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).

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.

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.

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.

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.

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.

Primary peri-anal adenocarcinoma of intestinal type - a new proposed entity.

AIMS: The currently recognised subtypes of anal canal/peri-anal adenocarcinoma are those arising from low rectal mucosa or columnar cuff, fistula-related tumours and anal gland carcinoma. This report presents two examples of a hitherto undescribed subtype of peri-anal adenocarcinoma with an intestinal phenotype. METHODS AND RESULTS: A 74-year-old man had a peri-anal tumour locally excised, whereas a 73-year-old female underwent an abdominoperineal resection for peri-anal Paget's disease with an underlying carcinoma. Neither patient had a history of perineal fistulae, Crohn's disease or previous gastrointestinal neoplasia, and neither showed clinical, radiological or endoscopic evidence of another abdominal or pelvic tumour. Both resection specimens contained adenocarcinoma, which were similar in demonstrating an intestinal morphology and CDX2 immunopositivity. The man has shown a disease-free outcome thus far, but the woman has suffered with nodal and pelvic recurrence within a few months of surgery. CONCLUSIONS: The name 'primary peri-anal adenocarcinoma of intestinal type' is proposed for this previously unrecognised subtype of perineal neoplasia. Awareness of its distinct existence - by recognising its intestinal morphology and immunophenotype while excluding metastasis from the intestinal tract - should help to collate data to determine its specific prognosis and to formulate its best management.

A33 shows similar sensitivity to but is more specific than CDX2 as an immunomarker of colorectal carcinoma.

AIMS: CDX2 is widely used as a sensitive and specific immunomarker for colorectal carcinoma (CRC), but neither its sensitivity nor its specificity is absolute. The aim of this study was to compare CDX1 and A33 with CDX2 as immunomarkers for CRC. METHODS AND RESULTS: As a pilot study, whole sections of 51 cases of liver metastatic carcinoma with different origins-colorectum (n = 32), breast (n = 3), oesophagogastric tract (n = 4), lung (n = 3), pancreas (n = 8), and prostate (n = 1)-were immunostained with CDX1, CDX2, and A33. A33 showed higher sensitivity as a CRC immunomarker, greater interobserver reproducibility for assessment of expression and less background cross-reactivity than CDX1. Therefore, only A33 was compared with CDX2 for a tissue microarray (TMA)-based study of primary adenocarcinomas with different origins: CRC (n = 55), liver deposits of metastatic CRC (n = 60), breast (n = 101), lung (n = 40), oesophagogastric tract (n = 134), ovary (n = 67), pancreas (n = 77), and prostate (n = 56). When the whole section and TMA cases of CRC were combined, A33 had a sensitivity of 95.9% and CDX2 had a sensitivity of 97.2%. When the whole section and TMA cases of non-colorectal carcinomas were combined, A33 had a specificity of 85.4% as a marker of CRC and CDX2 had a specificity of 64.3%. The higher specificity of A33 than of CDX2 as a CRC immunomarker was particularly seen among pancreatic and ovarian carcinomas. Furthermore, unlike what was seen with CDX2, none of the prostatic and lung carcinomas studied showed A33 positivity. CONCLUSIONS: A33 shows similar sensitivity to but is more specific than CDX2 as an immunomarker of CRC.

Gastrointestinal pathology in transplant patients.

The assessment of gastrointestinal (GI) specimens from transplant patients is complicated by the wide range of potentially rare pathologies that may be found in this clinical setting. Acute GI graft-versus-host disease (GvHD) is characterized by epithelial cell apoptosis, although there is increasing recognition that acute and/or chronic inflammation may also be present. By contrast, thus far there are no histological features known to be specific to chronic GI GvHD. Mycophenolate mofetil colitis may mimic both GvHD and inflammatory bowel disease, whereas both cytomegalovirus (CMV) and adenovirus infections can cause gland apoptosis. Post-transplant lymphoproliferative disorder should be considered if a Crohn's-like histological picture is seen, and granulomas in biopsies from umbilical cord blood recipients should raise a suspicion of cord colitis syndrome. Finally, the GI tract may be involved directly or indirectly by the disease that originally required haematopoietic stem cell or liver transplantation.

Abdominal monophasic synovial sarcoma is a morphological and immunohistochemical mimic of gastrointestinal stromal tumour.

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.

An immunohistochemical study of potential diagnostic and therapeutic biomarkers of wild-type gastrointestinal stromal tumours.

AIMS: The aims of this study were to investigate whether succinate dehydrogenase B (SDHB), insulin growth factor 1 receptor (IGF1R), HER2, epidermal growth factor receptor (EGFR) and/or BRAF V600E immunohistochemistry could screen for wild-type gastrointestinal stromal tumours (GISTs), and to determine what proportion of wild-type GISTs expressed these proteins and might therefore represent candidates for targeted therapies. METHODS AND RESULTS: Twenty-seven wild-type GISTs and 91 KIT-mutated or PDGFRA-mutated GISTs were immunostained for SDHB, IGF1R, HER2, and EGFR. A preliminary study of the BRAF VE1 antibody showed non-specific staining, and indicated it was neither a specific nor a sensitive marker of wild-type GISTs. SDHB loss showed 100% specificity but only 37% sensitivity as such a marker. EGFR and IGF1R were expressed by 63% and 33% of the wild-type GISTs but also by 56% and 32% of the KIT/PDGFRA mutant GISTs, respectively. Therefore, adding EGFR and/or IGF1R to SDHB as a panel only decreased the specificity of SDHB loss as a marker for wild-type status. CONCLUSIONS: All five antibodies failed, individually or collectively, to represent highly sensitive and highly specific markers for wild-type GIST. However, whereas HER2 has been excluded as a therapeutic biomarker, both EGFR and IGF1R are expressed by some wild-type GISTs and are therefore potential therapeutic targets.

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.

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.

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.

Gastrointestinal stromal tumours--an update for histopathologists.

This review aims to summarize recent knowledge gained about gastrointestinal stromal tumour (GIST) of particular relevance to histopathologists. KIT and PDGFRA mutation analyses can be useful for confirming a diagnosis of GIST, but there are some diagnostic limitations to these analyses, and so immunohistochemical markers currently remain crucial to the diagnostic process. Of these markers, CD117 and Discovered on GIST 1 (DOG1) are currently the most sensitive and specific markers of GIST, and recent data appear to disprove the fear that antigen retrieval causes false-positive CD117 immunostaining. The accurate prognostication of GIST has been greatly helped by the National Institutes of Health (NIH) and Armed Forces Institute of Pathology (AFIP) classification systems, although both systems still have limitations, and the behaviours of certain GIST subgroups are less well predicted by both systems. KIT and PDGFRA mutation analyses can help to predict the response of GISTs to receptor tyrosine kinase inhibitors, and both GISTs that respond and those that show resistance to these inhibitors may show characteristic pathological changes. Some GIST subgroups (e.g. Carney syndrome and paediatric GISTs) have had recently described clinicopathological and/or molecular characteristics which may help with the diagnosis and/or treatment of these specific neoplasms.

Gastrointestinal stromal tumours can express CD10 and epithelial membrane antigen but not oestrogen receptor or HMB45.

AIMS: Gastrointestinal stromal tumour (GIST) may share morphological and/or immunohistochemical features with various intra-abdominal neoplasms, including endometrial stromal sarcoma, perivascular epithelioid cell tumour (PEComa), melanoma and synovial sarcoma. Each of these various neoplasms has characteristic immunohistochemical markers, including epithelial membrane antigen (EMA), CD10, oestrogen receptor alpha (ERa) and/or HMB45, and therefore the primary aim of this study was to determine whether these markers are also expressed by GISTs. METHODS AND RESULTS: Standard size sections of 52 GISTs were immunostained for EMA, CD10, ERa and a melanoma marker cocktail (targeting HMB45 and melan-A). Ten GISTs (19%) showed CD10 immunopositivity. This positivity was confined almost completely to small intestinal GISTs, and was seen among spindle cell GISTs but not epithelioid or mixed cell-type GISTs. Five of the 52 GISTs (9.6%) showed EMA immunopositivity. This positivity was always focal and usually seen in a perivascular location. None of the GISTs showed immunopositivity for ERa or the melanoma marker cocktail. CONCLUSIONS: GISTs occasionally show CD10 immunopositivity (especially small intestinal spindle cell GISTs), and infrequently show focal EMA positivity. GISTs do not show immunopositivity for ERa or HMB45.