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Most absorption of nutrients takes place in the proximal small intestine, and the most common disorders leading to malabsorption are associated with a morphological abnormality in the duodenal mucosa that is appreciable in histological sections of biopsy specimens. Coeliac disease is the most well-known example, causing intraepithelial lymphocytosis, inflammation and villous atrophy in the duodenum. Remarkably similar inflammatory changes can be induced by other processes, including medications, e.g. angiotensin II receptor blockers and immune checkpoint inhibitors, immune dysregulation disorders, e.g. common variable immunodeficiency and autoimmune enteropathy, infections, collagenous sprue, and tropical sprue. However, there are often subtle histological differences from coeliac disease in the type of inflammatory infiltrate, the presence of crypt apoptosis, and the extent and type of inflammation beyond the duodenum. The clinical setting and serological investigation usually allow diagnostic separation, but some cases remain challenging. Histopathology is also important in assessing the response to treatment, such as the change in villous architecture caused by a gluten-free diet, or the response to cessation of a potentially causative medication. This review examines the practical role that histopathology of duodenal biopsy specimens plays in the assessment and management of inflammatory malabsorptive processes of the proximal small intestine, with a particular emphasis on coeliac disease.

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.

Traditional serrated adenoma (TSA) is the least common subtype of serrated colorectal polyp. Large protuberant lesions are easily recognised; however, the origins of TSAs are not known, and early forms have not been described. Some large TSAs present with a flat 'shoulder' component surrounding the central protuberant component. We hypothesised that small polyps with the same histology as these shoulder regions may represent early TSAs. Thus the primary aim of the study is to describe the histology of these presumptive early TSAs.We collected 70 small (10 mm) polyps that may represent early TSAs on the basis of typical TSA cytology covering the luminal surface. We also identified 12 large TSAs with a shoulder component resembling these small polyps. The study polyp patients had a mean age of 58 years, and 54% were female; the polyps had a mean diameter of 4.1 mm and were predominantly distal (71%). Morphologically, slit-like serrations were present in 81%, ectopic crypt formations were present in 67%, and a villous component was present in 47%. These histological features were similar to those of the 12 shoulder lesions. Immunohistochemical stains showed an absence of β-catenin nuclear expression in 96% of the small polyps, retained expression of MLH1 in 100%, and Ki67 positivity restricted to the crypt bases and ectopic crypt formations. BRAF and KRAS mutations were identified in 47% and 31% of the polyps, respectively. BRAF-mutated polyps were more likely than KRAS-mutated polyps to arise in a precursor polyp (82% versus 18%, P0.001), and were more likely to have slit-like serrations (100% versus 73%, P = 0.003).These morphological, immunohistochemical and molecular findings are similar to what has been reported in large TSAs, and support the hypothesis that these polyps represent early forms of TSA.

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.

Background Mutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next-generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. Methods Targeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n = 153); (2) CRC unselected by tumor immunohistochemical or microsatellite stability testing (n = 548); (3) young onset (age

Tumor testing of colorectal cancers (CRC) for mismatch repair (MMR) deficiency is an effective approach to identify carriers of germline MMR gene mutation (Lynch syndrome). The aim of this study was to identify MMR gene mutation carriers in two cohorts of population-based CRC utilizing a combination of tumor and germline testing approaches.

Ethanol in alcoholic beverages is a causative agent for colorectal cancer. Colorectal cancer is a biologically heterogeneous disease, and molecular subtypes defined by the presence of somatic mutations in BRAF and KRAS are known to exist. We examined associations between lifetime alcohol intake and molecular and anatomic subtypes of colorectal cancer. We calculated usual alcohol intake for 10-year periods from age 20 using recalled frequency and quantity of beverage-specific consumption for 38,149 participants aged 40-69 years from the Melbourne Collaborative Cohort Study. Cox regression was performed to derive hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between lifetime alcohol intake and colorectal cancer risk. Heterogeneity in the HRs across subtypes of colorectal cancer was assessed. A positive dose-dependent association between lifetime alcohol intake and overall colorectal cancer risk (mean follow-up = 14.6 years; n = 596 colon and n = 326 rectal cancer) was observed (HR = 1.08, 95% CI: 1.04-1.12 per 10 g/day increment). The risk was greater for rectal than colon cancer (phomogeneity = 0.02). Alcohol intake was associated with increased risks of KRAS+ (HR = 1.07, 95% CI: 1.00-1.15) and BRAF-/KRAS- (HR = 1.05, 95% CI: 1.00-1.11) but not BRAF+ tumors (HR = 0.89, 95% CI: 0.78-1.01; phomogeneity = 0.01). Alcohol intake is associated with an increased risk of KRAS+ and BRAF-/KRAS- tumors originating via specific molecular pathways including the traditional adenoma-carcinoma pathway but not with BRAF+ tumors originating via the serrated pathway. Therefore, limiting alcohol intake from a young age might reduce colorectal cancer originating via the traditional adenoma-carcinoma pathway.

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.

Individuals diagnosed with colorectal cancer (CRC) are at risk of developing a metachronous CRC. We examined the associations between personal, tumour-related and lifestyle risk factors, and risk of metachronous CRC. A total of 7,863 participants with incident colon or rectal cancer who were recruited in the USA, Canada and Australia to the Colon Cancer Family Registry during 1997-2012, except those identified as high-risk, for example, Lynch syndrome, were followed up approximately every 5 years. We estimated the risk of metachronous CRC, defined as the first new primary CRC following an interval of at least one year after the initial CRC diagnosis. Observation time started at the age at diagnosis of the initial CRC and ended at the age at diagnosis of the metachronous CRC, last contact or death whichever occurred earliest, or were censored at the age at diagnosis of any metachronous colorectal adenoma. Cox regression was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean follow-up of 6.6 years, 142 (1.81%) metachronous CRCs were diagnosed (mean age at diagnosis 59.8; incidence 2.7/1,000 person-years). An increased risk of metachronous CRC was associated with the presence of a synchronous CRC (HR = 2.73; 95% CI: 1.30-5.72) and the location of cancer in the proximal colon at initial diagnosis (compared with distal colon or rectum, HR = 4.16; 95% CI: 2.80-6.18). The presence of a synchronous CRC and the location of the initial CRC might be useful for deciding the intensity of surveillance colonoscopy for individuals diagnosed with CRC.

Most colorectal polyps are classified readily, but a subset of tubulovillous adenomas (TVA) with prominent serrated architecture causes diagnostic confusion. We aimed to (i) identify histological features that separate serrated TVAs from both conventional TVAs and traditional serrated adenomas (TSA) and (ii) perform a clinicopathological and molecular analysis to determine if the serrated TVA has unique features.We collected 48 serrated TVAs, 50 conventional TVAs and 66 BRAF wild-type TSAs for analysis. For each polyp we performed a clinicopathological assessment, BRAF and KRAS mutation profiling, cytosine-phosphate-guanosine (CpG) island methylator phenotype status, MGMT methylation and immunohistochemical assessment of seven markers [MutL homologue 1 (MLH1), p16, p53, β-catenin, Ki67, CK7 and CK20]. We found that serrated TVAs can be diagnosed reliably, and have features distinct from both conventional TVAs and TSAs. Compared to conventional TVAs, serrated TVAs are larger, more often proximal, more histologically advanced, show more CpG island methylation and more frequent KRAS mutation. Compared to TSAs they are more often proximal, show less CpG island methylation, more frequent MGMT methylation and more frequent nuclear staining for β-catenin.The serrated TVA can be diagnosed reliably and has unique features. It represents a precursor of KRAS mutated, microsatellite stable colorectal carcinoma.

To describe the clinical and pathological features of a series of patients with biopsy findings of a coeliac disease-like enteropathy in the setting of an acute illness.Eighteen cases of an abrupt-onset, self-limited illness with coeliac-like enteropathy (SLCE) were collected prospectively. Medication reaction, immune disorder, food allergy and parasitic infection were excluded. Coeliac disease was excluded by the transient nature of the illness and absence of tissue transglutaminase (TTG) elevation (nine of nine) or human leucocyte antigen (HLA)-DQ2/DQ8 haplotype (eight of nine). Clinical symptoms were recorded and histopathological findings in all gastrointestinal sites were quantified. Findings in the duodenum were compared to a coeliac disease control group. In 12 cases the clinical diagnosis was infective enteritis, probably viral in type. In six cases, a definite diagnosis was not established. Histological differences from coeliac disease included intra-epithelial neutrophil infiltration (P0.001), fewer intra-epithelial lymphocytes (P = 0.038) and uniform or crypt predominant intra-epithelial lymphocytosis in SCLE. One case displayed pan-gastrointestinal tract lymphocytosis. All resolved within 6 months.Histopathologists need to be aware that a coeliac disease-like enteropathy may occur in the setting of an acute gastrointestinal illness and resolve without sequelae.

The average age at diagnosis for colorectal cancer (CRC) in Australia is 69, and the age-specific incidence rises rapidly after age 50 years. The incidence has stabilized or is declining in older age groups in Australia during recent decades, possibly related to the increased uptake of screening and high-risk surveillance. In the same time frame, a rising incidence of CRC in younger adults has been well-documented in the United States. This rise in incidence in the young has not been reported from other countries that share long-term exposure to westernised urban lifestyles. Using data from the Australian Institute of Health and Welfare, we examined trends in national incidence rates for CRC under age 50 years and observed that rates in people under age 40 years have been rising for the last two decades. We further performed a review of the literature regarding CRC in young adults to outline the extent of current understanding, explore potential risk factors such as obesity, alcohol, and sedentary lifestyles, and to identify the questions remaining to be addressed. Although absolute numbers might not justify a population screening approach, the dispersal of young adults with CRC across the primary health-care system decreases probability of their recognition. Patient and physician awareness, aided by stool and emerging blood-screening tests and risk profiling tools, have the potential to aid in identification of those young adults who would most benefit from a colonoscopy through early detection of CRCs or by removal of advanced polyps.

Background The incidence of oesophageal adenocarcinoma (OA) isincreasing rapidly with nearly all OA arising from underlying Barrett’soesophagus (BO). The primary risk factors for BO are gastro-oesophagealrefl ux (GOR) and obesity. The risk of obesity remains after controlling forGOR, suggesting that non-refl ux obesity factors may be important. Themetabolic syndrome (MS) results from obesity related hormonal and systemicinfl ammatory changes and is associated with breast, prostate andcolon cancers. The association between MS and BO is unknown.Aim To conduct a case-control study to quantify the association betweenMS and BO.Methods We undertook a structured interview, clinical and anthropometricmeasures and fasting metabolic and hormonal studies within acase-control study conducted in Brisbane, Australia. We recruited 236cases with histologically confi rmed BO diagnosed 2003–6 and 237 controlsfrom the electoral roll, frequency matched by age and sex to cases.Odds ratios (OR) and 95% confi dence intervals (CI) were estimated usingmultivariable logistic regression analysis.Results The prevalence of MS was 63% in cases and 47% in controls (p= 0.0005). There was a signifi cantly increased risk of BO among thosewith MS (OR 1.91 95%CI 1.32–2.76). The risk was unaffected in a logisticregression model adjusting for age, sex, and use of aspirin, NSAIDs,alcohol and cigarettes (OR 1.91 95%CI 1.27–2.88). Further adjustment forBMI (OR 1.62 95%CI 1.03–2.54) and GOR (1.34 95%CI 0.80–2.23)modestly attenuated the association.Conclusions MS is associated with an increased risk of BO. This associationis not explained simply by higher BMI or GOR among cases. Themechanism of this association remains unknown but hormonal and systemicinfl ammatory changes associated with obesity are factors warrantingfurther study.

To determine whether cell size is related to HER-2/neu status and/or to Akt activation in breast carcinomas. HER-2/neu overexpression is observed in 20-30% of invasive breast carcinomas with poor pronostic features, but little is known about the cell phenotype associated with HER-2/neu activation. Akt has been found to be involved in the HER-2/neu signal transduction pathway and Akt activation has been associated with increased cell size in various models.A case-control study of invasive ductal carcinoma of the breast was carried out, including 21 cases displaying HER-2/neu overexpression and 20 HER-2/neu negative controls. Cytoplasmic and nuclear sizes were measured on digitized histological pictures using cell image analysis software. Akt expression analysis was performed by immunohistochemistry on formalin-fixed histological sections using an anti-phosphorylated-Akt (Ser473) antibody.HER-2/neu-overexpressing carcinomas had a mean nuclear size of 75 +/- 22.2 micro m(2) and a mean cytoplasmic size of 187 +/- 52.3 micro m(2). Both values were higher than the nuclear and cytoplasmic size of HER-2/neu-negative cases (nucleus = 58 +/- 24.5 micro m(2), cytoplasm = 133 +/- 56.6 micro m(2); P = 0.02 and P =0.003, respectively). Up to 75% of the tumours with a cell size over 140 micro m(2) were HER-2/neu-positive. Immunohistochemical Akt expression was observed in 19/40 (47.5%) cases. The immunoreactivity was localized in the cytoplasm in eight cases, on the cell membrane in four cases and at both sites in seven cases. One case was not interpretable. Comparison between HER-2/neu and Akt status showed that Akt was detectable at the cell membrane in 43% (9/21) of HER-2/neu-positive and in 10% (2/19) of HER-2/neu-negative cases (P = 0.02).HER-2/neu overexpression was consistently associated with increased cell size in invasive ductal carcinoma of the breast. This increase may be related to concomitant Akt activation. The assessment of activated pathways in HER-2/neu-overexpressing breast carcinomas may provide useful information for optimized individual HER-2/neu-targeted therapy.

To the Editor: Lynch syndrome (LS) (MIM#120435) is a cancer predisposition condition resulting from mutations within the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2). In a suspected LS family, tumors are assessed for microsatellite instability (MSI) and/or immunohistochemical (IHC) absence of MMR proteins, both of which are hallmarks of LS. To enable appropriate diagnosis, counseling and surveillance, the gene indicated by the IHC profile is screened for mutations via techniques such as denaturing high pressure liquid chromatography (DHPLC), sequencing and multiplex ligation-dependent probe amplification (MLPA). Using these approaches, mutations are identified in the majority of cases suspected of LS; however, there remains a substantial proportion of families for which mutations cannot be identified...