Biliary intraepithelial neoplasia: an international interobserver agreement study and proposal for diagnostic criteria.

Cholangiocarcinoma of the intrahepatic and extrahepatic bile ducts develops through a multistep histopathologic sequence. Premalignant or non-invasive neoplastic lesions of bile ducts have been historically called biliary dysplasia or atypical biliary epithelium. To this date, no standard terminology or classification system has been offered for these lesions. In 2005, a conceptual framework and diagnostic criteria for biliary intraepithelial neoplasia (BilIN) were proposed using the livers of patients with hepatolithiasis. We report herein an international interobserver agreement study on the diagnosis of biliary non-invasive neoplastic lesions with the goal to obtain a consensus on the terminology and grading. Seventeen pathologists from the United States, Europe and Asia participated in this study. They shared a digital file containing histological pictures of 30 foci of non-invasive neoplastic lesions selected from the biliary system of patients suffering from primary sclerosing cholangitis, choledochal cyst or hepatolithiasis. In the criteria, we proposed in 2005, BilIN was classified into three categories based on the degree of atypia: BilIN-1, BilIN-2 and BilIN-3. In this study, consensus was reached for the terminology of BilIN and the three-grade classification system. Interobserver agreement on the diagnosis was moderate (kappa-value=0.45). On the basis of the suggestions and opinions obtained from the 17 participants, the original criteria for BilIN were revised. We now propose a new consensus classification of BilIN that may assist in allowing a more uniform terminology for the diagnosis of biliary non-invasive neoplastic lesions. This classification should help to advance clinical and research applications.     

The impact of shock wave lithotripsy on male fertility: a critical analysis of existing evidence

We review the literature about the impact of shock wave lithotripsy (SWL) on male reproduction. Studies investigating the in vitro effect of shock waves on semen samples indicate that spermatozoa are vulnerable to SWL. According to animal studies, intratesticular bleeding is common, but pregnancy rates are not affected by shock waves. In the clinical setting, SWL causes an acute deterioration in sperm quality, but semen parameters return to baseline 3 months later. Long-term data on male fertility (ie, pregnancy rates) after SWL have yet to be reported and the significance of preexisting infertility has not been elucidated to date.     

Does previous failed ESWL have a negative impact of on the outcome of ureterorenoscopy? A matched pair analysis

This study aims to evaluate the outcome of ureteroscopy/ureterorenoscopy (URS) as a salvage procedure for stones resistant to extracorporeal shock wave lithotripsy (ESWL). Between January 2009 and January 2012, 313 patients with upper tract lithiasis were treated by URS. Among them, 87 (27.8 %) had undergone URS after prior ESWL failed to achieve stone clearance (Salvage group). These patients were matched with a group of patients who underwent URS as first-line modality (Primary group). Stone-free rates and adjuvant procedures represented the primary points for comparison. Secondary points for comparison included complications, procedure duration, total laser energy used and length of hospitalization. Matching was possible in all cases. Stone clearance rates were 73.6 and 82.8 % for the Salvage and Primary group, respectively. The difference in stone clearance rates between the two groups was not statistically significant (p = 0.186). A total of 11 patients (12.6 %) in the Primary group and 18 patients (20.7 %) in the Salvage group underwent an adjuvant procedure (p = 0.154). No statistically significant differences were noted in terms of complications, procedure duration and length of hospitalization. In the Primary group, the laser energy used for stone fragmentation was higher (p = 0.043). The rate of ureteric stenting at the end of the procedure was higher for the Salvage group (p = 0.030). Previous failed ESWL is not a predictor for unfavorable outcome of URS. Salvage URS is associated, however, with an increased need for ureteric stenting at the end of the procedure.     

Increased Frequency of Mutations in the Gene Responsible for Familial Mediterranean Fever (MEFV) in a Cohort of Patients with Ulcerative Colitis: Evidence for a Potential Disease-Modifying Effect?

The MEFV gene, responsible for familial Mediterranean fever (FMF), is involved in inflammatory reactions through altered leukocyte apoptosis, secretion of interleukin (IL)-1β, and activation of the NF-κ B pathway. Ulcerative Colitis (UC) and FMF are both characterized by a recurrent pattern of presentation with periods of remission and flares associated with neutrophilic infiltration at the site of injury. The aim of this study was to investigate the possible correlation between UC and MEFV gene alterations. Twenty-five consecutive, first-diagnosed and untreated UC patients, 28 control patients with rheumatoid arthritis, and 65 normal individuals were analyzed. Nonisotopic RNase Cleavage Assay (NIRCA) was applied as a first-step mutational screening method of exons 10 and 2 of MEFV gene; direct sequencing was subsequently performed to confirm the results. MEFVmutations were identified in 7 (3 M694V/0, 2 M680I/0, 1 E148Q/E148Q, and 1 A744S/0) out of 25 UC patients versus 1 (M694V/0) out of 28 rheumatoid arthritis patients (P = .0199) and 1 (M694V/0) out of 65 healthy controls (P = .0004). Four out of 7 patients with MEFVmutations had inflammatory arthritis, a clinical finding that was not observed in the 18 UC patients with unmutated MEFV (P = .0028). Patients with UC almost universally carried the T A C G MEFV exon 2 haplotype in contrast with normal individuals (P < .0001) and FMF patients (P = .0310). In conclusion the increased frequency of mutations of MEFV in UC patients, especially in those with episodic arthritis, suggests a possible modifying effect of MEFV in the disease process and its localization within the joint. The difference in distribution of MEFV exon 2 haplotypes between UC patients and both FMF patients and normal individuals, suggests that UC patients constitute a genetically distinct population. Larger, longitudinal studies are needed to confirm these initial findings.     

Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans

Epithelial cell adhesion molecule (EpCAM) is a surface marker on human hepatic stem/progenitor cells that is reported as absent on mature hepatocytes. However, it has also been noted that in cirrhotic livers of diverse causes, many hepatocytes have EpCAM surface expression; this may represent aberrant EpCAM expression in injured hepatocytes or, as we now hypothesize, persistence of EpCAM in hepatocytes that have recently derived from hepatobiliary progenitors. To evaluate this concept, we investigated patterns of EpCAM expression in hepatobiliary cell compartments of liver biopsy specimens from patients with all stages of chronic hepatitis B and C, studying proliferation, senescence and telomere lengths. We found that EpCAM(+) hepatocytes were rare in early stages of disease, became increasingly prominent in later stages in parallel with the emergence of ductular reactions, and were consistently arrayed around the periphery of cords of keratin 19(+) hepatobiliary cells of the ductular reaction, with which they shared EpCAM expression. Proliferating cell nuclear antigen (proliferation marker) and p21 (senescence marker) were both higher in hepatocytes in cirrhosis than in normal livers, but ductular reaction hepatobiliary cells had the highest proliferation rate, in keeping with being stem/progenitor cell-derived transit amplifying cells. Telomere lengths in EpCAM(+) hepatocytes in cirrhosis were higher than EpCAM(-) hepatocytes (P < 0.046), and relatively shorter than those in the corresponding ductular reaction hepatobiliary cells (P = 0.057). CONCLUSION: These morphologic, topographic, immunophenotypic, and molecular data support the concept that EpCAM(+) hepatocytes in chronic viral hepatitis are recent progeny of the hepatobiliary stem/progenitor cell compartment through intermediates of the transit amplifying, ductular reaction hepatobiliary cells.     

Liver transplantation for liver rupture due to light chain deposition disease: a case report

Light chain deposition disease (LCDD) is a rare pathologic condition distinct from amyloidosis. Amyloidosis is most often characterized by overproduction of lambda light chains, while kappa chains are overproduced in LCDD. In contrast to amyloid deposits, those of LCDD do not stain with Congo red and have a granular ultrastructure. LCDD primarily affects the kidney; clinically significant liver dysfunction is less common and less severe than renal disease. We describe a case of kappa chain deposition disease in a patient with plasma cell dyscrasia and platelet pool storage defect, which produced massive hepatomegaly and rupture of the liver leading to orthotopic liver transplantation. The liver weighed 6800 g and showed severe atrophy due to massive deposition of light chains. In this case, the deposits were composed of unbranched fibrils, which measured 12 to 20 nm in width, did not possess a hollow core, and were arranged randomly rather than in structured arrays.