, Setting, and Participants: A cross-sectional study was conducted comparing the number of US and Canadian physicians from 2007 to 2017 with a focus on pathologists, radiologists, and anesthesiologists. For the United States, the number of physicians was examined at the state population level with a focus on pathologists. New cancer diagnoses per pathologist were compared between the United States and Canada. These data from the American Association of Medical Colleges Center for Workforce Studies' Physician Specialty Data Books and the Canadian Medical Association Masterfile were analyzed from January 4, 2019, through March 26, 2019. Main Outcomes and Measures: Numbers of pathologists were compared with overall physician numbers as well as numbers of radiologists and anesthesiologists in the United States and Canada. Results: Between 2007 and 2017, the number of active pathologists in the United States decreased from 15 568 to 12 839 (-17.53%). In contrast, Canadian data showed an increase from 1467 to 1767 pathologists during the same period (+20.45%). When adjusted for each country's population, the number of pathologists per 100 000 population showed a decline from 5.16 to 3.94 in the United States and an increase from 4.46 to 4.81 in Canada. As a percentage of total US physicians, pathologists have decreased from 2.03% in 2007 to 1.43% in 2017. The distribution of US pathologists varied widely by state; per 100 000 population, Idaho had the fewest (1.37) and the District of Columbia had the most (15.71). When adjusted by new cancer cases per year, the diagnostic workload per US pathologist has risen by 41.73%; during the same period, the Canadian diagnostic workload increased by 7.06%. Conclusions and Relevance: The US pathologist workforce decreased in both absolute and population-adjusted numbers from 2007 to 2017. The current trends suggest a shortage of US pathologists.

BRCA1 Mutation Status and Follicular Fluid Exposure Alters NFκB Signaling and ISGylation in Human Fallopian Tube Epithelial Cells.

Germline BRCA1 or BRCA2 mutations (mtBRCA1 and mtBRCA2) increase risk for high-grade serous ovarian cancer (HGSOC), the most commonly diagnosed epithelial ovarian cancer histotype. Other identified risk factors for this cancer, which originates primarily in the distal fallopian tube epithelium (FTE), implicate ovulation, during which the FTE cells become transiently exposed to follicular fluid (FF). To test whether mtBRCA1 or mtBRCA2 nonmalignant FTE cells respond differently to periovulatory FF exposure than control patient FTE cells, gene expression profiles from primary FTE cultures derived from BRCA1 or BRCA2 mutation carriers or control patients were compared at baseline, 24 hours after FF exposure, and 24 hours after FF replacement with culture medium. Hierarchical clustering revealed both FF exposure and BRCA mutation status affect gene expression, with BRCA1 mutation having the greatest impact. Gene set enrichment analysis revealed increased NFκB and EGFR signaling at baseline in mtBRCA1 samples, with increased interferon target gene expression, including members of the ISGylation pathway, observed after recovery from FF exposure. Gene set enrichment analysis did not identify altered pathway signaling in mtBRCA2 samples. An inverse relationship between EGFR signaling and ISGylation with BRCA1 protein levels was verified in an immortalized FTE cell line, OE-E6/E7, stably transfected with BRCA1 cDNA. Suppression of ISG15 and ISGylated protein levels by increased BRCA1 expression was found to be mediated by decreased NFκB signaling. These studies indicate that increased NFκB signaling associated with decreased BRCA1 expression results in increased ISG15 and protein ISGylation following FF exposure, which may be involved in predisposition to HGSOC.

Case Report: Use of Tumor and Germline Y Chromosomal Analysis to Guide Surgical Management in a 46, XX Female Presenting With Gonadoblastoma With Dysgerminoma.

Gonadoblastomas are rare mixed gonadal tumors that are almost always found in individuals with 46, XY karyotype or some other form of Y chromosome mosaicism. It is extremely rare to diagnose gonadoblastoma in phenotypically normal 46, XX females. Herein, we present a 20-year-old 46, XX female diagnosed with gonadoblastoma and dysgerminoma. Use of cytogenetic and molecular analyses to identify the presence of Y chromosome material in peripheral blood, gonadal, and tumor tissue can exclude mosaicism to provide reassurance to undertake conservative surgical management and preserve fertility.

DNA Genotyping of Suspected Partial Hydatidiform Moles Detects Clinically Significant Aneuploidy.

The diagnosis of partial hydatidiform mole (PM) is especially difficult early in gestation as the morphology of nonmolar abortus (NMA) may mimic PM. Molecular genotyping analysis can definitively identify diandric triploidy, the genetic basis for PM, whereas NMA cases show a biparental inheritance. This 4-year retrospective study sought to determine what proportion of NMA cases which were initially suspected as being PM was aneuploid, and whether this knowledge of aneuploidy status is clinically useful. Cases with atypical villous morphology on histopathology suggestive of PM were subjected to molecular genotyping. The genotyping testing panel contained 19 highly polymorphic short-tandem repeat markers on chromosomes 13, 18, 21, X, and Y and 2 nonpolymorphic markers for sex determination. Informative molecular genotyping analysis was available in 127 cases (56 PMs and 71 NMAs). Aneuploidy was detected in 15/71 of NMAs (21.1%): 7 cases of trisomy 18, 3 of trisomy 13, 1 of trisomy 21, and 4 of monosomy X. It is concluded that most cases of aneuploid NMAs (11/15) detected by molecular genotyping analysis of atypical villous morphology cases are sporadic in type with a low or age-related recurrence risk. Nevertheless, this information may be useful in subsequent counseling and in women undergoing in vitro fertilization by directing preimplantation genetic diagnosis in subsequent cycles. In about a quarter of aneuploid NMAs (4/15) specific aneuploidy types which may be caused by unbalanced familial chromosome rearrangement are identified and are clinically important to patient management. Detection of clinically relevant aneuploidy in NMAs represents an important secondary benefit to the adoption of molecular genotyping analysis in suspected PM.

A Reappraisal of the Incidence of Placental Hydatidiform Mole Using Selective Molecular Genotyping.

OBJECTIVE: Reports on the incidence of hydatidiform mole (HM) have varied depending on study population and methodology. This institutional-based study was undertaken to identify the incidence of HM in a modern obstetric practice using advanced laboratory diagnostic techniques. METHODS: A retrospective review of consecutive hospital cases of HM was conducted for a 27-month period. Pathologic diagnoses of partial mole (PM) and complete mole (CM) were based on histopathologic assessment and selective use of p57 immunohistochemistry and molecular genotyping (MG) using formalin-fixed paraffin-embedded tissues. RESULTS: During the study period, 14,944 obstetric deliveries took place at our institution. Forty-nine cases of HM (18 CMs, 31 PMs) were identified. Histopathology with the selective use of p57 immunohistochemistry was used in 25 of 49 HMs (18 CMs, 7 PMs). Histopathologic features were equivocal in the remaining cases (24/49 cases), and adjunctive MG was performed; all were PMs. The incidence of HM was 3.3/1000 deliveries. Partial mole was more prevalent with a CM (PM ratio, 1:1.72). CONCLUSIONS: Our observed incidence of HM is greater than previous studies and is attributable to improved detection of PM cases. Molecular genotyping and cytogenetic evidence indicate that CM is almost half as common as PM. This ratio may be useful in benchmarking laboratory diagnosis and HM registries.

Human Papillomavirus-Related Ovarian Metastasis With Endocervical Adenocarcinoma: Report of 2 Cases and Review of Literature.

BACKGROUND: Most endocervical adenocarcinomas are associated with human papillomavirus (HPV) infection. Studies suggest that synchronous endocervical and ovarian tumors can contain identical HPV subtypes and that, in this setting, the ovarian tumors likely represent metastases from the endocervical adenocarcinoma rather than 2 independent primaries. However, there are still relatively few reports in the literature. RESULTS: We describe 2 patients with HPV-related endocervical adenocarcinoma or adenocarcinoma in situ who had metastatic ovarian tumors that simulated primary ovarian neoplasms. After total hysterectomy and bilateral salpingo-oophorectomy, patient 1, in her mid-40s, was diagnosed with endocervical adenocarcinoma in situ and patient 2, in her early 50s, was diagnosed with endocervical adenocarcinoma showing early focal stromal invasion. The ovarian tumors in both cases simulated independent borderline mucinous tumors without evidence of surface involvement or spread beyond the ovary. However, in both cases, the cervical and ovarian tumors showed diffuse, strong P16 staining and contained identical high-risk HPV subtypes (subtypes 16 and 18 in patient 1 and subtype 16 in patient 2). Patient 1 was treated with radiation therapy and remains recurrence free 5 years after diagnosis, and patient 2 has recently completed combined modality treatment with radiation therapy and cisplatin chemotherapy and remains recurrence free 10 months after diagnosis. CONCLUSIONS: A high index of suspicion and ancillary testing, including P16 immunostaining and molecular genetic testing for HPV, is required to properly diagnose and subclassify HPV-related endocervical adenocarcinoma metastatic to the ovary.

Placental Molar Disease: What are the Benefits and Barriers to the Adoption of a Comprehensive Diagnostic Service?

The molecular cytogenetic analysis of specimens (genotyping) suspicious for hydatidiform mole (HM) significantly improves diagnostic accuracy over histopathology and immunohistochemical analysis alone, particularly in the classification of partial mole. However, the implementation of this advance in diagnostics has been slow. This study sought to identify the major benefit and potential barriers to the adoption of genotyping. A pilot Placental Molar Diagnostic (PMD) Service was established combining histopathology, p57 immunohistochemistry, and molecular genotyping analysis for both in-house and referred-in cases suspicious for HM or with a preliminary diagnosis of HM. A retrospective analysis of 117 cases received in the first 16 mo was conducted to identify the utility of the PMD Service and factors or barriers which precluded optimal results. A final diagnosis of HM was made in 73 cases (37 complete HMs and 36 partial HMs). The remaining 44 cases were hydropic abortuses. Three potential barriers were identified that could lead to less than optimal results from a PMD Service: prevalence of noninformative genotyping, lack of any available or appropriate paraffin blocks, and inappropriate deferral of genotyping. The major utility of this pilot PMD Service was to increase the specificity of a diagnosis of HM, and avoid unnecessary clinical follow-up in 37% of cases with an initial suspicion or diagnosis of HM. Measures can be undertaken to address potential barriers to the implementation of a comprehensive placental diagnostic platform. Underutilization of molecular genotyping in the diagnosis of HM likely leads to inappropriate management and "downstream" costs in a significant proportion of patients suspected of having HM.

S100A7 overexpression is a predictive marker for high risk of malignant transformation in oral dysplasia.

Early detection of oral lesions (OLs) at high risk of cancer development is of utmost importance for intervention. There is an urgent unmet clinical need for biomarkers that allow identification of high-risk OLs. Recently, we identified and verified a panel of five candidate protein biomarkers namely S100A7, prothymosin alpha, 14-3-3ζ, 14-3-3σ and heterogeneous nuclear ribonucleoprotein K using proteomics to distinguish OLs with dysplasia and oral cancers from normal oral tissues. The objective of our study was to evaluate the potential of these candidate protein biomarkers for identification of oral dysplastic lesions at high risk of cancer development. Using immunohistochemistry, we analyzed expressions of these five candidate protein biomarkers in 110 patients with biopsy-proven oral dysplasia and known clinical outcome and determined their correlations with p16 expression and HPV 16/18 status. Kaplan-Meier survival analysis showed reduced oral cancer-free survival (OCFS) of 68.6 months (p = 0.007) in patients showing cytoplasmic S100A7 overexpression when compared to patients with weak or no S100A7 immunostaining in cytoplasm (mean OCFS = 122.8 months). Multivariate Cox regression analysis revealed cytoplasmic S100A7 overexpression as the most significant candidate marker associated with cancer development in dysplastic lesions (p = 0.041, hazard ratio = 2.36). In conclusion, our study suggested the potential of S100A7 overexpression in identifying OLs with dysplasia at high risk of cancer development.