Eosinophils have been implicated in the pathogenesis of ulcerative colitis and have been associated with disease course and therapeutic response. However, associations between eosinophil density, ...histologic activity, and clinical features have not been rigorously studied.
A deep learning algorithm was trained to identify eosinophils in colonic biopsies and validated against pathologists' interpretations. The algorithm was applied to sigmoid colon biopsies from a cross-sectional cohort of 88 ulcerative colitis patients with histologically active disease as measured by the Geboes score and Robarts histopathology index (RHI). Associations between eosinophil density, histologic activity, and clinical features were determined.
The eosinophil deep learning algorithm demonstrated almost perfect agreement with manual eosinophil counts determined by 4 pathologists (interclass correlation coefficients: 0.805-0.917). Eosinophil density varied widely across patients (median 113.5 cells per mm2, interquartile range 108.9). There was no association between eosinophil density and RHI (P = 0.5). Significant differences in eosinophil density were seen between patients with Montreal E3 vs E2 disease (146.2 cells per mm2 vs 88.2 cells per mm2, P = 0.005). Patients on corticosteroids had significantly lower eosinophil density (62.9 cells per mm2 vs 124.1 cells per mm2, P = 0.006). No association between eosinophil density and biologic use was observed (P = 0.5).
We developed a deep learning algorithm to quantify eosinophils in colonic biopsies. Eosinophil density did not correlate with histologic activity but did correlate with disease extent and corticosteroid use. Future studies applying this algorithm in larger cohorts with longitudinal follow-up are needed to further elucidate the role of eosinophils in ulcerative colitis.
The aim of this study to describe a new international dataset for pathology reporting of colorectal cancer surgical specimens, produced under the auspices of the International Collaboration on Cancer ...Reporting (ICCR).
Quality of pathology reporting and mutual understanding between colorectal surgeon, pathologist and oncologist are vital to patient management. Some pathology parameters are prone to variable interpretation, resulting in differing positions adopted by existing national datasets.
The ICCR, a global alliance of major pathology institutions with links to international cancer organizations, has developed and ratified a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Here we describe the production of a dataset for colorectal cancer resection specimens by a multidisciplinary panel of internationally recognized experts.
The agreed dataset comprises eighteen core (essential) and seven non-core (recommended) elements identified from a review of current evidence. Areas of contention are addressed, some highly relevant to surgical practice, with the aim of standardizing multidisciplinary discussion. The summation of all core elements is considered to be the minimum reporting standard for individual cases. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or non-core.
This first internationally agreed dataset for colorectal cancer pathology reporting promotes standardization of pathology reporting and enhanced clinicopathological communication. Widespread adoption will facilitate international comparisons, multinational clinical trials and help to improve the management of colorectal cancer globally.
Aims
Sessile serrated lesions (SSL) with dysplasia are uncommon polyps with a high risk of rapid malignant transformation. Most of these lesions have a BRAF mutation and 75% show loss of MLH1 ...expression in their dysplastic component. Different morphological patterns of dysplasia occurring in these polyps have recently been described. We hypothesised that a subset of SSLs with dysplasia mimicking the dysplasia seen in conventional adenoma (adenomatous dysplasia) may represent a collision lesion between an ordinary SSL and a conventional adenoma.
Methods and results
We selected 80 SSLs with dysplasia, including 19 with adenomatous dysplasia, 18 with serrated dysplasia and 43 with dysplasia not otherwise specified (NOS). BRAF mutation analysis was performed using molecular testing (allelic discrimination) and the mutation‐specific BRAF‐V600E immunohistochemistry (clone VE1). The overall BRAF‐V600E mutation rate was 84% in all lesions, 68% in SSLs with adenomatous dysplasia, 89% in SSLs with serrated dysplasia and 88% in SSLs with dysplasia NOS. From the 63 SSLs with dysplasia that were positive for the BRAF‐V600E mutation, a negative BRAF‐V600E immunostaining was observed in the dysplastic component of 83% of SSLs with adenomatous dysplasia, 0% of SSLs with serrated dysplasia and 3% of SSLs with dysplasia NOS (P < 0.001).
Conclusions
These findings suggest that SSLs with adenomatous dysplasia may not represent advanced SSLs, but instead may be a collision between a non‐dysplastic SSL and a conventional adenoma.
Sessile serrated adenomas are the precursor polyp of approximately 20% of colorectal carcinomas. Sessile serrated adenomas with dysplasia are rarely encountered and represent an intermediate step to ...malignant progression, frequently associated with loss of MLH1 expression. Accurate diagnosis of these lesions is important to facilitate appropriate surveillance, particularly because progression from dysplasia to carcinoma can be rapid. The current World Health Organization classification describes two main patterns of dysplasia occurring in sessile serrated adenomas, namely, serrated and conventional. However, this may not adequately reflect the spectrum of changes seen by pathologists in routine practice. Furthermore, subtle patterns of dysplasia that are nevertheless associated with loss of MLH1 expression are not encompassed in this classification. We performed a morphological analysis of 266 sessile serrated adenomas with dysplasia with concurrent MLH1 immunohistochemistry with the aims of better defining the spectrum of dysplasia occurring in these lesions and correlating dysplasia patterns with MLH1 expression. We found that dysplasia can be divided morphologically into four major patterns, comprising minimal deviation (19%), serrated (12%), adenomatous (8%) and not otherwise specified (79%) groups. Minimal deviation dysplasia is defined by minor architectural and cytological changes that typically requires loss of MLH1 immunohistochemical expression to support the diagnosis. Serrated dysplasia and adenomatous dysplasia have distinctive histological features and are less frequently associated with loss of MLH1 expression (13 and 5%, respectively). Finally, dysplasia not otherwise specified encompasses most cases and shows a diverse range of morphological changes that do not fall into the other subgroups and are frequently associated with loss of MLH1 expression (83%). This morphological classification of sessile serrated adenomas with dysplasia may represent an improvement on the current description as it correlates with the underlying mismatch repair protein status of the polyps and better highlights the range of morphologies seen by pathologists.
The influence of lifestyle factors on survival following a diagnosis of colorectal cancer (CRC) is not well established. We examined associations between lifestyle factors measured before diagnosis ...and CRC survival. The Melbourne Collaborative Cohort Study collected data on alcohol intake, cigarette smoking and physical activity, and body measurements at baseline (1990–1994) and wave 2 (2003–2007). We included participants diagnosed to 31 August 2015 with incident stages I–III CRC within 10‐years post exposure assessment. Information on tumor characteristics and vital status was obtained. Tumor DNA was tested for microsatellite instability (MSI) and somatic mutations in oncogenes BRAF (V600E) and KRAS. We estimated hazard ratios (HRs) for associations between lifestyle factors and overall and CRC‐specific mortality using Cox regression. Of 724 eligible CRC cases, 339 died (170 from CRC) during follow‐up (average 9.0 years). Exercise (non‐occupational/leisure‐time) was associated with higher CRC‐specific survival for stage II (HR = 0.25, 95% CI: 0.10–0.60) but not stages I/III disease (p for interaction = 0.01), and possibly for colon and KRAS wild‐type tumors. Waist circumference was inversely associated with CRC‐specific survival (HR = 1.25 per 10 cm increment, 95% CI: 1.08–1.44), independent of stage, anatomic site and tumor molecular status. Cigarette smoking was associated with lower overall survival, with suggestive evidence of worse survival for BRAF mutated CRC, but not with CRC‐specific survival. Alcohol intake was not associated with survival. Survival did not differ by MSI status. We have identified pre‐diagnostic predictors of survival following CRC that may have clinical and public health relevance.
What's new?
While survival following colorectal cancer (CRC) is improving, it remains unclear whether increasing survival is linked to specific health or lifestyle factors that were present before or after CRC diagnosis. In our study, based on data from the Melbourne Collaborative Cohort Study (MCCS), exercise prior to diagnosis was associated with higher CRC‐specific survival specifically for stage II patients. Waist circumference, by contrast, was associated with reduced CRC‐specific survival, while cigarette smoking was associated with lower overall survival. Cigarette smoking was also weakly linked to decreased survival in BRAF‐mutated CRC. No associations were detected between CRC survival and alcohol intake.
Screening colonoscopy has led to more colorectal carcinomas presenting at an early stage potentially curable by endoscopic resection. In this study, we examined the clinical and histological features ...of a contemporary series of malignant colorectal polyps (MCPs) with subsequent surgical resection.
We conducted a retrospective study on a consecutive series of MCPs from 239 patients, predominantly males (57.7%) with a median age of 66 years, and assessed histological parameters associated with residual disease on the surgical specimens.
Median MCP size was 18.6 mm, with 23.1% polyps measuring ≤10 mm. From the 140 surgical resection specimens, residual disease was identified in 20 cases, including 12 cases with metastatic lymph nodes and/or 9 cases with residual carcinoma in the large bowel wall. Histological parameters associated with nodal metastases were greater width and greater depth of the invasive component (p=0.001 and 0.006, respectively), poor differentiation (p=0.003) and a cribriform pattern (p=0.01). The risk of nodal metastases was 23.3% if two or three of these features were identified, while it was 0% and 4.5% if none or one was present, respectively. A positive margin was not associated with nodal metastasis and might be adequately treated by local endoscopic resection.
Surgical resection should be recommended if ≥2 of these adverse histological features are present and may be warranted if one feature is present. A positive margin may require additional local resection but not necessarily surgery if no other adverse factors are present.
Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for ...correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion.
Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures.
In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials.
Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.
Stenosis is a common complication of Crohn’s disease (CD) that has no effective medical therapy. Development of antifibrotic agents will require testing in randomized controlled trials. Computed ...tomography enterography- and magnetic resonance enterography-based technologies might be used to measure outcomes in these trials. These approaches have been validated in studies of patients with symptomatic strictures who underwent imaging evaluations followed by resection with histopathologic grading of the intestinal tissue for inflammation and/or fibrosis (the reference standard). Imaging findings have correlated with findings from quantitative or semiquantitative histologic evaluation of the degree of fibromuscular stenosis and/or inflammation on the resection specimen. However, it is not clear whether histologic findings are an accurate reference standard. We performed a systematic review of all published histologic scoring systems used to assess stenosing CD.
We performed a comprehensive search of Embase and MEDLINE of studies through March 13, 2019, that used a histologic scoring system to characterize small bowel CD and assessed inflammatory and fibrotic alterations within the same adult individual. All scores fitting the criteria were included in our analysis, independent of the presence of stricturing disease, as long as inflammation and fibrosis were evaluated separately but in the same scoring system.
We observed substantial heterogeneity among the scoring systems, which were not derived from modern principles for evaluative index development. None had undergone formal validity or reliability testing. None of the existing indices had been constructed according to accepted methods for the development of evaluative indices. Basic knowledge regarding their operating properties were lacking. Specific indices for evaluating the important pathologic component of myofibroblast hypertrophy or hyperplasia have not been proposed.
In a systematic review of publications, we found a lack of validated histopathologic scoring systems for assessment of fibromuscular stenosis. Data that describe the operating properties of existing cross-sectional imaging techniques for stenosing CD should be questioned. Development and validation of a histopathology index is an important research priority.
Germline mutations in the DNA base excision repair gene MUTYH are known to increase a carrier's risk of colorectal cancer. However, the risks of other (extracolonic) cancers for MUTYH mutation ...carriers are not well defined. We identified 266 probands (91% Caucasians) with a MUTYH mutation (41 biallelic and 225 monoallelic) from the Colon Cancer Family Registry. Mutation status, sex, age and histories of cancer from their 1,903 first‐ and 3,255 second‐degree relatives were analyzed using modified segregation analysis conditioned on the ascertainment criteria. Compared with incidences for the general population, hazard ratios (HRs) (95% confidence intervals CIs) for biallelic MUTYH mutation carriers were: urinary bladder cancer 19 (3.7–97) and ovarian cancer 17 (2.4–115). The HRs (95% CI) for monoallelic MUTYH mutation carriers were: gastric cancer 9.3 (6.7–13); hepatobiliary cancer 4.5 (2.7–7.5); endometrial cancer 2.1 (1.1–3.9) and breast cancer 1.4 (1.0–2.0). There was no evidence for an increased risk of cancers at the other sites examined (brain, pancreas, kidney or prostate). Based on the USA population incidences, the estimated cumulative risks (95% CI) to age 70 years for biallelic mutation carriers were: bladder cancer 25% (5–77%) for males and 8% (2–33%) for females and ovarian cancer 14% (2–65%). The cumulative risks (95% CI) for monoallelic mutation carriers were: gastric cancer 5% (4–7%) for males and 2.3% (1.7–3.3%) for females; hepatobiliary cancer 3% (2–5%) for males and 1.4% (0.8–2.3%) for females; endometrial cancer 3% (2%–6%) and breast cancer 11% (8–16%). These unbiased estimates of both relative and absolute risks of extracolonic cancers for people, mostly Caucasians, with MUTYH mutations will be important for their clinical management.
What's new?
People who have a mutation in the MUTYH gene have an increased risk of colorectal cancer. But are they also at higher risk for other types of cancer? In this study, the authors found that people with one mutated copy of MUTYH (monoallelic) have an increased risk of gastric, liver, breast and endometrial cancers, while people with two mutated copies (biallelic) have an increased risk of bladder and ovarian cancers. This information will be useful for risk assessment in patients and families who carry MUTYH mutations.
Most patients with Cowden syndrome have lesions in the gastrointestinal tract, characterized by multiple polyps of various histologic types in the large bowel, polyps in the upper gastrointestinal ...tract, and esophageal glycogenic acanthosis. However, pathologists are often unaware of the distinctive polyposis phenotype of Cowden syndrome. In this multicenter study, we report the spectrum of gastrointestinal manifestations in a series of 43 Cowden syndrome patients who had at least one endoscopy. The median age at the first endoscopy was 46 years and 58% were women. In 24 of 29 (83%) tested patients, a pathogenic germline mutation in PTEN was identified. The histology from 199 endoscopy procedures (67 upper gastrointestinal endoscopy and 132 colonoscopies) was reviewed. Hamartomatous polyps of the large bowel were the most common lesions, present in 85% of patients. Hamartomatous polyps showed varied histology, including lymphoid aggregates in 55% of patients, a lipomatous component in 52%, a ganglioneuromatous component in 52%, and a fibrous-rich component in 14%. Polyps with at least two different stromal components were found in 55% of patients. Inflammatory polyps were present in 21% of patients. Conventional adenomas and serrated polyps were identified in 48% and 62% of patients, respectively. In the upper gastrointestinal tract, the most common lesions were esophageal glycogenic acanthosis (37%), gastric hamartomatous polyps (47%), and duodenal hamartomatous polyps (20%). All patients with glycogenic acanthosis who had a colonoscopy had hamartomatous polyps of the large bowel. In five patients, the diagnosis of Cowden syndrome was established after the pathology report raised suspicion for the diagnosis. Pathologists who are aware of the characteristic admixture of lesions in Cowden syndrome can play an essential role in recommending referral to genetic counseling and gene testing. Early diagnosis of Cowden syndrome is important, as these patients and their relatives are at increased risk for developing multiple cancers.
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