Microscopic colitis: a population-based case series over a 9-year period in Northern Ireland.

AIM: We report clinicopathological experience of microscopic colitis (MC) in a population-based case series in Northern Ireland over a 9-year period. METHOD: The pathology laboratory information system within a large teaching centre serving two healthcare trusts was interrogated for cases coded between 2008 and 2016 as collagenous colitis (CC) or lymphocytic colitis (LC). Demographic, clinical and follow-up information was collected from healthcare records. RESULTS: A total of 326 new diagnoses of MC were identified, an average annual incidence of 6.7 per 100 000 population. The average annual incidence of CC and LC was 5.0 and 1.7 per 100 000 population, respectively. For coding reasons it is likely that LC data are incomplete. Of 191 cases diagnosed by specialist gastrointestinal pathologists, 141 patients had CC and 50 patients had LC. Both CC and LC predominantly involved women aged 60-79. Some 15% demonstrated endoscopic abnormalities. Endoscopic sampling protocols varied widely: 30% of individuals with CC and 32% of those with LC had the right and left colon sampled separately, with histology concordant in 95% of cases. Of the 191 cases, only one case (of LC) was refractory to treatment; the rest exhibited a clinical response. Only 35 patients had follow-up endoscopy and biopsies, and three of each diagnosis showed persistent disease on histology. CONCLUSION: Overall, CC and LC are benign conditions with similar demographics, clinical associations, management and outcomes. Separate sampling of the right and left colon is advised at colonoscopy if this diagnosis is being considered, but left colonic sampling, which can be performed at flexible sigmoidoscopy, will diagnose the vast majority of cases.

Report of the Association of Coloproctology of Great Britain and Ireland/British Society of Gastroenterology Colorectal Polyp Working Group: the development of a complex colorectal polyp minimum dataset.

AIM: The management of large non-pedunculated colorectal polyps (LNPCPs) is complex, with widespread variation in management and outcome, even amongst experienced clinicians. Variations in the assessment and decision-making processes are likely to be a major factor in this variability. The creation of a standardized minimum dataset to aid decision-making may therefore result in improved clinical management. METHOD: An official working group of 13 multidisciplinary specialists was appointed by the Association of Coloproctology of Great Britain and Ireland (ACPGBI) and the British Society of Gastroenterology (BSG) to develop a minimum dataset on LNPCPs. The literature review used to structure the ACPGBI/BSG guidelines for the management of LNPCPs was used by a steering subcommittee to identify various parameters pertaining to the decision-making processes in the assessment and management of LNPCPs. A modified Delphi consensus process was then used for voting on proposed parameters over multiple voting rounds with at least 80% agreement defined as consensus. The minimum dataset was used in a pilot process to ensure rigidity and usability. RESULTS: A 23-parameter minimum dataset with parameters relating to patient and lesion factors, including six parameters relating to image retrieval, was formulated over four rounds of voting with two pilot processes to test rigidity and usability. CONCLUSION: This paper describes the development of the first reported evidence-based and expert consensus minimum dataset for the management of LNPCPs. It is anticipated that this dataset will allow comprehensive and standardized lesion assessment to improve decision-making in the assessment and management of LNPCPs.

British Society of Gastroenterology/Association of Coloproctologists of Great Britain and Ireland guidelines for the management of large non-pedunculated colorectal polyps

These guidelines provide an evidence-based framework for the management of patients with large non-pedunculated colorectal polyps (LNPCPs), in addition to identifying key performance indicators (KPIs) that permit the audit of quality outcomes. These are areas not previously covered by British Society of Gastroenterology (BSG) Guidelines.A National Institute of Health and Care Excellence (NICE) compliant BSG guideline development process was used throughout and the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool was used to structure the guideline development process. A systematic review of literature was conducted for English language articles up to May 2014 concerning the assessment and management of LNPCPs. Quality of evaluated studies was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) Methodology Checklist System. Proposed recommendation statements were evaluated by each member of the Guideline Development Group (GDG) on a scale from 1 (strongly agree) to 5 (strongly disagree) with >80% agreement required for consensus to be reached. Where consensus was not reached a modified Delphi process was used to re-evaluate and modify proposed statements until consensus was reached or the statement discarded. A round table meeting was subsequently held to finalise recommendations and to evaluate the strength of evidence discussed. The GRADE tool was used to assess the strength of evidence and strength of recommendation for finalised statements.KPIs, a training framework and potential research questions for the management of LNPCPs were also developed. It is hoped that these guidelines will improve the assessment and management of LNPCPs.

Double immunohistochemistry enhances detection of lymphatic and venous invasion in early-stage colorectal cancer.

Lymphatic invasion (LI) and venous invasion (VI) are regarded as important risk factors of nodal disease in early-stage colorectal cancer (CRC) but with variable reporting and poor distinction of these parameters in previous studies. This study examines the application of a double immunohistochemistry (D-IHC) method to help detect and distinguish LI and VI, in comparison with haematoxylin and eosin (H&E) staining, in a clinical series of cases of stage pT1 CRC. The aims were to demonstrate feasibility of this methodology in routine practice and compare rates of LI and VI reporting with and without D-IHC application. D-IHC utilising CAM5.2 with the endothelial marker CD34 and with the specific lymphatic endothelial marker D2-40 was performed on parallel sections from single representative paraffin tissue blocks in 28 cases of stage pT1 CRC from routine clinical practice. D-IHC significantly increased rates of both LI and VI reporting, from 14.3 to 35.7 % and from 14.3 to 28.6 %, respectively. The D-IHC methodology described is technically feasible in routine practice and potentially offers a more sensitive and robust assay for detection and distinction of LI and VI in early CRC pathology reporting. The reproducibility and clinical significance of enhanced LI and VI detection by this method and the relative importance of LI and VI in this clinical setting require further study.

Spilled gallstones during laparoscopic cholecystectomy.

INTRODUCTION: Incidental gallbladder cancer is found in 0.6-2.1% of patients undergoing laparoscopic cholecystectomy for symptomatic gallstones. Patients with Tis or T1a tumours generally undergo no further intervention. However, spilled stones during surgery may have catastrophic consequences. We present a case and suggest aggressive management in patients with incidental gallbladder cancer who had spilled gallstones at surgery. CASE HISTORY: A 37-year-old woman underwent a laparoscopic cholecystectomy for symptomatic gallstones, during which some stones were spilled into the peritoneal cavity. Subsequent histological examination confirmed incidental pT1a gallbladder cancer. Hepatopancreatobiliary multidisciplinary team discussion agreed on regular six-monthly follow-up. The patient developed recurrent pain two years after surgery. Computed tomography revealed a lesion in segment 6 of the liver. At laparotomy, multiple tumour embedded gallstones were found on the diaphragm. Histological examination showed features (akin to the original pathology) consistent with a metastatic gallbladder tumour. CONCLUSIONS: This case highlights the potential for recurrence of early stage disease resulting from implantation of dysplastic or malignant cells carried through spilled gallstones. It is therefore important to know if stones were spilled during original surgery in patients with incidental gallbladder cancer following a laparoscopic cholecystectomy. Aggressive and early surgical management should be considered for these patients.

Integrating molecular diagnostics into histopathology training: the Belfast model.

Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information.

The role of surgery for pancreatic cancer: a 12-year review of patient outcome.

INTRODUCTION: Pancreatic cancer has a poor prognosis with <5% alive at 5 years, despite active surgical treatment. The study aim was to review patients undergoing pancreatic resection and assess the effect of clinical and pathological parameters on survival. PATIENTS AND METHODS: All patients who had undergone radical pancreatic surgery, January 1996 to December 2008, were identified from the unit database. Additional information was retrieved from the patient records. The demographic, clinical, and pathological records were recorded using Microsoft Excel. Survival was assessed using Kaplan-Meier and predictors of survival determined by multinominal logistic regression and log rank test. RESULTS: 126 patients were identified from the database. The majority (106) had a Whipple's procedure, 14 had a distal pancreatectomy and 6 had local periampullary excision. The average age of the Whipple's group of patients was 61.7 years (± 11.7) with most procedures performed for malignancy (n=100). Survival was worse with adenocarcinoma compared to all other pathologies (p=0.013), while periampullary tumours had a better prognosis compared to other locations (p=0.019). Survival decreased with poorer differentiation (p=0.001), increasing pT (p<0.001) and pN stage (p<0.001). Survival was worse with perineural (p=0.04) or lymphovascular invasion (p=0.05). A microscopic postive resection margin (R1) was associated with a worse survival (p=0.007). Tumour differentiation (p=0.001) and positive nodal status (p<0.001) were found to be independent predictors of mortality. CONCLUSION: Tumour differentiation and nodal status are important predictors of outcome. A positive resection margin is associated with a poorer survival.

Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer.

Patients suspected on clinical grounds to have hereditary non-polyposis colorectal cancer (HNPCC) may be offered laboratory testing in order to confirm the diagnosis and to facilitate screening of pre-symptomatic family members. Tumours from an affected family member are usually pre-screened for microsatellite instability (MSI) and/or loss of immunohistochemical expression of mismatch repair (MMR) genes prior to germline MMR gene mutation testing. The efficiency of this triage process is compromised by the more frequent occurrence of sporadic colorectal cancer (CRC) showing high levels of MSI (MSI-H) due to epigenetic loss of MLH1 expression. Somatic BRAF mutations, most frequently V600E, have been described in a significant proportion of sporadic MSI-H CRC but not in HNPCC-associated cancers. BRAF mutation testing has therefore been proposed as a means to more definitively identify and exclude sporadic MSI-H CRC cases from germline MMR gene testing. However, the clinical validity and utility of this approach have not been previously evaluated in a familial cancer clinic setting. Testing for the V600E mutation was performed on MSI-H CRC samples from 68 individuals referred for laboratory investigation of suspected HNPCC. The V600E mutation was identified in 17 of 40 (42%) tumours showing loss of MLH1 protein expression by immunohistochemistry but in none of the 28 tumours that exhibited loss of MSH2 expression (P < 0.001). The assay was negative in all patients with an identified germline MMR gene mutation. Although biased by the fact that germline testing was not pursued beyond direct sequencing in many cases lacking a high clinical index of suspicion of HNPCC, BRAF V600E detection was therefore considered to be 100% specific and 48% sensitive in detecting sporadic MSI-H CRC amongst those cases showing loss of MLH1 protein expression, in a population of patients with MSI-H CRC and clinical features suggestive of HNPCC. Accordingly, we recommend the incorporation of BRAF V600E mutation testing into the laboratory algorithm for pre-screening patients with suspected HNPCC, whose CRCs show loss of expression of MLH1. In such tumours, the presence of a BRAF V600E mutation indicates the tumour is not related to HNPCC and that germline testing of MLH1 in that individual is not warranted. We also recommend that in families where the clinical suspicion of HNPCC is high, germline testing should not be performed on an individual whose CRC harbours a somatic BRAF mutation, as this may compromise identification of the familial mutation.

KIT immunohistochemistry and mutation status in gastrointestinal stromal tumours (GISTs) evaluated for treatment with imatinib.

AIMS: With the availability of effective but expensive treatment in the form of imatinib, accurate diagnosis of gastrointestinal stromal tumour (GIST) is extremely important. The aims of this study were: to describe the clinicopathological, immunohistochemical and molecular features of cases referred to a cancer centre with a possible diagnosis of GIST; to identify pitfalls in the performance and interpretation of KIT immunohistochemistry; to define the role of KIT mutation testing in making a diagnosis of GIST. METHODS AND RESULTS: Morphological review, KIT immunohistochemistry and mutation testing were performed on all cases referred with a diagnosis of GIST or where the diagnosis was under serious consideration on the basis of KIT immunopositivity with a view to treating with imatinib. Thirty-seven cases met the inclusion criteria. Of these, 26 were classified as GIST and 11 as non-GIST. Most GISTs showed strong diffuse membranous, cytoplasmic or paranuclear KIT immunopositivity. Some non-GISTs demonstrated patchy cytoplasmic KIT immunopositivity related to the immunohistochemical protocol used in the external laboratory, which led to erroneous diagnoses of GIST in nine (24%) cases. KIT mutations involving exons 11 or 9 were identified in 22 (88%) GISTs tested and none of the non-GISTs. CONCLUSIONS: An accurate diagnosis of GIST can be made on clinicopathological and immunohistochemical criteria without the need for mutational analysis in most cases, provided proper attention is paid to the immunohistochemical protocol used and, most importantly, control material. False-positive diagnoses of GIST potentially leading to inappropriate treatment with imatinib are more common than missed diagnoses.

Gastrointestinal stromal tumour treated with neoadjuvant imatinib.

This report describes a case of unresectable primary gastrointestinal stromal tumour (GIST) treated with imatinib on a neoadjuvant basis, before subsequent successful surgical resection. After six months of imatinib, computed tomography and positron emission tomography imaging demonstrated a significant size reduction and complete metabolic response to treatment, rendering the tumour resectable. Mutational analysis showed an activating KIT mutation in exon 11. The pathological appearance of the resected tumour was heterogeneous with extensive necrosis, cystic and myxoid change, extensive hypocellularity, and patchy foci of residual viable tumour. The implications for this management option of radiological, pathological, and molecular assessment are discussed.

WHO reclassification of breast lymphomas.

Fourteen cases of breast lymphoma, identified from hospital records between 1990 and 2004, were reclassified according to the World Health Organisation criteria. Primary cases occurred more frequently and all cases were of B cell origin, predominantly involving the right breast. Most primary cases were diffuse large B cell lymphomas, whereas secondary cases were heterogeneous in type and most had a poor prognosis.

Fatal hepatic failure following accidental tramadol overdose.

A case of fatal overdose of tramadol is described, occurring in a 67-year-old man with painful rib fractures who accidentally ingested more than the recommended daily dose. The mode of death was acute liver failure due to fulminant hepatic necrosis. Post-mortem toxicology was negative apart from revealing a blood tramadol concentration well above the normal therapeutic range. This is the first report of fatal tramadol ingestion occurring in a therapeutic setting and also the first tramadol-related death where the mechanism was liver failure.

An unusual cause of biliary stricture in a patient with neurofibromatosis type 1.

The majority of biliary strictures occur as a consequence of iatrogenic injury to the extrahepatic biliary tract, with more than 80% following cholecystectomy. The laparoscopic era has led to heightened awareness of this problem. The occurrence of an iatrogenic stricture can be particularly devastating to both patient and surgeon. The literature highlights a number of factors involved in the aetiology of such traumatic stricture formation. We report an unusual case of a Bismuth 2 stricture of the proximal common hepatic duct,occurring in a patient with type 1 neurofibromatosis, following an iatrogenic bile duct injury that occurred during a laparoscopic cholecystectomy. Histological examination of the strictured region of bile duct removed at surgery demonstrated multiple neurofibromas of varying sizes present in the submucosa. Neurofibromatosis type 1 (von Recklinghausen disease) affects the gastrointestinal tract in up to 25% of cases, and in such cases is characterized by multiple submucosal neurofibromas. We believe this is the first reported case of a biliary stricture in a patient with neurofibromatosis type 1, which appeared to be as a consequence of neurofibromas in the submucosa of the bile duct.

The declining autopsy rate and clinicians' attitudes.

The autopsy rate has been declining worldwide for decades. This study determined the overall and differential autopsy rates for the Royal Victoria Hospital, Belfast for the years 1997-1999 inclusive. Trends were examined by comparison with previously collected data for the years 1990, 1991 and 1993. Reasons for the decline in autopsy rates as perceived by hospital clinicians were assessed by means of a questionnaire. Over the last decade, there has been a steady decline in the overall autopsy rate from 30.4% in 1990 to 18.4% in 1999. This is due to a decrease in the hospital autopsy rate from 21.6% in 1990 to 7.9% in 1999. The coroner's autopsy rate has remained comparatively unchanged at around 11%. The decline in the overall and hospital autopsy rates involves all of the principal bedholding directorates, but is most dramatic in medicine, surgery and intensive care, where hospital autopsy rates are currently 7% or less. The main reasons for this decline as perceived by clinicians are difficulty in obtaining consent from relatives and advances in modern diagnostic techniques. The findings of this enquiry are in keeping with trends elsewhere, despite repeated studies which clearly demonstrate the continuing value of the autopsy in clinical practice. Recent publicity concerning the retention of organs can only have an adverse affect. Pathologists and clinicians who value the autopsy must become actively engaged in both public and medical education. Renewed emphasis must be placed on the importance of the autopsy in teaching, training and clinically relevant research, and as a means of medical audit.