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.

Appendiceal Well-Differentiated Neuroendocrine Tumors: A Single-Center Experience and New Insights into the Effective Use of Immunohistochemistry.

Background. Appendiceal well-differentiated neuroendocrine tumor is the most common histological type of appendiceal tumor. The majority of tumors are found incidentally at the tip of the appendix, with few exceptions. Due to its primarily indolent nature, this entity presents unique pathological challenges, particularly in the appropriate use of immunohistochemistry which this study aims to clarify. Patients and methods. Patients diagnosed at University Health Network (Canada) between 2005-2019 were selected and reviewed. Results. We identified 70 patients and sex distribution was female 60%; median age 36.5 years. Among them, 63 patients underwent appendectomy, and seven had initial right hemicolectomy for non-appendix lesions. Mean tumor size was 5.0 mm. Tumor extent was submucosa (15%); muscularis propria (34%); subserosa or mesoappendix (42%); visceral peritoneum (8%). All were clinically non-functional and negative for nodal and distant metastasis. Ninety percent of tumors were WHO Grade 1; 10% were WHO Grade 2. Immunohistochemically, an average of six stains were performed per patient. Nearly all tumors were positive for chromogranin A, synaptophysin, CAM5.2, and CDX2. MIB-1 staining was < 3% in 58/63 tumors. Other immunohistochemical stainings performed were hormonal markers (serotonin, glucagon, pancreatic peptide, peptide YY). Subsequent right hemicolectomy was performed on five patients. All were followed up (median 4 years 8 months), and all were alive without recurrence except for one patient who died of another comorbidity. Conclusion. Tumors that are small, localized, and of low grade can be reasonably exempt from an extensive immunohistochemical panel in the absence of non-typical clinical and morphological features.

Establishment of a remote diagnostic histopathology service using whole slide imaging (digital pathology).

BACKGROUND: Whole slide imaging (WSI) has diverse applications in modern pathology practice, including providing histopathology services to remote locations. MATERIALS AND METHODS: Utilising an existing contractual partnership with a Northern Ontario group of hospitals, the feasibility of using WSI for primary diagnostic services from Toronto was explored by the dedicated working group. All aspects explored from information technology (IT), laboratory information system (LIS) integration, scanning needs, laboratory workflow and pathologist needs and training, were taken into account in the developing the rationale and business case. RESULTS: The financial outlay for a scanner was $CA180K (approximately £105.6 k) after discounts. There were no human resource requirements as staff were reorganised to cater for slide scanning. Additional IT/LIS costs were not incurred as existing connectivity was adapted to allow two site groups (gastrointestinal and skin) to pilot this study. Scanned slides were available for pathologist review 24-96 hours sooner than glass slides; there was a 2-day improvement for final authorised cases, and per annum savings were: $CA26 000 (£15.2 k) in courier costs, $CA60 000 (£35.2 k) travel and $CA45 000 (£26.4 k) in accommodation, meals and car rental expense. CONCLUSION: WSI is a viable solution to provide timely, high-quality and cost efficient histopathology services to underserviced, remote areas.

Review of pathology and cost benefit analysis of hernia sacs processed over a 19-year period.

AIM: Hernia sacs with pathological evaluation over a 19-year period were analysed with regards to pathological diagnoses, full costing and the impact on patient management. MATERIALS AND METHODS: The database of the Department of Pathology were searched over the study period (2001 to 2019 inclusive) for hernia sacs. The total cost of complete pathology examination was calculated on average numbers and rates of pay that existed over the study period. RESULTS: A total of 3619 hernia sacs from the abdominal, hiatus/diaphragmatic, inguinal and femoral hernias were retrieved. Of these 3592 cases (99.25%) had sections taken for histological evaluation. A total of 3437 cases representing 95.7% of all hernia sacs did not show any pathological abnormality. If non-neoplastic clinically insignificant lesions seen in hernia sacs is included, then 3552 of 3592 (98.9%) hernia sacs underwent full pathological evaluation for no patient benefit.On average two blocks or tissue sections per case were processed incurring a technical cost of $53 175.00. The total pathologist cost in reporting the 3592 cases was approximately $39 870.00 and rose to $40 410.00 when interpretation of ancillary tests was factored in. $95 328.90 (average $26.90 per specimen with a yearly average total cost of $5 017.31) was spent over the 19-year period in full pathological examination of 3592 hernia sacs. CONCLUSION: Given the low return on investment and the difficult to quantify time savings and reallocation, we do not advocate the routine sampling of hernia sacs. Gross examination will suffice in 99% of the cases. Selective cases may be sampled if clinically indicated.

Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome.

INTRODUCTION: Transcriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC. DESIGN: We first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes. RESULTS: We identified four morphological patterns that segregated into two components ('gland forming' and 'non-gland forming') based on the presence/absence of well-formed glands. A morphological cut-off (≥40% 'non-gland forming') was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as 'classical' using RNA-Seq. CONCLUSION: Our study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

Predicting Underlying Neoplasms in Appendiceal Mucoceles at CT: Focal Versus Diffuse Luminal Dilatation.

OBJECTIVE. The purpose of this study was to determine whether a novel morphologic characteristic of appendiceal mucoceles at CT-focal distal appendiceal dilatation with a segment of morphologically normal appendix proximally-could predict an underlying neoplastic pathologic abnormality before surgery and histopathologic assessment. MATERIALS AND METHODS. A retrospective study was performed that assessed CT cases from 2012 through 2014. Cases showing morphologic features of a mucocele were identified and categorized into two subgroups: focal distal dilatation with a segment of normal appendix proximally and generalized appendiceal dilatation. The underlying histopathologic diagnosis for each case was assessed and categorized as neoplastic or nonneoplastic. Several additional morphologic findings were also assessed. RESULTS. Forty-nine cases with confirmed histopathologic diagnoses were identified. Of those, 20 of 23 (87.0%) cases with the finding of focal distal dilatation had an underlying neoplastic cause, whereas 14 of 26 (53.8%) cases with generalized dilatation had an underlying neoplastic cause (p = 0.012). The findings of periappendiceal fat stranding (p = 0.004), mural calcification (p = 0.006), and degree of luminal dilatation (p = 0.002) also reached statistical significance. When seen in combination with focal distal dilatation, the positive predictive value for underlying neoplasm approached or reached 100%. CONCLUSION. Our study shows that isolated focal distal appendiceal dilatation with a segment of morphologically normal appendix proximally is significantly associated with an underlying neoplastic histopathologic cause. When seen in combination with mural calcification, a diameter of more than 2 cm, and absence of periappendiceal stranding, an underlying neoplastic cause is strongly suggested.

Gastric foveolar dysplasia: a survey of reporting habits and diagnostic criteria.

This study aimed to ascertain views, incidence of reporting and diagnostic criteria for gastric foveolar dysplasia. A questionnaire, a post-questionnaire discussion and microscopic assessment of selected cases was conducted by gastrointestinal pathologists to explore the above-stated aims. Fifty-four percent of respondents never or rarely diagnosed gastric foveolar-type dysplasia. The general consensus was that round nuclei, lack of nuclear stratification, presence of inflammation/damage and surface maturation favoured reactive change; while architectural abnormalities/complexity and nuclear enlargement mainly were used to separate low-grade from high-grade foveolar dysplasia. Immunohistochemistry was rarely used to make the diagnosis of dysplasia and was thought not to be of help in routine practice. Inter-observer agreement in grading of dysplasia versus reactive, and the type of dysplasia (foveolar versus adenomatous), was substantial/almost perfect amongst 35.7% and 21.4% of participants, respectively. This reflects low reproducibility in making these diagnoses. In conclusion, foveolar dysplasia was a rarely made diagnosis among 14 gastrointestinal pathologists, there are no uniform criteria for diagnosis and there is poor inter-observer agreement in separating low-grade foveolar dysplasia from reactive gastric mucosa and low-grade adenomatous dysplasia. Greater awareness and agreed criteria will prevent misdiagnosis of low-grade foveolar dysplasia as reactive, and vice versa.

Regression grading in neoadjuvant treated pancreatic cancer: an interobserver study.

AIM: Several regression grading systems have been proposed for neoadjuvant chemoradiation-treated pancreatic ductal adenocarcinoma (PDAC). This study aimed to examine the utility, reproducibility and level of concordance of three most frequently used grading systems. METHODS: Four gastrointestinal pathologists used the College of American Pathologists (CAP), Evans, MD Anderson Cancer Centre (MDA) regression grading systems to grade 14 selected cases (7-20 slides from each case) of neoadjuvant chemoradiation-treated PDAC. A postscoring discussion with each pathologist was conducted. The results were entered into a standardised data collection form and statistical analyses were performed. RESULTS: There was little concordance across the three systems. The Kendall coefficient of concordance agreement scores were: CAP: 2-poor, 2-fair; Evans: 1-fair, 1-moderate, 2-good; MDA: 1-poor, 2-moderate, 1-good. Interpretation in all three grades in the CAP grading system was a source of discrepancy. Furthermore, using fibrosis as a criterion to assess regression was contentious. In the Evans system, quantifying tumour destruction using arbitrary percentage cut-offs (ie, 9% vs 10%; 50% vs 51%, etc) was imprecise and subjective. Although the MDA system generated greatest concordance, this was due to 'oversimplification' surrounding wide, arbitrarily assigned thresholds of 5% of tumour. CONCLUSIONS: All systems lacked precision and clarity for accurate regression grading. Presently the clinical utility and impact of histological regression grading in patient management is questionable. There is a need to re-evaluate regression grading in the pancreas and establish a reproducible, clinically relevant grading system.

The first report of a previously undescribed EBV-negative NK-cell lymphoma of the GI tract presenting as chronic diarrhoea with eosinophilia.

A 74-year-old man presented with a 2-month history of watery diarrhoea. His complete blood count showed lymphopaenia and marked eosinophilia. Investigations for common infectious causes including Clostridium difficile toxin, stool culture, ova and parasites were negative. Endoscopy revealed extensive colitis and a CT of the abdomen identified numerous large abdominal lymph nodes suspicious for lymphoma. Multiple tissue samples were obtained; colon, mesenteric lymph node and bone marrow biopsy, as well as pleural fluid from a rapidly developing effusion, confirmed the presence of metastatic lymphoma with an immunophenotype most consistent with an aggressive variant of Epstein-Barr virus (EBV)-negative natural killer (NK)-cell lymphoma. The patient's clinical condition rapidly deteriorated and he died shortly following diagnosis. To the best of our knowledge, this is the first case report of a primary gastrointestinal EBV-negative NK-cell lymphoma, and its clinical presentation highlights the importance of a broad differential in the management of chronic diarrhoea.

Primary cystic peritoneal masses and mimickers: spectrum of diseases with pathologic correlation.

Cystic lesions within the peritoneum have been classified classically according to their lining on histology into four categories-endothelial, epithelial, mesothelial, and others (germ cell tumors, sex cord gonadal stromal tumors, cystic mesenchymal tumors, fibrous wall tumors, and infectious cystic peritoneal lesions). In this article, we will proceed to classify cystic peritoneal lesions focusing on the degree of radiological complexity into three categories-simple cystic, mildly complex, and cystic with solid component lesions. Many intra-abdominal collections within the peritoneal cavity such as abscess, seroma, biloma, urinoma, or lymphocele may mimic primary peritoneal cystic masses and need to be differentiated. Clinical history and imaging features may help differentiate intra-abdominal collections from primary peritoneal masses. Lymphangiomas are benign multilocular cystic masses that can virtually occur in any location within the abdomen and insinuate between structures. Ultrasound may help differentiate enteric duplication cysts from other mesenteric and omental cysts in the abdomen. Double-layered wall along the mesenteric side of bowel may suggest its diagnosis in the proper clinical setting. Characteristic imaging features of hydatid cysts are internal daughter cysts, floating membranes and matrix, peripheral calcifications, and collagenous pericyst. Non-pancreatic psuedocysts usually have a fibrotic thick wall and chylous content may lead to a fat-fluid level. Pseudomyxoma peritonei appears as loculated fluid collections in the peritoneal cavity, omentum, and mesentery and may scallop visceral surfaces. Many of the primary cystic peritoneal masses have specific imaging features which can help in accurate diagnosis and management of these entities. Knowledge of the imaging spectrum of cystic peritoneal masses is necessary to distinguish from other potential cystic abdominal mimicker masses.

Infection and esophageal cancer.

The following, from the 12th OESO World Conference: Cancers of the Esophagus, includes commentaries on infection and cancer, and includes commentaries on the influence of bacterial infections on mucin expression and cancer risk; the role of esophageal bacterial biota in the incidence of esophageal disease; the association between human papilloma virus (HPV) and esophageal squamous cell carcinoma; the role of HPV in esophageal adenocarcinoma; the role of Helicobacter pylori in cardiac carcinoma; and the role of Epstein-Barr virus infection in esophageal cancer.

Gastric biopsies: the gap between evidence-based medicine and daily practice in the management of gastric Helicobacter pylori infection.

BACKGROUND: Many consider histology to be the gold standard for Helicobacter pylori detection. Because the number and distribution of H pylori organisms vary, particularly in patients taking proton pump inhibitors (PPIs), the American Gastroenterological Association recommends discontinuing PPIs two weeks before endoscopy, and taking biopsies from both the body and antrum. OBJECTIVE: To assess the influence of clinical practice on the histopathological detection of H pylori infection. METHODS: Electronic patient records were evaluated for the sites of gastric sampling and PPI use at endoscopy. One hundred fifty cases with biopsies taken from both antrum and body were randomly selected for pathological re-review with special stains. The gastric regions sampled, H pylori distribution and influence of clinical factors on pathological interpretation were assessed. RESULTS: Between 2005 and 2010, 10,268 biopsies were taken to detect H pylori. Only one region was sampled in 60% of patients (antrum 47%, body 13%). Re-review of biopsies taken from both antrum and body indicated that the correct regions were sampled in only 85 (57%) patients. Of these, 54 were H pylori positive and 96 were H pylori negative. H pylori was present in the antrum in only 15% of the patients and body only in 21%. Of 96 H pylori-negative patients, two were reinterpreted as positive. Forty-seven per cent of patients were taking PPIs at endoscopy, contributing to both false-negative and false-positive diagnoses. CONCLUSION: Despite national and international guidelines for managing H pylori infection, the American Gastroenterological Association guidelines are infrequently adhered to, with PPIs frequently contributing to false diagnosis; sampling one region only increases the likelihood of missing active infection by at least 15%.

Incidental perivascular epithelioid cell tumor in an inguinal hernia sac.

Perivascular epithelioid tumors (PEComa) are uncommon mesenchymal neoplasms demonstrating positivity for muscular and melanocytic immuno-markers. Included in this category are angiomyolipoma, lymphangioleiomyomatosis, and clear cell sugar tumors. Lesions which do not fit into these categories are classified as "not otherwise specified". We present a case of an incidentally discovered PEComa within inguinal hernia sac contents in a 70-year-old woman. It consisted of spindled and epithelioid cells with bland oval nuclei, small nucleoli and clear to light eosinophilic cytoplasm. There was no atypia or mitoses. The lesion was strongly positive for HMB45 and smooth muscle actin. Pelvic soft tissue and peritoneal PEComas are rarely reported in literature and very little is known about their prognosis. We discuss the immunohistochemistry, differential diagnosis, and pathogenesis of PEComas.

Hernia sacs: is histological examination necessary?

The hernia sac is a common surgical pathology specimen which can occasionally yield unexpected diagnoses. The College of American Pathologists recommends microscopic examination of abdominal hernias, but leaves submission of inguinal hernias for histology to the discretion of the pathologist. To validate this approach at a tertiary care centre, we retrospectively reviewed 1426 hernia sacs derived from inguinal, femoral and abdominal wall hernias. The majority of pathologies noted were known to the clinician, including herniated bowel, lipomas and omentum. A malignancy was noted in three of 800 inguinal hernias and seven of 576 abdominal wall hernias; five of these lesions were not seen on gross examination. Other interesting findings in hernia sacs included appendices, endometriosis, a perivascular epithelioid cell tumour, and pseudomyxoma peritoneii. All hernia sacs should be examined grossly as most pathologies are grossly visible. The decision to submit inguinal hernias for histology may be left to the discretion of the pathologist, but abdominal and femoral hernias should be submitted for histology.

Light chain deposition disease affecting the gastrointestinal tract in the setting of post-living donor kidney transplantation.

Light chain deposition disease (LCDD) is an uncommon, clonal plasma cell proliferative disorder, in which monoclonal immunoglobulin light chains deposit in various tissues, resulting in organ dysfunction. Gastrointestinal (GI) involvement has been described in both primary and secondary amyloidosis, but has rarely been reported in LCDD, and only as an incidental finding. We report a case of LCDD in living related kidney transplant recipient presenting with severe GI dysmotility, weight loss and progressive allograft dysfunction. A diagnosis of LCDD was based on the kidney biopsy findings in the failing renal allograft, along with the presence of excess serum free kappa light chains and abnormal kappa:lambda ratio. Subsequent review of GI biopsies confirmed kappa light chain immunoglobulin deposition within the stomach. Further investigation suggested additional hepatic and cardiac involvement. The patient went on to receive bortezomib, achieving a biochemical response and stabilization of his advanced renal dysfunction; however, bortezomib was discontinued due to toxicity. The patient was subsequently treated with lenalidomide and dexamethasone, which were better tolerated. Further biochemical response and resolution of the GI symptoms was observed after 10 months of treatment. In summary, we present the first case of LCDD with symptomatic GI involvement, in which the diagnosis was established by intestinal biopsies. Our report also highlights the feasibility and effectiveness of lenalidomide in the treatment of LCDD.

International study group on rectal cancer regression grading: interobserver variability with commonly used regression grading systems.

The aim of this study was to ascertain the level of concordance among gastrointestinal pathologists for regression grading in rectal cancers treated with neoadjuvant chemoradiation. Seventeen gastrointestinal pathologists participated using the Mandard, Dworak, and modified rectal cancer regression grading systems to grade 10 representative slides that were selected from 10 cases of rectal cancer treated with long-course neoadjuvant chemoradiation. The slides were scanned with a whole-slide scanner generating dynamic digitized images. The results showed very little concordance across the 3 grading systems, with κ values of 0.28, 0.35, and 0.38 for the Mandard, Dworak, and modified rectal cancer regression grading systems, respectively. In only 1 of 10 study cases was there unanimous grading concordance using the modified rectal cancer regression grading system. It was felt that these systems lacked precision and clarity for reproducible, accurate regression grading. The study concluded that there was a need for a simple, reproducible regression grading system with clear criteria, a cumulative or composite score taking into account all sections of the tumor bed that is sampled rather than the worst section (highest grade), and there should be a uniform method of sampling of these specimens.

A multi-centre pathologist survey on pathological processing and regression grading of colorectal cancer resection specimens treated by neoadjuvant chemoradiation.

To ascertain the approach and degree of consensus of pathologists in the handling and regression grading of colorectal cancer resection specimens treated with neoadjuvant chemoradiation, a ten-part questionnaire was circulated to 18 gastrointestinal pathologists in eight countries. The questions were specific and addressed pertinent issues related to colorectal cancer with neoadjuvant chemoradiation. There is a lack of consensus on how to handle the specimen, number of sections taken, correlation with pre- and post-operative radiological imaging, and especially, regression grading schema employed. Consensus in the form of guidelines is required so that the pathological assessment of these specimens will provide clinically relevant information for patient management, irrespective of location.

Vasculopathic changes, a somatostatin-producing neuroendocrine carcinoma and a jejunal gastrointestinal stromal tumor in a patient with type 1 neurofibromatosis.

A 36-year-old male with neurofibromatosis type 1 (NF-1) presented with symptoms of obstructive jaundice. Imaging showed a periampullary mass, which on endoscopic retrograde cholangiopancreatography biopsy proved to be a somatostatinoma. A Whipple's procedure was performed and a somatostatinoma of the duodenum was confirmed. In addition, the patient had a gastrointestinal stromal tumor (GIST) of the jejunum with accompanying hyperplasia of interstitial cells of Cajal. The somatostatinoma was histologically characteristic with pseudoglandular and solid patterns together with psammoma bodies and lymphovascular invasion. The GIST did not display mutations in c-kit or platelet-derived growth factor receptor genes. The novel finding in this case was the presence of several vessels in the submucosa and muscularis propria of the duodenum displaying prominent intimal hyperplasia and in keeping with so-called neurofibromatosis-associated vasculopathy. These abnormal vessels were within and close to the somatostatinoma only and were not found away from the tumor. It is thought that the vasculopathy is related to NF-1 with abnormal neurofibromin possibly playing a role.