SMARCA4 Mutations in Carcinomas of the Esophagus, Esophagogastric Junction, and Stomach.

Deficiency of SMARCA4, a member of the SWI/SNF chromatin remodeling complex, has been described in a subset of undifferentiated gastroesophageal carcinomas with an aggressive clinical course. The full spectrum and frequency of SMARCA4 mutations in gastroesophageal cancer are unknown. We interrogated our institutional database and identified patients with gastroesophageal carcinomas who underwent cancer next-generation sequencing. We classified SMARCA4 mutations, assessed histologic features, and correlated SMARCA4 mutations with SMARCA4 protein expression by immunohistochemistry. SMARCA4 mutations were identified in gastroesophageal carcinomas from 107 (9.1%) of 1174 patients. Forty-nine SMARCA4 mutations, including 26 missense variants and 23 protein-truncating variants, were interpreted as pathogenic in 42 (3.6%) of 1174 patients. Thirty (71%) of 42 cancers with pathogenic SMARCA4 mutations were located in the esophagus or esophagogastric junction, and 12 cancers (29%) were located in the stomach. Sixty-four percent of carcinomas with pathogenic truncating SMARCA4 variants were poorly differentiated or undifferentiated compared with 25% of carcinomas with pathogenic missense variants. Eight of 12 carcinomas with truncating SMARCA4 variants and none of the 7 carcinomas with pathogenic SMARCA4 missense variants showed loss of SMARCA4 expression by immunohistochemistry. Four carcinomas with pathogenic truncating SMARCA4 variants were associated with Barrett esophagus. SMARCA4-mutated gastroesophageal cancers were enriched for APC (31%) and CTNNB1 (14%) mutations and exhibited similar frequency of TP53 (76%) and ARID1A (31%) mutations compared with gastroesophageal cancers without pathogenic SMARCA4 mutations. The median overall survival was 13.6 months for patients who presented with metastasis at diagnosis and 22.7 months for patients without metastasis. Overall, SMARCA4-mutated gastroesophageal cancers exhibit a spectrum of histologic grade, an association with Barrett esophagus, and a concurrent mutational pattern similar to SMARCA4-wild-type gastroesophageal adenocarcinomas. Although SMARCA4-deficient gastroesophageal carcinomas are associated with poorly differentiated and undifferentiated histology, the spectrum of histologic and molecular features suggests overlapping pathogenic pathways with conventional gastroesophageal adenocarcinomas.

High Interobserver Variability Among Pathologists Using Combined Positive Score to Evaluate PD-L1 Expression in Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma.

Reliable, reproducible methods to interpret programmed death ligand-1 (PD-L1) expression on tumor cells (TC) and immune cells (IC) are needed for pathologists to inform decisions associated with checkpoint inhibitor therapies. Our international study compared interpathologist agreement of PD-L1 expression using the combined positive score (CPS) under standardized conditions on samples from patients with gastric/gastroesophageal junction/esophageal adenocarcinoma. Tissue sections from 100 adenocarcinoma pretreatment biopsies were stained in a single laboratory using the PD-L1 immunohistochemistry 28-8 and 22C3 (Agilent) pharmDx immunohistochemical assays. PD-L1 CPS was evaluated by 12 pathologists on scanned whole slide images of these biopsies before and after a 2-hour CPS training session by Agilent. Additionally, pathologists determined PD-L1-positive TC, IC, and total viable TC on a single tissue fragment from 35 of 100 biopsy samples. Scoring agreement among pathologists was assessed using the intraclass correlation coefficient (ICC). Interobserver variability for CPS for 100 biopsies was high, with only fair agreement among pathologists both pre- (range, 0.45-0.55) and posttraining (range, 0.56-0.57) for both assays. For the 35 single biopsy samples, poor/fair agreement was also observed for the total number of viable TC (ICC, 0.09), number of PD-L1-positive IC (ICC, 0.19), number of PD-L1-positive TC (ICC, 0.54), and calculated CPS (ICC, 0.14), whereas calculated TC score (positive TC/total TC) showed excellent agreement (ICC, 0.82). Retrospective histologic review of samples with the poorest interpathologist agreement revealed the following as possible confounding factors: (1) ambiguous identification of positively staining stromal cells, (2) faint or variable intensity of staining, (3) difficulty in distinguishing membranous from cytoplasmic tumor staining, and (4) cautery and crush artifacts. These results emphasize the need for objective techniques to standardize the interpretation of PD-L1 expression when using the CPS methodology on gastric/gastroesophageal junction cancer biopsies to accurately identify patients most likely to benefit from immune checkpoint inhibitor therapy.

Presence of Tim3+ and PD-1+ CD8+ T cells identifies microsatellite stable colorectal carcinomas with immune exhaustion and distinct clinicopathological features.

Colorectal carcinoma (CRC) is the second leading cause of cancer mortality worldwide. CRC is stratified into two major groups: microsatellite stable (MSS) and microsatellite instability-high (MSI-H). MSS CRC constitutes the majority of cases, has worse overall prognosis, and thus far has failed to respond to immunotherapies targeting the immune checkpoint receptors PD-1, PD-L1, and CTLA-4. Here we examined the alternate immunotherapy targets Tim-3 and Lag-3, as well as PD-1, on immune cells in a cohort of MSS CRC using immunohistochemistry and flow cytometry together with mutational analysis and clinical data. We found that PD-1 was variably expressed across CD4+ tumor-infiltrating lymphocyte (TIL) subtypes, and Tim-3 was mostly restricted to CD4+ regulatory T cells. Lag-3, when detected by flow cytometry, was largely coexpressed with Tim-3 and PD-1 in CD4+ TILs. Furthermore, Tim-3+ PD-1+ CD8+ TILs accumulated in the tumor and exhibited a dysfunctional or 'exhausted' phenotype. Notably, we observed a subset of patients with a high proportion of Tim-3- PD-1- CD8+ TILs and, conversely, a low proportion of Tim-3+ PD-1+ CD8+ TILs, thus stratifying MSS CRC patients based on a feature of immune exhaustion (MSS-ImmEx). MSS-ImmExhi patients had abundant Tim-3+ PD-1+ CD8+ TILs, PD-1+ CD4+ effector, and regulatory T cells, and were enriched for left-sided colon tumors and mutations in the APC tumor-suppressor gene. We further investigated the spatial organization of Tim-3, Lag-3, PD-1, and PD-L1 by immunohistochemistry and found higher levels in the tumor margin; however, MSS-ImmExhi tumors exhibited a higher density of Tim-3+ cells in the tumor center over MSS-ImmExlow tumors. Immunofluorescence revealed a higher density of PD-1+ /CD8+ cells in the tumor center in this group. Our findings identify a subset of MSS CRC that exhibits evidence of higher prior immune activation (MSS-ImmExhi ) in which therapies targeting Tim-3 in conjunction with anti-PD-1 or other immunotherapies may provide clinical benefit. © 2022 The Pathological Society of Great Britain and Ireland.

Effects of socio-economic status and daily variation on municipal solid waste composition: a preliminary analysis for sustainable planning and development in Aligarh City.

In the context of developing countries such as India, with great differences in people's living standards and different communities, municipal solid waste (MSW) management is one of the most promising problems in front of municipal organizations. Unlike every city in India, Aligarh City also faces the same problem of municipal solid waste management. This problem not only affects the esthetic view but is also hazardous to people nearby health. Currently, solid waste collected is either dumped in landfill unscientifically or partially treated by A to Z waste management (limited) by composting. In the present study, an effort was made to know about the per capita waste generation and variations in the quantity of different components of the MSW in five different regions of the city with dissimilar living standards. Also, weekly variation was analyzed in the study. One-way ANOVA analysis using Statistical Package for the Social Sciences is performed to investigate the variations in the mean composition of different components. The per capita solid waste generation in Aligarh City was found to be 0.42 kg/person/day. From the analysis, we came to know that compostable component (35.4%) is the highest, then inert (24.6%), plastic (12.2%), paper (10%), textile (9.2%), and sand (8.6%). After analysis, the results can help sort out the problem of MSW management in the city by selecting appropriate units as per the composition of MSW.

International consensus to standardise histopathological scoring for small bowel strictures in Crohn's disease.

OBJECTIVE: 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. DESIGN: 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. RESULTS: 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. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

Clinically significant serrated polyp detection rates and risk for postcolonoscopy colorectal cancer: data from the New Hampshire Colonoscopy Registry.

BACKGROUND AND AIMS: Higher adenoma detection rates reduce the risk of postcolonoscopy colorectal cancer (PCCRC). Clinically significant serrated polyps (CSSPs; defined as any sessile serrated polyp, traditional serrated adenoma, large [≥1 cm] or proximal hyperplastic polyp >5 mm) also lead to PCCRC, but there are no data on associated CSSP detection rates (CSSDRs). We used data from the New Hampshire Colonoscopy Registry (NHCR) to investigate the association between PCCRC risk and endoscopist CSSDR. METHODS: We included NHCR patients with 1 or more follow-up events: either a colonoscopy or a colorectal cancer (CRC) diagnosis identified through linkage with the New Hampshire State Cancer Registry. We defined our outcome, PCCRC, in 3 time periods: CRC diagnosed 6 to 36 months, 6 to 60 months, or all examinations (6 months or longer) after an index examination. We excluded patients with CRC diagnosed at or within 6 months of the index examination, with incomplete examinations, or with inflammatory bowel disease. The exposure variable was endoscopist CSSDR at the index colonoscopy. Cox regression was used to model the hazard of PCCRC on CSSDR controlling for age, sex, index findings, year of examination, personal history of colorectal neoplasia, and having more than 1 surveillance examination. RESULTS: One hundred twenty-eight patients with CRC diagnosed at least 6 months after their index examination were included. Our cohort included 142 endoscopists (92 gastroenterologists). We observed that the risk for PCCRC 6 months or longer after the index examination was significantly lower for examinations performed by endoscopists with CSSDRs of 3% to <9% (hazard ratio [HR], .57; 95% confidence interval [CI], .39-.83) or 9% or higher (HR, .39; 95% CI, .20-.78) relative to those with CSSDRs under 3%. CONCLUSIONS: Our study is the first to demonstrate a lower PCCRC risk after examinations performed by endoscopists with higher CSSDRs. Both CSSDRs of 9% and 3% to <9% had statistically lower risk of PCCRC than CSSDRs of <3%. These data validate CSSDR as a clinically relevant quality measure for endoscopists.

Accuracy of a no-biopsy approach for the diagnosis of coeliac disease across different adult cohorts.

OBJECTIVE: We aimed to determine the predictive capacity and diagnostic yield of a 10-fold increase in serum IgA antitissue transglutaminase (tTG) antibody levels for detecting small intestinal injury diagnostic of coeliac disease (CD) in adult patients. DESIGN: The study comprised three adult cohorts. Cohort 1: 740 patients assessed in the specialist CD clinic at a UK centre; cohort 2: 532 patients with low suspicion for CD referred for upper GI endoscopy at a UK centre; cohort 3: 145 patients with raised tTG titres from multiple international sites. Marsh 3 histology was used as a reference standard against which we determined the performance characteristics of an IgA tTG titre of ≥10×ULN for a diagnosis of CD. RESULTS: Cohort 1: the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 54.0%, 90.0%, 98.7% and 12.5%, respectively. Cohort 2: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 50.0%, 100.0%, 100.0% and 98.3%, respectively. Cohort 3: the sensitivity, specificity, PPV and NPV for IgA tTG levels of ≥10×ULN at identifying individuals with Marsh 3 lesions were 30.0%, 83.0%, 95.2% and 9.5%, respectively. CONCLUSION: Our results show that IgA tTG titres of ≥10×ULN have a strong predictive value at identifying adults with intestinal changes diagnostic of CD. This study supports the use of a no-biopsy approach for the diagnosis of adult CD.

Histopathology Scoring Systems of Stenosis Associated With Small Bowel Crohn's Disease: A Systematic Review.

BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A Multi-institutional Study of Peritoneal Recurrence Following Resection of Low-grade Appendiceal Mucinous Neoplasms.

BACKGROUND: Peritoneal dissemination of low-grade appendiceal mucinous neoplasms (LAMNs), sometimes referred to as pseudomyxoma peritonei, can result in significant morbidity and mortality. Little is known about the natural history of localized (non-disseminated) LAMNs. OBJECTIVE: The goal of this study was to evaluate the risk of peritoneal recurrence in patients with localized LAMNs. METHODS: We performed a multi-institutional retrospective review of patients with pathologically confirmed localized LAMNs. Baseline characteristics, pathology, and follow-up data were collected. The primary endpoint was the rate of peritoneal recurrence. RESULTS: We identified 217 patients with localized LAMNs. Median age was 59 years (11-95) and 131 (60%) patients were female. Surgical management included appendectomy for 124 (57.1%) patients, appendectomy with partial cecectomy for 26 (12.0%) patients, and colectomy for 67 (30.9%) patients. Pathology revealed perforation in 46 patients (37.7% of 122 patients with perforation status mentioned in the report), extra-appendiceal acellular mucin (EAM) in 49 (22.6%) patients, and extra-appendiceal neoplastic cells (EAC) in 13 (6.0%) patients. Median follow-up was 51.1 months (0-271). Seven (3.2%) patients developed a peritoneal recurrence, with a median time to recurrence of 14.4 months (2.5-47.0). Seven (15.2%) patients with histologic evidence of perforation had recurrence, versus no patients (0%) without perforation (p < 0.001); five (10.2%) patients with EAM versus two (1.2%) patients without EAM (p = 0.007), and one (7.7%) patient with EAC versus six (2.9%) patients without EAC (p = 0.355) had recurrence. CONCLUSIONS: This multi-institutional study represents the largest reported series of patients with localized LAMNs. In the absence of perforation or extra-appendiceal mucin or cells, recurrence was extremely rare; however, patients with any of these pathologic findings require careful follow-up.

Medication-specific variations in morphological patterns of injury in immune check-point inhibitor-associated colitis.

AIMS: A varied spectrum of histopathological changes has been associated with immune checkpoint inhibitor (ICI) colitis. This study was performed to evaluate the prevalence of different histopathological patterns of injury in patients with ICI colitis and their association with specific immune check-point inhibitors. METHODS AND RESULTS: Biopsies from patients with clinically and histologically confirmed ICI colitis were reviewed blindly to determine the predominant pattern of injury and to quantitate discrete histological parameters using the Geboes score. Paneth cell metaplasia, intraepithelial lymphocytes, abnormal subepithelial collagen and degree of crypt epithelial apoptosis was also recorded. A total of 86 patients with ICI colitis (ipilimumab, n = 14; ipilimumab + nivolumab, n = 29; nivolumab, n = 20 and pembrolizumab, n = 23) were included. The patterns of injury identified included diffuse active colitis (n = 22), chronic active colitis (n = 22), lymphocytic colitis (LC, n = 16), collagenous colitis (CC, n = 14), graft-versus-host disease-like colitis (n = 7) and mixed colitis (n = 5). Patients on ipilimumab were more likely to have a diffuse active colitis pattern without features of chronicity (P < 0.01) and less likely to have LC (P < 0.05) compared to other ICIs. LC and CC were more common in patients on nivolumab and pembrolizumab relative to other groups (P < 0.05). Chronic active colitis was most frequent in nivolumab patients (P < 0.05), and these patients had received more ICI doses and had been on ICI treatment longer compared to other treatment groups. CONCLUSIONS: ICI colitis should be considered in the differential diagnosis of all the common inflammatory patterns of colitis and shows medication specific differences in patterns of injury.

Non-conventional dysplasias of the tubular gut: a review and illustration of their histomorphological spectrum.

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.

Morphological spectrum of immune check-point inhibitor therapy-associated gastritis.

AIMS: Immune check-point inhibitors are frequently used in the treatment of a variety of solid tumours. The mechanism of action of these drugs involves up-regulation of cytotoxic T cells, which can lead to a lack of self-tolerance and immune-related adverse events, including those involving the gastrointestinal tract. This study was performed to characterise the histological features of immune check-point inhibitor therapy-associated gastritis. METHODS AND RESULTS: Gastric biopsies from patients on immune check-point inhibitor therapy with clinical suspicion of drug-associated gastrointestinal injury were identified. The predominant histological pattern of injury, distribution of injury, degree of tissue eosinophilia and prominence of apoptosis were recorded. Presenting symptoms, treatment and follow-up data were obtained by medical chart review. The 12 patients included in the study group were treated with ipilimumab, nivolumab or pembrolizumab for a variety of tumours. Symptoms at presentation included nausea, vomiting and diarrhoea. Chronic active gastritis with intra-epithelial lymphocytosis and prominent apoptosis was seen in eight of 12 patients, and was the most useful combination for the diagnosis of drug-induced gastritis in these patients. Four patients showed focal enhancing gastritis with a lymphohistiocytic cuff around inflamed glands reminiscent of Crohn's disease. One of those four patients was homozygous for the ATG16L1 Crohn's disease-associated gene variant, but had no history of inflammatory bowel disease. Ten patients responded to medication withdrawal and steroid therapy, while two required treatment with infliximab. CONCLUSIONS: Awareness of the morphological spectrum of immune check-point inhibitor therapy-associated gastritis is important for the accurate diagnosis and prompt management of these patients.

Risk of Metachronous High-Risk Adenomas and Large Serrated Polyps in Individuals With Serrated Polyps on Index Colonoscopy: Data From the New Hampshire Colonoscopy Registry.

BACKGROUND & AIMS: Surveillance guidelines for serrated polyps (SPs) are based on limited data on longitudinal outcomes of patients. We used the New Hampshire Colonoscopy Registry to evaluate risk of clinically important metachronous lesions associated with SPs detected during index colonoscopies. METHODS: We collected data from a population-based colonoscopy registry that has been collecting and analyzing data on colonoscopies across the state of New Hampshire since 2004, including rates of adenoma and SP detection. Patients completed a questionnaire to determine demographic characteristics, health history, and risk factors for colorectal cancer, and were followed from index colonoscopy through all subsequent surveillance colonoscopies. Our analyses included 5433 participants (median age, 61 years; 49.7% male) with 2 colonoscopies (median time to surveillance, 4.9 years). We used multivariable logistic regression models to assess effects of index SPs (n = 1016), high-risk adenomas (HRA, n = 817), low-risk adenomas (n = 1418), and no adenomas (n = 3198) on subsequent HRA or large SPs (>1 cm) on surveillance colonoscopy (metachronous lesions). Synchronous SPs, within each index risk group, were assessed for size and by histology. SPs comprise hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), and traditional serrated adenomas. In this study, SSA/Ps and traditional serrated adenomas are referred to collectively as STSAs. RESULTS: HRA and synchronous large SP (odds ratio [OR], 5.61; 95% confidence interval [CI], 1.72-18.28), HRA with synchronous STSA (OR, 16.04; 95% CI, 6.95-37.00), and HRA alone (OR, 3.86; 95% CI, 2.77-5.39) at index colonoscopy significantly increased the risk of metachronous HRA compared to the reference group (no index adenomas or SPs). Large index SPs alone (OR, 14.34; 95% CI, 5.03-40.86) or index STSA alone (OR, 9.70; 95% CI, 3.63-25.92) significantly increased the risk of a large metachronous SP. CONCLUSIONS: In an analysis of data from a population-based colonoscopy registry, we found index large SP or index STSA with no index HRA increased risk of metachronous large SPs but not metachronous HRA. HRA and synchronous SPs at index colonoscopy significantly increased risk of metachronous HRA. Individuals with HRA and synchronous large SP or any STSA could therefore benefit from close surveillance.

An update on the morphology and molecular pathology of serrated colorectal polyps and associated carcinomas.

Our understanding of serrated colorectal polyps has increased dramatically over the past two decades and has led to a modern classification scheme for these lesions. Sessile serrated polyps with dysplasia represent the most clinically significant serrated polyp; however, the morphologic heterogeneity of dysplasia in sessile serrated polyps has only recently been recognized and correlated with MLH1 immunohistochemistry. Detailed morphologic analysis of traditional serrated adenomas has led to the recognition of flat and early forms of this polyp. Robust data on the risk of metachronous lesions in patients with serrated polyps are also beginning to emerge. This review will summarize our current understanding of serrated polyps and associated carcinomas with a focus on diagnostic criteria, morphologic heterogeneity, molecular findings, and natural history. Controversial issues in the diagnosis and classification of these polyps are also discussed.

Clinicopathologic and genetic characteristics of interval colorectal carcinomas favor origin from missed or incompletely excised precursors.

Interval colorectal cancers may arise from missed or incompletely excised precursors or from a unique rapid progression pathway. We compared the clinicopathologic and molecular profiles of interval and matched non-interval colorectal cancer to determine whether interval colorectal cancers harbor any unique genetic characteristics. Fifty one of 982 colorectal cancer (5.2%) were categorized as interval colorectal cancer, defined as colorectal cancer detected in a diagnostic examination prior to the next recommended colonoscopy and at least 1 year after the last colonoscopy. Clinicopathologic characteristics of interval colorectal cancer were compared to non-interval colorectal cancer matched 1:1 on age, gender, and tumor location. Molecular profile of a subset of interval colorectal cancer (n = 20) and matched (1:2) non-interval colorectal cancer (n = 40) were evaluated using next generation sequencing. Interval colorectal cancer were more likely to occur in the right colon (55% vs. 35%; p = 0.02) and in patients > 70 years of age (55% vs. 34%; p = 0.002). Clinicopathologic features and aberrant DNA mismatch repair protein expression were not significantly different between interval and matched non-interval colorectal cancer. The frequency and spectrum of genetic alterations was also similar in interval and matched non-interval colorectal cancer. Similar findings were seen when analysis was restricted to interval colorectal cancer diagnosed <5 years after last colonoscopy (n = 42). Interval and non-interval colorectal cancers share similar clinicopathologic and genetic profiles when matched for tumor location. Interval colorectal cancers and are more likely to develop from missed or incompletely excised precursors rather than a unique rapid progression pathway.

Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma.

Anti-programmed cell death protein 1 (PD-1) monoclonal antibodies are being increasingly tested in patients with advanced lymphoma. Following treatment, many of those patients are likely to be candidates for allogeneic hematopoietic stem cell transplant (HSCT). However, the safety and efficacy of HSCT may be affected by prior PD-1 blockade. We conducted an international retrospective analysis of 39 patients with lymphoma who received prior treatment with a PD-1 inhibitor, at a median time of 62 days (7-260) before HSCT. After a median follow-up of 12 months, the 1-year cumulative incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GVHD) were 44% and 23%, respectively, whereas the 1-year incidence of chronic GVHD was 41%. There were 4 treatment-related deaths (1 from hepatic sinusoidal obstruction syndrome, 3 from early acute GVHD). In addition, 7 patients developed a noninfectious febrile syndrome shortly after transplant requiring prolonged courses of steroids. One-year overall and progression-free survival rates were 89% (95% confidence interval [CI], 74-96) and 76% (95% CI, 56-87), respectively. One-year cumulative incidences of relapse and nonrelapse mortality were 14% (95% CI, 4-29) and 11% (95% CI, 3-23), respectively. Circulating lymphocyte subsets were analyzed in 17 patients. Compared with controls, patients previously treated with PD-1 blockade had significantly decreased PD-1+ T cells and decreased ratios of T-regulatory cells to conventional CD4 and CD8 T cells. In conclusion, HSCT after PD-1 blockade appears feasible with a low rate of relapse. However, there may be an increased risk of early immune toxicity, which could reflect long-lasting immune alterations triggered by prior PD-1 blockade.

Loss of SMAD4 protein expression in gastrointestinal and extra-gastrointestinal carcinomas.

AIMS: SMAD4 (DPC4) is a tumour suppressor gene that is dysregulated in various tumour types, particularly pancreaticobiliary and gastrointestinal carcinomas. Corresponding loss of protein expression has been reported in approximately 50% of pancreatic and 25% of colonic adenocarcinomas. In the evaluation of carcinoma of unknown primary site, immunohistochemical loss of SMAD4 expression is often used to suggest pancreaticobiliary origin, but there are limited data on the spectrum of SMAD4 expression in carcinomas of other sites. This study evaluates the frequency of SMAD4 loss in a large cohort of carcinomas from diverse anatomical sites. METHODS AND RESULTS: Immunohistochemistry for SMAD4 was performed on tissue microarrays or whole tissue sections of 1210 carcinomas from various organs: gastrointestinal tract, liver, pancreas/biliary tract, lung, breast, thyroid, kidney, ovary and uterus. Expression was considered lost when there was complete absence of staining in tumour cell nuclei, in the presence of intact staining in non-neoplastic cells. SMAD4 loss was seen in 58% of pancreatic adenocarcinomas, 27% of appendiceal adenocarcinomas, 19% of colorectal adenocarcinomas, 16% of cholangiocarcinomas, 10% of lung adenocarcinomas and <5% of oesophageal, breast, gastric and mucinous ovarian adenocarcinomas. All papillary thyroid, hepatocellular, non-mucinous ovarian, endometrial and renal cell carcinomas showed intact SMAD4 nuclear expression. CONCLUSION: In addition to pancreaticobiliary, appendiceal and colonic tumours, SMAD4 loss is also seen in a small subset of other carcinomas, specifically breast, lung, oesophageal and gastric adenocarcinomas, all of which are typically CK7-positive, similar to pancreaticobiliary carcinoma. Awareness of SMAD4 loss in these other carcinoma types is helpful in the evaluation of carcinomas of unknown or uncertain primary site.

Esophagitis in patients without gastroesophageal reflux disease or eosinophilic esophagitis: diagnostic considerations.

PURPOSE OF REVIEW: A multitude of inflammatory diseases other than gastroesophageal reflux disease (GERD) and eosinophilic esophagitis can affect the esophagus. Despite the deceptively simple organization of squamous mucosa and its limited number of inflammatory responses, a wide array of histologic patterns can be seen in inflammatory disorders involving the esophagus. Each such histologic pattern is associated with a limited number of underlying conditions, and the clinician can use this information to narrow the differential diagnosis. The purpose of this review is to review and discuss the pathologic diagnosis of esophagitis caused by conditions other than GERD or eosinophilic esophagitis, with an emphasis on recent developments in the field. RECENT FINDINGS: Recent studies suggest that lymphocytic esophagitis may be a histologic manifestation of esophageal motility disorders. Immunophenotypic features of infiltrating lymphocytes may be helpful in this scenario. immunoglobulin G4-related disease has been implicated as a cause of esophageal inflammation with ulceration, strictures, and mass-forming fibrosis, whereas epidermoid metaplasia has been linked molecularly to the squamous cell neoplasia pathway. SUMMARY: Improved knowledge and appreciation of the pathology of esophageal inflammation are needed to better understand the pathogenesis of various types of esophagitis, and to inform new approaches to the therapy and management of inflammatory esophageal diseases.

The dark side of the colon: current issues surrounding the significance, prevalence, detection, diagnosis and management of serrated polyps.

PURPOSE OF REVIEW: Hyperplastic polyps, once considered to have no malignant potential, are now recognized to be part of a larger group of polyps known as serrated polyps. Serrated polyps can progress to CRC through an epigenetic pathway known as CpG Island Methylator Phenotype (CIMP), characterized by hypermethylation of specific DNA regions such as the promoter regions of the DNA mismatch repair genes like MLH1. The CIMP pathway is tightly linked with mutations of the oncogene BRAF. There are three subtypes of serrated polyps - hyperplastic polyps, sessile serrated polyps (SSPs) and traditional serrated adenomas (TSAs). TSAs harbor cytologic dysplasia whereas hyperplastic polyps and SSPs are nondysplastic lesions. Currently, only SSPs and TSAs are believed to progress to CRC whereas hyperplastic polyps are thought to be benign with no malignant potential. This article will review the current evidence while highlighting some of the issues regarding serrated polyps. RECENT FINDINGS: One challenge has been pathologically distinguishing hyperplastic polyps from SSPs, which is an important distinction, given the potential for progression of SSPs to CRC. Other challenges regarding serrated polyps include adequate detection and resection. Surveillance guideline recommendations for some serrated polyps have been changed in current guidelines to reflect the malignant potential, recommending closer surveillance intervals than the 10-year follow-up that has been traditionally provided for hyperplastic polyps. SUMMARY: Given the difficulties in diagnosing as well as resecting, it is important for endoscopists to know how to detect, resect and manage follow-up in patients with serrated polyps.

Evaluation and reporting of biopsies from the columnar-lined esophagus and gastro-esophageal junction (GEJ).

This review is part of a collaboration between the American Registry of Pathology (the publisher of the Armed Forces Institute of Pathology Fascicles) and Annals of Diagnostic Pathology. It is in a series of expert recommendations on topics encountered in daily practice. The authors, two pathologists and a gastroenterologist, met on 19 January 2019 tasked with developing expert recommendations on reporting biopsies from the columnar lined esophagus and gastroesophageal junction. Our opinions for reporting revolve around noting the presence and absence of goblet cells and clues for confirming whether a sample is from the tubular esophagus. We also illustrate congeners of goblet cell. We present the information in the form of questions and answers.