Temporal changes in mammographic breast density and breast cancer risk among women with benign breast disease.

INTRODUCTION: Benign breast disease (BBD) and high mammographic breast density (MBD) are prevalent and independent risk factors for invasive breast cancer. It has been suggested that temporal changes in MBD may impact future invasive breast cancer risk, but this has not been studied among women with BBD. METHODS: We undertook a nested case-control study within a cohort of 15,395 women with BBD in Kaiser Permanente Northwest (KPNW; 1970-2012, followed through mid-2015). Cases (n = 261) developed invasive breast cancer > 1 year after BBD diagnosis, whereas controls (n = 249) did not have breast cancer by the case diagnosis date. Cases and controls were individually matched on BBD diagnosis age and plan membership duration. Standardized %MBD change (per 2 years), categorized as stable/any increase (≥ 0%), minimal decrease of less than 5% or a decrease greater than or equal to 5%, was determined from baseline and follow-up mammograms. Associations between MBD change and breast cancer risk were examined using adjusted unconditional logistic regression. RESULTS: Overall, 64.5% (n = 329) of BBD patients had non-proliferative and 35.5% (n = 181) had proliferative disease with/without atypia. Women with an MBD decrease (≤ - 5%) were less likely to develop breast cancer (Odds Ratio (OR) 0.64; 95% Confidence Interval (CI) 0.38, 1.07) compared with women with minimal decreases. Associations were stronger among women ≥ 50 years at BBD diagnosis (OR 0.48; 95% CI 0.25, 0.92) and with proliferative BBD (OR 0.32; 95% CI 0.11, 0.99). DISCUSSION: Assessment of temporal MBD changes may inform risk monitoring among women with BBD, and strategies to actively reduce MBD may help decrease future breast cancer risk.

Host, reproductive, and lifestyle factors in relation to quantitative histologic metrics of the normal breast.

BACKGROUND: Emerging data indicate that variations in quantitative epithelial and stromal tissue composition and their relative abundance in benign breast biopsies independently impact risk of future invasive breast cancer. To gain further insights into breast cancer etiopathogenesis, we investigated associations between epidemiological factors and quantitative tissue composition metrics of the normal breast. METHODS: The study participants were 4108 healthy women ages 18-75 years who voluntarily donated breast tissue to the US-based Susan G. Komen Tissue Bank (KTB; 2008-2019). Using high-accuracy machine learning algorithms, we quantified the percentage of epithelial, stromal, adipose, and fibroglandular tissue, as well as the proportion of fibroglandular tissue that is epithelium relative to stroma (i.e., epithelium-to-stroma proportion, ESP) on digitized hematoxylin and eosin (H&E)-stained normal breast biopsy specimens. Data on epidemiological factors were obtained from participants using a detailed questionnaire administered at the time of tissue donation. Associations between epidemiological factors and square root transformed tissue metrics were investigated using multivariable linear regression models. RESULTS: With increasing age, the amount of stromal, epithelial, and fibroglandular tissue declined and adipose tissue increased, while that of ESP demonstrated a bimodal pattern. Several epidemiological factors were associated with individual tissue composition metrics, impacting ESP as a result. Compared with premenopausal women, postmenopausal women had lower ESP [ß (95% Confidence Interval (CI)) = -0.28 (- 0.43, - 0.13); P < 0.001] with ESP peaks at 30-40 years and 60-70 years among pre- and postmenopausal women, respectively. Pregnancy [ß (95%CI) vs nulligravid = 0.19 (0.08, 0.30); P < 0.001] and increasing number of live births (P-trend < 0.001) were positively associated with ESP, while breastfeeding was inversely associated with ESP [ß (95%CI) vs no breastfeeding = -0.15 (- 0.29, - 0.01); P = 0.036]. A positive family history of breast cancer (FHBC) [ß (95%CI) vs no FHBC = 0.14 (0.02-0.26); P = 0.02], being overweight or obese [ß (95%CI) vs normal weight = 0.18 (0.06-0.30); P = 0.004 and 0.32 (0.21-0.44); P < 0.001, respectively], and Black race [ß (95%CI) vs White = 0.12 (- 0.005, 0.25); P = 0.06] were positively associated with ESP. CONCLUSION: Our findings revealed that cumulative exposure to etiological factors over the lifespan impacts normal breast tissue composition metrics, individually or jointly, to alter their dynamic equilibrium, with potential implications for breast cancer susceptibility and tumor etiologic heterogeneity.

Intraluminal tumor cells and prognostic accuracy of endometrial cancer stage criteria: A multi-institution study.

OBJECTIVE: Endometrial cancer stage is a strong prognostic factor; however, the current stage classification does not incorporate transtubal spread as determined by intraluminal tumor cells (ILTCs). We examined relationships between ILTCs and survival outcomes according to histological subtype and stage and examined whether identification of ILTCs improves prognostic accuracy of endometrial cancer staging. METHODS: We conducted a retrospective cohort study of women diagnosed with endometrial cancer at five academic hospitals between 2007 and 2012. Pathologists determined ILTC presence (no vs. yes) and location (free in lumen vs. attached to epithelial surface) based on pathology review of hematoxylin and eosin-stained sections of fallopian tubes. Associations between ILTCs with time to recurrence (TTR) and overall survival (OS) were examined with Cox proportional hazards models adjusted for other prognostic factors. Model discrimination metrics were used to assess the addition of ILTCs to stage for prediction of 5-year TTR and OS. RESULTS: In the overall study population (N = 1303), ILTCs were not independently associated with TTR (HR = 0.95, 95% CI = 0.69-1.32) or OS (HR = 0.97, 95% CI = 0.72-1.31). Among 805 women with stage I disease, ILTCs were independently associated with worse TTR (HR = 2.31, 95% CI = 1.06-5.05) and OS (HR = 2.16, 95% CI = 1.14-4.11). Upstaging early-stage cases with ILTCs present did not increase model discrimination. CONCLUSION: While our data do not suggest that endometrial cancer staging guidelines should be revised to include ILTCs, associations between ILTCs and reduced survival observed among stage I cases suggest this tumor feature holds clinical relevance for subgroups of endometrial cancer patients.

Associations Between Intraluminal Tumor Cell Involvement in Serially Examined Fallopian Tubes and Endometrial Carcinoma Characteristics and Outcomes.

Approximately 12% of routinely examined fallopian tubes of endometrial carcinoma (EC) cases have intraluminal tumor cells (ILTCs). ILTC associations with EC characteristics and outcomes are understudied, and unknown in serially examined and embedded tubal fimbriae. Glass slides of serially examined and embedded tubal fimbriae for 371 EC cases were independently reviewed by 2 pathologists who recorded ILTC presence and characterized them as mucosal if involved and floating if not. Disagreements were reviewed by a third pathologist, and agreement between any 2 determined final ILTC status. Clinico-pathologic associations and ILTC presence were tested for significance ( P <0.05) by univariable analysis, and stage and histotype determinants were included in a multivariable analysis. The Kaplan-Meier estimates and log-rank tests compared overall and EC-specific survival, and Cox proportional regression estimated hazard ratios. ILTCs were present in 56 (15.1%) cases: 30 mucosal and 26 floating. FIGO stage 3/4, lymph-vascular space invasion, deep myometrial invasion, nonendometrioid histotype, and adjunctive chemotherapy were significantly associated with ILTC presence, and only stage was significant in the multivariable analysis. Overall, 61 women died: 30 of whom died of EC. ILTCs were nonsignificantly associated with higher overall and EC-specific mortality and mucosal ILTCs had the highest hazard ratios (1.64 and 1.89, respectively). Serially examined and embedded tubal fimbriae have a higher prevalence of ILTCs than routinely examined tubes, and high FIGO stage is an independent determinant. A prognostic effect was not found, but the higher trending hazard ratios suggest additional study is needed to determine whether ILTCs and in particular mucosal ILTCs adversely affect prognosis.

Dataset for the Reporting of Carcinoma of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

Cervical carcinoma remains one of the most common cancers affecting women worldwide, despite effective screening programs being implemented in many countries for several decades. The International Collaboration on Cancer Reporting (ICCR) dataset for cervical carcinoma was first developed in 2017 with the aim of developing evidence-based standardized, consistent and comprehensive surgical pathology reports for resection specimens. This 4th edition update to the ICCR dataset on cervical cancer was undertaken to incorporate major changes based upon the updated International Federation of Obstetricians and Gynecologists (FIGO) staging for carcinoma of the cervix published in 2018 and the 5th Edition World Health Organization (WHO) Classification of Female Genital Tumors published in 2020 and other significant developments in pathologic aspects of cervical cancer. This updated dataset was developed by a panel of expert gynecological pathologists and an expert gynecological oncologist, with a period of open consultation. The revised dataset includes "core" and "noncore" elements to be reported; these are accompanied by detailed explanatory notes and references providing the rationale for the updates. Standardized reporting using datasets such as this helps facilitate consistency and accuracy, data collection across different sites and comparison of epidemiological and pathologic parameters for quality and research purposes.

Risk factors for breast cancer development by tumor characteristics among women with benign breast disease.

BACKGROUND: Among women diagnosed with invasive breast cancer, 30% have a prior diagnosis of benign breast disease (BBD). Thus, it is important to identify factors among BBD patients that elevate invasive cancer risk. In the general population, risk factors differ in their associations by clinical pathologic features; however, whether women with BBD show etiologic heterogeneity in the types of breast cancers they develop remains unknown. METHODS: Using a nested case-control study of BBD and breast cancer risk conducted in a community healthcare plan (Kaiser Permanente Northwest), we assessed relationships of histologic features in BBD biopsies and patient characteristics with subsequent breast cancer risk and tested for heterogeneity of associations by estrogen receptor (ER) status, tumor grade, and size. The study included 514 invasive breast cancer cases (median follow-up of 9 years post-BBD diagnosis) and 514 matched controls, diagnosed with proliferative or non-proliferative BBD between 1971 and 2006, with follow-up through mid-2015. Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using multivariable polytomous logistic regression models. RESULTS: Breast cancers were predominantly ER-positive (86%), well or moderately differentiated (73%), small (74% < 20 mm), and stage I/II (91%). Compared to patients with non-proliferative BBD, proliferative BBD with atypia conferred increased risk for ER-positive cancer (OR = 5.48, 95% CI = 2.14-14.01) with only one ER-negative case, P-heterogeneity = 0.45. The presence of columnar cell lesions (CCLs) at BBD diagnosis was associated with a 1.5-fold increase in the risk of both ER-positive and ER-negative tumors, with a 2-fold increase (95% CI = 1.21-3.58) observed among postmenopausal women (56%), independent of proliferative BBD status with and without atypia. We did not identify statistically significant differences in risk factor associations by tumor grade or size. CONCLUSION: Most tumors that developed after a BBD diagnosis in this cohort were highly treatable low-stage ER-positive tumors. CCL in BBD biopsies may be associated with moderately increased risk, independent of BBD histology, and irrespective of ER status.

Loss of ARID1B and SMARCB1 expression are specific for the diagnosis of dedifferentiated/undifferentiated carcinoma in tumours of the upper gynaecological tract and cervix.

AIMS: Genomic inactivation of ARID1B in ARID1A-inactivated tumour and genomic inactivation of SMARCB1 represent two recurrent mechanisms, core SWItch/sucrose non-fermentable (SWI/SNF) complex inactivation, that are associated with de-differentiation in endometrial carcinoma. Approximately one-third of dedifferentiated/undifferentiated endometrial carcinomas (DDEC/UEC) show loss of ARID1B expression with a minor subset showing loss of SMARCB1 expression, but little is known regarding the specificity of ARID1B or SMARCB1 loss in gynaecological tract tumours in general. The aim of this study was to examine the frequency of ARID1B and SMARCB1 loss by immunohistochemistry in a series of gynaecological tract epithelial/mesenchymal neoplasms. METHODS AND RESULTS: We evaluated 1849 tumours that included 748 endometrial carcinomas, 101 uterine carcinosarcomas/adenosarcomas, 64 uterine sarcomas, 221 cervical carcinomas and 715 ovarian carcinomas/borderline tumours by tissue microarrays (TMA). We observed ARID1B loss in 35 of 86 (41%) and SMARCB1 loss in three of 86 (3%) DDEC/UEC, but not in any other uterine tumour types examined. ARID1B-deficient DDEC/UEC also showed concurrent loss of ARID1A expression. All SMARCB1-deficient tumours showed loss of MLH1 and PMS2, while 29 of 35 ARID1B-deficient tumours showed loss of MLH1 and PMS2 or loss of MSH6. All ovarian carcinomas/borderline tumours and cervical carcinomas showed intact expression of ARID1B and SMARCB1. CONCLUSION: Our findings indicate that the loss of expression of ARID1B or SMARCB1 by immunohistochemistry is highly specific for undifferentiated carcinoma among tumours of the upper gynaecological tract and cervix, and therefore can be used to identify these highly aggressive malignant tumours.

Reproductive factors and risk of breast cancer by tumor subtypes among Ghanaian women: A population-based case-control study.

Higher proportions of early-onset and estrogen receptor (ER) negative cancers are observed in women of African ancestry than in women of European ancestry. Differences in risk factor distributions and associations by age at diagnosis and ER status may explain this disparity. We analyzed data from 1,126 cases (aged 18-74 years) with invasive breast cancer and 2,106 controls recruited from a population-based case-control study in Ghana. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for menstrual and reproductive factors using polytomous logistic regression models adjusted for potential confounders. Among controls, medians for age at menarche, parity, age at first birth, and breastfeeding/pregnancy were 15 years, 4 births, 20 years and 18 months, respectively. For women ≥50 years, parity and extended breastfeeding were associated with decreased risks: >5 births vs. nulliparous, OR 0.40 (95% CI 0.20-0.83) and 0.71 (95% CI 0.51-0.98) for ≥19 vs. <13 breastfeeding months/pregnancy, which did not differ by ER. In contrast, for earlier onset cases (<50 years) parity was associated with increased risk for ER-negative tumors (p-heterogeneity by ER = 0.02), which was offset by extended breastfeeding. Similar associations were observed by intrinsic-like subtypes. Less consistent relationships were observed with ages at menarche and first birth. Reproductive risk factor distributions are different from European populations but exhibited etiologic heterogeneity by age at diagnosis and ER status similar to other populations. Differences in reproductive patterns and subtype heterogeneity are consistent with racial disparities in subtype distributions.

Universal Testing to Identify Lynch Syndrome Among Women With Newly Diagnosed Endometrial Carcinoma.

BACKGROUND: Lynch syndrome (LS) is an autosomal dominant cancer syndrome caused by a germline mutation in the mismatch repair (MMR) genes. Protocols based on immunohistochemical expression of MMR proteins in cancer are used to identify patients with LS. METHODS: The universal LS screening protocol of the Tom Baker Cancer Centre (Calgary, AB) of all patients diagnosed between April 1, 2013 and April 1, 2015 with endometrioid carcinoma of the endometrium was audited through a retrospective chart review. LS status and frequency of protocol compliance at each of the key steps were calculated (Canadian Task Force Classification II-2). RESULTS: The cohort consisted of 375 patients. MMR immunohistochemical testing was requested for 321 (85.6%). Expression of at least one protein was lost in 86 (26.8%). Twenty-one (6.5%) patients were eligible for genetic counselling because PMS2, MSH2, or MSH6 protein expression was lost in 19, and two patients had a family history of LS. Eleven (91.7%) of 12 (57.1%) who attended had germline testing, and six (54.5%) showed a mutation diagnostic of LS. LS status among the cohort of 375 patients was positive in six (1.6%), negative in 294 (78.4%), and unknown in 75 (20%) because of protocol non-compliance. LS was confirmed in six (2%) of the 321 women who completed the protocol. CONCLUSION: This is the first audit of a Canadian-based universal LS screening protocol of patients with endometrial cancer. The success of the protocol is endorsed by the 80% compliance and by the 2% prevalence of LS, which is within the published range.

Pathologic Prognostic Factors in Endometrial Carcinoma (Other Than Tumor Type and Grade).

Although endometrial carcinoma (EC) is generally considered to have a good prognosis, over 20% of women with EC die of their disease, with a projected increase in both incidence and mortality over the next few decades. The aim of accurate prognostication is to ensure that patients receive optimal treatment and are neither overtreated nor undertreated, thereby improving patient outcomes overall. Patients with EC can be categorized into prognostic risk groups based on clinicopathologic findings. Other than tumor type and grade, groupings and recommended management algorithms may take into account age, body mass index, stage, and presence of lymphovascular space invasion. The molecular classification of EC that has emerged from the Cancer Genome Atlas (TCGA) study provides additional, potentially superior, prognostic information to traditional histologic typing and grading. This classifier does not, however, replace clinicopathologic risk assessment based on parameters other than histotype and grade. It is envisaged that molecular and clinicopathologic prognostic grouping systems will work better together than either alone. Thus, while tumor typing and grading may be superseded by a classification based on underlying genomic abnormalities, accurate assessment of other pathologic parameters will continue to be key to patient management. These include those factors related to staging, such as depth of myometrial invasion, cervical, vaginal, serosal surface, adnexal and parametrial invasion, and those independent of stage such as lymphovascular space invasion. Other prognostic parameters will also be discussed. These recommendations were developed from the International Society of Gynecological Pathologists Endometrial Carcinoma project.

FIGO Stage Is the Strongest Prognostic Factor in Adenocarcinoma of the Uterine Cervix.

OBJECTIVE: This study aimed to identify clinical and pathological determinants of invasive adenocarcinoma of the uterine cervix (AC) in a large, single-centre series serving a population of 1.5 million. METHODS: Data on clinical (n = 27) and pathological (n = 23) variables for 166 women with a diagnosis of AC treated between 2000 and 2013 were extracted from their charts and pathology reports. Overall survival (OS) was calculated, and significant determinants were identified using Kaplan-Meier analyses and log-rank tests, respectively (Canadian Task Force Classification II-2). RESULTS: This was a heterogeneous group of women with all stages of disease treated with conization, surgery, radiation, and systemic chemotherapy, alone or in combination. Mean age at diagnosis was 43; 86.7% had stage I disease, 9.6% had stage II, and only 3.6% had stage III and IV disease. Mean follow-up was 108 months. Many histotypes were diagnosed and grouped as mucinous (n = 103), endometrioid (n = 15), rare (n = 9), and adenosquamous (n = 39) types. Twenty-eight women had recurrent cancer and died of the disease; OS at 5 years was 85%. Five-year OS for women with stage I was 92%, compared with 40% for stage II or higher. Univariate analysis revealed that premenopausal status, tumour size, first-line treatment with chemotherapy, lymphovascular invasion, rare histological subtypes, stage, and receipt of second-line treatment were all significantly associated with a lower OS. Using multivariate analysis, only stage remained an independent factor. CONCLUSION: This is the largest single-centre Canadian series of invasive AC. Stage is the strongest prognostic factor in multivariate analysis; in contrast to other studies, lymph node status was not a significant determinant.

Post-colposcopy Management of ASC-US and LSIL Pap Tests (PALS Trial): Pilot RCT.

OBJECTIVE: Evidence supporting optimal follow-up of women with atypical squamous cells of undetermined significance (ASC-US) or low-grade squamous intraepithelial lesion cytology found to have low-grade disease or normal findings at initial colposcopy is weak. Surveillance options include continued colposcopy, discharge with Pap testing, or HPV testing at 12 months. This study was a pilot RCT comparing these three follow-up policies. The objectives were to determine the feasibility of an RCT and to compare the incidence of greater than or equal to high-grade squamous intraepithelial lesion (≥HSIL) in each of the follow-up policies. METHODS: A total of 133 women referred with ASC-US or low-grade squamous intraepithelial lesion cytology between June and August 2012 underwent initial colposcopy where incident ≥HSIL histology was ruled out. Of these women, 125 were randomly assigned to colposcopic surveillance, Pap testing, or HPV testing. Patients with high-risk results at any point were treated according to standard of care. Patient recruitment and adherence to follow-up were calculated using descriptive statistics. Accuracy of the three follow-up arms was calculated (Canadian Task Force Classification: IC). RESULTS: Recruitment rates were 80%, and adherence to protocol was 85% to 100%. Nine of 125 (7.2%) patients overall were found to have ≥HSIL histology at exit: one of 43 in the reference colposcopy group, and six of 41 and three of 41 in Pap and HPV arms, respectively. One early cancer was detected in the HPV arm. Sensitivity and specificity (CI) for each arm, respectively, were as follows: colposcopy N/A, 100% (88.1%-100%); Pap, 100% (47.8%-100%) and 85.7% (63.7%-97%); and HPV, 66.7% (9.4%-99.2%) and 68% (46.5%-85.1%). CONCLUSION: This pilot study demonstrated the operational and safety feasibility of an RCT in this patient population. Validation of clinical findings is necessary.

The Impact of Gynaecological Tumour Board Rounds on Patient Care.

OBJECTIVE: The goal of this study was to determine the impact of tumour board rounds (TBRs) on the additional management of patients with gynaecologic malignancy. METHODS: A retrospective chart review of 1604 patients discussed between January 2011 and December 2013 at gynaecologic TBRs was conducted to determine the frequency and type of diagnostic discrepancies found post-TBRs and their potential impact on additional patient management. A discrepancy was defined as major if it affected patient management by cancelling, initiating, or modifying treatment; otherwise, the discrepancy was minor. Data collected included patients' demographics, pre- and post-TBR diagnoses, and management. RESULTS: The patients' mean age was 57.6 ± 14.1. Endometrial disease accounted for (43%) of the TBRs. The remaining sites were ovarian (25%), cervical (23%), and others (9%). Overall, 13.2% (n = 212) had a discrepancy; 3.4% (n = 54) of these discrepancies were major, and 9.9% (n = 158) were minor. Most major discrepancies related to changes in the tumours' primary site or stage, and most minor discrepancies were related to changes in tumour histotype. Among the 54 (25.5%) major discrepancies, 18 (33.3%) occurred in patients who had their additional management cancelled, 17 (31.5%) required chemotherapy, 4 (7.4%) required a change in the chemotherapy regimen, 10 (18.5%) required additional surgery, and 5 (9.3%) required chemoradiation. CONCLUSION: The 13% frequency of discrepancies, approximately 26% of which were major and resulted in changes in patient management, highlights the importance of TBRs as a quality tool.

Processing of fallopian tube, ovary, and endometrial surgical pathology specimens: A survey of U.S. laboratory practices.

OBJECTIVE: Many high-grade serous carcinomas initiate in fallopian tubes as serous tubal intraepithelial carcinoma (STIC), a microscopic lesion identified with specimen processing according to the Sectioning and Extensive Examination of the Fimbria protocol (SEE-Fim). Given that the tubal origin of these cancers was recently recognized, we conducted a survey of pathology practices to assess processing protocols that are applied to gynecologic surgical pathology specimens in clinical contexts in which finding STIC might have different implications. METHODS: We distributed a survey electronically to the American Society for Clinical Pathology list-serve to determine practice patterns and compared results between practice types by chi-square (χ2) tests for categorical variables. Free text comments were qualitatively reviewed. RESULTS: Survey responses were received from 159 laboratories (72 academic, 87 non-academic), which reported diverse specimen volumes and percentage of gynecologic samples. Overall, 74.1% of laboratories reported performing SEE-Fim for risk-reducing surgical specimens (82.5% academic versus 65.7% non-academic, p < 0.05). In specimens from surgery for benign indications in which initial microscopic sections showed an unanticipated suspicious finding, 75.9% of laboratories reported using SEE-Fim to process the remainder of the specimen (94.8% academic versus 76.4% non-academic, p < 0.01), and 84.6% submitted the entire fimbriae. CONCLUSIONS: Changes in the theories of pathogenesis of high-grade serous carcinoma have led to implementation of pathology specimen processing protocols that include detailed analysis of the fallopian tubes. These results have implications for interpreting trends in cancer incidence data and considering the feasibility of developing a bank of gynecologic tissues containing STIC or early cancer precursors.

Tissue-based Immunohistochemical Biomarker Expression in Malignant Glandular Lesions of the Uterine Cervix: A Systematic Review.

Literature published between 1975 and 2015 was systematically reviewed to conduct a case-comparator study of tissue based, immunohistochemical biomarker expression among malignant glandular histotypes of the uterine cervix so as to identify differences that could have diagnostic utility. Of the 902 abstracts, 154 articles had a full review, and 52 were included. Biomarker positivity in cases of adenocarcinoma in situ (AIS) were compared with atypical lobular endocervical glandular hyperplasia and invasive histotypes grouped as mucinous, endometrioid, adenosquamous, serous clear cell, minimal deviation-gastric type, and mesonephric carcinomas (7 AIS case-comparators). The invasive histotypes were compared with each other (30 adenocarcinoma case-comparators). Biomarker positivity in all 37 case-comparators was calculated as weighted averages of histotype-specific estimates. Unsupervised hierarchical clustering examined differences in expression and were visualized via heatmaps and dendrograms. Of the 56 biomarkers tested, 1 or more of 15 showed a 50% or more difference in positive expression in 6 (86%) of the AIS and 21 (70%) of the adenocarcinoma case-comparators. There was no data on the comparison of serous clear cell to mesonephric carcinoma. AIS case-comparator biomarkers were HIK1083, alpha SMA, PAX8, VIL1, CEA, p53, p16, and CD10, and only alpha SMA had a difference of 100%. The adenocarcinoma case-comparator biomarkers were CEA, p53, Claudin18, HIK1083, p16, Calretinin, CD10, PR, Chromogranin, MUC6, Vimentin and p63, and none had a difference of 100%. Biomarker expression in the discrimination of AIS from invasive adenocarcinoma, and the invasive histotypes from each other is understudied. One or more of 15 biomarkers could have diagnostic utility.

Data Set for the Reporting of Carcinomas of the Cervix: Recommendations From the International Collaboration on Cancer Reporting (ICCR).

A comprehensive pathologic report is essential for optimal patient management, cancer staging and prognostication. In many countries, proforma reports are used but the content of these is variable. The International Collaboration on Cancer Reporting is an alliance formed by the Royal Colleges of Pathologists of Australasia and the United Kingdom, the College of American Pathologists, the Canadian Partnership Against Cancer and the European Society of Pathology, for the purpose of developing standardized, evidence-based reporting data sets for each cancer site. This will reduce the global burden of cancer data set development and reduplication of effort by different international institutions that commission, publish and maintain standardized cancer-reporting data sets. The resultant standardization of cancer-reporting benefits not only those countries directly involved in the collaboration but also others not in a position to develop their own data sets. We describe the development of an evidence-based cancer data set by the International Collaboration on Cancer Reporting expert panel for the reporting of primary cervical carcinomas and present the "required" and "recommended" elements to be included in the pathology report as well as an explanatory commentary. This data set encompasses the International Federation of Obstetricians and Gynaecologists and Union for International Cancer Control staging systems for cervical neoplasms and the updated World Health Organization classification of gynecologic tumors. The data set also addresses controversial issues such as tumor grading and measurement, including measurement of multifocal carcinomas. The widespread implementation of this data set will facilitate consistent and accurate data collection, comparison of epidemiological and pathologic parameters between different populations, facilitate research, and hopefully result in improved patient management.

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.

Approaches for triaging women who test positive for human papillomavirus in cervical cancer screening.

Substantial evidence exists to support the introduction of molecular testing for human papillomavirus (HPV) as the primary technology in cervical cancer screening. While HPV testing is much more sensitive than cytology for detection of high-grade precancerous lesions, it is less specific. To improve efficiency, it is therefore recommended that a specific test (like cytology) be used in triaging HPV positive women to colposcopy. A number of studies have been conducted that support the use of cytology alone or in conjunction with HPV genotyping for triage. The decision to incorporate genotyping also depends on the commercial HPV test that is selected since not all tests provide results for certain individual high-risk types. Regardless of whether policy officials decide to adopt a triage approach that incorporates genotyping, the use of liquid based cytology (LBC) may also improve screening performance by reducing diagnostic delays. With LBC, the same cell suspension from a single collection may be used for HPV testing and a smear can be immediately prepared if HPV status is positive. This was a critical lesson from a community based demonstration project in Montreal (VASCAR study), where conventional cytology exists and specimen co-collection was not permitted for ethical reasons, requiring HPV positive women to return for an additional screening visit prior to colposcopy.

Introduction of molecular HPV testing as the primary technology in cervical cancer screening: Acting on evidence to change the current paradigm.

Since being introduced in the 1940s, cervical cytology - despite its limitations - has had unequivocal success in reducing cervical cancer burden in many countries. However, we now know that infection with human papillomavirus (HPV) is a necessary cause of cervical cancer and there is overwhelming evidence from large-scale clinical trials, feasibility studies and real-world experience that supports the introduction of molecular testing for HPV as the primary technology in cervical cancer screening (i.e., "HPV primary screening"). While questions remain about the most appropriate age groups for screening, screening interval and triage approach, these should not be considered barriers to implementation. Many countries are in various stages of adopting HPV primary screening, whereas others have not taken any major steps towards introduction of this approach. As a group of clinical experts and researchers in cervical cancer prevention from across Canada, we have jointly authored this comprehensive examination of the evidence to implement HPV primary screening. Our intention is to create a common understanding among policy makers, agencies, clinicians, researchers and other stakeholders about the evidence concerning HPV primary screening to catalyze the adoption of this improved approach to cervical cancer prevention. With the first cohort of vaccinated girls now turning 21, the age when routine screening typically begins, there is increased urgency to introduce HPV primary screening, whose performance may be less adversely affected compared with cervical cytology as a consequence of reduced lesion prevalence post-vaccination.

Tissue-based Immunohistochemical Biomarker Accuracy in the Diagnosis of Malignant Glandular Lesions of the Uterine Cervix: A Systematic Review of the Literature and Meta-Analysis.

Immunohistochemistry is widely used to support a pathology diagnosis of cervical adenocarcinoma despite the absence of a systematic review and meta-analysis of the published data. This systematic review and meta-analysis was performed to investigate the sensitivity and specificity of immunohistochemistry biomarkers in the tissue-based diagnosis of cervical adenocarcinoma histotypes compared with normal endocervix and benign glandular lesions. The systematic review and meta-analysis used a PICOT framework and QUADAS-2 to evaluate the quality of included studies. The literature search spanned 40 years and ended June 30, 2015. Abstracts of identified records were independently screened by 2 of the authors who then conducted a full-text review of selected articles. Sensitivity and specificity of immunohistochemistry expression in malignant glandular lesions of the cervix classified per WHO 2003 compared with 5 benign comparators (normal/benign endocervix, and benign endocervical, endometrioid, gastric, and mesonephric lesions) were calculated. Of 902 abstracts screened, 154 articles were selected for full review. Twenty-five articles with results for 36 biomarkers were included. The only biomarker with enough studies for a meta-analysis was p16 and the definition of positive p16 staining among them was variable. Nevertheless, any positive p16 expression was sensitive, ranging from 0.94 to 0.98 with narrow confidence intervals (CIs), for adenocarcinoma in situ (AIS) and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical and endometrioid lesions. Specificity for AIS and mucinous adenocarcinomas was also high with narrow CIs compared with benign endocervical lesions. The specificity was high for AIS, 0.99 (0.24, 1.0), and mucinous adenocarcinoma, 0.95 (0.52, 1.0), compared with normal/benign endocervix but with wider CIs, and low with very wide CIs compared with benign endometrioid lesions: 0.31 (0.00, 0.99) and 0.34 (0.00, 0.99), respectively. Results from single studies showed that p16, p16/Ki67 dual stain, ProExC, CEA, ESA, HIK1083, Claudin 18, and ER loss in perilesional stromal cells were useful with high (≥0.75) sensitivity and specificity estimates in ≥1 malignant versus benign comparisons. None of the biomarkers had highly useful sensitivity and specificity estimates for AIS, mucinous adenocarcinomas, or minimal deviation adenocarcinoma/gastric adenocarcinoma compared with benign gastric or mesonephric lesions or for mesonephric carcinoma compared with normal/benign endocervix, benign endocervical, endometrial, or mesonephric lesions. Any expression of p16 supports a diagnosis of AIS and mucinous adenocarcinomas in comparison with normal/benign endocervix and benign endocervical lesions. The majority of studies did not separate mosaic/focal p16 staining from diffuse staining as a distinct pattern of p16 overexpression and this may have contributed to the poor performance of p16 in distinguishing AIS and mucinous adenocarcinomas from benign endometrioid lesions. Single studies support further investigation of 8 additional biomarkers that have highly useful sensitivity and specificity estimates for ≥1 malignant glandular lesions compared with ≥1 of the 5 benign comparators.