Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.

BACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).

Gastrointestinal Stromal Tumours (GISTs) with KRAS Mutation: A Rare but Important Subset of GISTs.

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the GI tract, usually found in the stomach, jejunum, and ileum. Typically, they are KIT or PDGFR-mutated, allowing for targetable treatments with tyrosine kinase inhibitors such as imatinib. Here, we present two KRAS-mutated wild-type gastrointestinal tumours (GISTs). Both cases occurred in the small bowel of females. Immunohistochemical studies on both tumours showed KIT and DOG-1 positivity, with SDHB retained. Molecular analysis revealed a KRAS G12D mutation and a KRAS G13D mutation, respectively. Wild-type GISTs are extremely uncommon. They typically occur in the stomach or the small bowel. KRAS is one of the genes implicated in this subset of GIST, with KRAS G12D being the most frequently encountered mutation. GIST KRAS mutations can arise alone or in conjunction with KIT, PDFRA, or BRAF mutations. Identification of these rare molecular subtypes is clinically important due to their resistance to imatinib therapy.

My approach to bowel ischaemia.

Resections of ischaemic bowel are one of the most common pathology specimens yet are often viewed as unappealing and diagnostically unrewarding. This article serves to dispel both misconceptions. It also provides guidance on how clinical information, macroscopic handling and microscopic assessment-and especially the interlinking of all three-can maximise the diagnostic yield of these specimens. This diagnostic process requires recognition of the wide range of causes of intestinal ischaemia, including several more recently described entities. Pathologists should also be aware of when and why such causes cannot be discerned from a resected specimen and of how certain artefacts or differential diagnoses can mimic ischaemia.

BSG 2024 IBD guidelines protocol (standard operating procedures).

INTRODUCTION: In the past 5 years, there have been several advances in the management of inflammatory bowel disease (IBD). We aim for a new guideline to update the most recent guideline published in 2019. We present the prospective operating procedure and technical summary protocol in the manuscript. METHODS: 'Grading of Recommendations Assessment, Development and Evaluation' (GRADE) will be followed in the development of the guideline, approach as laid out in the GRADE handbook, supported by the WHO. The guideline development group is formed by a variety of disciplines, across both primary and secondary care that took part in an online Delphi process and split into key areas. A final consensus list of thematic questions within a 'patient, intervention, comparison, outcome' format has been produced and agreed in the final phase of the Delphi process.There will be a detailed technical evidence review with source data including systematic reviews appraised with AMSATAR 2 tool (Assessment of multiple systematic reviews), randomised controlled trial data that will be judged for risk of bias with the Cochrane tool and observational studies for safety concerns assessed through the Robins-I tool. Based on the available evidence, some of the recommendations will be based on GRADE while others will be best practice statements.A full Delphi process will be used to make recommendations using online response systems.This set of procedures has been approved by the Clinical Services and Standards Committee, the British Society of Gastroenterology executive board and aligned with IBD UK standards.

A literature review and database of how the primary KIT/PDGFRA variant of a gastrointestinal stromal tumour predicts for sensitivity to imatinib.

It is well recognized that the primary KIT or PDGFRA variant of a gastrointestinal stromal tumour (GIST) can predict sensitivity to imatinib. However, these data are currently spread across a wide range of publications and have not been collated as one reference. A broad-ranging literature search was therefore performed to assemble such a database which should help optimize imatinib-based management of GIST patients henceforth. Having excluded wild type GISTs and results for imatinib used as adjuvant therapy, 79 publications (dated August 2001 to March 2022) underwent data extraction. These data on imatinib sensitivity were either derived from in vitro studies, predicted by in silico analysis or based on in vivo clinical patient response. Data interpretation carried some caveats: there was a potential for replication of patient-derived data between older and new publications; only predicted protein sequences were presented; the criteria used to record clinical response were not uniform across all publications; and imatinib dosage could vary between different clinical publications. However, these data showed broad agreement of imatinib sensitivity amongst similar subtypes of KIT or PDGFRA variant. There was also agreement between in vivo versus in vitro/in silico derived sensitivity data for most variants when both data types were available.

Demographic trends in the incidence of malignant appendiceal tumours in England between 1995 and 2016: Population-based analysis.

AIMS: Recent data suggest that the incidence of malignant appendiceal tumours is increasing. This study aimed to determine temporal trends in the incidence of malignant appendiceal tumours within England and a possible influence by demographic factors. METHODS: All incident cases of appendiceal tumours in patients aged 20 years and above were identified from the National Cancer Registration and Analysis Service database between 1995 and 2016 using ICD-9/10 codes. Cancers were categorized according to histology. Joinpoint regression analysis was used to investigate changes in age-standardized incidence rates by age, sex, histological subtype and index of multiple deprivation quintiles, based on socioeconomic domains (income, employment, education, health, crime, barriers to housing and services and living environment). Average annual per cent changes (AAPCs) were estimated by performing Monte-Carlo permutation analysis. RESULTS: A total of 7333 tumours were diagnosed and 7056 patients were analysed, comprising 3850 (54.6 per cent) neuroendocrine tumours (NETs), 1892 (26.8 per cent) mucinous adenocarcinomas and 1314 (18.6 per cent) adenocarcinoma (not otherwise specified). The overall incidence of appendiceal tumours increased from 0.3 per 100 000 to 1.6 per 100 000 over the study interval. Incidence rate increases of comparable magnitude were observed across all age groups, but the AAPC was highest among patients aged 20-29 years (15.6 per cent, 95 per cent c.i 12.7-18.6 per cent) and 30-39 years (14.2 per cent, 12.2-16.2 per cent) and lowest among those aged 70-79 years (6.8 per cent, 5.7-8.0 per cent). Similar incidence rate increases were reported across all socioeconomic deprivation quintiles and in both sexes. Analysis by grade of NET showed that grade 1 tumours accounted for 63 per cent between 2010 and 2013, compared with 2 per cent between 2000 and 2003. CONCLUSIONS: The incidence rate of malignant appendiceal tumours has increased significantly since 1995 and is mainly attributed to an increase in NETs. The increased diagnosis of low-grade NETs may in part be due to changes in pathological classification systems.

Clinical utility of GI pathology data: implications for practising pathologists.

Gastrointestinal (GI) tract pathology represents one of the largest individual specialties within cellular pathology departments globally. As with other specialties, clear communication with clinicians providing primary care for the patient is of utmost importance for optimal management and for appropriate use of resources such as endoscopy. A wide breadth of neoplastic and inflammatory conditions afflicts the GI tract. Here, we aim to illustrate how pathology reporting of GI tract specimens influences patient management and specifically how precise reporting of key parameters in different specimen types and different disease processes can directly impact patient care. We describe the potential clinical relevance of selected pathology data items pertinent to specific conditions and highlight areas of contention with respect to the significance of some pathology features. Recent guidelines are described where a change, for example, in diagnostic criteria for a condition is described, or criteria influencing further management such as endoscopic surveillance. The aim of this review is to focus on the clinical importance of careful written communication between the pathologist and primary clinician, illustrated by selective clinical scenarios involving the upper and lower GI tracts.

Simple biliary cysts of the liver can be lined by mucinous epithelium.

AIMS & METHODS: Simple biliary cysts of the liver are described to be lined by biliary epithelium and may be managed nonsurgically or by deroofing only. By contrast, its important differential diagnosis-mucinous cystic neoplasm (MCN)-is at least focally lined by mucinous epithelium, has malignant potential, and therefore should be resected. Following anecdotal observations in routine diagnostic practice, the following case series was assembled to confirm whether simple biliary cysts of the liver can be lined by mucinous epithelium. Detailed clinicoradiological review, including postoperative follow-up, was also completed to assess whether the presence of mucinous epithelium had any associations, including a risk of hepatobiliary neoplasia. RESULTS: Histological review of 21 simple biliary cysts received as surgical specimens over a 3- year period confirmed an absence of ovarian-like stroma in all cases. The lining epithelium of seven cysts showed focal supranuclear/apical mucin, as confirmed histochemically. Cysts with mucinous epithelium were generally larger and more often showed histological evidence of previous haemorrhage than cysts without this epithelium. There were no other statistically-significant differences in clinicoradiological features between cysts with and without mucinous epithelium, including at postoperative radiological follow-up. CONCLUSIONS: Focal mucinous epithelium can be present in at least one-third of surgically-managed, simple biliary cysts of the liver. Such epithelium may be metaplastic and should not be misinterpreted to indicate a diagnosis of MCN but, apart from this, appears to have no clinical significance. Ovarian-like stroma may therefore be the only histological feature that reliably distinguishes MCN from simple biliary cyst.

Sampling endoscopically normal large bowel mucosa from patients presenting with elevated faecal calprotectin levels is not clinically justified.

AIMS AND METHODS: Faecal calprotectin (FCP) measurement is used especially to investigate for inflammatory bowel disease (IBD). To assess the utility of sampling endoscopically normal large bowel among patients first presenting with elevated FCP, this study identified 115 such patients out of 652 patients with elevated FCP from approximately 6000 primary care tests processed over 15 months. RESULTS: 23 cohort patients showed histologically abnormal large bowel biopsies. Only four cases demonstrated acute inflammation and two such patients only showed scattered cryptitis and did not develop IBD. A third patient demonstrated similar histology but, following repeat colonoscopy, her elevated FCP was attributed to small intestinal inflammation. Only the fourth patient's large bowel biopsies showed features suggesting Crohn's disease, but this represented an IBD detection rate out of 115 sets of large bowel biopsies of 0.9%. CONCLUSIONS: Sampling of endoscopically normal large bowel among patients first presenting with elevated FCP is not clinically justified.

The Bowel Cancer Screening Programme Expert Board: an analysis of activity during 2017-2020.

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.

Calponin and MUC6 complement inhibin as diagnostic immunomarkers of serous cystadenoma in endoscopic ultrasound-guided aspiration/biopsy specimens.

AIMS: Because serous cystadenoma (SCA) does not usually require excision, it is critical to distinguish it from differential diagnoses which do, especially neuroendocrine tumour (NET). The gold standard for diagnosing SCA is assessment of endoscopic ultrasound-guided fine needle aspiration/biopsy (EUS-FNAB) material. Inhibin immunohistochemistry aids this assessment, but such positivity is not absolutely sensitive or specific to SCA. The following is the largest known study of SCA EUS-FNAB specimens and the first to compare four potential SCA immunomarkers between themselves and inhibin, compared against NET. METHODS AND RESULTS: Immunohistochemistry for calponin, mucin 6 (MUC6), glucose transporter 1 (GLUT1) and vascular endothelial growth factor A (VEGFA) was performed on 30 EUS-FNAB and three resection specimens of SCA and 32 EUS-FNAB specimens of NET. GLUT1 and VEGFA were suboptimal as diagnostic immunomarkers of SCA, being expressed by 10 and 44% of NETs, respectively. Further, their expression by cellular constituents of blood which often contaminate EUS-FNAB specimens hampered identification of neoplastic cells, especially in hypocellular samples. While 19% of NETs showed nuclear MUC6 positivity, cytoplasmic expression of the protein showed 100% specificity and sensitivity as an SCA marker. However, assessing MUC6 in EUS-FNAB specimens must also consider the protein's focal expression in physiological pancreatic, gastric or duodenal tissues, which can contaminate these specimens. Calponin was less sensitive (71% versus 100%) but more specific (100% versus 91%) than inhibin, although easier to assess in EUS-FNAB specimens than MUC6. CONCLUSIONS: Of the four potential immunomarkers of SCA suggested by the existing literature, calponin and MUC6 are useful complementary studies to inhibin for application to EUS-FNAB specimens.

Histopathological diagnosis of tumour deposits in colorectal cancer: a Delphi consensus study.

AIMS: Tumour deposits (TDs) are an important prognostic marker in colorectal cancer. However, the classification, and inclusion in staging, of TDs has changed significantly in each tumour-node-metastasis (TNM) edition since their initial description in TNM-5, and terminology remains controversial. Expert consensus is needed to guide the future direction of precision staging. METHODS AND RESULTS: A modified Delphi consensus process was used. Statements were formulated and sent to participants as an online survey. Participants were asked to rate their agreement with each statement on a five-point Likert scale and also to suggest additional statements for discussion. These responses were circulated together with anonymised comments, and statements were modified prior to carrying out a second online round. Consensus was set at 70%. Overall, 32 statements reached consensus. There were concerns that TDs were currently incorrectly placed in the TNM system and that their prognostic importance was being underestimated. There were concerns regarding interobserver variation and it was felt that a clearer, more reproducible definition of TDs was needed. CONCLUSIONS: Our main recommendations are that the number of TDs should be recorded even if lymph node metastases (LNMs) are also present and that nodules with evidence of origin [extramural venous invasion (EMVI), perineural invasion (PNI), lymphatic invasion (LI)] should still be categorised as TDs and not excluded, as TNM-8 specifies. Whether TDs should continue to be included in the N category at all is controversial, and did not achieve consensus; however, participants agreed that TDs are prognostically worse than LNMs and the N1c category is suboptimal, as it does not reflect this.

The diagnostic and clinical significance of granulomas in gastrointestinal biopsies from haematopoietic transplant patients.

AIMS: The diagnostic and clinical significance of granulomas in gastrointestinal (GI) biopsies from haematopoietic transplant patients remains disputed, especially following the proposal of cord colitis syndrome (CCS) as a new entity. The aim of the following study was to explore this controversy by identifying such biopsies with granulomas and detailing their clinicopathological associations. METHODS AND RESULTS: Twelve patients with granuloma-containing biopsies were identified from across three scenarios: prospectively during a GI pathologist's routine practice over a period of 5 years; retrospectively from a cohort of transplant patients with clinically validated GI graft versus host disease (GVHD); and retrospectively from a cohort of patients who had received umbilical cord blood (UCB). Their clinicopathological assessments (which included unique long-term patient follow-up) showed that granulomas are only rarely seen across all GI biopsies from haematopoietic transplant patients, and may uncommonly constitute a histological feature of GI GVHD. Granulomas-and especially well-defined, non-cryptolytic ones-are more commonly present in GI biopsies from UCB recipients, but do not show any accompanying histological features that are different from those seen in granuloma-containing biopsies from other patient groups. Furthermore, the three UCB recipients with granuloma-containing biopsies were clinically diagnosed with GVHD rather than CCS. Finally, polymorphic post-transplant lymphoproliferative disorder (PTLD) can present histologically as GI granulomatous inflammation that mimics Crohn's disease. CONCLUSIONS: Granulomas in GI biopsies of haematopoietic transplant patients may often indicate a treatable aetiology such as GVHD or PTLD. Granulomas are more commonly seen in GI biopsies from UCB recipients, but do not necessarily indicate a diagnosis of CCS.

Current dilemmas in the pathological staging of colorectal cancer: the results of a national survey.

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.

Next-generation sequencing demonstrates the rarity of short kinase variants specific to quadruple wild-type gastrointestinal stromal tumours.

AIM: There is no known specific biomarker or genetic signal for quadruple wild-type (qWT) gastrointestinal stromal tumours (GISTs). By next-generation sequencing (NGS) of different GIST subgroups, this study aimed to characterise such a biomarker especially as a potential therapeutic target. METHODS AND RESULTS: An NGS panel of 672 kinase genes was applied to DNA extracted from 11 wild-type GISTs (including three qWT GISTs) and 5 KIT/PDGFRA mutated GISTs. Short variants which were present in qWT GISTs but no other GIST subgroup were shortlisted. After removing common population variants, in silico-classified deleterious variants were found in CSNK2A1, MERTK, RHEB, ROCK1, PIKFYVE and TRRAP. None of these variants were demonstrated in a separate cohort of four qWT GISTs. CONCLUSIONS: Short kinase variants which are specific to qWT GISTs are rare and are not universally demonstrated by this whole subgroup. It is therefore possible that the current definition of qWT GIST still covers a heterogenous population.

Absence of nosocomial influenza and respiratory syncytial virus infection in the coronavirus disease 2019 (COVID-19) era: Implication of universal masking in hospitals.

Universal masking for healthcare workers and patients in hospitals was adopted to combat coronavirus disease 2019 (COVID-19), with compliance rates of 100% and 75.9%, respectively. Zero rates of nosocomial influenza A, influenza B, and respiratory syncytial virus infection were achieved from February to April 2020, which was significantly lower than the corresponding months in 2017-2019.

The important role of the histopathologist in clinical trials: challenges and approaches to tackle them.

High-quality histopathology is essential for the success of clinical trials. Histopathologists have a detailed understanding of tumour biology and mechanisms of disease, as well as practical knowledge of optimal tissue handling and logistical service requirements for study delivery, such as biomarker evaluation, tissue acquisition and turnaround times. As such, histopathologist input is essential throughout every stage of research and clinical trials, from concept development and study design to trial delivery, analysis and dissemination of results. Patient recruitment to trials takes place among all healthcare settings, meaning that histopathologists make an invaluable contribution to clinical trials as part of their routine day-to-day work that often goes unrecognised. More complex evaluation of surgical specimens in the neoadjuvant setting and ever-expanding minimum data sets add to the workload of every histopathologist, not just academic pathologists in tertiary centres. This is occurring against a backdrop of increasing workload pressures and a worldwide shortage of histopathologists and biomedical scientists. Providing essential histopathology support for trials at grassroots level requires funding for adequate resources including histopathologist time, education and training, biomedical scientist and administrative support and greater recognition of the contribution made by histopathology. This paper will discuss the many ways in which histopathologists are involved in clinical trials and the challenges faced in meeting the additional demands posed by trial participation and potential ways to address this, with a special emphasis on the UK model and the Cellular-Molecular Pathology Initiative (CM-Path).