Sequential hypothermic and normothermic perfusion preservation and transplantation of expanded criteria donor livers.

BACKGROUND: The purpose of this study was to assess the safety and feasibility of sequential hypothermic oxygenated perfusion and normothermic machine perfusion and the potential benefits of graft viability preservation and assessment before liver transplantation. METHODS: With the Food and Drug Administration and institutional review board approval, 17 expanded criteria donor livers underwent sequential hypothermic oxygenated perfusion and normothermic machine perfusion using our institutionally developed perfusion device. RESULTS: Expanded criteria donor livers were from older donors, donors after cardiac death, with steatosis, hypertransaminasemia, or calcified arteries. Perfusion duration ranged between 1 and 2 hours for the hypothermic oxygenated perfusion phase and between 4 and 9 hours for the normothermic machine perfusion phase. Three livers were judged to be untransplantable during normothermic machine perfusion based on perfusate lactate, bile production, and macro-appearance. One liver was not transplanted because of recipient issue after anesthesia induction and failed reallocation. Thirteen livers were transplanted, including 9 donors after cardiac death livers (donor warm ischemia time 16-25 minutes) and 4 from donors after brain death. All livers had the standardized lactate clearance >60% (perfusate lactate cleared to <4.0 mmol/L) within 3 hours of normothermic machine perfusion. Bile production rate was 0.2 to 10.7 mL/h for donors after brain death livers and 0.3 to 6.1 mL/h for donors after cardiac death livers. After transplantation, 5 cases had early allograft dysfunction (3 donors after cardiac death and 2 donors after brain death livers). No graft failure or patient death has occurred during follow-up time of 6 to 13 months. Two livers developed ischemic cholangiopathy. Compared with our previous normothermic machine perfusion study, the bile duct had fewer inflammatory cells in histology, but the post-transplant outcomes had no difference. CONCLUSION: Sequential hypothermic oxygenated perfusion and normothermic machine perfusion preservation is safe and feasible and has the potential benefits of preserving and evaluating expanded criteria donor livers.

Transplantation of declined livers after normothermic perfusion.

BACKGROUND: The persistent shortage of liver allografts contributes to significant waitlist mortality despite efforts to increase organ donation. Normothermic machine perfusion holds the potential to enhance graft preservation, extend viability, and allow liver function evaluation in organs previously discarded because considered too high-risk for transplant. METHODS: Discarded livers from other transplant centers were transplanted after assessment and reconditioning with our institutionally developed normothermic machine perfusion device. We report here our preliminary data. RESULTS: Twenty-one human livers declined for transplantation were enrolled for assessment with normothermic machine perfusion. Six livers (28.5%) were ultimately discarded after normothermic machine perfusion because of insufficient lactate clearance (>4.1 mmol/L after 4 hours), limited bile production (<0.5 mI/h), or moderate macrosteatosis, whereas 15 (71.5%) were considered suitable for transplantation. Normothermic machine perfusion duration was from 3 hours, 49 minutes to 10 hours, 29 minutes without technical problems or adverse events. No intraoperative or major early postoperative complications occurred in all transplanted recipients. No primary nonfunction occurred after transplantation. Seven livers had early allograft dysfunction with fast recovery, and 1 patient developed ischemic cholangiopathy after 4 months treated with biliary stents. All other patients had good liver function with a follow-up time of 8 weeks to 14 months. CONCLUSION: In total, 71.5% of discarded livers subjected to ex vivo normothermic machine perfusion were successfully transplanted after organ perfusion and assessment using an institutionally built device. This study challenges the current viability criteria reported in the literature and calls for a standardization of viability markers collection, an essential condition for the advancement of the field.

Ex Situ Liver Machine Perfusion: The Impact of Fresh Frozen Plasma.

The primary aim of this single-center, phase 1 exploratory study was to investigate the safety, feasibility, and impact on intrahepatic hemodynamics of a fresh frozen plasma (FFP)-based perfusate in ex situ liver normothermic machine perfusion (NMP) preservation. Using an institutionally developed perfusion device, 21 livers (13 donations after brain death and 8 donations after circulatory death) were perfused for 3 hours 21 minutes to 7 hours 52 minutes and successfully transplanted. Outcomes were compared in a 1:4 ratio to historical control patients matched according to donor and recipient characteristics and preservation time. Perfused livers presented a very low resistance state with high flow during ex situ perfusion (arterial and portal flows 340 ± 150 and 890 ± 70 mL/minute/kg liver, respectively). This hemodynamic state was maintained even after reperfusion as demonstrated by higher arterial flow observed in the NMP group compared with control patients (220 ± 120 versus 160 ± 80 mL/minute/kg liver, P = 0.03). The early allograft dysfunction (EAD) rate, peak alanine aminotransferase (ALT), and peak aspartate aminotransferase (AST) levels within 7 days after transplantation were lower in the NMP group compared with the control patients (EAD 19% versus 46%, P = 0.02; peak ALT 363 ± 318 versus 1021 ± 999 U/L, P = 0.001; peak AST 1357 ± 1492 versus 2615 ± 2541 U/L, P = 0.001 of the NMP and control groups, respectively). No patient developed ischemic type biliary stricture. One patient died, and all other patients are alive and well at a follow-up of 12-35 months. No device-related adverse events were recorded. In conclusion, with this study, we showed that ex situ NMP of human livers can be performed safely and effectively using a noncommercial device and an FFP-based preservation solution. Future studies should further investigate the impact of an FFP-based perfusion solution on liver hemodynamics during ex situ normothermic machine preservation.

Biliary Mucinous Cystic Neoplasm: a Classic Presentation of a Rare Neoplasm.

Biliary mucinous cystic neoplasms are rare parenchymal neoplasms with a considerable malignant potential. Due to a lack of diagnostic imaging criteria, histopathologic evaluation remains the definitive method of diagnosis. Resection is the treatment of choice. Here, the authors present a case of biliary mucinous neoplasm in a 39-year-old female with the associated radiographic and histopathologic findings.

Long-Term Outcomes in Indeterminate Colitis Patients Undergoing Ileal Pouch-Anal Anastomosis: Function, Quality of Life, and Complications.

INTRODUCTION: It is uncertain whether the outcomes of patients with indeterminate colitis (IC) undergoing ileal pouch-anal anastomosis (IPAA) deteriorate over time. The aim of this study was to determine the long-term pouch function, quality of life, complications, and incidence of Crohn's disease after IPAA for patients with IC compared to ulcerative colitis (UC). METHODS: A case matched analysis was performed on patients undergoing IPAA for pathologically confirmed IC or UC, between 1985 and 2014. Patients were case matched for age ± 5 years, gender, date of surgery ± 3 years, type of anastomosis and presence of a diverting loop ileostomy. All patients were followed up for greater than six months. RESULTS: 448 patients were case matched, the average age was 36.8 year old and 52.7 % of patients were male. Mean follow-up was 122.06 months (+/- 80.77 months). There were statistically and clinically comparable number of daytime bowel movements (5.7 v 5.5, p = 0.45), rates of incontinence (26.1 % v 18.3 %, p = 0.09) and nighttime seepage in patients (23.1 % v 28.4 %, p = 0.28) with IC and UC. Quality of life markers and patient restrictions were comparable between the two groups. Rates of pelvic sepsis (IC 8.5 %, UC 8.5 %, p = 0.99) and anastomotic leak (IC 3.1 %, UC 4.0 %, p = 0.61) were similar but fistula formation (IC 15.6 %, UC 8.0 %, p = 0.01) and IPAA Crohn's disease rates (IC 6.7 %, UC 2.7 %, p = 0.04) were significantly increased in IC patients. There was no statistically significant difference in pouch failure rates for IC and UC (5.8 % vs.4.9 %, p = 0.58). CONCLUSION: Patients undergoing IPAA for IC have a higher risk of post-operative fistulae and development of Crohn's disease, but comparable morbidity, functional outcomes, quality of life scores and pouch failure rates when compared to UC patients. Long-term data confirms that IPAA is a good surgical option in patients with IC.

Colorectal squamous cell carcinoma: a rare tumor with poor prognosis.

PURPOSE: Primary squamous cell carcinomas of the colon and rectum are extremely rare, with an incidence of less than 1% of colorectal malignancies. Our aim in this study was to evaluate patient characteristics, treatment strategy, and postoperative follow-up of patients with colorectal squamous cell carcinoma. METHODS: We reviewed our prospectively maintained colorectal cancer database for all patients who were diagnosed with colorectal squamous cell carcinoma between January 1990 and April 2009. RESULTS: Out of 5149 patients with colorectal malignancy, 11 patients (0.2%) met the study criteria. Median age at the time of diagnosis was 64. Median BMI was 28 kg/m2. The tumors were localized in the rectum (n = 8), right colon (n = 2), and sigmoid colon (n = 1). The pathologic stages of these tumors were I (n = 1), II (n = 4), III (n = 3), and IV (n = 3). Operations performed were abdominoperineal resection (n = 4), right colectomy (n = 2), total colectomy (n = 1), low anterior resection (n = 1), local excision (n = 1), sigmoidectomy (n=1) and end colostomy creation (n = 1). One patient received intraoperative radiotherapy. Postoperative chemotherapy was given to eight patients, and three patients received postoperative radiation therapy. Median follow-up after diagnosis was 42 months (12-96). Three patients developed recurrence after potentially curative surgery. Five patients died from metastatic disease during follow-up. CONCLUSION: Squamous colorectal cancer can be detected in any part of the colon, generally presents at a later stage, and is associated with a poor prognosis. Surgery is the mainstay of treatment. Various adjuvant chemoradiation treatments appear not to influence the outcome. Further cases need to be analyzed in order to find more effective treatment regimens.

Prevalence of celiac disease in cirrhosis and outcome of cirrhosis on a gluten free diet: a prospective study.

BACKGROUND & AIMS: Current consensus suggests CD to be a multi-systemic disease that could affect any organ system including the liver. It remains under-diagnosed in the US and its prevalence and management in cirrhotic patients has not been studied. Our aim was (1) to estimate the prevalence of CD in cirrhosis, (2) to characterize cirrhotic patients with abnormal celiac serology and normal small bowel biopsy and (3) to evaluate the effect of a GFD on the liver. METHODS: A total of 204 consecutive patients with biopsy proven cirrhosis scheduled for an upper endoscopy (EGD) to assess and treat gastro-esophageal varices (GEV) at the Cleveland Clinic between 5/1/2008 and 5/30/2010 were enrolled in the study and followed for 2 years. RESULTS: CD affects 2.5% of cirrhotic patients and more than twice the prevalence in the general population. Abnormal EMA >1/10 and high hTTG levels >20 IU can be used to diagnose CD in cirrhosis. Sensitivities and specificities are 100% for EMA and 80% and 94% for hTTG, respectively. After a GFD, patients with CD showed a return to normal levels of their celiac serology, small bowel biopsy and liver enzyme abnormalities. CONCLUSIONS: CD is at least twice more common in cirrhotic patients than in the general population and GFD improves liver tests. CD can occur coincidentally with other liver disorders and screening may be warranted during the evaluation of patients with cirrhosis. Abnormal EMA and high hTTG levels can be used to diagnose CD in cirrhosis.

Analytical performance of a formalin-fixed paraffin-embedded tissue-based 634-probe prognostic assay for predicting outcome of patients with stage II colon cancer.

A formalin-fixed paraffin-embedded tissue-based prognostic assay to assess the risk for recurrence in stage II colon cancer has recently been clinically validated. This study describes the analytical performance and quality control measures of the assay. The reportable range was determined to be [-1.129, 1.414] in risk score units. The accuracy was evaluated with a split sample comparison within the production lab and between the production lab and a reference lab. The concordance between the replicates within the production lab was 79% (95% confidence interval, 64%-91%). There was no evidence of bias, and the concordance was 78% (95% confidence interval, 61%-90%) between the labs. The lab-to-lab concordance was further evaluated by simulating risk scores from the full reportable range. The simulation suggested a higher concordance. The sensitivity study demonstrated that the percentage of tumor tissue did not impact the risk score and that RNA concentration of 9.5 ng/µL was a conservative determination of the analyte lower limit of quantification. From the precision study, the repeatability and reproducibility estimates were 0.1267 and 0.0548 in risk score units, respectively. Furthermore, multifaceted quality control measures were implemented, such as proper tissue processing steps, high-risk and low-risk controls, nontemplate control, and a gene expression-based classifier to evaluate the cDNA amplification kit, a key reagent in the assay. In conclusion, this study demonstrates the strong analytical performance of the assay and further supports its use as an objective standardized prognostic test for stage II colon cancer.

Re-examination of sinusoidal deposition of complement 4d in liver allografts: experience from a single institution.

Complement 4d (C4d) is a marker of complement activation that has been used to evaluate humoral rejection in renal and heart allografts. Studies suggested a role for C4d detection in liver allografts in diagnosing acute cellular and humoral rejection but none correlated this with the pre-transplant liver disease. Our study analyzed the association of C4d deposition in liver allografts with the pre-transplant liver disease. C4d deposition was evaluated by indirect immunofluorescence and correlated with lymphocytotoxic crossmatch results, post-transplant clinicopathological diagnosis and type of pre-transplant liver disease. Allograft biopsies were classified by the native liver disease. After excluding 20 patients with rare liver diseases; C4d deposition was evaluated in 506 biopsies from 310 patients including 25 with PSC, 198 with viral hepatitis and 87 with other diseases. C4d immunereactivity distribution was not different among biopsies from patients with different lymphocytotoxic crossmatch results. Sinusoidal C4d deposition was noted in 11.9% of biopsies and 15.2% of patients (in one or more biopsies). 26% (9/35) of biopsies from patients with PSC had sinusoidal C4d deposition; more frequently than from patients with viral hepatitis 12% (43/348) (p=0.04) and other liver diseases 7% (8/123) (p=0.005). In conclusion, C4d deposition in liver allografts is independent of the crossmatch results. It occurs with a variety of pathologic abnormalities and underlying liver diseases; but is more frequent in patients with PSC. This suggests that mechanisms other than allo-immunity activate complement. The mechanisms and clinical significance of C4d deposition in liver allografts in patients with PSC remain to be determined.

Serrated lesions of the appendix frequently harbor KRAS mutations and not BRAF mutations indicating a distinctly different serrated neoplastic pathway in the appendix.

Appendiceal serrated polyps often morphologically resemble their colorectal counterparts and most pathologists employ colorectal diagnostic terminology when evaluating appendiceal serrated lesions. We analyzed 132 appendiceal lesions for mutations in the RAS/RAF/MAPK pathway in an attempt to (1) determine the frequency of these mutations in appendiceal serrated lesions and (2) correlate the histopathologic features with molecular alterations. The study group of appendiceal serrated lesions (n = 46) was divided into a non-dysplastic group (28/46, subclassified as 7 hyperplastic polyps and 21 sessile serrated adenoma/polyps (SSA/P) using colorectal diagnostic terminology) and dysplastic group (18/46, subclassified as 9 SSA/Ps with cytological dysplasia, 7 traditional serrated adenomas, and 2 adenomas with prominent serrations). Appendiceal non-serrated dysplastic lesions (n = 86) comprised the control group. Of the 123 lesions analyzed, KRAS mutations were identified in 64 (52%) appendiceal lesions. No significant difference in the presence of KRAS mutations were identified between serrated non-dysplastic lesions (13/25, 52%), serrated dysplastic lesions (7/14, 50%) and the control group of non-serrated dysplastic lesions (44/84, 52%) (P = 1.0). Importantly, KRAS mutations were identified in lesions that were histologically identical to colorectal hyperplastic polyps (2/6, 33%), SSA/Ps (11/19, 58%), and SSA/Ps with cytological dysplasia (4/7, 57%). Of the 126 lesions tested, BRAF V600E mutations were identified in only 5 (4%) appendiceal lesions. Our results indicate that serrated lesions of the appendix often harbor KRAS mutations rather than BRAF mutations and suggest that the serrated pathway in the appendix is likely different than in the colon and rectum.

Endoscopic and histologic abnormalities of gastrointestinal tract in patients with hereditary hemochromatosis.

BACKGROUND: Patients with iron overload frequently complained of upper gastrointestinal (GI) symptoms. This study aimed to systemically evaluate the association between hereditary hemochromatosis (HH) and gut inflammation. PATIENTS AND METHODS: HH patients were identified using the ICD-9 codes. Inclusion criteria were patients with primary HH who had esophagogastroduodenoscopy (EGD) and/or colonoscopy with GI biopsies (N=39). Patients undergoing EGD with duodenal biopsy for the indication of "rule out celiac disease" were included in the control group (N=40). GI biopsy specimens were rereviewed and scored. RESULTS: Of the 39 patients with genetically confirmed primary HH in the study group, 28 (71.8%) had liver biopsy and 25 (89.3%) of them showed iron deposition. Twenty-five patients (64.1%) had EGD and 23 (59.0%) had colonoscopy. Histologic inflammation was identified in the esophagus in 2 patients (8.0%), stomach in 11 (44.0%), duodenum in 2 (8.7%), and colon in 3 (13.0%). Duodenal biopsy specimen was available for rereview in 16 patients (41.0%). Patient demographics were comparable between the 16 cases in the study group and the 40 cases in the control group. On histology, the frequency of intraepithelial lymphocytosis of small intestine was 25.5% in the HH cases versus 2.5% in controls (P=0.020). HH patients also had a greater proportion of intraepithelial neutrophil infiltration (31.2% vs. 2.5%, P=0.006) and lamina propria lymphocyte infiltration (31.2% vs. 0%, P=0.001) than controls. CONCLUSIONS: GI inflammation was common in HH patients, which from the different perspective, supports the notion that iron overload may lead to GI inflammation.

De novo inflammatory bowel disease and its mimics after organ transplantation.

Diarrhea is a common symptom after solid organ transplantation or hematopoietic stem cell transplantation, with a reported prevalence up to 72%. One of the uncommon causes for diarrhea in the posttransplant setting is development of de novo inflammatory bowel disease (IBD). The incidence of posttransplantation de novo IBD was shown to be higher than that in the general population (206 versus 20 per 100,000 cases annually). The frequency seems to be much higher following orthotopic liver transplantation than the transplantation of other solid organs. De novo IBD has also been described in the setting of bone marrow transplantation though not as commonly as after SOT. While IBD is considered an immune-mediated disorder and responds favorably to immunosuppressive, de novo IBD or IBD-like conditions can occur in the posttransplant period despite antirejection immunosuppressive therapy. Damage or pathogen-associated molecular pattern molecules and their associated ongoing inflammation within the transplanted organ and the recipients' intestine have been implicated as possible etiologies. Various viral, bacterial, and protozoal infections can mimic IBD in postorgan transplantation. Common IBD mimickers in the postbone marrow transplant setting are graft-versus-host disease, infectious enteritis/colitis, and less commonly "cord colitis" that is described in detail below. In this article, we discuss the epidemiology, clinical features, and outcomes of de novo IBD after transplantation and highlight their differences in presentation, diagnosis, and management.

Gene expression profiling of serrated polyps identifies annexin A10 as a marker of a sessile serrated adenoma/polyp.

Sessile serrated adenomas/polyps (SSA/Ps) are precursors of colon cancer, particularly those that exhibit microsatellite instability. Distinguishing SSA/Ps from the related, but innocuous, microvesicular hyperplastic polyp (MVHP) can be challenging. In this study seven gastrointestinal pathologists reviewed 109 serrated polyps and identified 60 polyps with histological consensus. Microarray analysis was performed on six distal consensus MVHPs < 9 mm, six proximal consensus SSA/Ps > 9 mm, and six normal colon biopsies (three proximal, three distal). Comparative gene expression analysis confirmed the close relationship between SSA/Ps and MVHPs as there was overlapping expression of many genes. However, the gene expression profile in SSA/Ps had stronger and more numerous associations with cancer-related genes compared with MVHPs. Three genes (TFF2, FABP6, and ANXA10) were identified as candidates whose expression can differentiate SSA/Ps from MVHPs, and the differences in expression were confirmed by quantitative RT-PCR. As ANXA10 showed the most promise in differentiating these polyps, the expression of ANXA10 was evaluated by immunohistochemistry in consensus SSA/Ps (n = 26), MVHPs (n = 21), and normal colon (n = 9). Immunohistochemical expression of ANXA10 was not identified in separate samples of normal colon or in the normal colonic epithelium adjacent to the serrated polyps. Consistent with the microarray and quantitative RT-PCR experiments, immunohistochemical expression of ANXA10 was markedly increased in SSA/Ps compared to MVHPs (p < 0.0001). An ANXA10 score ≥ 3 has a sensitivity of 73% and a specificity of 95% in the diagnosis of an SSA/P. In conclusion, we show that SSA/Ps and MVHPs have significant overlap in gene expression, but also important differences, particularly in cancer-related pathways. Expression of ANXA10 may be a potential marker of the serrated pathway to colon cancer.

Random biopsies during surveillance colonoscopy increase dysplasia detection in patients with primary sclerosing cholangitis and ulcerative colitis.

BACKGROUND AND AIM: Patients with primary sclerosing cholangitis (PSC) and ulcerative colitis (UC) are at increased risk of colon dysplasia. The role of random vs. target biopsies in these patients has not been investigated. Our aim was to evaluate the yield and clinical impact of random biopsies during surveillance colonoscopies in patients with PSC-UC. METHODS: Data from 71 patients (267 colonoscopies) with PSC and UC, who underwent surveillance colonoscopies and followed-up from 2001 to 2011 was obtained. Colonoscopy and pathology reports were reviewed to assess the yield of random biopsies. RESULTS: A total of 3975 (median 12) random biopsies were taken during surveillance colonoscopies. Overall, neoplasia was detected in 22 colonoscopies (16 patients): in 8 colonoscopies (36.4%) by targeted biopsies only and in 4 (18.2%) by both targeted and random biopsies. Neoplasia was detected in random biopsies only in 10 (45.5%) colonoscopies in 8 patients. On multivariate analysis, duration of UC (Odds ratio [OR]=1.40; 95% confidence interval [CI], 1.08-1.81; P=0.01), number of random biopsies (per increase by 8) (OR=1.64; 95% CI, 1.18-2.28; P=0.003) and target biopsies during colonoscopy (OR=9.08; 95% CI, 3.18-26.0; P<0.001) independently predicted the presence of dysplasia; endoscopic features of prior inflammation did not. CONCLUSIONS: Random biopsies significantly increase the yield of dysplasia in patients with PSC and UC even in the absence of endoscopic features of prior inflammation and significantly impact clinical outcomes.

Backwash ileitis and the risk of colon neoplasia in ulcerative colitis patients undergoing restorative proctocolectomy.

BACKGROUND: The significance of backwash ileitis (BWI) relating to the risk of colon neoplasia in ulcerative colitis (UC) patients is controversial. AIM: We investigated the association between BWI and the presence of colon neoplasia in the colectomy specimen. METHODS: From 4,198 UC patients in a prospectively maintained pouch database from 1983 to 2011, patients with extensive colitis and BWI (n = 178) in proctocolectomy were compared with 537 controls [extensive colitis (n = 385) and left-sided colitis (n = 152)] without ileal inflammation. RESULTS: Colon neoplasia (colon dysplasia and/or colon cancer) was seen in 32 (18 %) patients with BWI in contrast to 45 (11.7 %) with extensive colitis and 13 (8.6 %) with left-sided colitis alone (p = 0.03). Of those with BWI, colon cancer was seen in 10 patients (5.6 %), while low grade and high grade dysplasia were seen in 7 (3.9 %) and 15 (8.4 %) patients respectively. On multivariate analysis, the presence of BWI with extensive colitis [odds ratio (OR) = 3.53; 95 % confidence interval (CI) 1.01-12.30, p = 0.04], presence of primary sclerosing cholangitis (PSC) (OR = 5.79, 95 % CI 1.92-17.40, p = 0.002) and moderate to severe disease activity at UC diagnosis (OR 4.29, 95 % CI 2.06-9.01, p < 0.001) were associated with an increased risk for identifying any colon neoplasia. For colon cancer, the presence of PSC (OR = 11.30, 95 % CI 1.54-80.9, p = 0.01) was the only factor independently associated with an increased risk. CONCLUSIONS: The presence of BWI with extensive colitis was associated with the risk of identifying colon neoplasia but not cancer alone in the proctocolectomy specimen.

Reproducibility of the villous component and high-grade dysplasia in colorectal adenomas <1 cm: implications for endoscopic surveillance.

The presence of high-grade dysplasia (HGD) or villous component (VC) defines an advanced adenoma (AA) in patients with 1 or 2 adenomas <1 cm in size. Current consensus guidelines recommend that patients with AA undergo more intense postpolypectomy surveillance. In these clinical situations, the interobserver reliability in determining VC and HGD would play a major role in the credibility of these consensus guidelines. Therefore, the purpose of this study was to evaluate interobserver variability of VC and HGD in polyps <1 cm before and after the development of consensus criteria among gastrointestinal (GI) pathologists. Five GI pathologists independently evaluated 107 colorectal adenomas <1 cm, and classified them into tubular adenomas or adenomas with a VC (A-VC) and into low-grade dysplasia or HGD. Then a consensus conference was held and consensus criteria for VC and HGD were developed by group review. The same set of 107 slides were rereviewed independently by the same 5 GI pathologists. Interobserver variability using κ statistical analysis before and after the application of consensus criteria was assessed. A 1-sided z-test was used to determine whether κ scores increased after the consensus conference. Interobserver agreement before and after the consensus conference was poor for assessment of A-VC, HGD, and AA. These data calls into question the validity of basing clinical decisions on this distinction.

Distinguishing Barrett gastric foveolar dysplasia from reactive cardiac mucosa in gastroesophageal reflux disease.

Morphologic dysplasia remains the criterion standard of cancer risk in Barrett esophagus but poses many challenges including distinction from reactive inflammatory change. Gastric foveolar dysplasia, a newly described subtype comprising 15% to 20% of Barrett dysplasia, overlaps with reactive cardiac mucosa in gastroesophageal reflux disease (GERD). Despite the clinical importance of accurate distinction, the issue has not been studied. Review of 3698 biopsies from 461 Barrett patients yielded 160 biopsies with Barrett gastric foveolar dysplasia (74 low grade and 86 high grade). These were compared with inflamed cardia from 80 patients with GERD. Immunohistochemistry was performed for Lgl2, MUC2, MUC5AC, and MUC6. Comparing GERD with Barrett gastric foveolar dysplasia, surface nuclear stratification (85% versus 0%, P < .00001), upper mucosa-limited atypia (80% versus 0%, P < .0001), villiform architecture (52% versus 4%; P < .0001), full-thickness mucosal atypia (0% versus 100%, P < .00001), and crowded glandular architecture (0% versus 75%, P < .00001) all proved useful. Cytologic features were less helpful. Comparing low-grade gastric dysplasia alone, because its distinction from reactive cardia may be even more challenging, the listed features all remained significant. Loss or aberrant Lgl2 expression was much more typical of dysplasia (12% versus 99%; P = .0001). MUC proteins did not distinguish the groups. Surface nuclear stratification, "top-heavy" atypia, and noncrowded, villiform architecture were highly characteristic of reactive cardiac atypia in GERD, in comparison with the monolayered nuclei in crowded glands occupying the full mucosal thickness in Barrett gastric foveolar dysplasia. Loss or aberrant Lgl2 staining was useful in identifying Barrett gastric foveolar dysplasia.

Evaluation of upper and lower gastrointestinal histology in patients with ileal pouches.

BACKGROUND: Inflammatory complications of ileal pouch-anal anastomosis (IPAA), including pouchitis and Crohn's disease (CD) of the pouch, are common in patients with restorative proctocolectomy for ulcerative colitis. It is not clear whether these inflammatory conditions can affect upper GI tract. The aim of the study was to evaluate correlation between duodenal and pouch histology in patients with healthy and diseased pouches. METHODS: All IPAA patients who had esophagogastroduodenoscopy with biopsy after colectomy (N = 96) were included. H&E slides of gastric, duodenal, neo-terminal ileum, and pouch body biopsies were blindly re-reviewed by an expert GI pathologist for acute and chronic inflammation. Demographic and clinical variables and pouch outcome were analyzed. RESULTS: There was a significant correlation between acute inflammation in the duodenum as measured by neutrophil infiltration score and the presence of chronic pouchitis (kappa coefficient = 0.21, P < 0.05). Intraepithelial lymphocytosis of the duodenum, though uncommon, only occurred in patients with irritable pouch syndrome, chronic pouchitis, or CD of the pouch. Crypt distortion of duodenal epithelium was only seen in patients with inflammatory or structural diseases of the pouch, including acute (18.2%) and chronic (5%) pouchitis, CD of the pouch (14.3%), and surgical complications of the pouch (14.4%). CONCLUSION: Histologic evaluation of duodenal biopsy may provide additional information in patients with ileal pouches, as patients with normal histology of the pouch may have an abnormal duodenal histology.

Prediction of adenocarcinoma in esophagectomy specimens based upon analysis of preresection biopsies of Barrett esophagus with at least high-grade dysplasia: a comparison of 2 systems.

Distinguishing Barrett esophagus with high-grade dysplasia (BE-HGD) from intramucosal and submucosal adenocarcinomas on biopsies is challenging, yet important, in the choice of therapy. The current study evaluates preresection biopsies from patients who underwent esophagectomy for at least BE-HGD, to compare the recently published histologic categories by the University of Michigan (UM) and Cleveland Clinic (CC), correlate preresection and final resection diagnosis, and identify histologic features in biopsies that might be predictive of adenocarcinoma on esophagectomy. A total of 112 cases with a consensus biopsy diagnosis (agreement by ≥4 of 7 gastrointestinal pathologists) were statistically analyzed to identify histologic features that predicted adenocarcinoma on resection. Applying the UM criteria to the biopsy series showed excellent agreement with the CC system (κ=0.86) and significant correlation between preoperative and esophagectomy diagnoses (P<0.001). The likelihood of finding carcinoma on resection was significantly higher with the category of HGD with marked glandular distortion cannot exclude intramucosal adenocarcinoma [CC; odd ratio (OR), 2.8; P=0.046] or HGD suspicious for adenocarcinoma (UM; OR, 4.3; P=0.008), compared to HGD alone. The presence of "never-ending" glands (OR, 3.7; P=0.008), sheet-like growth (P<0.001), angulated glands (OR, 8.5; P<0.001), ≥3 dilated glands with intraluminal debris (OR, 2.6; P=0.05), and >1 focus of single-cell infiltration into the lamina propria (OR, 8.9; P<0.001) increased the odds of finding carcinoma on resection. The latter 2 variables remained independent predictors of adenocarcinoma in multivariable analysis. In conclusion, the CC and UM systems show excellent agreement and define histologic categories that can improve prediction of adenocarcinoma on resection.