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Abstract: Lung cancer is the leading cause of cancer death in the industrialised world and is becoming a significant cause of mortality in developing countries. The vast majority of cases are a result of cigarette smoking. A number of genetic alterations are found in lung cancer, especially those effecting p53, a tumour suppressor gene that appears particularly sensitive to damage by tobacco carcinogens. Not all smokers develop lung cancer, suggesting that some individuals have greater genetic susceptibility. Lung cancers are usually subdivided according to the 1999 World Health Organisation (WHO) classification. Adenocarcinoma, squamous cell carcinoma, small cell carcinoma and large cell carcinoma are the commonest subtypes. Adenocarcinoma is now the commonest primary lung tumour. Pathological diagnosis is usually made by examination of cytological preparations from sputum or bronchial lavage fluid, or by histological examination of small biopsies. The most useful pathological distinction to make is between small cell and non-small cell carcinoma as this has implications for patient management. Once the diagnosis of lung cancer is made, clinical, thoracoscopic and radiological findings are used to produce a clinical stage of the disease. This enables the most appropriate treatment to be planned and gives prognostic information. Surgical resection of the tumour offers the best chance of a cure but, sadly, the majority of patients present with clinically advanced disease and are unsuitable for such treatment. Radiotherapy and chemotherapy may be effective in selected patients. Effective palliative therapy is the goal for the majority of patients. [Copyright &y& Elsevier]

The introduction of bowel cancer population screening programs has had a profound impact on gastrointestinal pathology. While the focus is mainly on quality assurance of diagnoses relevant for the outcome of these programs (colorectal cancer and its precursors), incidental findings are increasingly diagnosed. The incidence of such findings is largely unknown. Therefore, we investigated the incidence of incidental findings within the national screening program of the Netherlands. From the Dutch nationwide pathology databank (PALGA), we retrieved all histological diagnoses of patients participating in the national bowel cancer screening program from the start in 2014 until 1/ 1/2021. Descriptive statistics were used. During these 7 years, in total 9407 other polyps and malignancies (262 per 10,000 colonoscopies) were diagnosed. The majority (65%) were classified as inflammatory polyps. The most common malignancies were neuroendocrine tumours (n = 198, 6 per 10,000 colonoscopies); less common were lymphomas (n = 64) and metastases (n = 33). Mesenchymal polyps, such as leiomyomas and lipomas, were relatively common (27 and 16 per 10,000 colonoscopies, respectively), in comparison with neural polyps such as perineuriomas, ganglioneuromas, and neurofibromas (respectively 3, 2, and 1 per 10,000 colonoscopies). This is the largest study into the incidence of nonconventional colorectal polyps and malignancies in a homogeneous cohort of asymptomatic patients. Several of these diagnoses may have consequences for treatment and followup, in particular the malignancies and detection of patients with hereditary cancer syndromes. [ABSTRACT FROM AUTHOR]

Background: The DoMore-v1-CRC marker was recently developed using deep learning and conventional haematoxylin and eosin-stained tissue sections, and was observed to outperform established molecular and morphological markers of patient outcome after primary colorectal cancer resection. The aim of the present study was to develop a clinical decision support system based on DoMore-v1-CRC and pathological staging markers to facilitate individualised selection of adjuvant treatment.Methods: We estimated cancer-specific survival in subgroups formed by pathological tumour stage (pT<4 or pT4), pathological nodal stage (pN0, pN1, or pN2), number of lymph nodes sampled (≤12 or >12) if not pN2, and DoMore-v1-CRC classification (good, uncertain, or poor prognosis) in 997 patients with stage II or III colorectal cancer considered to have no residual tumour (R0) from two community-based cohorts in Norway and the UK, and used these data to define three risk groups. An external cohort of 1075 patients with stage II or III R0 colorectal cancer from the QUASAR 2 trial was used for validation; these patients were treated with single-agent capecitabine. The proposed risk stratification system was evaluated using Cox regression analysis. We similarly evaluated a risk stratification system intended to reflect current guidelines and clinical practice. The primary outcome was cancer-specific survival.Findings: The new risk stratification system provided a hazard ratio of 10·71 (95% CI 6·39-17·93; p<0·0001) for high-risk versus low-risk patients and 3·06 (1·73-5·42; p=0·0001) for intermediate versus low risk in the primary analysis of the validation cohort. Estimated 3-year cancer-specific survival was 97·2% (95% CI 95·1-98·4; n=445 [41%]) for the low-risk group, 94·8% (91·7-96·7; n=339 [32%]) for the intermediate-risk group, and 77·6% (72·1-82·1; n=291 [27%]) for the high-risk group. The guideline-based risk grouping was observed to be less prognostic and informative (the low-risk group comprised only 142 [13%] of the 1075 patients).Interpretation: Integrating DoMore-v1-CRC and pathological staging markers provided a clinical decision support system that risk stratifies more accurately than its constituent elements, and identifies substantially more patients with stage II and III colorectal cancer with similarly good prognosis as the low-risk group in current guidelines. Avoiding adjuvant chemotherapy in these patients might be safe, and could reduce morbidity, mortality, and treatment costs.Funding: The Research Council of Norway. [ABSTRACT FROM AUTHOR]

Aims Synovial sarcomas may arise within retroperitoneal or pelvic tissues or, more rarely, within the luminal gastrointestinal tract. This case series aims to demonstrate how such primary abdominal synovial sarcomas may particularly mimic gastrointestinal stromal tumour ( GIST) on both morphological and immunohistochemical grounds. Methods and results Four cases of primary abdominal synovial sarcoma were reviewed morphologically and with immunohistochemistry, fluorescence in-situ hybridization with an SS18 break-apart probe, and KIT/ PDGFRA mutation analysis. The four patients comprised two males and two females, with a median age of 42 years (range: 17-59 years). Two synovial sarcomas arose within the stomach, one within the small-intestine mesentery, and the fourth within the retroperitoneum. All four tumours showed only a monophasic spindle cell component in the tissues available for review. All four tumours showed DOG1 immunopositivity, and three coexpressed CD117. Three tested cases did not show activating KIT or PDGFRA mutations, whereas all four cases showed chromosomal rearrangement of SS18. Conclusions A diagnosis of synovial sarcoma should be considered particularly if an abdominal spindle cell neoplasm shows a haemangiopericytomatous pattern and diffuse CD99 and CD56 immunopositivity. A confident distinction between abdominal synovial sarcoma and GIST requires KIT/ PDGFRA mutation analyses and specific molecular testing for synovial sarcoma. [ABSTRACT FROM AUTHOR]

Purpose: The differential diagnosis of epithelial misplacement from invasive cancer in the colon is a challenging endeavour, augmented by the introduction of bowel cancer population screening. The main aim of the work is to test, as a proof-of concept study, the ability of the infrared spectroscopic imaging approach to differentiate epithelial misplacement from adenocarcinoma in sigmoid colonic adenomatous polyps. Methods: Ten samples from each of the four diagnostic groups, normal colonic mucosa, adenomatous polyps with low grade dysplasia, epithelial misplacement in adenomatous polyps and adenocarcinoma, were analysed using IR spectroscopic imaging and data processing methods. IR spectral images were subjected to data pre-processing and cluster analysis based segmentation to identify epithelial, connective tissue and stromal regions. Statistical analysis was carried out using principal component analysis and linear discriminant analysis based cross validation, to classify spectral features according to the pathology, and the diagnostic attributes were compared. Results: The combined 4-group classification model on an average showed a sensitivity of 64%, a specificity of 88% and an accuracy of 76% for prediction based on a 'single spectrum', whilst a 'majority-vote' prediction on an average showed a sensitivity of 73%, a specificity of 90% and an accuracy of 82%. The 2-group model, for the differential diagnosis of epithelial misplacement versus adenocarcinoma, showed an average sensitivity and specificity of 82.5% for prediction based on a 'single spectrum' whilst a 'majority-vote' classification showed an average sensitivity and specificity of 90%. A 92% area under the curve (AUC) value was obtained when evaluating the classifier using the Receiver Operating Characteristics (ROC) curves. Conclusions: IR spectroscopy shows promise in its ability to differentiate epithelial misplacement from adenocarcinoma in tissue sections, considered as one of the most challenging endeavours in population-wide diagnostic histopathology. Further studies with larger series, including cases with challenging diagnostic features are required to ascertain the capability of this modern digital pathology approach. In the long-term, IR spectroscopy based pathology which is relatively low-cost and rapid, could be a promising endeavour to consider for integration into the existing histopathology pathway, in particular for population based screening programmes where large number of samples are scrutinised. [ABSTRACT FROM AUTHOR]

Aims: The inception of the National Health Service Bowel Cancer Screening Programme in England in 2006 highlighted the fact that the differential diagnosis between the presence of epithelial misplacement and adenocarcinoma occurring in colorectal adenomas is problematic. The pathology Expert Board (EB) was created to facilitate the review of difficult cases by a panel of three experienced gastrointestinal pathologists. This article describes a review of the work of the EB over a 4‐year period (2017–2020). Methods and results: Four hundred and thirty polyps were referred to the EB from 193 pathologists and 76 hospitals during this time. The EB diagnosis was benign for 67%, malignant for 28%, and equivocal for 2% (with no consensus in the remainder). The most common diagnosis change made by the EB was from malignant to benign—made in 50% of polyps referred with an initially malignant diagnosis. The level of agreement between the individual EB members was 'good' (kappa score of 0.619) but that between the EB and the referring diagnosis was 'poor' (kappa score of 0.149). Data from one EB member indicated that the presence of lamina propria, features of torsion and cytological similarity between the superficial and deep glands were predictors of a benign diagnosis, whereas the presence of irregular neoplastic glands, a desmoplastic reaction and lymphovascular invasion were commonly observed features in polyps with a malignant diagnosis. Conclusion: Diagnostic agreement between EB members is better than that between the EB and referring pathologists. There was a consistent trend for the EB to change diagnoses from malignant to benign. [ABSTRACT FROM AUTHOR]

Aims: Accurate and consistent pathological staging of colorectal carcinoma (CRC) in resection specimens is especially crucial to guide adjuvant therapy. The aim of this study was to assess whether certain staging scenarios yield discordant opinions in the setting of current international and UK national guidelines. Methods and results: Members of the UK Gastrointestinal Pathology External Quality Assurance Scheme were invited to complete an anonymous, on‐line survey that presented 15 scenarios related to pT or pR staging of CRC, and three questions about the respondent. The survey invitation was e‐mailed to 405 pathologists, and 184 (45%) responses were received. The respondents had discordant opinions on whether and how CRC pT or pR staging is affected by: acellular mucin lakes and duration after short‐course radiotherapy; the nature of the carcinoma at a resection margin or peritoneal surface; and microscopic evidence of perforation. This discordance was rarely related to the respondent's occupation type, and was not related to duration of work as a consultant or the staging guidelines used. Conclusions: This survey confirms that there remain several clinically critical but unresolved pT and pR staging issues for CRC. These issues therefore deserve attention in future versions of international and national staging guidelines. [ABSTRACT FROM AUTHOR]

Aims: To research and identify how often complicated diverticular disease of the appendix [appendiceal diverticular disease (ADD)] shows histological mimicry of low‐grade appendiceal mucinous neoplasms (LAMNs) and to provide guidance on the useful histopathological features that allow the appropriate diagnosis to be made. Methods and results: Seventy‐four cases of complicated appendiceal diverticular disease were identified from two specialist centres. Of the second opinion/consultation cases, 71% of the ADD cases had been diagnosed by referring pathologists as LAMNs. Salient pathological features were identified and agreed upon to reach the applicable diagnosis. For a diagnosis of complicated diverticulosis, particularly when associated with mucus cysts, the following morphological features were regarded as important: relative retention of the normal mucosal architecture with lamina propria and a maintained crypt architecture, crypts arranged in regular array, epithelial hyperplasia and a lack of nuclear abnormalities extending the length of the crypts. In a formal case–control study undertaken on 30 cases with each diagnosis, ADD and LAMN, loss of lamina propria, a filiform architecture and hypermucinosis were significantly associated with low‐grade appendiceal mucinous neoplasms. Mucosal neuromas were significantly associated with diverticular disease of the appendix. Conclusions: To our knowledge, this study represents the largest series in the world literature and serves to highlight the important pathological features to distinguish complicated diverticular disease of the appendix from LAMNs, and emphasises the difficulties experienced by diagnostic pathologists in diagnosing complicated appendiceal diverticulosis. This is important, as LAMNs have a significant risk of transcoelomic spread, while complicated appendiceal diverticulosis has no such risk. [ABSTRACT FROM AUTHOR]

Background: Chromatin organisation affects gene expression and regional mutation frequencies and contributes to carcinogenesis. Aberrant organisation of DNA has been correlated with cancer prognosis in analyses of the chromatin component of tumour cell nuclei using image texture analysis. As yet, the methodology has not been sufficiently validated to permit its clinical application. We aimed to define and validate a novel prognostic biomarker for the automatic detection of heterogeneous chromatin organisation.Methods: Machine learning algorithms analysed the chromatin organisation in 461 000 images of tumour cell nuclei stained for DNA from 390 patients (discovery cohort) treated for stage I or II colorectal cancer at the Aker University Hospital (Oslo, Norway). The resulting marker of chromatin heterogeneity, termed Nucleotyping, was subsequently independently validated in six patient cohorts: 442 patients with stage I or II colorectal cancer in the Gloucester Colorectal Cancer Study (UK); 391 patients with stage II colorectal cancer in the QUASAR 2 trial; 246 patients with stage I ovarian carcinoma; 354 patients with uterine sarcoma; 307 patients with prostate carcinoma; and 791 patients with endometrial carcinoma. The primary outcome was cancer-specific survival.Findings: In all patient cohorts, patients with chromatin heterogeneous tumours had worse cancer-specific survival than patients with chromatin homogeneous tumours (univariable analysis hazard ratio [HR] 1·7, 95% CI 1·2-2·5, in the discovery cohort; 1·8, 1·0-3·0, in the Gloucester validation cohort; 2·2, 1·1-4·5, in the QUASAR 2 validation cohort; 3·1, 1·9-5·0, in the ovarian carcinoma cohort; 2·5, 1·8-3·4, in the uterine sarcoma cohort; 2·3, 1·2-4·6, in the prostate carcinoma cohort; and 4·3, 2·8-6·8, in the endometrial carcinoma cohort). After adjusting for established prognostic patient characteristics in multivariable analyses, Nucleotyping was prognostic in all cohorts except for the prostate carcinoma cohort (HR 1·7, 95% CI 1·1-2·5, in the discovery cohort; 1·9, 1·1-3·2, in the Gloucester validation cohort; 2·6, 1·2-5·6, in the QUASAR 2 cohort; 1·8, 1·1-3·0, for ovarian carcinoma; 1·6, 1·0-2·4, for uterine sarcoma; 1·43, 0·68-2·99, for prostate carcinoma; and 1·9, 1·1-3·1, for endometrial carcinoma). Chromatin heterogeneity was a significant predictor of cancer-specific survival in microsatellite unstable (HR 2·9, 95% CI 1·0-8·4) and microsatellite stable (1·8, 1·2-2·7) stage II colorectal cancer, but microsatellite instability was not a significant predictor of outcome in chromatin homogeneous (1·3, 0·7-2·4) or chromatin heterogeneous (0·8, 0·3-2·0) stage II colorectal cancer.Interpretation: The consistent prognostic prediction of Nucleotyping in different biological and technical circumstances suggests that the marker of chromatin heterogeneity can be reliably assessed in routine clinical practice and could be used to objectively assist decision making in a range of clinical settings. An immediate application would be to identify high-risk patients with stage II colorectal cancer who might have greater absolute benefit from adjuvant chemotherapy. Clinical trials are warranted to evaluate the survival benefit and cost-effectiveness of using Nucleotyping to guide treatment decisions in multiple clinical settings.Funding: The Research Council of Norway, the South-Eastern Norway Regional Health Authority, the National Institute for Health Research, and the Wellcome Trust. [ABSTRACT FROM AUTHOR]

Food allergies are increasing globally, including numbers of allergens, the sensitization rate, and the prevalence rate. To protect food-allergic individuals in the community, food allergies need to be appropriately managed. This paper describes current Australian food allergen management practices. In Australia, the prevalence of food allergies, the anaphylaxis rate, and the fatal anaphylaxis rate are among the highest in the world. Interagency and stakeholder collaboration is facilitated and enhanced as Australia moves through past, current, and ongoing food allergen challenges. As a result, Australia has been a global leader in regulating the labeling of common allergens in packaged foods and their disclosure in foods not required to bear a label. Moreover, the food industry in Australia and New Zealand has developed a unique food allergen risk management tool, the Voluntary Incidental Trace Allergen Labelling program, which is managed by the Allergen Bureau. This paper summarizes insights and information provided by the major stakeholders involved to protect food-allergic consumers from any allergic reaction. Stakeholders include government; consumer protection, regulation, and enforcement agencies; the food industry; and food allergen testing and food allergen/allergy research bodies in Australia. The ongoing goal of all stakeholders in food allergen management in Australia is to promote best practice food allergen management procedures and provide a wide choice of foods, while enabling allergic consumers to manage their food allergies and reduce the risk of an allergic reaction. [ABSTRACT FROM AUTHOR]

Label-free imaging of cells and tissues is a promising tool to study the molecular alterations for improved cancer diagnosis. In this regard, the vibrational spectroscopic method of FTIR imaging has been employed to study the histo-pathological features and the alterations were correlated to a disease state. The aim of this study was to see if higher magnification images resulting in pixel sizes smaller than the diffraction limit of mid-IR wavelengths with two NA objectives could provide cellular and subcellular resolution of key diagnostic features. To this effect, FTIR spectroscopic imaging has been carried out directly on paraffinized colon tissue sections using a benchtop imaging system consisting of two different IR objectives with a NA of 0.81 and 0.62. The high NA objective (0.81) at a high magnification (63×) provided a pixel size of 0.63 × 0.63 μm 2 in comparison to the standard magnification (12×) where the pixel size is 3.3 × 3.3 μm 2 . The second objective (0.62 NA) at a high magnification (36×) provided a pixel size of 1.1 × 1.1 μm 2 in comparison to the standard magnification (7×) pixel size of 5.5 × 5.5 μm 2 . The spectral images were corrected for paraffin and other spectral interferences using a modified EMSC algorithm and subjected to cluster analysis in order to appreciate the histopathological details. Comparison of the IR cluster analysis results to adjacent haematoxylin and eosin stained tissue sections, which were used as the morphological controls, revealed various levels of histological and cellular organization. Together with large scale features such as the glandular and connective tissue regions, small scale features like goblet cells, interfaces between tissue types especially the peri-cryptal fibroblastic sheath were observed. Noticeable differences between the intracellular mucin and secreted mucin were also observed. However, it appears that high power mid-IR radiation sources would be beneficial, especially when measuring in rapid clinically relevant timescales. [ABSTRACT FROM AUTHOR]

The diagnostic difficulties of differentiating epithelial misplacement from invasive cancer in colorectal adenomatous polyps have been recognised for many years. Nevertheless, the introduction of population screening in the UK has resulted in extraordinary diagnostic problems. Larger sigmoid colonic adenomatous polyps, which are those most likely to show epithelial misplacement, are specifically selected into such screening programmes, because these polyps are likely to bleed and screening is based on the detection of occult blood. The diagnostic challenges associated with this particular phenomenon have necessitated the institution of an 'Expert Board': this is a review of the first five years of its practice, during which time 256 polyps from 249 patients have been assessed. Indeed, the Expert Board contains three pathologists, because those pathologists do not necessarily agree, and a consensus diagnosis is required to drive appropriate patient management. However, this study has shown substantial levels of agreement between the three Expert Board pathologists, whereby the ultimate diagnosis has been changed, from that of the original referral diagnosis, by the Expert Board for half of all the polyps, in the substantial majority from malignant to benign. In 3% of polyp cases, the Expert Board consensus has been the dual diagnosis of both epithelial misplacement and adenocarcinoma, further illustrating the diagnostic difficulties. The Expert Board of the Bowel Cancer Screening Programme in the UK represents a unique and successful development in response to an extraordinary diagnostic conundrum created by the particular characteristics of bowel cancer screening. [ABSTRACT FROM AUTHOR]

Objective Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. Methods Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNAwas determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. Results Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. Conclusions Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus. [ABSTRACT FROM AUTHOR]

Abstract: Raman spectroscopy has previously been identified as a suitable technique for the analysis of biological samples and recent technological advancements have allowed more rapid forms of spectral mapping to be undertaken. This promising approach potentially allows more biochemical information to be obtained than would normally be possible using a standard chemical stain, however specialised techniques are required to analyse the hyperspectral datasets acquired. In this work Self Organising Maps (SOM) are applied in combination with Principal Component Analysis (PCA) to analyse a single human colon polyp sample containing varying histological features. It is demonstrated that using SOM to compress the data is robust to outlying spectral features allowing greater contrast in the image for the identification of subtle features. As a secondary outcome, the SOM method also provides an alternative visualisation approach that can be used to identify regions of histological interest within a sample. [Copyright &y& Elsevier]

There are distinct challenges implicit to the development of minimally invasive endoscopic surgery for the eradication of early neoplasia in Barrett's oesophagus. Endoscopic resection and ablation of high-grade dysplasia and mucosal cancer offer alternative therapeutic options to those unsuitable or unwilling to contemplate radical surgical excision. It may also become the treatment of choice in the future. Technological developments enable the instantaneous and non-invasive diagnosis of microscopic tissue abnormalities in vivo. This is made possible by improving the level of information that can be obtained from the tissue. As well as the two-dimensional surface morphology image, which the traditional endoscope can view, we have used new techniques to enable structure at depth, using Optical Coherence Tomography, to be imaged in high resolution. Other advances, using Raman spectroscopy, enable the early endoscopic detection of biochemical and molecular changes in tissue that precede any changes in morphology, thus enabling earlier diagnosis of tissue abnormalities. This King James IV lecture details our recent work, to develop advanced imaging for the diagnosis of malignancy and pre-malignancy. After detection endoscopic photodynamic therapy and endoscopic mucosal resection can provide eradication of mucosal neoplasia. Following photodynamic therapy there was complete eradication of all high-grade dysplasia and intramucosal carcinoma in 40 of 42 patients with a maximum endoscopic follow-up period of 72 months. Following endoscopic resection of 95 patients, the mean survival for intramucosal adenocarcinoma and high-grade dysplasia was 40.6 and 60.8 months respectively. [ABSTRACT FROM AUTHOR]

Introduction: Lymphocyte-rich inflammation of the esophageal mucosa has gained increased awareness among pathologists and clinicians recently. Patients usually present with symptoms of esophageal dysfunction, including dysphagia and food bolus impaction. Endoscopy may show changes similar to eosinophilic esophagitis but may also be entirely normal ('microscopic esophagitis'). Three morphological subtypes or variant forms have been described which include lymphocytic, lichenoid and lymphocyte-predominant esophagitis. These need to be discriminated against other distinct causes of esophageal lymphocytosis, such as gastro-esophageal reflux disease and Candida infection., Areas Covered: This review provides an overview of diagnostic criteria and clinical associations of the disorder and presents an algorithmic approach to diagnosis. A comprehensive literature review was conducted using PubMed, Medline and Google Scholar databases to identify articles related to lymphocyte-rich esophageal inflammation, published up to March 2024., Expert Opinion: Lymphocyte-rich inflammation needs to be included in the differential diagnosis and clinical work-up of patients with esophageal dysfunction. There is currently considerable morphological overlap among published subtypes or variant forms. Follow-up studies of affected individuals are needed to formalize diagnostic parameters and identify the clinical course of disease in order to optimize treatment modalities.

Anal cancer, mainly squamous cell carcinoma, is rare but increasing in prevalence, as is its precursor lesion, anal squamous dysplasia. They are both strongly associated with human papillomavirus infection. The 2-tiered Lower Anogenital Squamous Terminology classification, low-grade SIL and high-grade SIL, is preferred to the 3-tiered anal intraepithelial neoplasia classification because of better interobserver agreement and clearer management implications. Immunohistochemistry with p16 is helpful to corroborate the diagnosis of squamous dysplasia. Similarly, immunohistochemistry is helpful to differentiate primary Paget disease from secondary Paget disease, which is usually due to anal squamous mucosal/epidermal involvement by primary rectal adenocarcinoma., Competing Interests: Disclosure Neither author has any conflicts of interest to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

I hope that this treatise adds to the excellent reviews by Varma and colleagues, emphasising the importance of accurate macroscopic assessment and report provision. I have especially highlighted the importance of not divorcing the clinical data and the macroscopic analysis from the microscopic assessment as all are required to provide an accurate and cogent overall composition. The review has also identified areas where the evolution of pathological practice has gone a little awry and requires to be modified and/or justified with evidence base. There is also an emphasis on block economy, as there is no doubt that considerable savings can be made if more attention is paid to more judicious block selection. It is also commended that subspecialties other than gastrointestinal pathology introduce reporting quality standards, like lymph node harvest numbers and other important prognostic and management indicators, to improve the quality of macroscopic pathology worldwide to the benefit of our service users and their patients., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The clinical management of patients with dysplasia in chronic inflammatory bowel disease (IBD) is currently guided by Riddell et al.'s grading system (negative, indefinite, low grade, high grade) from 1983 which was based primarily on nuclear cytoarchitectural characteristics. Although most dysplasia in IBD resembles sporadic adenomas morphologically, other distinctive potential cancer precursors in IBD have been described over time. Recognizing the need for a updated comprehensive classification for IBD-associated dysplasia, an international working group of pathologists with extensive clinical and research experience in IBD devised a new classification system and assessed its reproducibility by having each participant assess test cases selected randomly from a repository of electronic images of potential cancer precursor lesions. The new classification system now encompasses three broad categories and nine sub-categories: 1) intestinal dysplasia (tubular/villous adenoma-like, goblet cell deficient, crypt cell, traditional serrated adenoma-like, sessile serrated lesion-like and serrated NOS), 2) gastric dysplasia (tubular/villous and serrated), and 3) mixed intestinal-gastric dysplasia. In the interobserver analysis, 67% of the diagnoses were considered definitive and achieved substantial inter-rater agreement. The key distinctions between intestinal and gastric lesions and between serrated and non-serrated lesions achieved substantial and moderate inter-rater agreement overall, respectively, however, the distinctions among certain serrated sub-categories achieved only fair agreement. Based on the Riddell grading system, definite dysplasia accounted for 86% of the collective responses (75% low grade, 11% high grade). Based on these results, this new classification of dysplasia in IBD can provide a sound foundation for future clinical and basic IBD research., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The range of lesions with a serrated appearance within the large intestine has expanded and become more complex over the last 30 years. The majority of these were previously known as metaplastic polyps but are today called hyperplastic polyps (HPs). HPs show two main growth patterns: microvesicular and goblet cell-rich. The former type shows morphological and molecular similarities (eg, BRAF mutations) to the more recently described sessile serrated lesion (SSL). In this review, we debate whether these lesions represent a biological spectrum or separate entities. Whichever view is held, microvesicular HPs and SSLs are distinct from the goblet cell-rich HP and the traditional serrated adenoma (TSA), which may themselves share molecular changes (eg, KRAS mutations), with the goblet cell-rich HP representing a precursor to the TSA. Both SSLs and the goblet cell-rich HP-TSA pathway are routes to colorectal cancer within the serrated pathway and overlaps between them can occur, for example, a ( BRAF -mutated) TSA may arise from an SSL., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

This review describes the indications and contraindications for endoscopic biopsy, in routine practice, of the upper gastrointestinal (GI) tract. We accept that this review provides grounds for controversy, as our stance in certain situations is counter to some national guidelines. Nevertheless, we provide evidence to support our viewpoints, especially on efficiency and economic grounds. We describe the particular controversies concerning the biopsy assessment of Barrett's oesophagus, chronic gastritis and the duodenum in the investigation of coeliac disease. We accept that there are indications for more extensive upper GI biopsy protocols in children than in adults; the latter constitute our main focus in this article. We would encourage detailed discussion between pathologists and their endoscopy colleagues about the indications, or lack of them, for routine upper GI endoscopic biopsy, as studies have shown that adherence to agreed guidelines has resulted in a very considerable diminution in the biopsy workload without compromising patient management. Furthermore, where biopsy is indicated, we emphasise the importance of accompanying clinical information provided to the pathologist, in particular regarding biopsy site(s), and regular feedback to endoscopists to improve and maintain the quality of such information. Finally, local dialogue is also advised, when necessary, to indicate to endoscopists the need to appropriately segregate biopsies into separate, individually labelled specimens, to maximise the information that can be derived by pathological evaluation and thereby improve the quality of the final pathology report., (© 2020 John Wiley & Sons Ltd.)

Objective: To describe and investigate the potential causes of the isolated caecal patch lesion, a previously undescribed endoscopic phenomenon of a lesion fulfilling endoscopic and histopathological criteria for chronic inflammatory bowel disease but without evidence of similar inflammatory pathology elsewhere at colonoscopy., Methods: Cases were collected prospectively by one specialist gastrointestinal pathologist over a 10-year period. Full endoscopic and histopathological analysis was undertaken and follow-up sought to understand the likely cause(s) of the lesions., Results: Six cases are described. Two had very close links with ulcerative colitis, one predating the onset of classical distal disease and the other occurring after previous demonstration of classical distal ulcerative colitis. Two occurred in younger patients and we postulate that these lesions may predict the subsequent onset of chronic inflammatory bowel disease. Finally two can be reasonably attributed to the effects of non-steroidal inflammatory agent therapy., Conclusions: Caecal patch lesions can be demonstrated in isolation. Despite the strong association of caecal patch lesions with ulcerative colitis, solitary lesions may well have disparate causes but nevertheless possess a close relationship with chronic inflammatory bowel disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning., Methods: More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival., Findings: 828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72-5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07-4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion., Interpretation: A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes., Funding: The Research Council of Norway., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background and Study Aims:  The majority of polyps removed at colonoscopy are diminutive (≤ 5 mm) to small (< 10 mm) and there are few guidelines for the best way for these polyps to be removed. We aimed to assess the feasibility and effectiveness of cold biopsy forceps polypectomy with pre-lift (CBPP) for polyps ≤ 7 mm. Our aims were to assess completeness of histological resection of this technique, to identify factors contributing to this and assess secondary considerations such as timing, retrieval and complication rates., Patients and Methods: We conducted a prospective cohort study on consecutive patients receiving a colonoscopy at Cheltenham General Hospital, as part of the National Bowel Cancer Screening Program (BCSP) in England. The study included only polyps that were judged as ≤ 7 mm by the colonoscopist. A small sub-mucosal pre-lift injection was administered prior to removal of the polyp using cold biopsy forceps. One or more biopsies were taken until the polyp was confidently assessed visually as being completely removed by the colonoscopist. The entire polypectomy site was then removed en bloc by endomucosal resection (EMR) with a margin of at least 1 to 2 mm around defect. This was sent for histopathological analysis to assess completeness of resection. Polypectomy timing, tissue retrieval, number of bites required for visual resection and complications were recorded at the time of the procedure., Results: Sixty-four patients were recruited and consented. Of them, 42 patients had a total of 60 polyps resected. Three patients had inflammatory polyps and were excluded from the study, leaving 57/60 polyps for final analysis. Seventeen were hyperplastic and 40 adenomatous polyps. Retrieval was complete for all 57 polyps and there were no complications both during or post- polypectomy. The complete resection rate (CRR) was 86 %. The technique was more effective in smaller polyps with 91.7 % of diminutive polyps (≤ 5 mm) completely excised., Conclusions: CBPP is a safe and highly effective technique for polyps < 5 mm with a high complete resection and retrieval rate. The time taken for the procedure is significantly greater than cold forceps alone, or cold snare as seen in other studies.

Histopathological assessment of biopsy and resection specimens of chronic inflammatory bowel disease (CIBD), or possible CIBD, forms a significant component of the routine workload in most tissue pathology laboratories. In this review, we have chosen selected areas of particular diagnostic difficulty in CIBD pathology, providing key advice for pathology reporting. Those mimics of CIBD which have the greatest potential for misdiagnosis are discussed, particularly the wide range of infectious colitides which represent possible diagnostic pitfalls. The most important distinguishing features between the two main forms of CIBD, ulcerative colitis and Crohn's disease, are addressed, first in relation to resection specimens, and then with emphasis on features which may also be diagnostically useful in endoscopic biopsy material. The importance of assessment of the index endoscopic specimen is stressed, before treatment has been instigated, along with careful correlation with clinical and endoscopic features. Problems in the assessment of post-surgical CIBD specimens are described and then the role of upper gastrointestinal pathology specimens in diagnosing both Crohn's disease and ulcerative colitis, with increased recognition of upper gastrointestinal tract involvement in the latter condition. Finally, with recent developments in endoscopic surveillance techniques and local excision options, modern approaches to reporting and managing neoplasia complicating CIBD are reviewed.

Two issues commonly arise for pathologists reporting adenomatous polyps of the colorectum. Particularly problematic within large sigmoid colonic adenomas is the distinction between benign misplacement of epithelium into the submucosa and invasive malignancy. This distinction requires careful morphologic evaluation of key discriminatory features, assisted only rarely by the application of selected adjunctive immunohistochemistry. Following a diagnosis of adenocarcinoma within a polypectomy or other local excision specimen, systematic assessment is required of features that may indicate the risk of residual local and/or nodal neoplastic disease and inform management decision-making regarding the need for further endoscopic or surgical intervention., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

More than 60 years have elapsed since Barrett described the condition that continues to bear his name. Despite much research, clinical and basic, the defining features and the diagnosis of columnar-lined esophagus (CLO) are still embroiled with controversy and uncertainty. For pathologists, these controversies are notorious. The disease has been defined by the pathological demonstration of "specialized intestinal metaplasia" and yet there is compelling evidence that this approach is flawed due to sampling issues, poor levels of agreement between expert pathologists as to what constitutes "goblet cells," and the fact that most glandular epithelium in the esophagus is "intestinalized," even if goblet cells are not demonstrable. We believe that reliance on such pathological features can result in erroneous diagnoses of CLO and that the endoscopic diagnosis of CLO is more reliable with pathology corroborative in uncertain cases, when there is stricturing and/or ulceration and in shorter segment disease. Intriguingly, there are recent research findings that elucidate our understanding of the pathogenesis and the derivation of CLO and the way that initial gastric metaplasia converts to the unstable and neoplasia-associated intestinal phenotype. Even so, more research is required to enable a better understanding of the pathogenesis of CLO and to further improve the current management of the disease and its neoplastic complications.

Colorectal cancer screening is widely promulgated in many parts of the world and population screening is occurring in many countries, especially in western Europe. Although, intuitively, it might be thought that the pathology resulting from screening should be straightforward, being mainly that of polyp diagnosis and the biopsy diagnosis and staging of established adenocarcinoma, in fact experience has shown that there are several areas of considerable difficulty and controversy. In the UK somewhat different programmes, all based on faecal occult blood (FOB) screening, have been developed and each has generated similar pathological conundra. These include the biopsy diagnosis of adenocarcinoma, colorectal serrated pathology, the diagnosis and management of polyp cancers and last, but certainly not least, the phenomenon of the large sigmoid colonic adenomatous polyp with epithelial misplacement/pseudo-invasion. Polyp cancers provide especially difficult management conundra and discussion of that management within a multidisciplinary team-based management meeting is regarded as essential in the UK. Large adenomatous polyps of the sigmoid colon with epithelial misplacement are selected into FOB-based screening programmes and have provided extraordinary diagnostic challenges. Finally, the quality assurance procedures introduced for screening can ensure a considerable overall improvement in the quality of lower gastrointestinal tract pathological reporting., (© 2015 John Wiley & Sons Ltd.)

Inflammatory bowel diseases (IBDs) are lifelong disorders predominantly present in developed countries. In their pathogenesis, an interaction between genetic and environmental factors is involved. This practice guide, prepared on behalf of the European Society of Pathology and the European Crohn's and Colitis Organisation, intends to provide a thorough basis for the histological evaluation of resection specimens and biopsy samples from patients with ulcerative colitis or Crohn's disease. Histopathologically, these diseases are characterised by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the cell types present, but these features frequently overlap. If a definitive diagnosis is not possible, the term indeterminate colitis is used for resection specimens and the term inflammatory bowel disease unclassified for biopsies. Activity of disease is reflected by neutrophil granulocyte infiltration and epithelial damage. The evolution of the histological features that are useful for diagnosis is time- and disease-activity dependent: early disease and long-standing disease show different microscopic aspects. Likewise, the histopathology of childhood-onset IBD is distinctly different from adult-onset IBD. In the differential diagnosis of severe colitis refractory to immunosuppressive therapy, reactivation of latent cytomegalovirus (CMV) infection should be considered and CMV should be tested for in all patients. Finally, patients with longstanding IBD have an increased risk for the development of adenocarcinoma. Dysplasia is the universally used marker of an increased cancer risk, but inter-observer agreement is poor for the categories low-grade dysplasia and indefinite for dysplasia. A diagnosis of dysplasia should not be made by a single pathologist but needs to be confirmed by a pathologist with expertise in gastrointestinal pathology.