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Background: Biliary dysplasia, a precursor of cholangiocarcinoma (CCA), is a common complication of primary sclerosing cholangitis. Patients with high-grade dysplasia (HGD) or early CCA who have received oncological treatment are candidates for liver transplantation. The preoperative diagnosis of CCA or HGD is challenging, and the sensitivity of biliary brush cytology (BC) is limited., Methods: By using next-generation sequencing (NGS), we retrospectively analyzed archived tissue samples (n=62) obtained from explanted liver tissue and CCA samples to identify oncogenic mutations that occur during primary sclerosing cholangitis carcinogenesis. BC samples were prospectively collected from patients with primary sclerosing cholangitis (n=97) referred for endoscopic retrograde cholangiography to measure the diagnostic utility of NGS combined with BC compared with traditional cytology alone., Results: Mutations in KRAS, GNAS, FLT3, RNF43, TP53, ATRX, and SMAD4 were detected in archived CCA or HGD samples. KRAS, GNAS, TP53, CDKN2A, FBXW7, BRAF, and ATM mutations were detected in prospectively collected brush samples from patients with histologically verified CCA or HGD. One patient with low-grade dysplasia in the explanted liver had KRAS and GNAS mutations in brush sample. No mutations were observed in brush samples or archived tissues in liver transplantation cases without biliary neoplasia. While KRAS mutations are common in biliary neoplasms, they were also observed in patients without biliary neoplasia during surveillance., Conclusions: In summary, NGS of BC samples increased the sensitivity of detecting biliary neoplasia compared with traditional cytology. Performing NGS on BC samples may help diagnose HGD or early CCA, benefiting the timing of liver transplantation., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Evidence for the benefit of scheduled imaging for early detection of hepatobiliary malignancies in primary sclerosing cholangitis (PSC) is limited. We aimed to compare different follow-up strategies in PSC with the hypothesis that regular imaging improves survival., Methods: We collected retrospective data from 2975 PSC patients from 27 centres. Patients were followed from the start of scheduled imaging or in case of clinical follow-up from 1 January 2000, until death or last clinical follow-up alive. The primary endpoint was all-cause mortality., Results: A broad variety of different follow-up strategies were reported. All except one centre used regular imaging, ultrasound (US) and/or magnetic resonance imaging (MRI). Two centres used scheduled endoscopic retrograde cholangiopancreatography (ERCP) in addition to imaging for surveillance purposes. The overall HR (CI95%) for death, adjusted for sex, age and start year of follow-up, was 0.61 (0.47-0.80) for scheduled imaging with and without ERCP; 0.64 (0.48-0.86) for US/MRI and 0.53 (0.37-0.75) for follow-up strategies including scheduled ERCP. The lower risk of death remained for scheduled imaging with and without ERCP after adjustment for cholangiocarcinoma (CCA) or high-grade dysplasia as a time-dependent covariate, HR 0.57 (0.44-0.75). Hepatobiliary malignancy was diagnosed in 175 (5.9%) of the patients at 7.9 years of follow-up. Asymptomatic patients (25%) with CCA had better survival if scheduled imaging had been performed., Conclusions: Follow-up strategies vary considerably across centres. Scheduled imaging was associated with improved survival. Multiple factors may contribute to this result including early tumour detection and increased endoscopic treatment of asymptomatic benign biliary strictures., (© 2022 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background: Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease that may lead to liver cirrhosis or cholangiocarcinoma. Liver histology and fibrosis stage are predictive markers of disease progression, and histological cirrhosis is defined as a significant endpoint. PSC-specific histological scoring methods are lacking at present. We aimed to develop a tailored classification system for PSC, the PSC histoscore, based on histological features associated with disease progression., Methods: In total, 300 PSC patients diagnosed between 1988 and 2018 were enrolled; their data were collected from the PSC registry (Helsinki University Hospital), and liver specimens were obtained from the Biobank of Helsinki. Five histological features included in the adapted Nakanuma scoring system and three additional parameters typical for PSC histology were evaluated and compared with the clinical and laboratory data. A compound endpoint consisting of liver transplantation, development of cholangiocarcinoma, or death was used as outcome measurement., Results: Stage (fibrosis, bile duct loss, ductular reaction, and chronic cholestasis) and grade (portal inflammation, portal edema, hepatitis activity, and cholangitis activity) parameters were found to be independent predictive risk factors for the compound endpoint (P < 0.001). High disease grade (2-6) and stage (2-4) better correlated with clinical endpoints when evaluated with the PSC histoscore system compared to the adapted Nakanuma classification. The risk for disease progression in sequential endoscopic retrograde cholangiography (ERC) examinations was increased with elevated total PSC histoscores., Conclusion: The PSC histoscore is a novel histological classification system for PSC. Our findings support the applicability of liver histology as a marker for disease progression., (© 2022 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background and Aims: Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC)., Approach and Results: We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%)., Conclusions: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC., (© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.)

Aim: To investigate markers for high-grade dysplasia for the optimal timing of liver transplantation in patients with primary sclerosing cholangitis (PSC)., Methods: Earlier data support a dysplasia-carcinoma sequence, even low- to high-grade dysplasia, in PSC-associated cholangiocarcinoma (CCA). Surveillance using endoscopic retrograde cholangiography (ERC) and brush cytology aims to detect cases of biliary dysplasia, and liver transplantation is an option in cases with suspicion of malignancy in brushing. This study investigated markers to identify patients with high-grade biliary dysplasia for optimal timing in early liver transplantation. Patients undergoing surveillance using ERC and brush cytology during 2008-2014 and who were diagnosed with biliary dysplasia in explanted liver or CCA until February 2016 were included in the study. Demographic data, cholangiography findings, laboratory values, cytological morphology and DNA ploidy were analysed., Results: Thirty PSC patients had biliary neoplasia in the explanted liver during the study period. Sixteen of these patients had low-grade dysplasia, 10 patients had high-grade dysplasia, and 4 patients had CCA. Fifteen PSC patients diagnosed with CCA were not transplanted. Patients with low-grade dysplasia were younger. Alkaline phosphatase or carcinoembryonic antigen values did not differ between groups during surveillance, but carbohydrate antigen 19-9 was higher in CCA patients. No difference in PSC duration, ERC scores, suspicious cytology, or ploidy analysis was found between groups. No difference was observed between fibrosis stage in explanted livers. Low- and high-grade dysplasia could not be differentiated before liver transplantation based on liver enzymes, tumour markers, ERC scores, brush cytology or DNA ploidy., Conclusion: Repeated suspicion of neoplasia in brush cytology should be an indication for evaluations of liver transplantation prior to the development of CCA., Competing Interests: Conflict-of-interest statement: We have no financial relationships to disclose.

Objective: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease leading to bile duct strictures and fibrosis, and predisposing to cholangiocarcinoma (CCA). Biliary dysplasia is a known precursor of CCA. In our unit, PSC patients undergo regular surveillance with ERC and brush cytology (BC), and liver transplantation is an option in case with biliary dysplasia. We evaluated the risk factors for biliary dysplasia and CCA based on ERC imaging, BC and liver function tests., Patients and Methods: Seven hundred and eighty-eight ERCs were performed with BC for 447 PSC patients. ERC images were evaluated using the modified Amsterdam score, neutrophilic inflammation was assessed in BC, and liver function tests were collected. Ploidy analysis with DNA flow cytometry was performed in cases with advanced PSC or previous suspicious BC/aneuploidy. The endpoint was either a benign disease course (follow-up for ≥2.4 years after the latest ERC), benign histology, biliary dysplasia or CCA., Results: Benign disease course was seen in 424/447 (including 23 cases with biliary dysplasia), and CCA in 17 (3.8%) patients. Gallbladder carcinoma/carcinoma in situ was diagnosed in three patients. Advanced ERC findings, male gender, suspicious BC, aneuploidy in flow cytometry, inflammation, and elevation of ALP, bilirubin, ALT, AST, GGT, CEA and CA19-9 represented significant risk factors for CCA in univariate analysis., Conclusions: PSC patients with advanced bile duct disease and elevated liver enzymes, CEA or CA19-9, inflammation or suspicious BC are most likely to develop CCA. These patients may benefit from surveillance with BC if early liver transplantation is possible.

Background and Study Aims: Primary sclerosing cholangitis (PSC) is associated with increased risk of biliary dysplasia and cholangiocarcinoma (CCA). The aim of this study was to evaluate the role of early endoscopic retrograde cholangiography (ERC) with systematic brush cytology to identify risk factors associated with biliary neoplasia., Patients and Methods: Patients who were referred for their first ERC for suspicion of PSC between January 2006 and October 2011 were included in the study. Brush cytology specimens were scored as benign, suspicious, or malignant. End points were CCA, biliary dysplasia, benign histology, or benign disease course for ≥ 2 years., Results: PSC was diagnosed in 261 patients (125 men, 136 women), most of whom were asymptomatic (n = 211). Cholangiographic changes were mild in 57.1 %. Men presented with advanced disease more often than women. Brush cytology was benign in 243, suspicious in 16, and malignant in 2 patients. Follow-up completed in 249 patients indicated a benign disease course in 232 patients. Seven patients were diagnosed with CCA and eight had biliary dysplasia in the explanted liver. Thus, 15 patients had biliary neoplasia, and suspicious or malignant brush cytology had been detected in 8 of them at initial brushing. Advanced extrahepatic cholangiographic changes with elevated aminotransferases at diagnosis seemed to be associated with increased risk of biliary neoplasia., Conclusions: Even in mostly asymptomatic patients with PSC, 42.9 % had advanced disease and 6.9 % presented with suspicious or malignant brush cytology at first ERC. Advanced extrahepatic ERC changes with elevated aminotransferases at diagnosis might be risk factors for biliary neoplasia., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: Detection of biliary dysplasia in PSC is essential for proper timing of liver transplantation to prevent the development of cholangiocancer, which is considered a contraindication for liver transplantation in most centres. In patients with PSC, differential diagnosis of benign, premalignant and malignant biliary strictures is difficult., Aims: This prospective study aimed to evaluate the role of DNA analysis in combination with brush cytology, scored ERCP findings, and tumour markers to detect hepatobiliary dysplasia and malignancy., Material and Methods: Brush samples for cytology and for evaluation of DNA content analysed with flow cytometry came from 102 consecutive PSC patients referred for ERCP. Symptoms, serum Ca19-9 and CEA were determined at the time of index biliary examination. ERCP findings were scored for intra- and extrahepatic changes. The end-points were liver transplantation or diagnosis of malignancy or dysplasia., Results: Most of the patients were asymptomatic at the time of ERCP: 73% had no symptoms, and 12% had only mild symptoms. An aneuploid DNA content was evident in 20 (20%) patients, and cells suspected for malignancy in 22 (21%). Seven patients had both aneuploidity and cytology (7%) suspicious for malignancy. An end-point, diagnosis of malignancy or liver transplantation was achieved in 42 patients. Combining DNA ploidity and cytology in patients at the end-point, sensitivity was 72%, specificity 82%, positive predictive value 86% and negative predictive value 67%., Discussion and Conclusion: In this mostly asymptomatic PSC-patient population, 33% demonstrated abnormal brush cytology or aneuploidity. Determining DNA ploidy and brush cytology during ERCP offers a useful tool for identifying those PSC patients who are at high risk of developing cholangiocancer., (© 2011 John Wiley & Sons A/S.)

Background/aims: Primary sclerosing cholangitis (PSC) is associated with a high risk of cholangiocarcinoma. Our aim was to evaluate the diagnostic value of trypsinogen-1, trypsinogen-2, tumour-associated trypsin inhibitor, human chorionic gonadotropin beta and trypsin-2-alpha(1)-antitrypsin for cholangiocarcinoma and to compare them with CA19-9 and CEA., Methods: The study consisted of 84 patients with either PSC or cholangiocarcinoma or both referred for liver transplantation or other liver surgery. The serum concentrations were determined by time-resolved immunofluorometric assays., Results: Forty-six patients were transplanted due to PSC; in 3 of the explanted livers cholangiocarcinoma was found incidentally. All transplanted patients had severe biliary strictures together with cirrhosis or pre-cirrhosis. Twenty-nine of 38 patients with cholangiocarcinoma were candidates for intervention. In all, 8 patients had both PSC and cholangiocarcinoma. Receiver-operating characteristics curve analysis showed that serum trypsinogen-2 had the highest accuracy in differentiating between cholangiocarcinoma and PSC. The area under the curve (AUC) value was 0.804 for trypsinogen-2 and 0.613 for CA19-9. Serum trypsinogen-2 also showed the highest accuracy for differentiation between PSC and PSC with simultaneous cholangiocarcinoma with an AUC value of 0.759., Conclusions: Our results suggest that serum trypsinogen-2 is a most useful marker for diagnosing patients with cholangiocarcinoma, and it is superior to serum CA19-9 and CEA.

Background and Aims: A new definition of dominant stricture (NDS) has recently been defined for patients with primary sclerosing cholangitis (PSC). Prevalence and clinical features of this, compared to traditional dominant stricture (TDS), have not been reported. Methods: In this single‐centre longitudinal prospective cohort study, all PSC patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) between October 2021 and 2022 were recruited. Symptoms of cholestasis, laboratory values (P‐alkaline phosphatase, P‐Bilirubin), Helsinki PSC‐score, brush cytology findings and need for endoscopic therapy (i.e. dilation, stenting) were prospectively collected. Results: Overall, 228 patients with PSC underwent 248 ERCPs. NDS was detected in 43 (17%; 36 patients) and TDS without NDS (TDS group) was detected in 62 (25%; 58 patients) ERCPs, respectively; in the remaining 143 ERCPs, neither TDS nor NDS was seen (no dominant stricture [NoDS] group). PSC duration (median 8 years) and patient's age did not differ between the three groups; males presented more often with NDS. Patients with NDS were more often symptomatic, had higher cholestatic liver enzymes, advanced bile duct disease and markers of biliary inflammation (p <.001). Patients with NDS needed dilation (81%) and stenting (21%) more often than the TDS group (60% and 5%, respectively). Dysplasia in brush cytology was more common in TDS (5%) and NDS (9%) than in NoDS (3%) groups (p =.04), but did not differ between TDS and NDS groups. Conclusions: Dominant stricture according to the new definition developed in 17% of PSC patients in our cohort and identifies patients with more advanced disease, biliary inflammation and need of endo‐therapy. [ABSTRACT FROM AUTHOR]

Background: Antitumoral immune response has a crucial role in constraining cancer. However, previous studies on cholangiocarcinoma (CCA), a rare and aggressive cancer, have reported contradictory findings on the prognostic impact of tumorinfiltrating T-lymphocytes. We aimed to clarify the effect of tumor-infiltrating CD3+ and CD8+ lymphocytes and PD-1/PD-L1 expression on CCA prognosis. Methods: CD3+, CD8+, and PD-1+ lymphocyte densities, as well as PD-L1 expression rate were analyzed from stained tissue microarray samples from the tumor center and invasive margin of 47 cholangiocarcinomas. The association of CD3+ and CD8+ based Immune cell score (ICS) and its components with overall survival was evaluated, adjusting for age, sex, TNM stage, radicality of surgery, tumor location, and PD-L1 expression on immune cells. Results: Low ICS was a strong independent prognostic factor for worse overall survival (Hazard ratio 9.27, 95% confidence interval 2.72-31.64, P<0.001). Among the ICS components, high CD8+ lymphocyte infiltration at the tumor center had the most evident impact on patient outcome. PD-1 and PD-L1 expression on immune cells did not have a significant impact on overall survival alone; however, PD-L1 positivity seemed to impair survival for ICSlow subgroup. Conclusion: Identifying patient subgroups that could benefit from immunotherapy with PD-1/PD-L1 pathway blockade may help improve treatment strategies for this aggressive cancer. Our findings highlight the importance of evaluating the immune contexture in cholangiocarcinoma, as ICS serves as a strong independent prognostic and selective factor for patients who might benefit from immunotherapy. [ABSTRACT FROM AUTHOR]

Background & Aims: Endoscopic retrograde cholangiography (ERCP) has been considered the gold standard for the diagnosis and follow‐up of primary sclerosing cholangitis, but it has been replaced by less invasive magnetic resonance imaging and cholangiopancreatography (MRI‐MRCP). However, the role of these two techniques in the evaluation of disease activity and severity needs to be elucidated. Methods: Patients with primary sclerosing cholangitis (n: 48, male 31, median age: 35.7; 28.0‐44.2) who underwent ERCP and MRI‐MRCP within ±3 months for diagnosis or follow‐up, were reviewed. ERCP and MRI‐MRCP images were scored using the modified Amsterdam score. Serum and biliary cytology markers of disease activity and severity were related to the imaging findings. Agreement on the assessment of the ERCP/MRCP score was calculated by kappa‐statistics. Spearman′s ρ was calculated when appropriate. Results: The agreement between ERCP and MRCP in scoring bile duct changes for disease severity was only moderate (weighted kappa: 0.437; 95% CI: 0.211‐0.644 for intra‐ and 0.512; 95% CI: 0.303‐0.720 for extra‐hepatic bile ducts). ERCP and MRCP intra‐hepatic scores were associated to the surrogate marker alkaline phosphatase (P = .02 for both). A weak correlation between MRCP score for extra‐hepatic bile ducts and liver transplantation/death was found (Spearman's ρ = .362, 95% CI: 0.080‐0.590, P = .022). A weak correlation between intra‐ (Spearman′s ρ = .322, 95% CI: 0.048‐0.551, P = .022) and extra‐hepatic (Spearman's ρ = .319, 95% CI: 0.045‐0.549, P = .025) peribiliary enhancement on contrast‐enhanced MRI and severity of biliary cytologic classification was found. Conclusions: The overall agreement between ERCP and MRI‐MRCP in assessing disease severity was moderate for intra‐ and extra‐hepatic bile ducts. MRI‐MRCP seems to have a minor role as surrogate marker of disease activity and progression in PSC. [ABSTRACT FROM AUTHOR]

Objective: The etiopathogenesis and risk for development of biliary neoplasia in primary sclerosing cholangitis (PSC) are largely unknown. Microbes or their metabolites have been suggested to play a role. To explore this potential microbial involvement, we evaluated the differences in biliary microbiota in PSC patients at an early disease stage without previous endoscopic retrograde cholangiography (ERC) examinations, advanced disease stage, and with biliary dysplasia or cholangiocarcinoma. Design: Bile samples from the common bile duct were collected from 46 controls and 80 patients with PSC during ERC (37 with early disease, 32 with advanced disease, and 11 with biliary dysplasia). DNA isolation, amplification, and Illumina MiSeq sequencing were performed for the V1-V3 regions of the bacterial 16S rRNA gene. Results: The most common phyla found were Bacteroidetes, Firmicutes, Proteobacteria, Fusobacteria, and Actinobacteria. The most common families were Prevotellaceae, Streptococcaceae, Veillonellaceae, Fusobacteriaceae, and Pasteurellaceae, and the most common genera were Prevotella, Streptococcus, Veillonella, Fusobacterium, and Haemophilus. The bacterial communities of non-PSC subjects and early stage PSC patients were similar. Alpha diversity was lower in patients with biliary dysplasia/cholangiocarcinoma than in other groups. An increase in Streptococcus abundance was positively correlated with the number of ERC examinations. Streptococcus abundance was also positively correlated with an increase in disease severity, even after controlling for the number of ERC examinations. Conclusions: Our findings suggest that the aetiology of PSC is not associated with changes in bile microbial communities, but the genus Streptococcus may play a pathogenic role in the progression of the disease. [ABSTRACT FROM AUTHOR]

Background and Aims Primary sclerosing cholangitis is associated with a high risk of cholangiocarcinoma. Here, we investigated the value of surveillance for dysplasia using brush cytology, to determine the optimal timing of liver transplantation in primary sclerosing cholangitis. We compared our preoperative findings, with the final explanted liver histopathology. Methods 126 consecutive patients were transplanted for primary sclerosing cholangitis from 1984 to 2012. Patients were divided into two groups: symptomatic (n=91), and asymptomatic (n=35). Results Brush cytology was available for 101 patients; 66 symptomatic and 35 asymptomatic. Suspicious cytological findings were found in nine patients (14%) in the symptomatic group and 17 (49%) in the asymptomatic group. DNA flow cytometry was available for 49 patients (25 symptomatic, 24 asymptomatic), with aneuploidy detected in six patients (24%) in the symptomatic group and 15 (63%) in the asymptomatic group. Explanted liver histology showed biliary dysplasia or cholangiocarcinoma in 11 symptomatic patients (12%) and 15 asymptomatic patients (43%). A combination of cytological and DNA flow cytometry findings resulted in a test sensitivity of 68%, with a specificity of 86%. Ten-year survival in the asymptomatic group was 91%. Conclusions Dysplasia surveillance using brush specimens may help to select those patients likely to benefit from early liver transplantation. It remains unclear as to whether surveillance with brush cytology improves long-term survival, but there is presently no better method with which to predict transplantation timing. [ABSTRACT FROM AUTHOR]