Citations

ObjectivesThere have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices.MethodsTwo experts in interventional endoscopy spearheaded an evidence‐based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three‐round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5‐point Likert scale.ResultsForty‐two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision‐making; seven statements on postresection evaluation; and eight statements on postresection care.ConclusionsAn international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow‐up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

Abstract Recent advances in the field of immuno‐oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the simultaneous detection of multiple protein biomarkers in a single tissue section, thereby expanding opportunities for molecular and immune profiling while preserving tissue samples. By establishing the phenotype of individual tumour cells when distributed within a mixed cell population, the identification of clinically relevant biomarkers with high‐throughput multiplex immunophenotyping of tumour samples has great potential to guide appropriate treatment choices. Moreover, the emergence of novel multi‐marker imaging approaches can now provide unprecedented insights into the tumour microenvironment, including the potential interplay between various cell types. However, there are significant challenges to widespread integration of these technologies in daily research and clinical practice. This review addresses the challenges and potential solutions within a structured framework of action from a regulatory and clinical trial perspective. New developments within the field of immunophenotyping using multiplexed tissue imaging platforms and associated digital pathology are also described, with a specific focus on translational implications across different subtypes of cancer. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Validated nonbiopsy methods to assure duodenal mucosal healing in celiac disease are lacking, yet ongoing mucosal injury is associated with anemia, osteoporosis, and lymphoma. Most providers utilize clinical data as surrogates of mucosal status to avoid additional esophagogastroduodenoscopy. The reliability of such surrogates to predict mucosal recovery has been incompletely evaluated. The aim of this study was to rigorously assess patterns of histologic mucosal recovery at follow-up in celiac disease and to correlate findings with clinical data. Gastrointestinal pathologists from 13 centers evaluated initial and follow-up duodenal biopsies from 181 celiac disease patients. Marsh scores and intraepithelial lymphocytes (IELs)/100 enterocytes were assessed blindly. Histology at follow-up was correlated with symptoms, immunoglobulin A anti–tissue transglutaminase titers and gluten-free diet adherence. Fifty-six/181 (31%) patients had persistent villous blunting and 46/181 (25%) patients had just persistently elevated IELs at follow-up, with only 79/181 (44%) patients having complete histologic remission. IEL normalization (82/181; 45%) lagged villous recovery (125/181;69%). In a minority of patients, villous blunting was limited to proximal duodenal biopsies. No correlation was found between Marsh scores and symptoms, normalization of immunoglobulin A anti–tissue transglutaminase serology, or diet adherence. Children showed greater recovery of Marsh score (P<0.001) and IELs (P<0.01) than adults. Persistent mucosal injury is common in celiac disease, with discordant villous/IEL normalization. Pathologist awareness of expected findings in celiac disease follow-up biopsies, including their frequent lack of correlation with clinical data, is important for patient management, and has implications for eligibility criteria for therapeutics currently in development.

Abstract Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review, we provide an overview of two approaches for reporting and analyzing spatial data (raster versus vector‐based). We then provide a compendium of spatial immune cell metrics that have been reported in the literature, summarizing prognostic associations in the context of a variety of cancers. We conclude by discussing two well‐described clinical biomarkers, the breast cancer stromal tumor infiltrating lymphocytes score and the colon cancer Immunoscore, and describe investigative opportunities to improve clinical utility of these spatial biomarkers. © 2023 The Pathological Society of Great Britain and Ireland.

AbstractThe clinical significance of the tumor‐immune interaction in breast cancer is now established, and tumor‐infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple‐negative (estrogen receptor, progesterone receptor, and HER2‐negative) breast cancer and HER2‐positive breast cancer. How computational assessments of TILs might complement manual TIL assessment in trial and daily practices is currently debated. Recent efforts to use machine learning (ML) to automatically evaluate TILs have shown promising results. We review state‐of‐the‐art approaches and identify pitfalls and challenges of automated TIL evaluation by studying the root cause of ML discordances in comparison to manual TIL quantification. We categorize our findings into four main topics: (1) technical slide issues, (2) ML and image analysis aspects, (3) data challenges, and (4) validation issues. The main reason for discordant assessments is the inclusion of false‐positive areas or cells identified by performance on certain tissue patterns or design choices in the computational implementation. To aid the adoption of ML for TIL assessment, we provide an in‐depth discussion of ML and image analysis, including validation issues that need to be considered before reliable computational reporting of TILs can be incorporated into the trial and routine clinical management of patients with triple‐negative breast cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Abstract Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.

Abstract Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett’s esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett’s and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q &lt; 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

INTRODUCTION: Volumetric laser endomicroscopy (VLE) is a high-resolution imaging modality used in Barrett’s esophagus (BE) surveillance. Established VLE scoring systems use a combination of features to guide BE dysplasia diagnosis but it remains unclear whether these features are sufficient to reach optimal VLE diagnostic performance. This study explores an exhaustive list of VLE features using one-to-one imaging to pathology correlation to develop optimal VLE diagnostic models for BE dysplasia. METHODS: In this prospective, multi-center (5 sites) study, patients with dysplastic BE underwent VLE with laser targeted regions of interest (ROIs), followed by standard surveillance endoscopy and biopsy directed to laser-marked sites. Histology was reviewed by two GI pathologists (MV, RO) who achieved a consensus diagnosis (gold-standard). ROIs were dysplastic if low-grade dysplasia (LGD), high-grade dysplasia (HGD) or intramucosal adenocarcinoma (IMC) was present. Two VLE experts (CLL, GJT) reviewed ROIs and corresponding endoscopic images to identify and define a set of VLE features associated with BE dysplasia. A multi-variable logistic regression model based on least absolute shrinkage and selection operator (LASSO) method was developed to determine the optimal diagnostic performance of these features. A decision tree model with high clinical usability also was developed to evaluate VLE diagnostic performance for real-time image interpretation. RESULTS: A total of 461 VLE ROIs with matching histology were obtained from 150 patients (Table 1). A final dataset of 55 neoplastic (LGD, 12; HGD, 24; IMC, 19) and 56 randomly selected non-dysplastic ROIs were reviewed. Twenty-eight VLE features were identified describing layering, signal intensity, surface topography, and glandular characteristics. LASSO logistic regression modeling identified 5 VLE features which when utilized optimized diagnostic performance with an area under the curve (AUC) for BE dysplasia of 0.95 (Figure 1). To improve clinical usability, a decision tree model was optimized to three levels with an AUC of 0.90 (Figure 2). CONCLUSION: This study represents the most comprehensive review of VLE features associated with BE dysplasia to date. The proposed high-performing diagnostic models suggest that VLE can be used efficiently and effectively to enhance BE surveillance by identifying ROIs for targeted biopsy. Further validation of the proposed VLE models will determine their clinical utility.

AimsGastric heterotopia (GH) has been described throughout the gastrointestinal tract. However, the colorectal region is an extremely rare location for it. We describe the clinicopathological features of GH of the colon, rectum and anus.Methods and resultsWe identified 33 cases in 20 males and 13 females (median age = 54 years; range = 4 months–73 years). Sites included the rectum (n = 26), anus (n = 4), ileocaecal junction (n = 1), ascending colon (n = 1) and descending colon (n = 1). Presenting symptoms (n = 27) included haematochezia (41%) and altered bowel habits (4%); 15 patients (55%) were asymptomatic. On colonoscopy (n = 31), all appeared as solitary lesions (median size = 6.5 mm, range = 2–55 mm), either as polyps (61%), raised erythematous patches (23%), an ulcer (10%), within a rectal diverticulum (3%) or a haemorrhoid (3%). Patients were managed by polypectomy. One with an associated carcinoma in the area of GH underwent resection. No morbidity related to GH itself was reported following excision. Histologically, heterotopic gastric mucosa was oxyntic (85%), mixed oxyntic and non‐oxyntic (12%) and not specified (3%) types. In five patients a pyloric gland adenoma (PGA) arose from heterotopic gastric mucosa, two of which contained a focus of invasive adenocarcinoma. One case had associated surface foveolar‐type low‐grade dysplasia. Another had associated adenocarcinoma arising from the heterotopic mucosa. One example harboured Helicobacter pylori organisms.ConclusionsWe highlight the features of GH in the distal GIT – the ‘outlet patch’. Association with PGA, surface dysplasia and adenocarcinoma suggests that lower tract GH can undergo neoplastic transformation.