Citations

Abstract Background: Inherited susceptibility is an important contributor to colorectal cancer risk, and rare variants in key genes or pathways could account in part for the missing proportion of colorectal cancer heritability. Methods: We conducted an exome-wide association study including 2,327 cases and 2,966 controls of European ancestry from three large epidemiologic studies. Single variant associations were tested using logistic regression models, adjusting for appropriate study-specific covariates. In addition, we examined the aggregate effects of rare coding variation at the gene and pathway levels using Bayesian model uncertainty techniques. Results: In an exome-wide gene-level analysis, we identified ST6GALNAC2 as the top associated gene based on the Bayesian risk index (BRI) method [summary Bayes factor (BF)BRI = 2604.23]. A rare coding variant in this gene, rs139401613, was the top associated variant (P = 1.01 × 10–6) in an exome-wide single variant analysis. Pathway-level association analyses based on the integrative BRI (iBRI) method found extreme evidence of association with the DNA repair pathway (BFiBRI = 17852.4), specifically with the nonhomologous end joining (BFiBRI = 437.95) and nucleotide excision repair (BFiBRI = 36.96) subpathways. The iBRI method also identified RPA2, PRKDC, ERCC5, and ERCC8 as the top associated DNA repair genes (summary BFiBRI ≥ 10), with rs28988897, rs8178232, rs141369732, and rs201642761 being the most likely associated variants in these genes, respectively. Conclusions: We identified novel variants and genes associated with colorectal cancer risk and provided additional evidence for a role of DNA repair in colorectal cancer tumorigenesis. Impact: This study provides new insights into the genetic predisposition to colorectal cancer, which has potential for translation into improved risk prediction.

AimsTo develop and validate a deep learning algorithm to quantify a broad spectrum of histological features in colorectal carcinoma.Methods and resultsA deep learning algorithm was trained on haematoxylin and eosin‐stained slides from tissue microarrays of colorectal carcinomas (N = 230) to segment colorectal carcinoma digitised images into 13 regions and one object. The segmentation algorithm demonstrated moderate to almost perfect agreement with interpretations by gastrointestinal pathologists, and was applied to an independent test cohort of digitised whole slides of colorectal carcinoma (N = 136). The algorithm correctly classified mucinous and high‐grade tumours, and identified significant differences between mismatch repair‐proficient and mismatch repair‐deficient (MMRD) tumours with regard to mucin, inflammatory stroma, and tumour‐infiltrating lymphocytes (TILs). A cutoff of >44.4 TILs per mm2 carcinoma gave a sensitivity of 88% and a specificity of 73% in classifying MMRD carcinomas. Algorithm measures of tumour budding (TB) and poorly differentiated clusters (PDCs) outperformed TB grade derived from routine sign‐out, and compared favourably with manual counts of TB/PDCs with regard to lymphatic, venous and perineural invasion. Comparable associations were seen between algorithm measures of TB/PDCs and manual counts of TB/PDCs for lymph node metastasis (all P < 0.001); however, stronger correlations were seen between the proportion of positive lymph nodes and algorithm measures of TB/PDCs. Stronger associations were also seen between distant metastasis and algorithm measures of TB/PDCs (P = 0.004) than between distant metastasis and TB (P = 0.04) and TB/PDC counts (P = 0.06).ConclusionsOur results highlight the potential of deep learning to identify and quantify a broad spectrum of histological features in colorectal carcinoma.

The increasing use of gastrointestinal endoscopic procedures has led to the recognition by histopathologists of non‐conventional (or special‐type) dysplasias of the gastrointestinal tract. These lesions can be recognised in association with prevalent underlying gastrointestinal conditions, such as Barrett oesophagus, chronic atrophic gastritis, and inflammatory bowel disease. The diagnosis of these special types can be challenging, and their biological behaviours are not fully characterised. The aim of this review is to provide a global view of non‐conventional dysplastic lesions observed in the various segments of the tubular gastrointestinal tract and describe their salient features. Furthermore, as the clinical implications of these various subtypes have not been broadly tested in practice and are not represented in most management guidelines, we offer guidance on the best management practices for these lesions.

Background Secondary carcinoma involving the gastrointestinal (GI) tract is an uncommon finding in biopsy specimens. The diagnosis can be challenging for tumours mimicking a primary carcinoma and when the clinical context is unknown. Methods and results A multicentre retrospective study was performed to evaluate the clinical and histological features of a series of secondary carcinoma in GI biopsies. A total of 197 cases from 190 patients (median age = 67 years; 57% females) were reviewed. In 16% of patients, the primary carcinoma was unknown. Most lesions presented endoscopically as mucosal or submucosal masses (58%). In 13%, the endoscopy was non‐suspicious for malignancy. The most common tumours were carcinomas of the breast (38%), kidney (13%), lung (12%), prostate (8%) and ovary (7%). The sites of involvement were the stomach (34%), colon (27%), rectum (18%), duodenum (13%), oesophagus (5%), jejunum (3%) and anus (0.5%). Histological patterns of infiltration were mucosal (76%), submucosal (41%), lymphatic (14%), and epithelial colonisation (8%). Submucosal infiltration was found significantly more frequently in carcinomas of the prostate (67%) and lung (62%), compared with carcinomas of the ovary (27%) and breast (23%). Histological obstructive changes were observed in 36% of all cases, with the highest rate in prostate carcinoma (53%) and the lowest rate in kidney carcinoma (8%). Conclusion Awareness of the main clinical and histological patterns of secondary carcinomas in GI tract biopsies may help pathologists to raise the possibility of this uncommon diagnosis and confirm it with the judicious use of immunohistochemistry.

LINKED CONTENTThis article is linked to Cushing et al and Cushing and Ananthakrishnan papers. To view these articles, visit https://doi.org/10.1111/apt.15568 and https://doi.org/10.1111/apt.15621.

BACKGROUND: Cross-sectional studies in ulcerative colitis (UC) have shown at best a moderate association between histologic and clinical measures of disease activity, but few longitudinal studies have evaluated this relationship. As endoscopy and histology are both independent predictors of clinical outcomes in UC, there remains a need to assess these measures in parallel to demonstrate clinical benefit. HICKORY (NCT02100696) is an ongoing Phase 3 study evaluating etrolizumab in anti-tumor necrosis factor (aTNF)–experienced patients with moderate-to-severe UC. The correlation between histologic changes and established disease activity measures at end of induction (week 14) was assessed using data from the open-label induction (OLI) cohort of HICKORY. METHODS: Study analysis is based on data from patients in the OLI cohort who received ≥1 dose of etrolizumab 105 mg subcutaneously every 4 weeks during the 14-week induction phase. Baseline and week 14 biopsies were scored by 1 of 4 central readers using the Nancy histologic index (NHI) and the Robarts histopathology index (RHI) in patients who had active baseline histology (NHI >1 and RHI >3) and complete scoring at week 14 (n = 97). Binary week 14 histologic outcomes were characterized by presence or absence of neutrophils (NHI ≤1 or RHI ≤3 and Geboes subgrades 2B.0/3.0). Mayo Clinic score (MCS) endoscopic subscore (ES) was used to assess endoscopy. Pairwise associations were quantified by Spearman correlation (ρ; for correlation between change from baseline scores) and Cohen kappa coefficients (κ; for agreement among week 14 outcomes). ΔNHI and ΔRHI were compared to determine presence of a minimum clinically important difference (MCID) in MCS (∆MCS ≥3 from baseline). RESULTS: At week 14, 22% (21/97), 23% (22/97), and 8% (8/97) of patients achieved resolution of neutrophilic inflammation based on either NHI or RHI/Geboes, endoscopic improvement (ES ≤ 1), and endoscopic remission (ES = 0), respectively. Among patients with endoscopic improvement and endoscopic remission, neutrophilic resolution was achieved in 55% (12/22) and 75% (6/8) of patients, respectively. ΔNHI and ΔRHI were highly correlated (ρ = 0.91). There was weak to no association between ΔNHI/ΔRHI/ΔES and Δfecal calprotectin (ρ = –0.02 to 0.38), ΔC-reactive protein (ρ = 0.03 to 0.07), Δalbumin (ρ = –0.19 to –0.10), Δhemoglobin (ρ = –0.22 to –0.19), and Δsegmented neutrophils in the blood (ρ = –0.06 to 0.01). Weak correlations were observed between ΔNHI/ΔRHI and ΔES (ρ = 0.26–0.27), Δrectal bleeding (ρ = 0.24–0.28), and Δstool frequency (ρ = 0.40–0.42). Correlations between NHI, RHI/Geboes, and ES with symptomatic outcomes were weak (κ = 0.28–0.45). Difference in the mean grouped by achievement of ΔMCS ≥3 suggests MCIDs in ΔNHI and ΔRHI of 1.2 and 8.6, respectively. CONCLUSION(S): The analysis showed weak to moderate agreement between changes in histologic scores and changes in endoscopic scores, and weak to no agreement between changes in histologic scores and changes in laboratory results at week 14. There was a weak correlation between histologic scores and symptoms at the end of induction. MCID results suggest that both the NHI and RHI appear to effectively evaluate neutrophilic resolution, making the changes in score more clinically interpretable.

LINKED CONTENTThis article is linked to Pai et al and Rowe papers. To view these articles, visit https://doi.org/10.1111/apt.15503 and https://doi.org/10.1111/apt.15537.

Drug induced liver injury is a very frequent cause of hepatotoxicity and within that group, herbal and dietary supplements are a well described subcategory. The following clinical vignette describes the case of a young man with acute hepatitis secondary to the use of Ilex paraguariensis, also known as yerba mate, which is a herbal product commonly drunk in South America. This is the first written case of mate tea induced hepatotoxicity.

Mastocytosis is a rare and heterogeneous group of disorders that may be limited to the skin and even spontaneously regress or may have a systemic presentation with multi-organ involvement and poor outcome. Among the extracutaneous sites, gastrointestinal tract is often affected, but nonspecific clinical manifestations combined with subtle histological findings of the disease makes the diagnosis of gastrointestinal mastocytosis rather hard. In absence of a high index of suspicion, gastrointestinal involvement is easily overlooked. We report a challenging case of systemic mastocytosis presenting with isolated gastrointestinal manifestations without skin involvement, in which the diagnosis was missed at first evaluation of intestinal biopsies.