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BACKGROUND Colon cancer survival is dependent on metastatic potential and treatment. Large RNA-sequencing data sets may assist in identifying colon cancer-specific biomarkers to improve patient outcomes. OBJECTIVE This study aimed to identify a highly specific biomarker for overall survival in colon adenocarcinoma by using an RNA-sequencing data set. DESIGN Raw RNA-sequencing and clinical data for patients with colon adenocarcinoma (n = 271) were downloaded from The Cancer Genome Atlas. A binomial regression model was used to calculate differential RNA expression between paired colon cancer and normal epithelium samples (n = 40). Highly differentially expressed RNAs were examined. SETTINGS This study was conducted at the University of Louisville using data acquired by The Cancer Genome Atlas. PATIENTS Patients from US accredited cancer centers between 1998 and 2013 were analyzed. MAIN OUTCOME MEASURES The primary outcome measures were recurrence-free and overall survival. RESULTS The median age was 66 years (147/271 men, 180/271 White patients). Thirty RNAs were differentially expressed in colon adenocarcinoma compared with paired normal epithelium, using a log-fold change cutoff of ±6. Using median expression as a cutoff, 4 RNAs were associated with worse overall survival: decreased ZG16 (log-rank = 0.023), aquaporin 8 (log-rank = 0.023), and SLC26A3 (log-rank = 0.098), and increased COL1A1 (log-rank = 0.105). On multivariable analysis, low aquaporin 8 expression (HR, 1.748; 95% CI, 1.016-3.008; p = 0.044) was a risk factor for worse overall survival. Our final aquaporin 8 model had an area under the curve of 0.85 for overall survival. On subgroup analysis, low aquaporin 8 was associated with worse overall survival in patients with high microsatellite instability and in patients with stage II disease. Low aquaporin 8 expression was associated with KRAS and BRAF mutations. Aquaporin 8 immunohistochemistry was optimized for clinical application. LIMITATIONS This was a retrospective study. CONCLUSION Aquaporin 8 is a water channel selectively expressed in normal colon tissue. Low aquaporin 8 expression is a risk factor for worse overall survival in patients who have colon cancer. Aquaporin 8 measurement may have a role as a colon-specific prognostic biomarker and help in patient risk stratification for increased surveillance. See Video Abstract at http://links.lww.com/DCR/B603. LA DISMINUCIN DE LA EXPRESIN TUMORAL DE LA ACUAPORINA DEL CANAL DE AGUA ESPECFICO DEL COLON SE ASOCIA CON UNA REDUCCIN DE LA SUPERVIVENCIA GENERAL EN EL ADENOCARCINOMA DE COLON ANTECEDENTES:La supervivencia del cancer de colon depende del potencial metastasico y del tratamiento. Grandes conjuntos de datos de secuenciacion de ARN pueden ayudar a identificar biomarcadores especificos del cancer de colon para mejorar los resultados de los pacientes.OBJETIVO:Identificar un biomarcador altamente especifico para la supervivencia general en el adenocarcinoma de colon utilizando un conjunto de datos de secuenciacion de ARN.DISENO:La secuenciacion de ARN sin procesar y los datos clinicos para pacientes con adenocarcinoma de colon (n = 271) se descargaron de The Cancer Genome Atlas. Se utilizo un modelo de regresion binomial para calcular la expresion diferencial de ARN entre muestras de cancer de colon emparejadas y muestras de epitelio normal (n = 40). Se examinaron los ARN expresados de forma altamente diferencial.ENTORNO CLINICO:Este estudio se realizo en la Universidad de Louisville utilizando datos adquiridos por The Cancer Genome Atlas.PACIENTES:Se analizaron pacientes de centros oncologicos acreditados en Estados Unidos entre 1998-2013.PRINCIPALES MEDIDAS DE VALORACION:Las principales medidas de valoracion fueron la supervivencia general y libre de recurrencia.RESULTADOS:La mediana de edad fue de 66 anos (147/271 hombres, 180/271 caucasicos). Treinta ARN se expresaron diferencialmente en el adenocarcinoma de colon en comparacion con el epitelio normal emparejado, utilizando un limite de cambio logaritmico de ± 6. Utilizando la expresion mediana como punto de corte, cuatro ARN se asociaron con una peor supervivencia general: disminucion de ZG16 (rango logaritmico = 0,023), acuaporina8 (rango logaritmico = 0,023) y SLC26A3 (rango logaritmico = 0,098) y aumento de COL1A1 (log -rango = 0,105). En el analisis multivariable, la baja expresion de acuaporina8 (HR = 1,748, IC del 95%: 1,016-3,008, p = 0,044) fue un factor de riesgo para una peor supervivencia global. Nuestro modelo de aquaporin8 final tuvo un AUC de 0,85 para la supervivencia global. En el analisis de subgrupos, la acuaporina8 baja se asocio con una peor supervivencia general en pacientes con MSI-H y en pacientes en estadio II. La baja expresion de acuaporina8 se asocio con mutaciones de KRAS y BRAF. La inmunohistoquimica de aquaporina8 se optimizo para su aplicacion clinica.LIMITACIONES:Este fue un estudio retrospectivo.CONCLUSION:La acuaporina8 es un canal de agua expresado selectivamente en el tejido normal del colon. La baja expresion de AQP8 es un factor de riesgo de peor supervivencia global en pacientes con cancer de colon. La medicion de aquaporina8 puede tener un papel como un biomarcador de pronostico especifico del colon y ayudar en la estratificacion del riesgo del paciente para una mayor vigilancia. Consulte Video Resumen en http://links.lww.com/DCR/B603.

The advisability of performing ileal pouch-anal anastomosis for patients with indeterminate colitis is debated. Indeterminate colitis is found in up to 15% of inflammatory bowel disease colectomy specimens. We determined long-term outcomes in patients diagnosed with indeterminate colitis undergoing ileal pouch-anal anastomosis.Fifty-six patients were included with a mean follow-up of 14 ± 7 years. Long-term behavior was defined based on surgeon assessment as "Crohn disease-like" in patients who subsequently developed clear signs of Crohn disease and as "non-Crohn disease-like." Long-term function was assessed using the Cleveland Global Quality of Life and Pouch Functional Score.Thirty-nine percent of patients developed Crohn disease-like behavior, and 61% developed non-Crohn disease-like behavior. Both groups experienced a high rate of pouchitis (57%). Crohn disease-like patients required more anti-inflammatory/immunomodulatory medications (95% vs 18%, P .001), dilatations for afferent-limb strictures (41% vs 0%, P .001), and pouch reoperations (32% vs 6%, P = .02). Eight patients required pouch excision or diversion (7 with Crohn disease-like behavior). The Pouch Functional Score was equivalent between groups.Long-term function after ileal pouch-anal anastomosis for the majority of indeterminate colitis patients was good. Approximately 40% eventually exhibited Crohn disease-like behavior, but the majority had acceptable function and quality of life. Ileal pouch-anal anastomosis is an appropriate surgical option for indeterminate colitis patients after informed consent.

Background & Aims Collagenous colitis (CC) is an inflammatory bowel disorder with unknown etiopathogenesis involving HLA-related immune-mediated responses and environmental and genetic risk factors. We carried out an array-based genetic association study in a cohort of patients with CC and investigated the common genetic basis between CC and Crohn's disease (CD), ulcerative colitis (UC), and celiac disease. Methods DNA from 804 CC formalin-fixed, paraffin-embedded tissue samples was genotyped with Illumina Immunochip. Matching genotype data on control samples and CD, UC, and celiac disease cases were provided by the respective consortia. A discovery association study followed by meta-analysis with an independent cohort, polygenic risk score calculation, and cross-phenotype analyses were performed. Enrichment of regulatory expression quantitative trait loci among the CC variants was assessed in hemopoietic and intestinal cells. Results Three HLA alleles (HLA-B∗08:01, HLA-DRB1∗03:01, and HLA-DQB1∗02:01), related to the ancestral haplotype 8.1, were significantly associated with increased CC risk. We also identified an independent protective effect of HLA-DRB1∗04:01 on CC risk. Polygenic risk score quantifying the risk across multiple susceptibility loci was strongly associated with CC risk. An enrichment of expression quantitative trait loci was detected among the CC-susceptibility variants in various cell types. The cross-phenotype analysis identified a complex pattern of polygenic pleiotropy between CC and other immune-mediated diseases. Conclusions In this largest genetic study of CC to date with histologically confirmed diagnosis, we strongly implicated the HLA locus and proposed potential non-HLA mechanisms in disease pathogenesis. We also detected a shared genetic risk between CC, celiac disease, CD, and UC, which supports clinical observations of comorbidity.

One of the most serious complications faced by patients with inflammatory bowel disease (IBD) is the potential development of colorectal cancer (CRC). There is a compelling need to enhance the accuracy of cancer screening of IBD patients. MicroRNAs (miRNAs) are small nonprotein-coding RNAs that play important roles in CRC oncogenesis. In this study, we report differential miRNA expression in IBD patients with associated CRC from non-neoplastic tissue to dysplasia and eventually cancer. In addition, we identify and examine the role of dysregulated miRNAs in the TP53 pathway. In our CD patients, six miRNAs were upregulated from non-neoplastic tissue to dysplasia, but downregulated from dysplasia to cancer (miR-122, miR-181a, miR-146b-5p, let-7e, miR-17, miR-143) (P < 0.001). Six differentially expressed miRNAs affected the TP53 pathway (miR-122, miR-214, miR-372, miR-15b, let-7e, miR-17) (P < 0.001). Using two human colon cancer cell lines (HT-29 and HCT-116), E2F1, an upstream regulator of TP53, was downregulated in both cell lines transfected with let-7e (P < 0.05) as well as in HCT-116 cells transfected with miR-17 (P < 0.05). Additionally, cyclin G, a cell-cycle regulator miR-122 target was downregulated in both cell lines (P < 0.05). Unique differentially expressed miRNAs were observed in CD-associated CRC progression. Six of these miRNAs had a tumorigenic effect on the TP53 pathway; the effect of three of which was studied using cell lines.

Inflammatory bowel disease (IBD; MIM# 266600) is subdivided on the basis of clinical findings as either Crohn's disease (CD), ulcerative colitis (UC), or indeterminate colitis (IC). Three previously described mutations within the IBD susceptibility gene CARD15 (R702W, G908R, 1007fs) increase susceptibility to CD with a terminal ileal and/or ileocolonic location and fibrostenosing behavior. We undertook an association study using 477 unrelated IBD patients (248 CD, 172 UC, 57 IC) and 104 population controls to determine whether these previously described associations could be replicated in a small, accurately phenotyped cohort. Case-control and family-based approaches were employed to analyze CARD15 mutant allele and haplotype data. Analyses were initially performed in unstratified IBD cohorts. The R702W mutant allele was associated with CD on case-control analysis (q=0.036, P=.004), and 1007fs with CD on pedigree disequilibrium testing (P=.020). All 3 CARD15 mutations increased susceptibility to a variety of CD subphenotypic manifestations, including early-onset CD in individuals with a family history of IBD, and CD complicated by extraintestinal disease. We also present evidence to suggest that R702W may predispose to a more generalized form of CD. Additionally, we confirm that CARD15 mutations are associated with terminal ileal/ileocolonic, and to a lesser extent, fibrostenosing CD.

Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.

The pathogenesis of Crohn's disease (CD), an idiopathic inflammatory bowel disease, is attributed, in part, to intestinal bacteria that may initiate and perpetuate mucosal inflammation in genetically susceptible individuals. Paneth cells (PC) are the major source of antimicrobial peptides in the small intestine, including human alpha-defensins HD5 and HD6. We tested the hypothesis that reduced expression of PC alpha-defensins compromises mucosal host defenses and predisposes patients to CD of the ileum. We report that patients with CD of the ileum have reduced antibacterial activity in their intestinal mucosal extracts. These specimens also showed decreased expression of PC alpha-defensins, whereas the expression of eight other PC products either remained unchanged or increased when compared with controls. The specific decrease of alpha-defensins was independent of the degree of inflammation in the specimens and was not observed in either CD of the colon, ulcerative colitis, or pouchitis. The functional consequence of alpha-defensin expression levels was examined by using a transgenic mouse model, where we found changes in HD5 expression levels, comparable to those observed in CD, had a pronounced impact on the luminal microbiota. Thus, the specific deficiency of PC defensins that characterizes ileal CD may compromise innate immune defenses of the ileal mucosa and initiate and/or perpetuate this disease.

Recent studies have demonstrated decreased numbers of interstitial cells of Cajal in patients suffering from severe chronic constipation as measured by c-Kit (CD117) and CD34 immunohistology. In this study, we wished to determine whether there were abnormalities in the number of neurons of the Auerbach's plexus, their CD117 and CD34 immunoreactivity, or the thickness of colon wall sections in patients with refractory slow transit colonic constipation as compared with control subjects. Specimens from 13 patients who had undergone subtotal colectomy for severe chronic constipation refractory to medical treatment were compared with normal controls. Enteric neurons of Auerbach's plexus were counted, and thickness of the circular and longitudinal layer of the muscularis externa as well as total muscularis externa was measured. Quantitative assessment of anti-CD117 and anti-CD34 immunoreactivity was performed using an Automated Cellular Imaging System and expressed as fractional scores. Except for a decreased circular muscle layer thickness in the constipated patients, no statistically significant differences were observed between the two groups. In particular, there was no relationship between CD117/CD34 fractional staining score and the duration or severity of disease, despite the selection of highly symptomatic individuals requiring colonic resection. Using quantitative immunohistochemistry for CD117/CD34, we could not detect a relationship between fractional CD117/CD34 staining score and chronic constipation as compared to controls.

The classification of ulcerative colitis (UC), Crohn disease (CD), and indeterminate colitis (IC) as forms of inflammatory bowel disease (IBD) is based on clinical, radiological, and histological criteria. The genetic basis of IBD is well founded, and susceptibility loci have been identified on several different chromosomes. We aimed to define genotype–phenotype relationships and interactions with the IBD susceptibility gene CARD15for various IBD susceptibility loci (IBD1, IBD2, IBD5, IBD6, IBD7, and chromosome 4) by characterizing previously described peak LOD score short tandem repeat (STR) markers. The study population consisted of 484 severely affected Caucasian patients with IBD, 144 healthy controls, and 348 nonaffected first-degree relatives of IBD patients. Associations were defined with the use of population- and family-based methodology. Correction for multiple testing was performed with a method based on an experimental false discovery rate. We provide novel evidence to show that IBD2 is involved in susceptibility to IC and terminal ileal CD in this population, with overrepresentation of IBD2 STR D12S83 (GenBank Z16592.1) allele 7 (g.49_60del[CA]6) in IC (q = 0.038, P = 0.014) and underrepresentation of allele 8 (g.51_60del[CA]5) in terminal ileal CD (q = 0.038, P = 0.016). The association of IBD2 with IC was confirmed by family-based testing. We also provide novel evidence to show that IBD5 is involved in susceptibility to IC and colonic/ileocolonic CD in this population, with overrepresentation of IBD5 STR D5S1984 (GenBank Z52623.1) allele 5 (g.183_186del[CA]2) in both IC (q = 0.040, P = 0.005) and colonic/ileocolonic CD (q = 0.040, P = 0.004). Evidence is also given for potential interactions between CARD15and IBD2/IBD5. Other findings include an association of IBD2 with UC, and an association of IBD1 with terminal ileal and colonic/ileocolonic CD. Hum Mutat 25:156–166, 2005. © 2005 Wiley-Liss, Inc.

PURPOSE: Stapling of the ileal pouch-anal anastomosis with preservation of the anal transitional zone remains controversial because of concerns about the potential risk of dysplasia and cancer. The natural history and optimal treatment of anal transitional zone dysplasia ten or more years after surgery are unknown. This study establishes the risk of dysplasia in the anal transitional zone and the outcome of a conservative management policy for anal transitional zone dysplasia, with a minimum of ten years' follow-up after ileal pouch-anal anastomosis. METHODS: A total of 289 patients undergoing anal transitional zone-sparing stapled ileal pouch-anal anastomosis for inflammatory bowel disease between 1986 and 1990 were studied. Patients undergoing anal transitional zone-sparing ileal pouch-anal anastomosis who were studied with serial anal transitional zone biopsies for at least ten years postoperatively were included (n = 178). Median follow-up was 130 (range, 120-157) months. RESULTS: Anal transitional zone dysplasia developed in 8 patients 4 to 123 (median, 9) months after surgery. There was no association with gender, age, preoperative disease duration, or extent of colitis, but the risk of anal transitional zone dysplasia was significantly associated with cancer or dysplasia as a preoperative diagnosis or in the proctocolectomy specimen. Dysplasia was high grade in two patients and low grade in six. Two patients with low-grade dysplasia on two or more occasions after detection of low-grade dysplasia underwent completion mucosectomy and perineal pouch advancement with neo-ileal pouch-anal anastomosis. One patient with high-grade dysplasia on two occasions was to undergo completion mucosectomy, but this was not technically feasible. Partial mucosectomy with vigorous anal transitional zone biopsy was performed with close postoperative surveillance. Biopsies were negative for dysplasia. The second recently diagnosed patient with high-grade dysplasia underwent examination under anesthesia with negative anal transitional zone biopsies and will be kept under close surveillance. No cancer in the anal transitional zone was found during the study period. The 4 other patients with low-grade dysplasia on 1 or 2 occasions were treated expectantly and have been dysplasia free for a median of 119 (range, 103-133) months. CONCLUSIONS: Anal transitional zone dysplasia after stapled ileal pouch-anal anastomosis is infrequent and is usually self-limiting. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone with a minimum of ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, mucosectomy with perineal pouch advancement and neo-ileal pouch-anal anastomosis is recommended.

Background & Aims: Pouchitis often is diagnosed based on symptoms alone.In this study, we evaluate whether symptoms correlate with endoscopic and histologic findings in patients with ulcerative colitis and an ileal pouch-anal anastomosis. Methods: Symptoms, endoscopy, and histology were assessed in 46 patients using Pouchitis Disease Activity Index (PDAI).Patients were classified as either having pouchitis (PDAI score ≥7; N=22) or as not having pouchitis (PDAI score Results: Patients with pouchitis had significantly higher mean total PDAI scores, symptom scores, endoscopy scores, and histology scores.There was a similar magnitude of contribution of each component score to the total PDAI for the pouchitis group.Of note, 25% of patients with symptoms suggestive of pouchitis did not meet the PDAI diagnostic criteria for pouchitis.In both groups, the correlation coefficients between symptom, endoscopy, and histology scores were near zero (range, −0.26 to 0.20; P > 0.05). Conclusions: The symptom, endoscopy, and histology scores each contribute to the PDAI and appear to be independent of each other.Symptoms alone do not reliably diagnose pouchitis. GASTROENTEROLOGY 2001;121:261-267

A susceptibility locus for inflammatory bowel disease (IBD) on chromosome 16 (IBD1) has been linked to Crohn's disease in genome-wide linkage studies. We performed a case–control study with two markers for this locus using leukocyte DNA from 127 Crohn's patients, 83 ulcerative colitis patients, and 74 control patients. Allele, genotype, and haplotype frequencies of the polymerase chain reaction products were determined using autoradiography. Haplotype frequencies differed for ulcerative colitis and Crohn's disease, particularly for haplotype CC (22% ulcerative colitis vs 10% Crohn's disease, P = 0.002 χ2 = 10.0) and haplotype CD (18% Crohn's disease vs 9% ulcerative colitis, P = 0.025 χ2 = 5.02). These data demonstrate the association of the IBD1 locus with both ulcerative colitis and Crohn's disease in a group of unrelated IBD patients. The use of such microsatellite markers when combined with others, might help distinguish ulcerative colitis from Crohn's disease in patients with ambiguous clinical and histological features.

PURPOSE: Preservation of the anal transitional zone during ileal pouch-anal anastomosis is still controversial because of the risk of dysplasia and the theoretical risk of associated cancer. Without long-term follow-up data, the natural history and optimal treatment of anal transitional zone dysplasia are unknown. The aim of this study was to determine the long-term risk of dysplasia in the anal transitional zone and to evaluate the outcome of a conservative management policy for anal transitional zone dysplasia. METHODS: Two hundred ten patients undergoing anal transitional zone-sparing ileal pouch-anal anastomosis for ulcerative or indeterminate colitis between 1987 and 1992 and who were studied with serial anal transitional zone biopsies for at least five years postoperatively were included. Median follow up was 77 (range, 60–124) months. RESULTS: Anal transitional zone dysplasia developed in seven patients 4 to 51 (median, 11) months postoperatively. There was no association with gender, age, preoperative disease duration or extent of colitis, but the risk of anal transitional zone dysplasia was significantly increased in patients with prior cancer or dysplasia in the colon or rectum. Dysplasia was high grade in one and low grade in six. Two patients each with low-grade dysplasia detected on three separate occasions underwent mucosectomy 29 and 38 months after detection of low-grade dysplasia, but no cancer was found. The five other patients with dysplasia on one or two occasions were treated expectantly and were apparently dysplasia-free for a median of 72 (range, 48–100) months. CONCLUSIONS: Anal transitional zone dysplasia after ileal pouch-anal anastomosis is infrequent, is most common in the first two to three years postoperatively and may apparently disappear on repeated biopsy. Anal transitional zone preservation did not lead to the development of cancer in the anal transitional zone after five to ten years of follow-up. Long-term surveillance is recommended to monitor dysplasia. If repeat biopsy confirms persistent dysplasia, anal transitional zone excision with neoileal pouch-anal anastomosis is recommended.

The reported risk of progression from low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or carcinoma (CA) in Barrett's esophagus varies. However, the validity of a diagnosis of LGD may be questioned because of interobserver variability.A search of the Cleveland Clinic Foundation surgical pathology files between 1986 and 1997 yielded biopsy specimens from 43 patients with Barrett's esophagus diagnosed and coded as LGD. Patients with concurrent or prior diagnoses of HGD or carcinoma were excluded. The LGD cases were randomized and blindly reviewed by three gastrointestinal (GI) pathologists along with cases originally diagnosed as Barrett's esophagus without dysplasia (ND; n = 28), indefinite for dysplasia (IND; n = 14), or HGD (n = 15). Each pathologist classified every biopsy specimen as ND, IND, LGD, or HGD, and interobserver agreements were determined by kappa statistics (K). Follow-up data were available on 25 patients originally diagnosed with LGD. Progression was defined as a subsequent diagnosis of HGD or CA on esophageal biopsy or resection specimens.Agreement between two GI pathologists for a diagnosis of LGD was fair (K = 0.28) and poor (K = 0.21 and -0.04). Individual GI pathologists agreed with the original diagnosis of LGD in 70%, 56%, and 16% of cases. The 25 patients with follow-up included 21 men and four women (mean age, 67 yr) with a mean follow-up of 26 months (range: 2-84 months). Seven patients (28%) with follow-up developed HGD (five patients) or CA (two patients), 2-43 months (median: 11 months) after a diagnosis of LGD. The individual GI pathologists' diagnosis did not correlate with progression. However, when at least two GI pathologists agreed on LGD, there was a significant association with progression (seven of 17 patients, 41%, p = 0.04). When all three GI pathologists agreed on a diagnosis of LGD, four of five patients progressed (p = 0.012). In contrast, of the eight patients with follow-up and no agreement among GI pathologists for a diagnosis of LGD, none progressed.A high degree of interobserver variability is seen in the histological diagnosis of Barrett's esophagus-related LGD. Although the number of observations is low, a consensus diagnosis of LGD among GI pathologists suggests an increased risk of progression from LGD to HGD or carcinoma.

OBJECTIVE: Crohn’s disease (CD) and ulcerative colitis (UC) may both affect the colon. However, in approximately 10–20% of these cases, it is impossible to distinguish between these two entities either clinically or histologically, and a diagnosis of indeterminate colitis (IC) is made. Correct diagnosis is important because surgical treatment and long-term prognosis differ for UC and CD. The purpose of this study was to determine the extent of interobserver agreement among board-certified pathologists and a specialist gastrointestinal (GI) pathologist regarding the histological diagnosis of colonic inflammatory bowel disease (IBD). METHODS: A total of 24 university medical center pathologists from eight institutions evaluated 84 colectomy specimens and 35 sets of biopsy specimens from 119 consecutive patients with colonic IBD. A specialist GI pathologist subsequently reviewed all cases without knowledge of clinical data and prior diagnosis. RESULTS: The GI pathologist’s diagnoses differed from the initial diagnoses in 45% of surgical specimens and 54% of biopsy specimens. Of 70 cases initially diagnosed as UC, 30 (43%) were changed to CD or IC, whereas 4 of 23 cases (17%) initially diagnosed as CD were changed to UC or IC. The κ coefficient for the overall agreement of initial diagnoses with the specialist GI pathologist’s diagnoses was −0.01 (p = 0.98). CONCLUSIONS: There is significant interobserver variation in the histological diagnosis of colonic IBD. This may have a profound effect on clinical patient care and, especially, on the choice of operation. More accurate diagnostic criteria are needed to facilitate patient care and to optimize treatment outcome.

Solitary endobronchial papillomas in adults are rare neoplasms. Only sporadic cases have been documented. The histologic classification of these tumors remains problematic, and little is known about their clinical behavior. The clinical and pathologic features of 13 endobronchial papillomas and a single endobronchiolar papilloma were reviewed. In situ hybridization for human papillomavirus (HPV) types 6/11, 16/18, and 31/33/51 was performed on seven cases. Twenty-seven additional well-documented cases were identified in a literature review. Human papillomavirus studies were performed in four of the previously reported cases. The 41 neoplasms combined from the Armed Forces Institute of Pathology and literature review were divided into three groups according to their histologic features. Thirty-one of 41 (76%) patients were men. The ages of the patients ranged from 26 to 74 years (median, 57 years). Three morphologically distinct histologic types were recognized; 27 squamous cell papillomas, 7 glandular papillomas, and 7 mixed squamous and glandular papillomas. Squamous papillomas: 23 of 27 (85%) patients were men, and the median age was 54 years. Six of eleven (55%) of these patients smoked. Twenty-six lesions were exophytic and a single lesion had an inverted pattern. Seven of 24 (29%) lesions featured cytologic atypia and 5 of 24 (14%) had viral cytopathic effect. Five of seven (71%) cases examined for HPV DNA were positive. Three of 18 (17%) recurred. Glandular papillomas: Four of seven (57%) patients were women. The mean age was 67 years. One of five (20%) patients smoked. Five lesions were central, and two were peripheral. Four lesions had columnar epithelium, and three had ciliated epithelium. One of six (17%) lesions recurred. Mixed papillomas: five of seven (71%) patients were men. The median age was 64 years. Three of five (60%) patients smoked. Three of seven (43%) lesions featured cytologic atypia. Four of five lesions were examined for HPV DNA and all were negative. No lesions recurred. This study demonstrates that solitary endobronchial papillomas can be separated into three distinct morphologic categories. Squamous cell and mixed papillomas are predominantly lesions of male smokers in their 6th decade. Although cytologic atypia is observed in many cases, the rarity of these tumors and difficulty in separating papillomas from endobronchial papillary squamous carcinomas make generalizations regarding the risk of progression to carcinoma tenuous at best. Human papillomavirus appears to play a pathogenetic role in some squamous cell papillomas, but not in mixed papillomas, yet its presence in the squamous lesions does not correlate with recurrence or malignancy. The first report of an inverted squamous cell papilloma indicates clinical features similar to the more common exophytic squamous cell papillomas. Glandular papillomas, the rarest of all endobronchial papillomas, are found in an older age group than squamous and mixed papillomas, and most-patients are nonsmokers. Based on these findings, all endobronchial papillomas should be completely excised.

Summary Background Endothelial cells that line microvascular blood vessels have an important role in inflammation through their ability to bind and recruit circulating leucocytes. Endothelial cells from the intestines of patients with chronically inflamed Crohn's disease and ulcerative colitis—the two forms of inflammatory bowel disease—display an increased leucocyte-binding capacity in vitro. We investigated whether this enhanced leucocyte binding is a primary or an acquired defect. Methods We cultured human intestinal microvascular endothelial cells (HIMEC) from the uninvolved intestine and chronically inflamed bowel of three patients with inflammatory bowel disease (two Crohn's disease, one ulcerative colitis). We assessed HIMEC binding to polymorphonuclear leucocytes and U937 cells by means of an adhesion assay. Findings After activation with interleukin-1β or lipopolysaccharide, HIMEC from the chronically inflamed tissue in all three patients with inflammatory bowel disease bound twice as many polymorphonuclear leucocytes and U937 cells as endothelial cells from uninvolved tissue. Interpretation Enhanced leucocyte binding by HIMEC from chronically inflamed tissue in patients with inflammatory bowel disease is an acquired defect since it is not found in the uninvolved intestinal segments from the same individuals. Because interaction between endothelial cells and leucocytes is a key regulatory step in the inflammatory process, this enhanced binding may contribute to the pathophysiology of chronic intestinal inflammation.

BACKGROUND & AIMS: A less costly cancer surveillance method for Barrett's esophagus is desirable. The aim of this study was to compare nonendoscopic balloon cytology with biopsy and brush cytology for detecting dysplasia and carcinoma in patients with Barrett's esophagus. METHODS: Patients in a surveillance program underwent balloon cytology before endoscopy with biopsy and brush cytology. Results of cytology were compared with those of histology. RESULTS: Adequate columnar epithelium was obtained in 52 of 63 (83%) patients with balloon cytology and 59 of 61 (97%) with brush cytology. Balloon cytology obtained abnormal cells in 6 of 8 patients with adenocarcinoma, 2 of 2 patients with high-grade dysplasia, and 2 of 8 patients with low-grade dysplasia. Sensitivity of balloon cytology for high-grade dysplasia or carcinoma was 80% but only 25% for low-grade dysplasia. No patients without dysplasia or carcinoma had abnormal cells. Brush cytology was abnormal in all 11 patients with high-grade dysplasia or carcinoma but only 2 of 9 patients with low-grade dysplasia (sensitivity, 22%). Two of 39 patients without dysplasia had abnormal cells (specificity, 95%). Balloon cytology cost was sixfold less than endoscopy with biopsy. CONCLUSIONS: Balloon cytology detected 80% of patients with high-grade dysplasia or carcinoma when sampling was adequate. Brush cytology data suggest that a more abrasive balloon may improve balloon cytology sensitivity. The potential cost savings of balloon cytology compared with endoscopic cancer surveillance in Barrett's esophagus support further studies of this technique. (Gastroenterology 1997 Jun;112(6):1787-97)

Background: Laser-induced fluorescence spectroscopy has the potential to detect colonic dysplasia in vivo. However, previous studies have limited their analyses to multivariate regression techniques and unblinded retrospective evaluation. The purpose of this study was to develop a probability-based algorithm to detect colonic dysplasia using laser-induced fluorescence spectroscopy and to evaluate it in a blinded manner. Methods: Fluorescence spectra were collected from normal mucosa and colonic polyps during colonoscopy using 370 nm excitation. Tissue was classified as normal, hyperplastic, or adenomatous by histologic examination. Preliminary data was used to devise an algorithm to differentiate tissue type based on probability distributions of the fluorescence intensity at 460 nm and the ratio of the intensity at 680 nm to that at 600 nm. The algorithm was then tested in a blinded fashion. Results: The algorithm correctly determined the tissue type in 88% of cases, equal to the agreement of independent pathologists. Sensitivity, specificity, and positive predictive value for the detection of dysplasia was 90%, 95%, and 90%, respectively. Conclusions: Dysplasia was detected in vivo using fluorescence spectroscopy and a probability-based algorithm. This method may form the basis for a new surveillance technique for patients with increased risk for dysplastic transformation. (Gastrointest Endosc 1996;44:168-76.)

Background: Specialized columnar epithelium in Barrett's esophagus resembles gastric intestinal metaplasia, which selectively stains with methylene blue. Methods: We prospectively evaluated the safety, accuracy, reproducibility, cost, and diagnostic yield of methylene blue–directed biopsy in detecting specialized columnar epithelium and dysplasia in Barrett's esophagus. We performed upper endoscopy with methylene blue–directed biopsy and obtained 236 large cup biopsy specimens (145 stained, 91 unstained) from 14 patients with Barrett's esophagus of any length (Group 1) and 12 control patients. Biopsy specimens were independently examined by two pathologists unaware of the endoscopic results. Results: Methylene blue stained specialized columnar epithelium in 18 of the 26 patients, including those with intramucosal carcinoma (1), high-grade dysplasia (1), and indefinite/low-grade dysplasia (6). Methylene blue staining pattern, which was focal in 72% and diffuse in 28% of patients, was reproduced in 8 patients who had repeat staining within 4 weeks. The overall accuracy of methylene blue staining for detecting specialized columnar epithelium was 95%. The diagnostic yield of methylene blue staining for specialized columnar epithelium in "control" patients was 42%. The risk for dysplasia in stained biopsy specimens was greater than in unstained ones (odds ratio 17.7, p = .0004). Conclusions: Methylene blue mucosal staining is a safe, inexpensive, reproducible, and highly accurate method of diagnosing specialized columnar epithelium in Barrett's esophagus. (Gastrointest Endosc 1996;44:1-7.)

Idiopathic granulomatous gastritis (IGG) is a diagnosis made only by excluding other causes of granulomatous gastritis, such as infection, foreign bodies, and systemic granulomatous diseases. Recently, several investigators have questioned the existence of IGG. We reviewed the slides and clinical data of all cases of granulomatous gastritis seen at the Cleveland Clinic between 1975 and 1994. In addition to routine hematoxylin and eosin stains, slides from all cases were stained with Ziehl-Neelsen, Gomori's methenamine silver, and Giemsa stains. Clinical information and follow-up were available for 42 patients. The clinicopathologic diagnoses of the 42 patients with granulomatous gastritis were as follows: Crohn's disease (n = 23), three of whom had concomitant chronic active gastritis with Helicobacter pylori infection; sarcoidosis (n = 9), four of whom had concomitant chronic active gastritis with H. pylori infection; chronic active gastritis with H. pylori infection and no other systemic illness (n = 2); distal esophageal adenocarcinoma and chronic active gastritis (n = 2); mucosa-associated lymphoid tissue (MALT) lymphoma with chronic active gastritis and presumed H. pylori infection (n = 2); peptic ulcer complications (n = 2); hypertrophic gastropathy with chronic active gastritis (n = 1); and possible Crohn's disease (n = 1). We conclude that (a) in most cases of granulomatous gastritis, a diagnosis of Crohn's disease or sarcoidosis could be established; (b) the background inflammatory pattern was helpful in suggesting a diagnostic category for granulomatous gastritis; (c) granulomatous gastritis is not associated with H. pylori per se; however, if known cases of Crohn's disease and sarcoidosis are excluded, an association between H. pylori and granulomatous gastritis cannot be ruled out; and (d) IGG, if it exists, is extremely rare.

Treatment for invasive adenocarcinoma in colorectal polyps (malignant polyps) is controversial. The aim of this study was to evaluate our institutional treatment strategy for malignant polyps.Malignant polyps were designated as having favorable histology (grade I or II carcinoma with at least a 2-mm free margin) or unfavorable histology (grade III invasive adenocarcinoma, invasive adenocarcinoma with an unassessable margin, or a margin of2 mm). Malignant polyps with favorable histology were considered treated adequately by endoscopic polypectomy, whereas further therapy was recommended for malignant polyps with unfavorable histology. Recurrence, residual adenocarcinoma in a follow-up resection specimen, or metastasis during follow-up were considered adverse outcomes.Of the 47 patients identified, 17 (36%) had favorable histology. Sixteen patients (94%) were treated with polypectomy alone. None had an adverse outcome (median follow-up, 70 months). Thirty patients (64%) had unfavorable histology, and 21 patients (70%) underwent colectomy. Five patients underwent radiation therapy alone. Four patients underwent no additional therapy. Ten of 30 patients with unfavorable histology had adverse outcomes that differed significantly from the favorable histology group (P = 0.03).Endoscopic polypectomy alone is adequate therapy for malignant polyps with favorable histology.

Enterocolic lymphocytic phlebitis (ELP) is a recently described disease characterized by phlebitis in the wall and mesentery of the colon and small bowel. Unlike other systemic or localized vasculitic diseases that can have similar gastrointestinal manifestations, there is no involvement of the arterial system or evidence of systemic vasculitis. The lymphocytic phlebitis affects not only the grossly involved intestinal segment but also the apparently healthy bowel. The diagnosis of ELP is histologic, and other systemic vasculitis must be ruled out. Surgical resection of the bowel not only provides the diagnostic tissue but also leads to resolution of the symptoms. In the literature, ELP has most commonly been reported to present as an acute abdomen. We describe a case of ELP presenting as a large abdominal mass, without evidence of an acute abdomen. This mass was actually diffusely thickened colonic serosa, caused by extensive organizing fat necrosis and marked edema of the serosa and bowel wall.

Clinicopathologic features and surgical treatment of 15 patients with primary anorectal malignant melanoma were studied retrospectively. There was a female preponderance (2:1). The median age was 66 years. Common initial symptoms were rectal bleeding (87%) and/or anal pain (33%); 25% of the melanomas were amelanotic. The maximum tumor size ranged between 0.8 and 8.4 cm (median 3.0 cm). Of the tumors evaluated histologically (n = 12), tumor thickness ranged from 0.9 to 11.3 mm (median 6.1 mm). All melanomas invaded at least into the subepithelial tissue (n = 8) and/or the submucosa of the distal rectum (n = 4), with extension into the internal anal sphincter (n = 5) and lamina propria (n = 3). Endoluminal ultrasound accurately demonstrated depth of invasion in 3 of 3 patients. Three (20%) patients with distant metastases at initial presentation had a mean survival of 8 mo; one of these primary melanomas measured 0.8 cm. Of 12 patients undergoing "curative" treatments--4 by abdominoperineal resection (APR) and 8 by local excision (LE), the incidence of loco-regional recurrence was similar (2/4 and 5/8). All these 7 patients with loco-regional recurrence developed distant metastases within 3 months. The mean survival was similar between APR and LE in the total group (25 mo vs 20 mo), in the decreased (27 mo vs 24 mo) and in those treated with a curative intent (29 mo vs 22 mo). There was no long-term survivor but four patients remained tumor-free up to 19 mo after APR (n = 1) or LE (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Solitary rectal ulcer syndrome (SRUS) often goes unrecognized or is misdiagnosed. Of 98 patients with a final clinicopathologic diagnosis of SRUS, an initially incorrect diagnosis had been made in 25 patients (26 percent). In these 25 patients with a misdiagnosis, the median age was 43 years and the female-to-male ratio was 3.2∶1. The median duration of incorrect diagnosis was five years (range, three months to 30 years), and seven patients received prednisone (>30 mg/day) for a mistaken diagnosis of inflammatory bowel disease. The main clinical symptoms were rectal bleeding (84 percent) and a disturbance of bowel function (56 percent). Rectal prolapse was present in 13 patients. Original rectal biopsy specimens from 23 patients were reviewed; inadequate specimens and failure to recognize diagnostic features of SRUS contributed to delayed diagnosis in 13 and 10 patients, respectively. The most common clinicopathologic mis-diagnoses in SRUS patients with rectal ulcers or mucosal hyperemia were Crohn's disease and mucosal ulcerative colitis. In patients with “polypoid” SRUS, diagnostic confusion was usually with a neoplastic polyp. Persistent bowel symptoms and rectal lesions led to review of the presentations and repeat biopsy directed toward the edge of the rectal ulcers or from within the polypoid or hyperemic rectal lesions, finally establishing the diagnosis of SRUS. Intractable symptoms led to surgery in 15 patients (60 percent), with symptomatic improvement in over two-thirds.

Background. The antibody Ki-67 binds to nuclei in all cell cycle phases except GO and can be used to measure growth fraction. Because proliferative activity has been linked to prognosis in neoplasia, the authors analyzed 100 cases of colorectal carcinoma, each with 3 or more years of follow-up, using Ki-67 immunostaining. Methods. The Ki-67-positive nuclear area and total nuclear area of carcinoma cells in 20 microscopic fields were measured by computed morphometry. A Ki-67 score (percent positive nuclear area × 100) was calculated. The following characteristics also were recorded for each case: patient age and sex, tumor site and size, modified Dukes' stage, spread beyond bowel wall, lymph node status, tumor grade, histologic type, extramural venous spread, tumor growth pattern, fibrosis, lymphocytic infiltration, and mitotic rate. Results. Ki-67 scores ranged from 1 to 90 (mean, 34.6). Ki-67 scores were higher in Stage A disease (versus Stage B, C, and D disease) but were not associated with survival. Survival curves differed by stage, lymph node metastases, infiltrative growth pattern, lymphocytic infiltration, fibrosis, extramural venous spread, and tumor grade in a univariate analysis. The infiltrative growth pattern (P = 0.04) and lymphocytic infiltration (P = 0.003) were features associated independently with survival after adjusting for modified Dukes' stage. Furthermore, the lack of a significant lymphocytic infiltrate was associated with a death rate 3.4 times greater than that occurring in patients with Stage B disease with a significant infiltrate. Conclusions. The authors conclude that proliferative activity in colorectal carcinoma as measured by Ki-67 immunostaining was not associated with prognosis.

Vasoactive intestinal peptide is a neuropeptide with potent modulatory activity on intestinal immunity and may be implicated in the pathogenesis of inflammatory bowel disease (IBD). Previous studies have reported abnormal morphology of vasoactive intestinal peptide-stained enteric nerves, in addition to increased, normal or decreased levels of extractable peptide in Crohn's disease (CD) and ulcerative colitis (UC) tissues. These observations have not been correlated with the amount of enteric nerve fibers or the degree of mucosal inflammation. The investigation was intended to determine whether abnormalities of vasoactive intestinal peptide in IBD are related to quantitative changes of enteric nerve fibers or mucosal inflammation, and whether they are specific for CD or UC. To do this, digitized morphometric analysis was applied to a large number of IBD and control colonic surgical specimens that were immunostained for vasoactive intestinal peptide and S100 protein and scored for severity of inflammation. The results showed that, as compared with controls, there is a marked decrease of vasoactive intestinal peptide-immunoreactive nerve fibers in the lamina propria and submucosa (P less than 0.0001), and of S100-immunoreactive nerve fibers in the lamina propria (P less than 0.0001) of patients with IBD. In the lamina propria but not the submucosa, the variation of decrease is significantly associated with the severity (P less than 0.0001) but not the type (P greater than 0.9) of IBD because it is detected in both CD and UC. We conclude that in IBD there is loss of mucosal neuropeptidic innervation that is intimately associated with inflammation. This loss probably represents a nonspecific event subsequent to damage to enteric nerve fibers but may contribute to disruption of local immunoregulation.

Because inadequate tissue fixation can contribute to poor histologic preparations, compromising diagnosis of pathology, we refixed and reprocessed tissues retrieved from paraffin blocks to determine whether we could improve results. Samples of various normal, inflamed and neoplastic tissues, fixed in 4% formaldehyde solution for 4 to 24 hr, were routinely processed and embedded in paraffin. Four-pm sections were stained with hematoxylin and eosin to serve as control slides. The paraffin blocks were then melted; the remaining tissue was divided into 4 pieces, deparaffinized in xylene and rehydrated in graded alcohols. Three of the 4 pieces were refixed for 18 hr in 4% formaldehyde, Hollande solution, or B5 solution. All 4 pieces of each tissue sample were then reprocessed, embedded in paraffin, sectioned at 4 pm, and stained with hematoxylin and eosin. The control slides and the refixed and reprocessed slides were compared. The histologic/cytologic detail of 9 (38%) reprocessed alone, 11 (46%) form...

Diverticular-associated colitis significantly overlaps clinically with primary inflammatory bowel disease. However, the clinical and the pathologic features of diverticular-associated colitis suggest that it is a distinct clinical entity.We performed a systematic review by use of multiple health care databases and gray literature, following predefined inclusion and exclusion criteria to determine the clinical, endoscopic, and pathologic features of diverticular-associated colitis, and recurrence rates following medical and surgical treatment.Two hundred twenty-seven participants were selected from 18 eligible studies, including our own patients (n = 13). The average age of disease onset was 64 years. The typical symptoms included tenesmus, hematochezia, and diarrhea. One hundred sixty-three of the 227 patients in these studies were classified as having diverticular-associated colitis, of which 142 were managed medically. Twenty-eight patients eventually required an operation. One-quarter (37 of 163) of the patients had recurrence of symptoms with an average follow-up time of three years.Diverticular-associated colitis is a distinct entity that presents with segmental colitis and a variety of clinical, endoscopic, and pathologic features. Diverticular-associated colitis should be considered in the presence of recurrent symptoms after resection for diverticulitis.