Overdiagnosis of high-grade dysplasia in Barrett's esophagus: a multicenter, international study.

Numerous histological mimics of high-grade dysplasia in Barrett's esophagus predispose to overdiagnosis and potential serious mismanagement, including unnecessary esophagectomy. This study investigates the prevalence and sources of this problem. Biopsies from 485 patients diagnosed with Barrett's high-grade dysplasia were screened for a multi-institutional, international Barrett's endoscopic ablation trial. Screening included review of the original diagnostic slides and an additional protocol endoscopy with an extensive biopsy sampling. Observer variability by the study pathologists was assessed through two blinded diagnostic rounds on 437 biopsies from 26 random study endoscopies. Study diagnostic reassessments revealed significantly lower rates of high-grade dysplasia. Only 248 patients (51%) were confirmed to have high-grade dysplasia. The remaining patients had inflamed gastric cardia without Barrett's (n=18; 7%), Barrett's without dysplasia (n=35; 15%), indefinite change (n=61; 26%), low-grade dysplasia (n=79; 33%), adenocarcinoma (n=43; 18%), and other (n=1; <1%), yielding an alarming total of 194 or 40% of patients who were overdiagnosed with Barrett's high-grade dysplasia. Study pathologists achieved a high-level agreement (90% three-way inter-observer agreement per biopsy, Kappa value 0.77) for high-grade dysplasia. Confounding factors promoting overdiagnosis included Barrett's inflammatory atypia (n=182), atypia limited to the basal metaplastic glands (n=147), imprecise criteria for low grade neoplasia (n=102), tangential sectioning artifact (n=59), and reactive gastric cardiac mucosa (n=38). A total of 194 patients (40%) were overdiagnosed with Barrett's high-grade dysplasia, as affirmed by the extensive screening process and high-level study pathologist agreement. The multiple diagnostic pitfalls uncovered should help raise pathologists' awareness of this problem and improve diagnostic accuracy.

Hepatobiliary pathology.

PURPOSE OF REVIEW: Recent studies pertaining to the histopathology of the liver and biliary tract are reviewed. RECENT FINDINGS: Several studies are reviewed which describe the histologic features and clinical behavior of 'plasma cell hepatitis' in the posttransplant setting. Cytokeratin 7, EMA, and CD68 were found to be useful immunohistochemical stains in fibrolamellar hepatocellular carcinoma and may aid in the distinction between this variant and classic hepatocellular carcinoma. Arginase-1, another immunohistochemical stain, was found to have improved sensitivity over HepPar-1 in the diagnosis of classic hepatocellular carcinoma. Metabolic syndrome is common in children with nonalcoholic fatty liver disease and may be an indicator of more severe disease activity and fibrosis. Histologic features were described that may aid in the distinction between the steroid-responsive IgG4-associated cholangitis and the steroid-nonresponsive primary sclerosing cholangitis. In addition, immunohistochemical stains for IgM and IgG may be helpful in distinguishing between autoimmune liver diseases, with primary biliary cirrhosis and its antimitochondrial-negative variant, autoimmune cholangitis, being the two autoimmune liver diseases with a predominance of IgM-positive plasma cells. SUMMARY: Several informative studies pertaining to hepatobiliary pathology were published this year, with topics including posttransplant plasma cell hepatitis, familial hemophagocytic lymphohistiocytosis, pediatric nonalcoholic fatty liver disease, and the use of immunohistochemical stains specific for various immunoglobulin subtypes.

Squamous overgrowth is not a safety concern for photodynamic therapy for Barrett's esophagus with high-grade dysplasia.

BACKGROUND & AIMS: Photodynamic therapy with porfimer sodium combined with acid suppression (PHOPDT) is used to treat patients with Barrett's esophagus (BE) with high-grade dysplasia (HGD). A 5-year phase 3 trial was conducted to determine the extent of squamous overgrowth of BE with HGD after PHOPDT. METHODS: Squamous overgrowth was compared in patients with BE with HGD randomly assigned (2:1) to receive PHOPDT (n=138) or 20 mg omeprazole twice daily (n=70). Patients underwent 4-quadrant jumbo esophageal biopsies every 2 cm throughout the pretreatment length of BE until 4 consecutive quarterly follow-up results were negative for HGD and then biannually up to 5 years or treatment failure. Endoscopies were reviewed by blinded gastroenterology pathologists. RESULTS: Histologic assessment of 33,658 biopsies showed no significant difference (P> .05) in squamous overgrowth between groups when compared per patient (30% vs 33%) or per biopsy (0.5% vs 1.3%), or when the average number of biopsies with squamous overgrowth were compared per patient (0.48 vs 0.66). The highest grade of neoplasia per endoscopy was not found exclusively beneath squamous mucosa in any patient. CONCLUSIONS: No difference was observed in squamous overgrowth between patients given PHOPDT plus omeprazole compared with only omeprazole. Squamous overgrowth did not obscure the most advanced neoplasia in any patient. Treatment of HGD with PHOPDT in patients with BE does not present a long-term risk of failure to detect subsquamous dysplasia or carcinoma.

Colonic perforation as a complication of collagenous colitis in a series of 12 patients.

OBJECTIVES: The rare complication of colonic perforation in collagenous colitis following colonoscopy or barium enema is reported in this series of 12 patients. METHODS: Patients with collagenous colitis complicated by perforation were collected from the authors' consultation files between 1992 and 2007. Colectomy and biopsy specimens were reviewed and the corresponding clinical data were analyzed. RESULTS: The patients ranged in age from 44 to 80 yr, with a female-to-male ratio of 11:1. Perforation occurred during colonoscopy in 2 patients, within 0-5 days following colonoscopy in 8 patients, and during barium enema in 2 patients. The most notable colonoscopic findings were bleeding linear ulcers of the right colon in 9 patients, several of which developed under direct visualization during endoscopy. The perforation culminated in right hemicolectomy in 11 patients. Linear fissuring ulcers were identified in the resections of 8 patients along with features of perforation, including pneumatosis in 4 patients and barium extravasation within the muscularis propria in 2 patients. CONCLUSIONS: This is the largest published series to date, and the first to uncover several novel clinicopathologic features of perforation in collagenous colitis, including the right colonic predilection (corresponding to disease severity), the association with not only colonoscopy, but also barium enema, the occurrence of recognizable perforation actually developing during the procedure, and a more detailed information on the marked histologic severity of these patients' collagenous colitis. An awareness of this rare but potentially fatal complication of collagenous colitis may facilitate its diagnosis and management.

Liver histology of acute brucellosis caused by Brucella melitensis.

As a major organ of the mononuclear phagocytic system, the liver is probably involved in all cases of brucellosis. In this prospective study, liver slides prepared from percutaneous liver biopsy samples of 20 patients with clinical and laboratory evidence of acute brucellosis due to Brucella melitensis were examined for the presence or absence of granulomas by pathologists in Iran and the United States. Nineteen men and one woman ranging in age from 14 to 62 years were studied. All patients had clinical signs and symptoms compatible with acute brucellosis, and all had significantly elevated titers of antibodies to Brucella in their serum. Liver function tests were mildly elevated in 11 (55%) cases, and C-reactive protein was positive in 15 (65%) patients. Thirteen (65%) patients had blood cultures positive for B melitensis. Iranian and American pathologists reported granulomas in 3 (15%) and in 4 (20%) cases, respectively. There was agreement between Iranian and American pathologists in 17 (85%) cases. The most prevalent findings were mild portal or lobular lymphocytic inflammation (16 cases). Two cases revealed noncaseating epithelioid granulomas, and 2 had microgranulomas. The results show that all patients had microscopic evidence of liver involvement. The predominant histologic finding was mild portal or lobular inflammation with lymphocytes. Granulomas were present in only 4 cases.

Liver histology and alanine aminotransferase levels in children and adults with chronic hepatitis C infection.

BACKGROUND: Chronic hepatitis C is often a mild disease in children, but whether this is related to younger age or shorter duration of infection is unclear. Histologic severity has been shown to correlate with duration of infection regardless of age. OBJECTIVES: We compared histologic findings in children and adults with chronic hepatitis C while controlling for sex, duration of infection, hepatitis C virus (HCV)-RNA level, and genotype. METHODS: Twenty-one children and 52 adults whose infection was less than 20 years in duration and who had undergone a liver biopsy were included. Two blinded liver pathologists reviewed the liver biopsies and scored inflammatory activity and fibrosis using the modified Knodell scoring system. RESULTS: The groups were the same with respect to HCV-RNA level (P=0.8), and genotype (P=0.6) but differed in duration of disease (P=0.01) and sex composition (P=0.005). Covariate analysis showed no influence of genotype, duration of infection, or HCV-RNA level on outcome. In controlling for sex, children had significantly milder liver disease and alanine aminotransferase (ALT) elevations. CONCLUSIONS: With equal duration of infection, HCV-RNA level, and genotype, children have lower serum ALT levels and less severe liver disease than adults infected with HCV.

Hepatic iron overload in alcoholic end-stage liver disease is associated with iron deposition in other organs in the absence of HFE-1 hemochromatosis.

BACKGROUND: End-stage cirrhosis in the absence of hereditary hemochromatosis (HHC) can be associated with moderate to marked hepatic iron overload, especially in liver disease as a result of alcohol and/or hepatitis C. However, no published studies have addressed extrahepatic iron deposition in this setting. METHOD: A retrospective case series from three autopsied patients who died from end-stage cirrhosis associated with significant hepatic iron overload. Histology of vital organs was performed to detect extrahepatic iron deposition. HFE genotyping for the C282Y and H63D mutations was determined from archival tissue. Hepatic iron index and hepatic iron concentration (HIC) were quantified from formalin-fixed, paraffin-embedded tissue. Medical records were reviewed for possible causes of iron overload. RESULTS: Two patients were H63D heterozygous (H63D +/-) and one was wild type (C282Y -/-, H63D -/-). Histology revealed evidence of stainable iron in the heart and pancreas of all three subjects. Additionally, stainable iron was seen in the stomach in one subject and in the thyroid, pituitary, choroid plexus and testes in another subject. HIC ranged from 4354 to 6834 microg/g dry weight and HII from 1.8 to 2.2 (micromol/g/years). CONCLUSION: Iron overload secondary to end-stage liver disease can be associated with iron deposition in other organs in the absence of HFE-1 HHC.

Photodynamic therapy with porfimer sodium for ablation of high-grade dysplasia in Barrett's esophagus: international, partially blinded, randomized phase III trial.

BACKGROUND: Barrett's esophagus (BE) may lead to high-grade dysplasia (HGD) and adenocarcinoma. The objective was to examine the impact of treating patients with BE and with HGD by using porfimer sodium (POR) and photodynamic therapy (PDT) for ablating HGD and reducing the incidence of esophageal adenocarcinoma. METHODS: The design was a multicenter, partially blinded (pathology), randomized clinical trial conducted in patients with BE who have HGD. There were 30 contributing centers. A total of 485 patients were screened, with 208 in the intent-to-treat population and 202 in the safety population. Patients were randomized on a 2:1 basis to compare PDT with POR plus omeprazole (PORPDT) with omeprazole only (OM). The main outcome measurement was complete HGD ablation occurring at any time during the study period. RESULTS: There was a significant difference (p < 0.0001) in favor of PORPDT (106/138 [77%]) compared with OM (27/70 [39%]) in complete ablation of HGD at any time during the study period. The occurrence of adenocarcinoma in the PORPDT group (13%) (n=18) was significantly lower (p < 0.006) compared with the OM group (28%) [corrected] (n=20). The safety profile showed 94% of patients in the PORPDT group and 13% of patients in the OM group had treatment-related adverse effects. The limitations of the study were that PDT therapy may have had to be applied more than once and that patients spent more time in treatment. The patients and the physicians were not blinded to the treatment. CONCLUSIONS: PORPDT in conjunction with omeprazole is an effective therapy for ablating HGD in patients with BE and in reducing the incidence of esophageal adenocarcinoma.

Pilot study of the relationship between histologic progression and hepatic iron concentration in chronic hepatitis C.

Hepatic iron deposition is common in patients with chronic hepatitis C (HCV) and may play a role in progression of liver disease. This pilot study examines the relationship between hepatic iron concentration (HIC) and histologic progression over time in patients with HCV. HIC was retrospectively measured in 14 patients with HCV who had 2 serial liver biopsies prior to the era of interferon therapy. The mean interval between biopsies was 56 +/- 46 months. Mean Knodell score worsened between first and second biopsies (10.0 +/- 2.8 versus 12.4 +/- 3.3; P = 0.007). There was increased portal inflammation (3.2 +/- 0.4 versus 3.6 +/- 0.5; P = 0.028) and fibrosis (1.8 +/- 1.3 versus 2.7 +/- 1.2; P = 0.002), but no significant change in piecemeal necrosis or lobular degeneration. There was no significant change in HIC between first and second biopsy (P = 0.66). However, HIC was noted to increase significantly among patients with cirrhosis on initial biopsy or those who progressed to cirrhosis (P = 0.009). In this pilot study, histologic progression in patients with precirrhotic HCV was not associated with an increase in HIC, whereas hepatic iron accumulation was observed in 3 patients once cirrhosis was present. The interaction between progression of hepatitis C and iron deposition warrants further study.