Multiple Pathologists Research Articles

Association of SARS-CoV-2 placental histopathology findings with maternal–fetal comorbidities and severity of COVID-19 hypoxia

Objective SARS-CoV-2 is known to impact multiple organ systems, with growing data to suggest the potential for placental infection and resultant pathology. Understanding how maternal COVID-19 disease can affect placental histopathology has been limited by small study cohorts with mild disease, review by multiple pathologists, and potential confounding by maternal–fetal comorbidities that can also influence placental findings. This study aims to identify pathologic placental findings associated with COVID-19 disease and severity, as well as to distinguish them from changes related to coexisting maternal–fetal comorbidities. Methods This is an observational study of 61 pregnant women with confirmed SARS-CoV-2 infection who delivered and had a placental histological evaluation at NYU Langone Health between March 19, 2020 and June 30, 2020. Primary outcomes were the prevalence of placental histopathologic features and their association with maternal–fetal comorbidities and severity of COVID-19 related hypoxia. Analysis was performed using Fisher’s exact test and t-test with p < 0.05 considered significant. Results Sixty-one placentas were included in the study cohort, 71% from pregnancies complicated by at least one maternal–fetal comorbidity. Twenty-five percent of placentas were small for gestational age and 77% exhibited at least one feature of maternal vascular malperfusion. None of the histopathologic features in the examined placentas were associated with the presence of any specific maternal–fetal comorbidity. Thirteen percent of the cohort required maternal respiratory support for COVID-19 related hypoxia. Villous trophoblast necrosis was associated with maternal supplemental oxygen requirement (67 vs. 33%, p = 0.04) and intubation (67 vs. 33%, p = 0.01). Conclusion In pregnancies complicated by COVID-19 disease, there was a high prevalence of placental histopathologic changes identified, particularly features of maternal vascular malperfusion, which could not be attributed solely to the presence of maternal–fetal comorbidities. The significantly increased prevalence of villous trophoblast necrosis in women needing respiratory support suggests a connection to the severity of COVID-19 illness.

Attention-Guided deep atrous-residual U-Net architecture for automated gland segmentation in colon histopathology images

In digital pathology, gland segmentation plays a dominant part in the diagnosis and quantification of colon cancer. Thus, this paper presents a clinically relevant deep learning-based automated gland segmentation technique called Attention-Guided deep Atrous-Residual U-Net that aims to seize small and intricate variations in medical images whilst preserving spatial information. It is a modified U-Net architecture that comprises enhanced learning capability as its Atrous-Residual units extract more discriminative and multi-level feature representations while alleviating the diminishing-gradient issue. Its Attention units extract more gland-specific detailed features, perform target refinement, and help in comparable semantic features concatenation. Its Transitional Atrous units incorporate dense multi-scale features and handle resolution degradation problems. Also, various data augmentation and stain normalization techniques are utilized to improve its generalization capability. Extensive experiments are performed using two publicly available datasets (GlaS challenge and CRAG) and a private hospital dataset HosC that helps to build invariance of the proposed architecture towards digital variability present in clinical applications and verifying its robustness. The proposed model achieves competitive results over existing state-of-art techniques having a significant improvement in F1-score (at least 2% for GlaS and 3.7% for CRAG), Object-Dice Index (at least 2.3% for GlaS and 3.5% for CRAG), and Object-Hausdorff Distance (at least 2.89% for GlaS and 3.11% for CRAG). Also, for the private HosC dataset, it achieves an F1-score of 0.947, Object-Dice Index of 0.912, and Object-Hausdorff Distance of 89.78. In addition, the final output results are validated by multiple pathologists in terms of their score i.e., for GlaS (0.9184 for test A and 0.91 for test B), 0.9032 for CRAG, and 0.904 for HosC that verify its clinical relevancy and suitability in the facilitation of the proposed model for gland detection and segmentation applications in clinical practice. It can further aid the pathologists to create a precise diagnosis and plan of treatment.

Characteristics of complete tibial fractures in California racehorses.

Tibial fractures cause ~3% of racehorse deaths. Pre-existing stress fractures have been associated with multiple racing and training fractures, but not complete tibial fractures. To describe racehorse tibial fractures and compare signalment and exercise histories of affected and control racehorses. Retrospective analysis of necropsy reports. Racehorses that had a complete tibial fracture (1990-2018) were retrospectively reviewed. Signalment and exercise histories of affected horses were compared to 1) racehorses that died because of non-tibial musculoskeletal injuries or 2) non-musculoskeletal cause and 3) age, sex, event-matched control racehorses. Tibial fracture prevalence was described relative to California racehorses that had at least one official work or race. Age, sex and limb distributions were compared between affected and control horses (Chi-square, Fisher's Exact test). Exercise history data were reduced to counts and rates of official high speed works, races and layups (periods without an official high speed work or race >60days). Variables were compared among groups using matched logistic regression (P≤.05). Tibial fractures in 115 horses (97% unilateral; 50% left, 47% right) occurred most commonly during training (68%) and in 2- to 3-year-old horses (73%). Fractures were predominantly comminuted (93%), diaphyseal (44%) and oblique (40%). Of 61 cases examined for callus, 64% had periosteal callus associated with fracture, most commonly in proximal (65%) and distal diaphyseal (27%) locations. Of 28 racehorses with known exercise history, 57% never raced and 36% had a layup. Affected horses had fewer official-timed works and events (official high speed works and races), number of active days and accumulated less distance in events and works (P<.05) than control horses. Retrospective review of necropsy reports by multiple pathologists over 28years. Tibial fractures were associated with pre-existing stress fracture early in career. Most fractures were associated with proximolateral stress fractures.

Pathologists should probably forget about kappa. Percent agreement, diagnostic specificity and related metrics provide more clinically applicable measures of interobserver variability

Kappa statistics have been widely used in the pathology literature to compare interobserver diagnostic variability (IOV) among different pathologists but there has been limited discussion about the clinical significance of kappa scores. Five representative and recent pathology papers were queried using clinically relevant specific questions to learn how IOV was evaluated and how the clinical applicability of results was interpreted. The papers supported our anecdotal impression that pathologists usually assess IOV using Cohen's or Fleiss' kappa statistics and interpret the results using some variation of the scale proposed by Landis and Koch. The papers did not cite or propose specific guidelines to comment on the clinical applicability of results. The solutions proposed to decrease IOV included the development of better diagnostic criteria and additional educational efforts, but the possibility that the entities themselves represented a continuum of morphologic findings rather than distinct diagnostic categories was not considered in any of the studies.A dataset from a previous study of IOV reported by Thunnissen et al. was recalculated to estimate percent agreement among 19 international lung pathologists for the diagnosis of 74 challenging lung neuroendocrine neoplasms. Kappa scores and diagnostic sensitivity, specificity, positive and negative predictive values were calculated using the majority consensus diagnosis for each case as the gold reference diagnosis for that case. Diagnostic specificity estimates among multiple pathologists were > 90%, although kappa scores were considerably more variable. We explain why kappa scores are of limited clinical applicability in pathology and propose the use of positive and negative percent agreement and diagnostic specificity against a gold reference diagnosis to evaluate IOV among two and multiple raters, respectively.

Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays for patient selection in triple negative breast cancer.

The US Food and Drug Administration (FDA) approved the PD-L1 immunohistochemical assay, SP142, as a companion test to determine eligibility for atezolizumab therapy in patients with advanced triple negative breast cancer (TNBC) but data in lung cancer studies suggest the assay suffers from poor reproducibility. We sought to evaluate reproducibility and concordance in PD-L1 scoring across multiple pathologists. Full TNBC sections were stained with SP142 and SP263 assays and interpreted for percentage (%) immune cell (IC) staining by 19 pathologists from 14 academic institutions. Proportion of PD-L1 positive cases (defined as ≥1% IC) was determined for each assay as well as concordance across observers. We utilized a new method we call Observers Needed to Evaluate Subjective Tests (ONEST) to determine the minimum number of evaluators needed to estimate concordance between large numbers of readers, as occurs in the real-world setting. PD-L1 was interpreted as positive with the SP142 assay in an average 58% of cases compared with 78% with SP263 (p < 0.0001). IC positive continuous scores ranged from 1 to 95% (mean = 20%) and 1 to 90% (mean = 10%) for SP263 and SP142, respectively. With SP142, 26 cases (38%) showed complete two category (<1% vs. ≥1%) concordance; with SP263, 38 cases (50%) showed complete agreement. The intraclass correlation coefficient (ICC) for two category scoring of SP263 and SP142 was 0.513 and 0.560. ONEST plots showed decreasing overall percent agreement (OPA) as observer number increased, reaching a low plateau of 0.46 at ten observers for SP263 and 0.41 at eight observers for SP142. IC scoring with both assays showed poor reproducibility across multiple pathologists with ONEST analysis suggesting more than half of pathologists will disagree about IC scores. This could lead to many patients either receiving atezolizumab when they are unlikely to benefit, or not receiving atezolizumab when they may benefit.

Abstract PD5-01: Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative breast cancer

Abstract Background: The IMpassion130 study demonstrated prolonged overall survival when atezolizumab, a PD-L1 inhibitor, was added to nab-paclitaxel in PD-L1 positive patients with advanced triple negative breast cancer (TNBC). Approximately 40% of tumors were PD-L1 positive, utilizing a cutoff of ≥ 1% immune cell (IC) staining with the Ventana SP142 immunohistochemical (IHC) assay. The Food and Drug Administration (FDA) approved this assay as a companion test to determine patient eligibility for atezolizumab therapy. However, literature in lung cancer shows that pathologists have a high discordance in assessing PD-L1 on IC. The FDA companion test documentation for SP142 shows high inter-laboratory reproducibility with nearly 95% overall percent agreement (OPA) between 2 readers for 2 category scoring of IC (positive versus negative) in TNBC in a central laboratory. PD-L1 testing for breast cancer is now becoming widespread in pathology laboratories. The goal of this study was to assess concordance in PD-L1 scoring between 19 pathologists from 14 institutions examining the same 86 TNBC tissues stained with the SP142 and SP263 antibodies. We also present a new method to determine the minimum number for evaluators needed to estimate concordance between large numbers of readers as occurs in real life setting. Methods: Full tissue sections were stained exactly as prescribed on the label on the Ventana Benchmark with the SP142 and SP263 PD-L1 assays. Sixty-eight and 76 cases were evaluable respectively. Stained slides were scanned and digital files distributed to pathologists who independently scored cases as either negative (&amp;lt; 1% IC staining) or positive (≥ 1% IC staining) and estimated the % of IC staining for positive cases. We applied a method that we call Observers Needed to Evaluate Subjective Tests (ONEST). For any combination of pathologists, we can quantify the degree of overall agreement using the proportion of tissue samples upon which all selected pathologists agreed, which can lead to a plot of non-increasing trajectory of agreement as the number of pathologists increases. We computed and plotted the empirical estimate of the overall agreement with the 95% confidence interval (CI) from 1000 randomly selected permutations of the pathologists. Results: PD-L1 was interpreted as positive with SP263 in an average of 78% of cases compared to 58% with the SP142 assay (p&amp;lt;.0001). IC positive continuous scores ranged from 1-95% (mean=20%) and 1-90% (mean=10%) for SP263 and SP142. Complete 2 category (positive vs negative) scoring concordance across all observers was achieved in 38 cases (50%) with SP263 and 26 cases (38%) with SP142. The intraclass correlation coefficient (ICC) for 2 category scoring of SP263 and SP142 was 0.513 and 0.560 respectively. ONEST plots made for each assay for 19 pathologists showed a decrease in OPA as number of observers increased, reaching a low plateau of approximately 0.46 at 10 observers for SP263 and 0.42 at 8 observers for SP142. Conclusions: Utilizing the FDA approved SP142 assay, we found a higher prevalence of PD-L1 positive tumors than published in the IMpassion130 trial but lower prevalence than seen with the SP263 assay. The different proportion of positive cases seen with two different assays highlights the need to establish cutoffs for each assay to correspond with clinical benefit. The ICC of scoring immune cells with both PD-L1 assays showed poor reproducibility across multiple pathologists. The ONEST analysis finds a plateau with 10 pathologists, only reaching an OPA of 0.4 for immune cell assessment. This suggests that more than half of the pathologists in real world situations may mis-assign patient IC scores. This could lead to a high percentage of patients either receiving atezolizumab, when they are unlikely to benefit or not receiving atezolizumab when they may benefit. Citation Format: Emily Suzanne Reisenbichler, Gang Han, Vasiliki Pelekanou, Vesal Yaghoobi, Fahad S Ahmed, Andrew Bellizzi, Veerle Bossuyt, Jane Brock, Kimberly Cole, Oluwole Fadare, Omar Hameed, Krisztina Hanley, Beth T Harrison, M G Kuba, Amy Ly, Dylan Miller, Mirna Podoll, Anja C Roden, Mary A Sanders, Kamaljeet Singh, Shi Wei, Hannah Wen, Lajos Pusztai, David L Rimm. Prospective multi-institutional evaluation of pathologist assessment of PD-L1 assays in triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD5-01.

Validation of a geropathology grading system for aging mouse studies.

An understanding of early-onset mechanisms underlying age-related changes can be obtained by evaluating changes that precede frailty and end of life using histological characterization of age-related lesions. Histopathology-based information as a component of aging studies in mice can complement and add context to molecular, cellular, and physiologic data, but there is a lack of information regarding scoring criteria and lesion grading guidelines. This report describes the validation of a grading system, designated as the geropathology grading platform (GGP), which generated a composite lesion score (CLS) for comparison of histological lesion scores in tissues from aging mice. To assess reproducibility of the scoring system, multiple veterinary pathologists independently scored the same slides from the heart, lung, liver, and kidney from two different strains (C57BL/6 and CB6F1) of male mice at 8, 16, 24, and 32months of age. There was moderate to high agreement between pathologists, particularly when agreement within a 1-point range was considered. CLS for all organs was significantly higher in older versus younger mice, suggesting that the GGP was reliable for detecting age-related pathology in mice. The overall results suggest that the GGP guidelines reliably distinguish between younger and older mice and may therefore be accurate in distinguishing between experimental groups of mice with more, or less, age-related pathology.

Deep Semi Supervised Generative Learning for Automated Tumor Proportion Scoring on NSCLC Tissue Needle Biopsies

The level of PD-L1 expression in immunohistochemistry (IHC) assays is a key biomarker for the identification of Non-Small-Cell-Lung-Cancer (NSCLC) patients that may respond to anti PD-1/PD-L1 treatments. The quantification of PD-L1 expression currently includes the visual estimation by a pathologist of the percentage (tumor proportional scoring or TPS) of tumor cells showing PD-L1 staining. Known challenges like differences in positivity estimation around clinically relevant cut-offs and sub-optimal quality of samples makes visual scoring tedious and subjective, yielding a scoring variability between pathologists. In this work, we propose a novel deep learning solution that enables the first automated and objective scoring of PD-L1 expression in late stage NSCLC needle biopsies. To account for the low amount of tissue available in biopsy images and to restrict the amount of manual annotations necessary for training, we explore the use of semi-supervised approaches against standard fully supervised methods. We consolidate the manual annotations used for training as well the visual TPS scores used for quantitative evaluation with multiple pathologists. Concordance measures computed on a set of slides unseen during training provide evidence that our automatic scoring method matches visual scoring on the considered dataset while ensuring repeatability and objectivity.

Hotspot enumeration of CD8+ tumor-infiltrating lymphocytes using digital image analysis in triple-negative breast cancer yields consistent results

Tumor-infiltrating lymphocytes (TILs) have emerged as prognostic in triple-negative breast cancer (TNBC). We aimed to assess the consistency of hotspot placement and TIL enumeration among multiple pathologists. Additionally, we assessed hotspot TIL count consistency by comparing hotspot counts in 3 separate locations within a single whole-tissue section. Anti-CD8 immunohistochemistry was performed on a representative section from 66 cases of primary TNBC, which were then scanned as whole-slide images. Quantification of the tissue area and combined stromal and intratumoral CD8+ TILs was performed using digital image analysis (DIA) within 2.2 mm-diameter circle hotspots. TIL counts were quantified as absolute counts and densities (absolute count/tissue area in micrometers2). For each case, 6 pathologists placed a single hotspot, defined as an area with the subjectively highest CD8+ immunoreactivity, within the tumor bed. Separately for each case, a single pathologist placed hotspots in 3 different locations within a single tumor section. Intraclass correlation coefficients (ICCs) were generated following TIL enumeration via DIA. ICCs for single hotspot placement by 6 pathologists were 0.96 for density and 0.97 for absolute counts, respectively. In 32% of cases (21/66), all the hotspots placed by the 6 pathologists were in the same location. When evaluating hotspots in 3 different locations within a tumor, the ICC was 0.95 for both density and absolute counts. Hotspot evaluation by DIA is a reproducible method for CD8+ TIL quantification, and the use of hotspots may reduce TIL count variation caused by intratumoral TIL heterogeneity.

Abstract 4015: A comparative study of PD-L1 IHC 22C3 and 28-8 FDA-approved diagnostic assays in cancer

Abstract Background: Higher levels of PD-L1 expression at the surface of tumor cells have been associated with increased response to anti-PD-1 therapies (Santabarbara G et al. Ann Transl Med. 2016;4:215; Borghaei H et al. N Engl J Med. 2015;373:1627-1639; Brahmer J et al. N Engl J Med. 2015;373:123-135). The FDA has 2 approved tests associated with the use of these agents. The Dako PD-L1 IHC 22C3 kit is approved as a companion diagnostic for the use of pembrolizumab in the first- and second-line non-small-cell lung cancer (NSCLC) settings, where diagnostic testing is required for its use. The Dako PD-L1 IHC 28-8 kit is approved as a complementary diagnostic for nivolumab therapy in second-line NSCLC, where testing is not required for its use. NeoGenomics Laboratories stained a subset of the samples received for PD-L1 testing with both 22C3 and 28-8 on the same biopsy specimen. This dataset presents an opportunity to explore real-world concordance testing for 22C3 and 28-8 antibodies. Methods: The analysis was performed on a dataset obtained from Symphony Health Solutions describing the PD-L1 biomarker test results and annotations reported by NeoGenomics Laboratories between Oct 7, 2015, and Aug 31, 2016. A total of 5217 biomarker test results were available for 4528 patients afflicted by diverse malignancies. Concordance testing was performed on 556 unique patients that had a single 22C3/28-8 pairing collected from the same biopsy specimen. All staining was performed using the FDA-approved in vitro diagnostic assay using the 22C3 antibody or the 28-8 antibody on the Dako Link 48. Cases were reviewed and scored randomly across multiple pathologists, who received special training and certification in scoring. All statistical analyses were performed in SAS. Results: Paired biopsy specimens stained with both 22C3 and 28-8 displayed high degrees of correlation (Spearman’s correlation co-efficient = 0.97). In addition, Bland-Altman analysis revealed that the mean difference in the percentage of tumor cells positively stained for PD-L1 between the paired 22C3 and 28-8 assay findings was 0.48% [95% prediction limit (-12.41% to 13.37%)]. Across expression levels both antibodies displayed a similar probability of being interpreted as greater than one another (43 of 556 where 28-8&amp;gt;22C3 and 40 of 556 where 22C3&amp;gt;28-8), with no clear direction of a single antibody displaying greater sensitivity. When analyzed at the ≥ 1%, ≥ 5%, ≥ 10%, ≥ 25% and ≥ 50% thresholds, the overall rate of agreement was between 96.8% and 98.2% and associated with a level of agreement (Cohen’s kappa) between 0.92 and 0.96. Conclusion: Both the 22C3 and 28-8 diagnostic assays show strong agreement in a single central laboratory real-world setting. These data, in conjunction with recent findings from analytical comparability studies reported elsewhere, support the potential interchangeability of these assays for diagnostic interpretation. Citation Format: Cory Batenchuk, Maher Albitar, Sucha Sudarsanam, Vladislav Chizhevsky, Chelsea Jin, Virginia A. Burns. A comparative study of PD-L1 IHC 22C3 and 28-8 FDA-approved diagnostic assays in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4015. doi:10.1158/1538-7445.AM2017-4015

Characteristics of a Breast Pathology Consultation Practice.

- Intradepartmental consultation is a routine practice commonly used for new diagnoses. Expert interinstitutional case review provides insight into particularly challenging cases. - To investigate the practice of breast pathology consultation at a large tertiary care center. - We reviewed breast pathology cases sent for private consultation and internal cases reviewed by multiple pathologists at a tertiary center. Requisitions and reports were evaluated for diagnostic reason for consultation, rate of multiple pathologist review at the tertiary center, use of immunohistochemistry, and, for private consultation cases, type of sender and concordance with the outside diagnosis. - In the 985 private consultation cases, the most frequent reasons for review were borderline atypia (292 of 878; 33.3%), papillary lesion classification (151 of 878; 17.2%), evaluating invasion (123 of 878; 14%), subtyping carcinoma (75 of 878; 8.5%), and spindle cell (67 of 878; 7.6%) and fibroepithelial (65 of 878; 7.4%) lesion classification. Of 4981 consecutive internal cases, 358 (7.2%) were reviewed, most frequently for borderline atypia (90 of 358; 25.1%), subtyping carcinoma (63 of 358; 17.6%), staging/prognostic features (59 of 358; 16.5%), fibroepithelial lesion classification (45 of 358; 12.6%), evaluating invasion (37 of 358; 10.3%), and papillary (20 of 358; 5.6%) and spindle cell (18 of 358; 5.0%) lesion classification. Of all internal cases, those with a final diagnosis of atypia had a significantly higher rate of review (58 of 241; 24.1%) than those with benign (119 of 2933; 4.1%) or carcinoma (182 of 1807; 10.1%) diagnoses. Immunohistochemistry aided in diagnosis of 39.7% (391 of 985) and 21.2% (76 of 359) of consultation and internally reviewed cases, respectively. - This study confirms areas of breast pathology that represent diagnostic challenge and supports that pathologists are appropriately using expert consultation.

Deep Learning for Classification of Colorectal Polyps on Whole-slide Images

Context: Histopathological characterization of colorectal polyps is critical for determining the risk of colorectal cancer and future rates of surveillance for patients. However, this characterization is a challenging task and suffers from significant inter- and intra-observer variability. Aims: We built an automatic image analysis method that can accurately classify different types of colorectal polyps on whole-slide images to help pathologists with this characterization and diagnosis. Setting and Design: Our method is based on deep-learning techniques, which rely on numerous levels of abstraction for data representation and have shown state-of-the-art results for various image analysis tasks. Subjects and Methods: Our method covers five common types of polyps (i.e., hyperplastic, sessile serrated, traditional serrated, tubular, and tubulovillous/villous) that are included in the US Multisociety Task Force guidelines for colorectal cancer risk assessment and surveillance. We developed multiple deep-learning approaches by leveraging a dataset of 2074 crop images, which were annotated by multiple domain expert pathologists as reference standards. Statistical Analysis: We evaluated our method on an independent test set of 239 whole-slide images and measured standard machine-learning evaluation metrics of accuracy, precision, recall, and F1 score and their 95% confidence intervals. Results: Our evaluation shows that our method with residual network architecture achieves the best performance for classification of colorectal polyps on whole-slide images (overall accuracy: 93.0%, 95% confidence interval: 89.0%-95.9%). Conclusions: Our method can reduce the cognitive burden on pathologists and improve their efficacy in histopathological characterization ofcolorectal polyps and in subsequent risk assessment and follow-up recommendations.

Asbestos textile production linked to malignant peritoneal and pleural mesothelioma in women: Analysis of 28 cases in Southeast China.

Chrysotile had been used in asbestos textile workshops in Southeast China but a clear relation to mesothelioma is lacking. All patients diagnosed with mesothelioma from 2003 to 2010 at Yuyao People's Hospital were re-evaluated by multiple expert pathologists with immunohistochemistry and asbestos exposure data were collected. Of 43 patients with a mesothelioma diagnosis, 19 peritoneal and nine pleural cases were finally diagnosed as mesothelioma. All were females, and the mean age of the patients with peritoneal or pleural mesothelioma was 52.4 and 58.2 years, respectively. All these cases had a history of domestic or occupational exposure to chrysotile. Two-thirds of the patients were from two adjoining towns with multiple small asbestos textile workshops. Contamination of tremolite was estimated to be less than 0.3%. This is a report of mesothelioma in women exposed to chrysotile asbestos at home and at work, with an over-representation of peritoneal mesothelioma.

PWE-345 Use of “villosity” to select individuals progressing to colonoscopy – an unreliable tool

Introduction The Bowelscope screening programme offers “one-off” sigmoidoscopy to individuals at the age of 55. Those deemed at high risk following sigmoidoscopy are referred for colonoscopy. An adenoma with a villous or tubulovillous component is deemed high risk and should instigate colonoscopy. Determining whether a polyp is tubular or tubulovillous is subjective and prone to inter-observer variation. The BCSP pathology guidelines state “it is accepted that a neoplastic villus almost defies definition”. This review was designed to explore the variability of reporting villous morphology in the national Bowel Cancer Screening Program (BCSP) screening centres in Yorkshire, Humber and North Eastern (Y, H and NE) regions and to investigate the level of agreement between individual BCSP pathologists. Method 32 consultant pathologists active in the BCSP in Y, H and NE region viewed H and E glass slides from 12 bowel cancer screening polyps and categorised each as tubular, tubulovillous or villous. Following viewing, each case was presented to the group with a brief discussion of the features. Pathologists then used individual electronic voting buttons to classify each case into one of the three categories. Following the workshop, lead pathologists at the BCSP screening units in the Y, H and NE region provided the relative proportions of tubular, tubulovillous and villous adenomas reported in their screening centre in the previous 12 months. Results The graph below shows the percentage of pathologists classifying each of the twelve polyps in one of the three categories. No single case achieved consensus, with many showing a spread of classification little better than chance. Agreement was best on whether a polyp was a pure villous adenoma or not. Across the Y, H and NE region the proportion of adenomas reported as “tubulovillous”, ranged from 5.5 to 25%, with a median of 17%. These figures may disguise more marked individual variation as the figures from each screening centre represent the combined output of multiple individual pathologists and multiple departments. Pure villous adenomas were rare, median 0.6% of all adenomas, range 0.1 to 1.8%. Conclusion Use of “villosity” to predict need for colonoscopy is prone to marked inter-observer variation. Using villosity may lead to unacceptable variation in colonoscopy rates with the potential for unpredictable overburden on resources. Better definitions of what constitutes a villus are required, along with training to improve consistency in recognition, before it can be used as a reliable risk predictor in a national screening program. Disclosure of interest None Declared.

Effect of a stylet on a histological specimen in EUS-guided fine-needle tissue acquisition by using 22-gauge needles: a multicenter, prospective, randomized, controlled trial

EUS-guided FNA (EUS-FNA) has become the most efficacious way to obtain specimens from a solid lesion adjacent to the GI tract. Previous reports regarding the use of a stylet during EUS-FNA were all based on cytological diagnosis and have showed no significant superiority in terms of diagnostic yield. To clarify the noninferiority of EUS-FNA without a stylet (S-) compared with EUS-FNA with a stylet (S+) on histological assessment. A prospective, single-blind, randomized, controlled crossover study. Five tertiary referral centers in Japan. Patients referred for EUS-FNA of a solid lesion. EUS-FNA S+ and S- in a total of 4 alternate passes with randomization to S+ first or S- first. The primary endpoint was the acquisition rate of an appropriate and sufficient specimen for histological assessment. The secondary endpoints were cellularity, contamination, bloodiness, diagnostic ability, and diagnostic accuracy. We enrolled 107 patients (110 lesions) and analyzed 220 specimens each in the S+ and S- groups. The acquisition rate of appropriate and sufficient specimens in the S+ group was 121 of 220 (55.0%) and 122 of 220 (55.5%) in the S- group. The difference in the acquisition rate of the specimen (S- minus S+) based on the generalized estimating equation was 0.42% (95% confidence interval,-6.72% to 7.56%), which was less than 10% of the prespecified noninferiority margin of this study. With regard to cellularity, contamination, bloodiness score, diagnostic ability, and diagnostic accuracy, there were no significant differences between both groups. There were no dropouts in the study. A variety of target lesions, multiple pathologists, lack of an assessment of intraobserver and interobserver variability, and a single-blind study for the pathologists. EUS-FNA S- is noninferior to EUS-FNA S+ on histological assessment. ( UMIN000008695.).

Su1965 Digital Microscopy Is a Valid Alternative to Conventional Microscopy for Diagnosing Barrett's Esophagus

Introduction Management of Barrett esophagus (BE) relies heavily on the histopathological assessment of biopsies. This assessment is subjective and associated with significant intraand inter-observer variation. Most guidelines recommend review of biopsies by expert pathologists in case of low-grade or high-grade dysplasia (LGD/HGD). Conventional review of microscopy slides, however, is impractical and does not allow intercollegiate conferences or annotations of relevant findings in images for feedback. A digital revision platform would overcome these practical limitations. Aims & Methods In preparation of a national BE digital revision platform we compared the diagnostic accuracy of conventional and digital microscopy for diagnosing BE+/-dysplasia by a panel of expert pathologists. Sixty BE biopsy slides (NDBE; n=25, LGD; n=20; HGD; n=15) were scanned at x20 magnification. Five expert BE pathologists independently assessed all slides four times in 2 alternating rounds of digital and conventional microscopy. Assessments were supervised by a research fellow and the order of rounds as well as the order of the slides was randomized. Pathologists were blinded for the original diagnosis and identifying slide features. Intra-observer and pairwise inter-observer agreement were calculated using custom weighted Cohen's kappa in four categories (NDBE; IND; LGD; HGD). Kappa scores were expressed as fraction of maximum possible kappa score for each cross table. Results The mean intra-observer agreement was 0.63 for the 2 rounds of digital assessment and 0.74 for the two rounds of conventional assessment. Mean pairwise inter-observer agreement was 0.61 and 0.64 for first and second round of digital microscopy, respectively. For the two rounds of conventional microscopy, mean pairwise inter-observer agreement was 0.62 and 0.66 respectively. In 48/ 60 (80%) of digital and in 50/60 (83%) of conventional microscopy reviews a majority diagnosis was reached after the first reading. Conclusion Diagnostic agreement of digital microscopy is comparable to conventional microscopy in the setting of an expert pathology platform for BE histology. This study validates the use of digital histopathological assessment of BE biopsies and will be used as the underlying infrastructure for a nationwide, web-based BE revision platform in the near future. This will overcome many logistical and practical issues concerned with conventional histologic review by multiple pathologists.

Cirrhosis regression in hepatitis C patients with sustained virological response after antiviral therapy: a meta-analysis.

Chronic hepatitis C may be associated with cirrhosis, liver failure and hepatocellular carcinoma. Studies have demonstrated improved clinical outcome in patients who achieved a sustained viral response (SVR). A systematic literature search was performed to identify studies that assessed the association between SVR and cirrhosis regression. The main outcome studied was cirrhosis regression in patients with a SVR as compared with patients without a SVR. Six studies totalling 443 patients were included. Dichotomous outcomes were reported as risk ratios (RR) with 95% confidence intervals (CI). Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 [Confidence Interval (CI) 1.45-4.97, P < 0.01] in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favour of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow-up between biopsies. The relative risk for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36-month was 4.33 (CI 1.1-17.0, P = 0.04) as compared to a relative risk of 1.79 (CI 1.26-2.29, P < 0.01) in studies with a mean or median time between the follow-up biopsy of less than 36-month. Our results suggest that the majority of patients with cirrhosis who achieve a SVR develop cirrhosis regression. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression.

Su1038 APRI As a Non-Invasive and Inexpensive Predictor of Hepatic Fibrosis in a Primarily Uninsured African American Population With Chronic Hepatitis C

Background Chronic hepatitis C may be associated with cirrhosis, liver failure, and hepatocellular carcinoma. Recent studies have suggested histologic regression of cirrhosis in patients with sustained virologic response to anti-viral therapy. Objective Perform a meta-analysis of studies to determine the impact of sustained virologic response on the reversibility of cirrhosis after anti-viral therapy. Methods We used PubMed and Cochrane Library databases to identify all studies that assessed the association between SVR and cirrhosis regression in patients with HCV. Data was extracted regarding patient demographics, clinical characteristics, liver biopsy length, duration between biopsies, fibrosis scoring system, baseline biopsy score, anti-viral therapy, length of treatment, viral genotype, baseline viral load, and regression of cirrhosis. Six studies totaling 443 patients were included. Results Of the 443 patients with cirrhosis, 137 achieved a SVR. Of these 137 patients who achieved an SVR, 73 (53%) patients had regression of cirrhosis. The risk ratio of cirrhosis regression was 2.69 (Confidence Interval [CI] 1.45-4.97, p<0.01) in patients who achieved a SVR. The risk of cirrhosis regression was consistently in favor of patients who achieved a SVR regardless of the length of the biopsy or whether the biopsy was reviewed by a single or multiple pathologists. The risk ratio of cirrhosis regression was related to the duration of follow up between biopsies. The relative risk ratio for regression of cirrhosis in studies in which the mean or median time for the follow-up liver biopsy was greater than 36 months was 4.33 (CI 1.1-17.0, p= 0.04) as compared to a relative risk ratio of 1.79 (CI 1.26-2.29, p<0.01) in studies with a mean or median time between the follow-up biopsy of less than 36 months. Conclusions Our results suggest that the majority of patients with cirrhosis who achieve a SVR have regression of their cirrhosis. Time between biopsies appears to be an important determinant of the likelihood of cirrhosis regression, with more regression likely with longer follow up.

Two cases of Low-Grade adenosquamous carcinoma of breast arising within complex sclerosing lesions in females under 20 years of age

Background and Aims Low-grade adenosquamous carcinoma (LGASC) of breast is a rare subtype of metaplastic carcinoma. An association with complex sclerosing lesions (CSL) has been described in older patients. 1,2 LGASC has not been previously reported in the literature in patients under the age of 20. We describe two cases of LGASC arising within large CSL in 18-year-old and a 19-year-old females. This study discusses the diagnostic difficulties and differential diagnoses of this entity, as well as the relationship between LGASC and CSL. Methods The two cases were received as part of the routine surgical workload at our laboratory. The slides were reviewed by multiple pathologists at our institution and both cases were referred to Prof. Ian Ellis for expert opinion. Results Immunohistochemistry features were consistent with LGASC. 3 The diagnoses were confirmed by Prof. Ellis. Discussion Although LGASC is classified as a variant of metaplastic carcinoma, it has a better prognosis with the principal risk being local recurrence. Thus distinction from benign entities, adequate excision and appropriate management is important, especially in young patients where treatment complications and cosmetic result are significant considerations. The pathogenesis of LGASC remains uncertain, however these cases add further evidence to the association between LGASC and CSL.

Saturated fatty acids activate ERK signaling to downregulate hepatic sortilin 1 in obese and diabetic mice

Hepatic VLDL overproduction is a characteristic feature of diabetes and an important contributor to diabetic dyslipidemia. Hepatic sortilin 1 (Sort1), a cellular trafficking receptor, is a novel regulator of plasma lipid metabolism and reduces plasma cholesterol and triglycerides by inhibiting hepatic apolipoprotein B production. Elevated circulating free fatty acids play key roles in hepatic VLDL overproduction and the development of dyslipidemia. This study investigated the regulation of hepatic Sort1 in obesity and diabetes and the potential implications in diabetic dyslipidemia. Results showed that hepatic Sort1 protein was markedly decreased in mouse models of type I and type II diabetes and in human individuals with obesity and liver steatosis, whereas increasing hepatic Sort1 expression reduced plasma cholesterol and triglycerides in mice. Mechanistic studies showed that the saturated fatty acid palmitate activated extracellular signal-regulated kinase (ERK) and inhibited Sort1 protein by mechanisms involving Sort1 protein ubiquitination and degradation. Consistently, hepatic ERK signaling was activated in diabetic mice, whereas blocking ERK signaling by an ERK inhibitor increased hepatic Sort1 protein in mice. These results suggest that increased saturated fatty acids downregulate liver Sort1 protein, which may contribute to the development of dyslipidemia in obesity and diabetes.