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Albertini E, Miranda L, Maloberti T, de Biase D, Vasuri F. Morphologic and molecular diagnostic criteria of malignancies in biliary strictures. Histol Histopathol 2025; 40:443-452. [PMID: 39381890 DOI: 10.14670/hh-18-811] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/10/2024]
Abstract
The differential diagnosis of benign and malignant biliary strictures is not always feasible and still represents a major diagnostic challenge, mainly due to the scarcity of the tissue retrieved for proper cytological or histopathological diagnosis. The present review focuses on morphological criteria in the diagnosis of biliary strictures, in the course of primary sclerosing cholangitis and other pathologies, starting from the limits of the cytological and histological evaluation, as well as the ancillary methodologies currently available in Pathology laboratories The current guidelines suggest fluorescence in situ hybridization for the analysis of chromosomes 3, 7, and 17 polysomies and deletion of the 9p21 locus; however, other more promising techniques are on the horizon for both patient care and research purposes, such as Next-Generation Sequencing, able to analyze multiple genes simultaneously in a cost-effective fashion. Lastly, the most recent approaches proposed in the literature for the differential diagnosis of biliary stricture are described, such as circulating tumor DNA, miRNAs, and DNA methylation, among others.
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Affiliation(s)
- Elisa Albertini
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- School of Anatomic Pathology, Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Lucia Miranda
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Thais Maloberti
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Dario de Biase
- Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Bologna, Italy
| | - Francesco Vasuri
- Pathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
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Khataniar H, Habib H, Ruiz M, Dharia A, Magoo S, Kulkarni A. Rare Presentation of Eosinophilic Cholangitis in a 32-Year-Old Man. ACG Case Rep J 2025; 12:e01641. [PMID: 40084063 PMCID: PMC11905968 DOI: 10.14309/crj.0000000000001641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 02/11/2025] [Indexed: 03/16/2025] Open
Abstract
Eosinophilic cholangitis (EC) is a rare condition characterized by eosinophilic infiltration of the bile ducts, often mimicking diseases like primary sclerosing cholangitis or cholangiocarcinoma. We report the case of a 32-year-old man with severe epigastric pain and elevated liver function tests. Initial imaging revealed common bile duct dilation and multiple strictures, initially suggestive of primary sclerosing cholangitis. Multiple endoscopic retrograde cholangiopancreatographies with brushings showed benign cytology but revealed polysomy on fluorescence in situ hybridization. A biopsy confirmed EC. High-dose corticosteroids led to significant clinical improvement. This case underscores the importance of considering EC in the differential diagnosis of biliary diseases, as timely diagnosis and treatment can lead to excellent outcomes.
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Affiliation(s)
| | - Hany Habib
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA
| | - Molly Ruiz
- Drexel University College of Medicine, Pittsburgh, PA
| | - Ashni Dharia
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA
| | | | - Abhijit Kulkarni
- Division of Gastroenterology, Hepatology and Nutrition, Allegheny Health Network, Pittsburgh, PA
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Miller LJ, Holmes IM, Chen-Yost HI, Smola B, Lew M, Pang J. Detecting Cholangiocarcinoma in the Setting of Primary Sclerosing Cholangitis: Is Biliary Tract Fluorescence In Situ Hybridization Helpful? Cytopathology 2025; 36:150-155. [PMID: 39366926 DOI: 10.1111/cyt.13452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 02/27/2024] [Accepted: 09/19/2024] [Indexed: 10/06/2024]
Abstract
INTRODUCTION/OBJECTIVE Biliary brushing cytology (BB) to detect cholangiocarcinoma (CCA) is integral in the surveillance of patients with primary sclerosing cholangitis (PSC). Since reactive changes can mimic carcinoma, indeterminant results are frequent. Fluorescence in situ hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of CCA. This study evaluates the performance of FISH for detecting CCA in patients with and without PSC. MATERIALS AND METHODS A query of our pathology database for atypical and suspicious BB with concurrent FISH results was performed from 2014 to 2021. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed to identify patients with PSC and CCA. CCA was confirmed by pathology or clinical impression. RESULTS Of the 65 patients (103 BB) in the PSC cohort, 59 patients (94 BB) without CCA and 6 patients (9 BB) with CCA were identified. 33 non-PSC patients (41 BB) with CCA were included for comparison. Positive FISH was highest in non-PSC patients with CCA (10/41 BB, 24%). Positive FISH was seen in both PSC with (1/9 BB, 11%) and without (2/94 BB, 2%) CCA. CONCLUSIONS FISH positivity was lower than expected and was positive in PSC patients without CCA. These results question the clinical utility of FISH for CCA surveillance in PSC patients.
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Affiliation(s)
- Lauren J Miller
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Isabella M Holmes
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
| | | | - Brian Smola
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Madelyn Lew
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Judy Pang
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan, USA
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Aggarwal M, Simadibrata DM, Kipp BR, Prokop LJ, Barr Fritcher EG, Schneider A, Cooley MA, Gores GJ, Eaton J, Roberts LR, Chandrasekhara V. Diagnostic Accuracy Performance of Fluorescence In Situ Hybridization (FISH) for Biliary Strictures: A Systematic Review and Meta-Analysis. J Clin Med 2024; 13:6457. [PMID: 39518600 PMCID: PMC11546496 DOI: 10.3390/jcm13216457] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Revised: 10/22/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Background and Aims: This systematic review and meta-analysis aims to compare the performance of UroVysion® FISH based on the different definitions of a positive result used in published literature with the goal of determining the optimal FISH definition for detecting pancreaticobiliary malignancy. Methods: A systematic literature search identified studies from database inception to Sept 2024 that evaluated the diagnostic performance of FISH in determining malignancy among patients with biliary strictures. All thresholds for positive FISH, as defined by the individual study, were included in this review. Subgroup analysis was performed based on the definitions of positive FISH as follows: (1) polysomy only; (2) polysomy, tetrasomy, or trisomy; and (3) polysomy or 9p deletion. Results: Eighteen studies comprising 2516 FISH specimens were analyzed, including 1133 (45.0%) with malignancy. Using a threshold for positivity as defined in individual studies, the overall sensitivity of FISH was 57.6% (95% confidence interval [CI], 49.4-65.4%), and the overall specificity was 87.8% (95% CI, 79.2-93.2%). Subgroup analysis showed that polysomy as the threshold for positive FISH yielded a sensitivity of 49.4% (95% CI, 43.2-55.5%), with an increased specificity of 96.2% (95% CI, 92.7-98.1%), while polysomy + tetrasomy/trisomy as positive FISH resulted in an increased sensitivity of 64.3% (95% CI 55.4-72.2%) but a decreased specificity of 78.9% (95% CI 64.4-88.5%). The addition of 9p deletion to polysomy as the criteria for a positive test resulted in a non-significant increase in sensitivity (54.7% (95% CI 42.4-66.5%) while maintaining specificity (95.1% (95% CI 84.0-98.6%). Conclusions: Based on these findings, polysomy only or polysomy/9p deletion should be considered as the criterion for defining a positive FISH test to improve diagnostic sensitivity while maintaining high specificity.
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Affiliation(s)
- Manik Aggarwal
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
| | - Daniel M. Simadibrata
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
| | - Benjamin R. Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; (B.R.K.); (E.G.B.F.); (A.S.)
| | - Larry J. Prokop
- Department of Library Services, Mayo Clinic, Rochester, MN 55905, USA;
| | - Emily G. Barr Fritcher
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; (B.R.K.); (E.G.B.F.); (A.S.)
| | - Amber Schneider
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; (B.R.K.); (E.G.B.F.); (A.S.)
| | - Matthew A. Cooley
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN 55905, USA;
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
| | - John Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
| | - Vinay Chandrasekhara
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200, First St SW, Rochester, MN 55905, USA; (M.A.); (D.M.S.); (G.J.G.); (L.R.R.)
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Miller LJ, Holmes IM, Chen-Yost HI, Smola B, Lew M, Betz BL, Brown NA, Pang J. Performance of fluorescence in situ hybridization in biliary brushings with equivocal cytology: an institutional experience. J Am Soc Cytopathol 2024; 13:285-290. [PMID: 38589274 DOI: 10.1016/j.jasc.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 03/12/2024] [Accepted: 03/12/2024] [Indexed: 04/10/2024]
Abstract
INTRODUCTION Biliary brushing (BB) cytology has a sensitivity of 15%-65% and specificity approaching 100% for detecting malignancy. Fluorescence in-situ hybridization (FISH) using the UroVysion probe set has been advocated to enhance the detection of malignancies with reported sensitivity of 43%-84%. We sought to evaluate the performance of FISH in BB with equivocal cytology at our institution. MATERIALS AND METHODS Patients with atypical and suspicious BB with concurrent diagnostic FISH performed at our institution from 2014 to 2021 were identified through a query of our pathology database. FISH (using UroVysion probe set containing centromere enumeration probes to chromosomes 3, 7, and 17) was positive if at least 5 cells demonstrated polysomy. Electronic medical records were reviewed for pathology results and outcomes. Patients were classified malignant if they had positive pathology or documented clinical impression of malignancy and benign if they had negative pathology and/or documented benign clinical course for at least 12 months. RESULTS We identified 254 equivocal BB (238 atypical/16 suspicious) with concurrent FISH results from 191 patients (105 benign, 86 malignant). 12% (22/191) of patients were FISH positive. Twenty-four percent (21/86) of patients with malignancy had positive FISH but were nonspecific for pancreaticobiliary/ampullary adenocarcinomas. Almost all positive FISH were associated with malignancy (21/22; 95%). There was 1 positive FISH in a patient with primary sclerosing cholangitis who had a benign outcome. CONCLUSIONS The small number of positive FISH results in BB with equivocal cytology raises the question of the optimal criteria for malignancy. Using only polysomy could result in lower sensitivity.
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Affiliation(s)
- Lauren J Miller
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan
| | | | | | - Brian Smola
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan
| | - Madelyn Lew
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan
| | - Bryan L Betz
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan
| | - Noah A Brown
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan
| | - Judy Pang
- Department of Pathology, Michigan Medicine, Ann Arbor, Michigan.
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Zhuang XX, Liu T, Wei LB, Gao JR. Construction of chronic glomerulonephritis‑related lncRNA‑mRNA regulatory network and lncRNA‑-miRNA‑mRNA ceRNA network by bioinformatics analysis. Exp Ther Med 2023; 26:403. [PMID: 37522060 PMCID: PMC10375445 DOI: 10.3892/etm.2023.12102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 06/16/2023] [Indexed: 08/01/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are ncRNA transcripts >200 nucleotides that are important genetic regulators. LncRNAs can directly regulate mRNA through a lncRNA-mRNA regulatory mode and can also regulate mRNA through competitive binding to micro (mi)RNA, which is generally known as the competitive endogenous RNA (ceRNA) network. The present study evaluated the functional roles and regulatory networks of lncRNAs in chronic glomerulonephritis (CGN). The proliferative ability of mouse glomerular mesangial cells (GMCs) induced by different concentrations of lipopolysaccharide (LPS) was assessed using the Cell Counting Kit-8 assay, and RNA sequencing (RNA-seq) was performed to identify differentially expressed lncRNAs in LPS-induced GMCs. Based on the sequencing results, six lncRNAs were selected for validation using reverse transcription-quantitative PCR (RT-qPCR). Furthermore, the lncRNA-mRNA regulatory network and the lncRNA-miRNA-mRNA ceRNA network were constructed to assess the role and mechanism of CGN-related lncRNAs. To elucidate the biological functions of lncRNAs, Gene Ontology (GO) biological process term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed on all mRNAs involved in the lncRNA-mRNA regulatory network and in the ceRNA network. A total of 1,532 differentially expressed lncRNAs, including 594 upregulated lncRNAs and 938 downregulated lncRNAs, were identified using RNA-seq. The results of RT-qPCR validation were consistent with RNA-seq results. An lncRNA-mRNA regulatory network, including 236 lncRNAs and 556 mRNAs, and a ceRNA network, including 6 lncRNAs, 18 miRNAs and 419 mRNAs, were successfully constructed. The GO biological process term enrichment and KEGG pathway enrichment analyses demonstrated that those lncRNAs were often related to inflammatory response and substance metabolism. The present study identified key CGN-related lncRNAs in LPS-induced GMCs, and further demonstrated a global view of the lncRNA-mRNA regulatory network and ceRNA network involved in CGN. These results offered novel insights into the roles of lncRNAs in the pathogenesis of CGN and identified potential diagnostic biomarkers.
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Affiliation(s)
- Xing-Xing Zhuang
- Department of Pharmacy, Chaohu Hospital of Anhui Medical University, Chaohu, Anhui 238000, P.R. China
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| | - Tao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| | - Liang-Bing Wei
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
| | - Jia-Rong Gao
- Department of Pharmacy, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, Anhui 230012, P.R. China
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Cadamuro M, Al-Taee A, Gonda TA. Advanced endoscopy meets molecular diagnosis of cholangiocarcinoma. J Hepatol 2023; 78:1063-1072. [PMID: 36740048 DOI: 10.1016/j.jhep.2023.01.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/22/2022] [Accepted: 01/18/2023] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma remains an aggressive and deadly malignancy that is often diagnosed late. Intrinsic tumour characteristics and the growth pattern of cancer cells contribute to the challenges of diagnosis and chemoresistance. However, establishing an early and accurate diagnosis, and in some instances identifying targetable changes, has the potential to impact survival. Primary sclerosing cholangitis, a chronic cholangiopathy prodromal to the development of a minority of cholangiocarcinomas, poses a particular diagnostic challenge. We present our diagnostic and theranostic approach to the initial evaluation of cholangiocarcinomas, focusing on extrahepatic cholangiocarcinoma. This involves a multipronged strategy incorporating advanced imaging, endoscopic methods, multiple approaches to tissue sampling, and molecular markers. We also provide an algorithm for the sequential use of these tools.
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Affiliation(s)
| | - Ahmad Al-Taee
- Carle Illinois College of Medicine, University of Illinois Urbaba-Champaign, Champaign County, IL, USA
| | - Tamas A Gonda
- Division of Gastroenterology and Hepatology, New York University, New York, NY, USA.
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Bowlus CL, Arrivé L, Bergquist A, Deneau M, Forman L, Ilyas SI, Lunsford KE, Martinez M, Sapisochin G, Shroff R, Tabibian JH, Assis DN. AASLD practice guidance on primary sclerosing cholangitis and cholangiocarcinoma. Hepatology 2023; 77:659-702. [PMID: 36083140 DOI: 10.1002/hep.32771] [Citation(s) in RCA: 141] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 07/26/2022] [Indexed: 01/28/2023]
Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology , University of California Davis Health , Sacramento , California , USA
| | | | - Annika Bergquist
- Karolinska Institutet , Karolinska University Hospital , Stockholm , Sweden
| | - Mark Deneau
- University of Utah , Salt Lake City , Utah , USA
| | - Lisa Forman
- University of Colorado , Aurora , Colorado , USA
| | - Sumera I Ilyas
- Mayo Clinic College of Medicine and Science , Rochester , Minnesota , USA
| | - Keri E Lunsford
- Rutgers University-New Jersey Medical School , Newark , New Jersey , USA
| | - Mercedes Martinez
- Vagelos College of Physicians and Surgeons , Columbia University , New York , New York , USA
| | | | | | - James H Tabibian
- David Geffen School of Medicine at UCLA , Los Angeles , California , USA
| | - David N Assis
- Yale School of Medicine , New Haven , Connecticut , USA
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Chazouilleres O, Beuers U, Bergquist A, Karlsen TH, Levy C, Samyn M, Schramm C, Trauner M. EASL Clinical Practice Guidelines on sclerosing cholangitis. J Hepatol 2022; 77:761-806. [PMID: 35738507 DOI: 10.1016/j.jhep.2022.05.011] [Citation(s) in RCA: 152] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/16/2022] [Indexed: 02/07/2023]
Abstract
Management of primary or secondary sclerosing cholangitis is challenging. These Clinical Practice Guidelines have been developed to provide practical guidance on debated topics including diagnostic methods, prognostic assessment, early detection of complications, optimal care pathways and therapeutic (pharmacological, endoscopic or surgical) options both in adults and children.
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Baroud S, Sahakian AJ, Sawas T, Storm AC, Martin JA, Abu Dayyeh BK, Topazian MD, Levy MJ, Roberts LR, Gores GJ, Petersen BT, Chandrasekhara V. Impact of trimodality sampling on detection of malignant biliary strictures compared with patients with primary sclerosing cholangitis. Gastrointest Endosc 2022; 95:884-892. [PMID: 34871554 DOI: 10.1016/j.gie.2021.11.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 11/12/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Malignant biliary strictures can be difficult to diagnose, with up to 20% considered indeterminate after initial tissue sampling. This study aimed to determine the performance characteristics of transpapillary biopsy sampling (TPB) and fluorescence in situ hybridization (FISH) in isolation or in combination with standard brush cytology (BC) in patients who received trimodality sampling for biliary strictures. METHODS This single-center retrospective cohort study included patients with biliary strictures undergoing ERCP with trimodality sampling between September 2014 and April 2019. Performance characteristics for each diagnostic test alone and in combination were calculated. RESULTS Two hundred four patients underwent trimodality biliary sampling, including 104 (51.0%) with malignancy. The diagnostic sensitivity for malignancy with BC (17.3%) significantly improved with dual modality (BC+FISH, 58.7%; BC+TPB, 40.4%) or trimodality sampling (68.3%; P < .001 for all comparisons). Trimodality sampling improved diagnostic sensitivity for malignancy compared with BC+FISH (P = .002) and BC+TPB (P < .001). There was no statistically significant difference in the sensitivity of trimodality sampling in detecting cholangiocarcinoma (79.7%) compared with pancreatic cancer (62.5%; P = .1). Among 57 patients with primary sclerosing cholangitis (PSC), the sensitivity of detecting biliary malignancy (n = 20) was 20% for BC and significantly improved with the addition of FISH (80%; P < .001) but not with TPB (35.0%; P = .25). Trimodality sampling did not further improve diagnostic sensitivity (85%) over BC+FISH (80%) for malignancy in the setting of PSC (P = 1). CONCLUSIONS Trimodality sampling improves the diagnostic sensitivity for the detection of malignant biliary strictures with no significant difference in sensitivity for cholangiocarcinoma compared with pancreatic cancer. However, in patients with PSC, trimodality sampling was not superior to BC+FISH.
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Affiliation(s)
- Serge Baroud
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Alexander J Sahakian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Tarek Sawas
- Division of Digestive and Liver Diseases, University of Texas Southwestern, Dallas, Texas, USA
| | - Andrew C Storm
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - John A Martin
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Barham K Abu Dayyeh
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark D Topazian
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Michael J Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Bret T Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Vinay Chandrasekhara
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Chromosomal aberrations, visualized using UroVysion® fluorescence in-situ hybridization assay, can predict poor prognosis in formalin-fixed paraffin-embedded tissues of cholangiocarcinoma patients. Hum Pathol 2022; 126:31-44. [DOI: 10.1016/j.humpath.2022.05.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/29/2022] [Accepted: 05/09/2022] [Indexed: 12/12/2022]
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Scheid JF, Rosenbaum MW, Przybyszewski EM, Krishnan K, Forcione DG, Iafrate AJ, Staller KD, Misdraji J, Lennerz JK, Pitman MB, Pratt DS. Next-generation sequencing in the evaluation of biliary strictures in patients with primary sclerosing cholangitis. Cancer Cytopathol 2021; 130:215-230. [PMID: 34726838 DOI: 10.1002/cncy.22528] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) is a well-described risk factor for the development of cholangiocarcinoma (CCA). Early detection of CCA in these patients is of great importance because it expands options for therapeutic interventions, including liver transplantation. Current diagnostic tests for the evaluation of biliary strictures are limited to biliary brushing (BB) cytology and fluorescence in situ hybridization (FISH). Next-generation sequencing (NGS) has become an important diagnostic tool in oncology and may be a useful tool for diagnosing CCA on BBs. It is not clear how NGS performs when it is added to BB cytology and FISH in patients with PSC. METHODS This study reports the authors' experience with NGS performed as a prospective cotest with cytology and FISH on BBs obtained from 60 patients with PSC followed at Massachusetts General Hospital. A duct with malignancy was defined as a high-risk (HR) stricture with either high-grade dysplasia or CCA. RESULTS NGS was better than FISH and cytology in detecting HR strictures, which showed multiple genetic mutations in all cases. NGS provided specific mutational information, and NGS results were reproducible in longitudinal samples. CONCLUSIONS Adding NGS to BB cytology and FISH in the evaluation of biliary strictures for patients with PSC may provide additional information that could help to inform clinical management.
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Affiliation(s)
- Johannes F Scheid
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Eric M Przybyszewski
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kumar Krishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Anthony J Iafrate
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kyle D Staller
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Jochen K Lennerz
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Daniel S Pratt
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts.,Autoimmune and Cholestatic Liver Center, Massachusetts General Hospital, Boston, Massachusetts
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13
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Mettman D, Saeed A, Shold J, Laury R, Ly A, Khan I, Golem S, Olyaee M, O'Neil M. Refined pancreatobiliary UroVysion criteria and an approach for further optimization. Cancer Med 2021; 10:5725-5738. [PMID: 34374212 PMCID: PMC8419786 DOI: 10.1002/cam4.4043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 04/12/2021] [Accepted: 05/13/2021] [Indexed: 12/21/2022] Open
Abstract
Pancreatobiliary strictures are a common source of false negatives for malignancy detection. UroVysion is more sensitive than any other method but remains underutilized because of conflicting sensitivities and specificities due to a lack of standardized cutoff criteria and confusion in interpreting results in the context of primary sclerosing cholangitis. We set out to determine the sensitivities and specificities of UroVysion, brushing cytology, forceps biopsies, and fine needle aspiration (FNAs) for pancreatobiliary stricture malignancy detection. A retrospective review was performed of all biopsied pancreatobiliary strictures at our institution over 5 years. UroVysion was unquestionably the most sensitive method and all methods were highly specific. Sensitivity was highest while maintaining specificity when a malignant interpretation was limited to cases with 5+ cells with the same polysomic signal pattern and/or loss of one or both 9p21 signals. Only UroVysion detected the metastases and a neuroendocrine tumor. In reviewing and analyzing the signal patterns, we noticed trends according to location and diagnosis. Herein we describe our method for analyzing signal patterns and propose cutoff criteria based upon observations gleaned from such analysis.
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Affiliation(s)
- Daniel Mettman
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Azhar Saeed
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Janna Shold
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Raquele Laury
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Andrew Ly
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Irfan Khan
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Shivani Golem
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Mojtaba Olyaee
- Department of Internal MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
| | - Maura O'Neil
- Department of Pathology and Laboratory MedicineUniversity of Kansas Medical CenterKansas CityKSUSA
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14
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Fung BM, Tabibian JH. Primary sclerosing cholangitis-associated cholangiocarcinoma: special considerations and best practices. Expert Rev Gastroenterol Hepatol 2021; 15:487-496. [PMID: 33682586 DOI: 10.1080/17474124.2021.1900732] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/05/2021] [Indexed: 10/22/2022]
Abstract
Introduction: Primary sclerosing cholangitis (PSC) is a rare, heterogenous, chronic cholestatic liver disease that causes fibro-inflammatory destruction of the intra- and/or extrahepatic bile ducts. The disease course may be variable, though in many cases it ultimately leads to biliary cirrhosis and its associated complications. PSC is also associated with malignancies, in particular cholangiocarcinoma (CCA), a dreaded neoplasm of the biliary tract with a poor prognosis. Risk stratification and surveillance for this malignancy are important components of the care of patients with PSC.Areas covered: In this review, we discuss important considerations in the clinical epidemiology, risk factors, diagnosis, and surveillance of PSC-associated CCA.Expert opinion: Despite growing awareness of PSC, high-quality evidence regarding the management of PSC and its associated risk of CCA remains limited. Early diagnosis of PSC-associated CCA remains difficult, and treatment options are limited, especially when diagnosed at later stages. The recent introduction of recommendations for CCA surveillance will likely improve outcomes, though an optimal surveillance approach has yet to be validated prospectively. Further research is needed in the development of high-accuracy (and noninvasive) surveillance and diagnostic tools that may facilitate earlier diagnosis of CCA and potential disease cure.
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Affiliation(s)
- Brian M Fung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine - Phoenix, Phoenix, AZ, USA
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA, USA
- David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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15
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Wang X, Fu XH, Qian ZL, Zhao T, Duan AQ, Ruan X, Zhu B, Yin L, Zhang YJ, Yu WL. Non-invasive detection of biliary tract cancer by low-coverage whole genome sequencing from plasma cell-free DNA: A prospective cohort study. Transl Oncol 2021; 14:100908. [PMID: 33059123 PMCID: PMC7550068 DOI: 10.1016/j.tranon.2020.100908] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/23/2020] [Accepted: 09/30/2020] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND The diagnosis of biliary tract cancer (BTC) is challenging in clinical practice. We performed a prospective study to evaluate the value of plasma copy number variation (CNV) assays in diagnosing BTC. METHODS 47 treatment-naïve patients with suspicious biliary lesions were recruited. Plasma samples were collected at admission. Cell-free DNA was analyzed by low coverage whole genome sequencing, followed by CNV analyses via a customized bioinformatics workflow, namely the ultrasensitive chromosomal aneuploidy detector. RESULTS 29 patients were pathologically diagnosed as BTC, including 8 gallbladder cancers (GBCs) and 21 cholangiocarcinomas (CCs). Cancer patients had more CNV signals as compared with benign patients (26/29 vs. 2/18, P < 0.001). The most frequent copy number gains were chr3q (7/29) and chr8q (6/29). The most frequent copy number losses were chr7p (6/29), chr17p (6/29), and chr19p (6/29). The sensitivity and specificity of plasma CNV assays in diagnosing BTC were 89.7% and 88.9%, respectively. For CA 19-9 (cutoff: 37 U/ml), the sensitivity was 58.6% and the specificity was 72.2%. The diagnostic accuracy of CNV assays significantly outperformed CA 19-9 (AUC 0.91 vs. 0.62, P = 0.004). Compared with CA 19-9 alone, the adding of CNV profiles to CA 19-9 increased the sensitivity in diagnosing GBC (75.0% vs. 25.0%) and CC (100% vs. 52.4%). Higher CNV burden was also associated with decreased overall survival (Hazard ratio = 4.32, 95% CI 2.06-9.08, P = 0.033). DISCUSSION Our results suggest that BTC harbors rich plasma CNV signals, and their assays might be useful for diagnosing BTC.
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Affiliation(s)
- Xiang Wang
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Xiao-Hui Fu
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Zi-Liang Qian
- Suzhou Hongyuan Biotech Inc, Biobay, Suzhou 215123, China; Prophet Genomics Inc, San Jose, CA 95131, United States
| | - Teng Zhao
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - An-Qi Duan
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Xiang Ruan
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Bin Zhu
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Lei Yin
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China
| | - Yong-Jie Zhang
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China.
| | - Wen-Long Yu
- Department of Biliary Tract Surgery, Shanghai Eastern Hepatobiliary Surgery Hospital, Second Military Medical University/Navy Medical University, Shanghai 200438, China.
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16
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Martinez NS, Trindade AJ, Sejpal DV. Determining the Indeterminate Biliary Stricture: Cholangioscopy and Beyond. Curr Gastroenterol Rep 2020; 22:58. [PMID: 33141356 DOI: 10.1007/s11894-020-00797-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/16/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Indeterminate biliary strictures (IDBS) continue to be an area of frustration for clinicians. Standard endoscopic retrograde cholangiopancreatography (ERCP) with conventional brush cytology and/or forceps biopsy has a low sensitivity for distinguishing benign from malignant biliary strictures. A delay in diagnosis of malignancy has consequences for subsequent therapy or surgery. In this article, we review current and emerging technologies that may aid in this diagnostic dilemma. RECENT FINDINGS Several technologies have been utilized in IDBS to establish a diagnosis which include peroral cholangioscopy, confocal laser endomicroscopy, endoscopic ultrasound with fine needle aspiration, intraductal ultrasound, optical coherence tomography, fluorescence in situ hybridization, next generation sequencing, integrated molecular pathology, and DNA-image cytometry. While cholangioscopy and confocal laser endomicroscopy have become standards of care in expert centers for the evaluation of patients with IDBS, there are several endoscopic and molecular modalities that may also aid in establishing a diagnosis. Further head-to-head prospective diagnostic studies as well as cost-efficacy studies are needed.
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Affiliation(s)
- Nichol S Martinez
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA
| | - Arvind J Trindade
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA
| | - Divyesh V Sejpal
- Northwell Health, Zucker School of Medicine at Hofstra/Northwell, 300 Community Drive, Manhasset, NY, 11030, USA.
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17
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Song J, Li Y, Bowlus CL, Yang G, Leung PSC, Gershwin ME. Cholangiocarcinoma in Patients with Primary Sclerosing Cholangitis (PSC): a Comprehensive Review. Clin Rev Allergy Immunol 2020; 58:134-149. [PMID: 31463807 DOI: 10.1007/s12016-019-08764-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CCA) is the most common malignancy in patients with primary sclerosing cholangitis (PSC) and carries a high rate of mortality. Although the pathogenesis of CCA in PSC is largely unknown, inflammation-driven carcinogenesis concomitant with various genetic and epigenetic abnormalities are underlying factors. The majority of CCA cases develop from a dominant stricture (DS), which is defined as a stricture with a diameter < 1.5 mm in the common bile duct or < 1.0 mm in the hepatic duct. In PSC patients presenting with an abrupt aggravation of jaundice, pain, fatigue, pruritus, weight loss, or worsening liver biochemistries, CCA should be suspected and evaluated utilizing a variety of diagnostic modalities. However, early recognition of CCA in PSC remains a major challenge. Importantly, 30-50% of CCA in PSC patients are observed within the first year following the diagnosis of PSC followed by an annual incidence ranging from 0.5 to 1.5 per 100 persons, which is nearly 10 to 1000 times higher than that in the general population. Cumulative 5-year, 10-year, and lifetime incidences are 7%, 8-11%, and 9-20%, respectively. When PSC-associated CCA is diagnosed, most tumors are unresectable, and no effective medications are available. Given the poor therapeutic outcome, the surveillance and management of PSC patients who are at an increased risk of developing CCA are of importance. Such patients include older males with large-duct PSC and possibly concurrent ulcerative colitis. Thus, more attention should be paid to patients with these clinical features, in particular within the first year after PSC diagnosis. In contrast, CCA is less frequently observed in pediatric or female PSC patients or in those with small-duct PSC or concurrent Crohn's disease. Recently, new biomarkers such as antibodies to glycoprotein 2 have been found to be associated with an increased risk of developing CCA in PSC. Herein, we review the literature on the pathogenesis, incidence, clinical features, and risk factors, with a focus on various diagnostic modalities of PSC-associated CCA.
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Affiliation(s)
- Junmin Song
- Department of Gastroenterology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, People's Republic of China.,Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Yang Li
- Department of Intensive Care Unit (ICU), Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, Liaoning, 110004, People's Republic of China
| | - Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California, 451 Health Sciences Drive, Suite 6510, Davis, CA, 95616, USA
| | - GuoXiang Yang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA
| | - Patrick S C Leung
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, 451 Health Science Drive, Suite 6510, Davis, CA, 95616, USA.
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18
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Lee H, Rabinovitch PS, Mattis AN, Kakar S, Choi WT. DNA flow cytometric analysis of paraffin-embedded tissue for the diagnosis of malignancy in bile duct biopsies. Hum Pathol 2020; 99:80-87. [PMID: 32272125 DOI: 10.1016/j.humpath.2020.04.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 04/01/2020] [Indexed: 01/22/2023]
Abstract
Differentiation of reactive versus neoplastic epithelial changes can be challenging in bile duct biopsies. The samples are often scant, distorted, and mixed with significant inflammation, ulceration, and/or debris. Histological confirmation of malignancy is often required before the initiation of surgical therapy, and an erroneous diagnosis of malignancy can lead to unnecessary clinical management. Aneuploidy assessment by DNA flow cytometry was performed on formalin-fixed paraffin-embedded (FFPE) tissue from 63 bile duct biopsies: 10 with a malignant diagnosis (7 with adenocarcinoma and 3 with at least high-grade dysplasia [HGD]); 3 with an atypical diagnosis showing rare atypical glands/cells, concerning but not definite for malignancy; 28 likely reactive biopsies with acute/chronic inflammation, ulceration, and/or mild nuclear atypia; and 22 additional benign biopsies without significant inflammation, ulceration, or nuclear atypia. Aneuploidy was detected in 7 (70%) of the 10 biopsies with definite neoplasia (5 of 7 adenocarcinoma cases and 2 of 3 at least HGD cases), all 3 (100%) atypical biopsies, and none of the 50 benign biopsies. All 3 atypical cases with aneuploidy were subsequently found to have adenocarcinoma (n = 2) or HGD (n = 1). Among the 2 cases of at least HGD with aneuploidy, 1 case developed adenocarcinoma, but no follow-up information was available in the other case. The remaining 1 case of at least HGD, despite having normal DNA content, was found to have adenocarcinoma on follow-up. None of the 50 benign cases (further supported by normal DNA content) developed adenocarcinoma within a mean follow-up time of 37 months (range: 0-282 months). The estimated sensitivity of aneuploidy as a diagnostic marker of malignancy (adenocarcinoma and HGD) was 70%, with the specificity of 100%, positive predictive value of 100%, and negative predictive value of 94%. In conclusion, DNA flow cytometry using FFPE tissue from bile duct biopsies demonstrates a high rate of aneuploidy (70%) in malignant cases and normal DNA content in all benign biopsies. Although the sample size is small, the results indicate that this assay can be potentially useful in challenging atypical cases, where morphological evaluation is limited by scarcity of atypical glands/cells, inflammation, and/or ulceration.
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Affiliation(s)
- Hannah Lee
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA
| | | | - Aras N Mattis
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA; University of California at San Francisco, Liver Center, San Francisco, CA, 94143, USA
| | - Sanjay Kakar
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA
| | - Won-Tak Choi
- University of California at San Francisco, Department of Pathology, San Francisco, CA, 94143, USA.
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19
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Abstract
PURPOSE OF REVIEW Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease characterized by progressive fibroinflammatory destruction of the intrahepatic and/or extrahepatic bile ducts. It is associated with a significantly increased risk of malignancy, particularly cholangiocarcinoma (CCA). In this review, we discuss what is currently known about the epidemiology of and risk factors for CCA in PSC as well as recent advances in its prevention, diagnosis, and surveillance. RECENT FINDINGS An area of major focus has been finding novel biomarkers (in serum, bile, and urine) for CCA. With the advancement of computing power, metabolomic and proteomic approaches, among other methods, may provide enhanced capability for differentiating between benign and malignant bile duct disease. Another area of focus has been the approach to CCA surveillance in PSC; a recent study has found that CCA surveillance in patients with PSC is associated with improved outcomes, including increased survival, thus advocating for its importance. SUMMARY Despite ongoing advancements in the study of PSC-associated CCA, early diagnosis of CCA remains difficult, treatment options are limited, and prognosis is often consequently poor. Continued research in the development of high-accuracy diagnostic tools, novel biomarkers, and surveillance techniques may help to increase the likelihood of diagnosing CCA at earlier stages, when therapeutic options have the highest likelihood of resulting in cure.
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Affiliation(s)
- Brian M Fung
- UCLA-Olive View Internal Medicine Residency Program
| | - James H Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-UCLA Medical Center, Sylmar, California, USA
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20
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Grimsrud MM, Folseraas T. Pathogenesis, diagnosis and treatment of premalignant and malignant stages of cholangiocarcinoma in primary sclerosing cholangitis. Liver Int 2019; 39:2230-2237. [PMID: 31216595 DOI: 10.1111/liv.14180] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 05/13/2019] [Accepted: 05/31/2019] [Indexed: 12/20/2022]
Abstract
Patients with primary sclerosing cholangitis (PSC) confer a high risk of cholangiocarcinoma (CCA). The molecular mechanisms of CCA development in PSC are incompletely understood, but pro-oncogenic processes resulting from chronic biliary inflammation are presumably of central importance. Distinguishing benign from malignant biliary strictures in PSC patients is challenging and accurately diagnosing CCA in PSC often requires a multifaceted approach involving imaging, serological testing, biliary brush cytology and fluorescence in situ hybridization (FISH). Lack of early detection tools leads to a late diagnosis in the majority of cases. Surgical resection or liver transplantation represent the only curative intent treatments in PSC-CCA, but is only an option for the small subset of patients where CCA is detected at an early stage. Current palliative treatment modalities result in only a modest increase in survival. Overall, PSC-CCA carries a dismal prognosis with a 5-year survival less than 20%. Advances aiming at improving strategies for early detection, treatment and surveillance of CCA will be essential to provide better future patient care for PSC patients. Herein, we review the pathogenetic mechanisms for PSC-CCA as well as strategies for diagnosing and managing premalignant and malignant stages of CCA in PSC.
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Affiliation(s)
- Marit M Grimsrud
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Section for Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
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21
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Bowlus CL, Lim JK, Lindor KD. AGA Clinical Practice Update on Surveillance for Hepatobiliary Cancers in Patients With Primary Sclerosing Cholangitis: Expert Review. Clin Gastroenterol Hepatol 2019; 17:2416-2422. [PMID: 31306801 DOI: 10.1016/j.cgh.2019.07.011] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Revised: 06/19/2019] [Accepted: 07/08/2019] [Indexed: 02/07/2023]
Abstract
DESCRIPTION The purpose of this clinical practice update is to define key principles in the surveillance of hepatobiliary cancers including cholangiocarcinoma, gallbladder adenocarcinoma, and hepatocellular carcinoma in patients with primary sclerosing cholangitis (PSC). METHODS The recommendations outlined in this expert review are based on available published evidence including observational studies and systematic reviews, and incorporates expert opinion where applicable. BEST PRACTICE ADVICE 1: Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age. BEST PRACTICE ADVICE 2: Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months BEST PRACTICE ADVICE 3: Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC. BEST PRACTICE ADVICE 4: Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture. BEST PRACTICE ADVICE 5: Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma. BEST PRACTICE ADVICE 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20. BEST PRACTICE ADVICE 7: The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm. BEST PRACTICE ADVICE 8: Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology and Hepatology, University of California Davis School of Medicine, Davis, California.
| | - Joseph K Lim
- Section of Digestive Diseases, Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, Arizona; Arizona State University, Phoenix, Arizona
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22
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Fung BM, Tabibian JH. Biliary endoscopy in the management of primary sclerosing cholangitis and its complications. LIVER RESEARCH (BEIJING, CHINA) 2019; 3:106-117. [PMID: 31341699 PMCID: PMC6656407 DOI: 10.1016/j.livres.2019.03.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic, idiopathic, cholestatic liver disease characterized by inflammation and fibrosis of the intrahepatic and/or extrahepatic bile ducts. It can affect individuals of all age groups and gender, has no established pharmacotherapy, and is associated with a variety of neoplastic (e.g. cholangiocarcinoma) and non-neoplastic (e.g. dominant strictures) hepatobiliary complications. Given these considerations, endoscopy plays a major role in the care of patients with PSC. In this review, we discuss and provide updates regarding endoscopic considerations in the management of hepatobiliary manifestations and complications of PSC. Where evidence is limited, we suggest pragmatic approaches based on currently available data and expert opinion.
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Affiliation(s)
- Brian M. Fung
- University of California Los Angeles-Olive View Internal Medicine Residency Program, Sylmar, CA, USA
| | - James H. Tabibian
- Division of Gastroenterology, Department of Medicine, Olive View-University of California Los Angeles Medical Center, Sylmar, CA, USA
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23
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Primary Sclerosing Cholangitis: A Concise Review of Diagnosis and Management. Dig Dis Sci 2019; 64:632-642. [PMID: 30725292 DOI: 10.1007/s10620-019-05484-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 01/19/2019] [Indexed: 02/08/2023]
Abstract
Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterized by progressive idiopathic stricturing of the biliary system, typically leading to cirrhosis, end-stage liver disease, and colonic or hepatobiliary malignancy. Its presentation is often that of asymptomatic alkaline phosphatase elevation. When symptoms are present, they typically include fatigue, pruritus, or jaundice. The diagnosis can be confirmed via cholangiography, either magnetic resonance cholangiography (MRCP) or endoscopic retrograde cholangiography if the former is inconclusive. The clinical course is marked by progressive liver disease leading to cirrhosis with its attendant complications of portal hypertension, often including recurrent episodes of cholangitis. Greater elevation in alkaline phosphatase or liver stiffness is associated with worse clinical outcomes. Management includes endoscopic treatment of symptomatic biliary strictures and evaluation of dominant strictures as no adequate medical treatment is available. Multiple medical therapies are under evaluation. Ultimately, liver transplantation may be necessary for management of decompensated cirrhosis or disabling symptoms. There is also a markedly increased risk of cancer, notably including cholangiocarcinoma and gallbladder and colorectal cancers (particularly in patients with colitis). Cancer screening can be done with semi-annual liver imaging (MRCP or ultrasound) and colonoscopy every 1-2 years in those with colitis.
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24
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von Seth E, Ouchterlony H, Dobra K, Hjerpe A, Arnelo U, Haas S, Bergquist A. Diagnostic performance of a stepwise cytological algorithm for biliary malignancy in primary sclerosing cholangitis. Liver Int 2019; 39:382-388. [PMID: 30507030 DOI: 10.1111/liv.14007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 10/31/2018] [Accepted: 11/03/2018] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND AIMS Detection of early cholangiocarcinoma (CCA) in primary sclerosing cholangitis (PSC) is challenging. The aim of this study was to evaluate the diagnostic accuracy of a stepwise approach to biliary brush cytology with sequential use of fluorescence in-situ hybridization (FISH) for the detection of biliary malignancy in PSC. METHOD We retrospectively studied consecutive patients with PSC who underwent biliary brushings at Karolinska University Hospital between 2009 and 2015 (n = 208). Brush samples were categorized as benign, equivocal (atypical or suspicious) and malignant. Equivocal cases were further analysed with FISH. Samples with a malignant cytology or positive FISH were considered positive. The diagnosis was determined after 12 months of follow-up. RESULTS The diagnosis CCA was confirmed in 15 patients (7%), high-grade dysplasia in three patients, and low-grade dysplasia in five patients at follow-up. Using the diagnostic algorithm, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) for a diagnosis of CCA were 80% (95%CI 52%-96%), 96% (95%CI 92%-98%), 60% (95%CI 36%-81%) and 98% (95% CI 95%-100%). In patients with equivocal cytology (n = 61), the sensitivity for CCA diagnosis increased to 100% (95%CI 72%-100%) with a lower PPV of 58% (95%CI 34%-78%). The diagnostic accuracy for detection of CCA in all patients was 95% (95%CI 91%-97%). CONCLUSION Biliary brush cytology with sequential use of FISH in equivocal cases seems to be a highly predictive diagnostic test for CCA in PSC. These results support the use of FISH when cytology is equivocal for detection of biliary malignancy in PSC.
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Affiliation(s)
- Erik von Seth
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge (MedH), Karolinska Institutet, Stockholm, Sweden
| | - Helena Ouchterlony
- Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge (MedH), Karolinska Institutet, Stockholm, Sweden
| | - Katalin Dobra
- Division of Pathology, Department of Laboratory Medicine (LabMed), Karolinska Institutet, Stockholm, Sweden
| | - Anders Hjerpe
- Division of Pathology, Department of Laboratory Medicine (LabMed), Karolinska Institutet, Stockholm, Sweden
| | - Urban Arnelo
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Division of Surgery, Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Stephan Haas
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge (MedH), Karolinska Institutet, Stockholm, Sweden
| | - Annika Bergquist
- Division of Hepatology, Department of Upper GI Diseases, Karolinska University Hospital, Stockholm, Sweden.,Unit of Gastroenterology and Rheumatology, Department of Medicine Huddinge (MedH), Karolinska Institutet, Stockholm, Sweden
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25
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Sarkisian AM, Sharaiha RZ. Malignant Biliary Obstruction of the Hilum and Proximal Bile Ducts. ERCP 2019:385-393.e3. [DOI: 10.1016/b978-0-323-48109-0.00040-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ahmad J. Metal, magnet or transplant: options in primary sclerosing cholangitis with stricture. Hepatol Int 2018; 12:510-519. [PMID: 30430358 DOI: 10.1007/s12072-018-9906-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 10/20/2018] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the biliary tree of unknown etiology leading to stricturing and dilation. There is currently no effective medical therapy for PSC and liver transplantation (LT) remains the ultimate treatment for severe disease defined as repeated episodes of cholangitis, decompensated biliary cirrhosis or in exceptional cases, cholangiocarcinoma (CCA). Patients often present with a "dominant" stricture and the therapeutic endoscopist plays an important role in management to improve biliary patency using a variety of techniques that involve sampling, balloon dilation and temporary stenting. Newer modalities such as self-expanding metal stents or magnetic compression anastomosis that have been used in other diseases may have a role to play in PSC but should remain investigational. Liver transplantation for PSC is curative in most cases but the optimal timing remains unclear. The lifetime risk of CCA is 10-15% in PSC patients and LT is often not possible at the time of diagnosis. Multiple studies have tried to identify risk factors and to diagnose CCA at an early stage when surgical resection may be possible or LT can be performed. However, deceased donor organs for LT remain in short supply throughout the world so even identifying PSC patients with CCA at an early stage may not be beneficial unless a live donor organ is available.
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Affiliation(s)
- Jawad Ahmad
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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27
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Tabibian JH, Baron TH. Endoscopic management of primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol 2018; 12:693-703. [PMID: 29883229 DOI: 10.1080/17474124.2018.1483719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 05/30/2018] [Indexed: 12/14/2022]
Abstract
Primary sclerosing cholangitis (PSC) is a rare but clinically important cholestatic liver disease. Histopathologically and cholangiographically, PSC is characterized by intra- and/or extra-hepatic bile duct inflammation and fibro-obliteration, which ultimately leads to biliary cirrhosis and related sequelae, including development of hepatobiliary and colorectal carcinomata. PSC can be diagnosed at essentially any age and carries a median survival of 15-20 years, regardless of age at diagnosis, and is a foremost risk factor for cholangiocarcinoma. Given the chronic and progressive nature of PSC, its inherent association with both neoplastic and non-neoplastic biliary tract complications, and the lack of effective pharmacotherapies, alimentary and biliary tract endoscopy plays a major role in the care of patients with PSC. Areas covered: Here, we provide a narrative review on endoscopic management of PSC, including established and evolving applications to the diagnosis and treatment of both its benign and malignant complications. Expert commentary: Due to the rarity of PSC and the considerable patient-years required to rigorously study major endpoints, there remains a paucity of high-quality evidence regarding its management. As the advanced endoscopic repertoire expands, so has the interest in developing best practices in PSC, which we discuss herein.
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Affiliation(s)
- James H Tabibian
- a Division of Gastroenterology, Department of Medicine , Olive View-UCLA Medical Center , Sylmar , CA , USA
| | - Todd H Baron
- b Division of Gastroenterology and Hepatology , University of North Carolina at Chapel Hill , Chapel Hill , NC , USA
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Hilscher MB, Tabibian JH, Carey EJ, Gostout CJ, Lindor KD. Dominant strictures in primary sclerosing cholangitis: A multicenter survey of clinical definitions and practices. Hepatol Commun 2018; 2:836-844. [PMID: 30027141 PMCID: PMC6049068 DOI: 10.1002/hep4.1194] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Revised: 02/28/2018] [Accepted: 04/01/2018] [Indexed: 12/12/2022] Open
Abstract
Dominant strictures (DSs) of the biliary tree occur in approximately 50% of patients with primary sclerosing cholangitis (PSC) and may cause significant morbidity. Nevertheless, the definition and management of DSs lacks consensus. We aimed to better understand current perceptions and practices regarding PSC-associated DSs. We conducted an anonymous, 23-question, survey-based study wherein electronic surveys were distributed to 131 faculty in the Division of Gastroenterology and Hepatology at the three Mayo Clinic campuses (Rochester, Scottsdale, and Jacksonville) as well as the affiliated practice network. Responses were aggregated and compared, where applicable, to practice guidelines of the American Association for the Study of Liver Diseases and European Association for the Study of the Liver. A total of 54 faculty (41.2%) completed the survey, of whom 24 (44.4%) were hepatologists, 21 (38.9%) gastroenterologists, and 9 (16.7%) advanced endoscopists. One of the major study findings was that there was heterogeneity among participants' definition, evaluation, management, and follow-up of DSs in PSC. The majority of participant responses were in accordance with societal practice guidelines, although considerable variation was noted. Conclusion: Despite the prevalence and morbidity of DSs in PSC, clinical perceptions and practices vary widely among hepatologists, gastroenterologists, and advanced endoscopists who manage these patients, even within a single health care system. Further studies are needed to address these variations, develop general and evidence-based consensus, and increase adherence to societal guidelines. (Hepatology Communications 2018;2:836-844).
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Affiliation(s)
| | - James H. Tabibian
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMN
- Division of GastroenterologyOlive View‐University of California Los Angeles Medical CenterSylmarCA
| | | | | | - Keith D. Lindor
- Division of Gastroenterology and HepatologyMayo ClinicScottsdaleAZ
- College of Health SolutionsArizona State UniversityPhoenixAZ
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29
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Taghavi SA, Eshraghian A, Niknam R, Sivandzadeh GR, Bagheri Lankarani K. Diagnosis of cholangiocarcinoma in primary sclerosing cholangitis. Expert Rev Gastroenterol Hepatol 2018; 12:575-584. [PMID: 29781738 DOI: 10.1080/17474124.2018.1473761] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Accepted: 05/02/2018] [Indexed: 02/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a chronic inflammatory disease of the hepatobiliary system characterized by chronic inflammation, progressive fibrosis, stricture formation and destruction of extrahepatic and intrahepatic bile ducts. Areas covered: The increased incidence of cholangiocarcinoma (CCA) in PSC has been well documented and can be explained by the continuous inflammation in the biliary tree leading to an enhanced dysplasia-carcinoma sequence. Although PSC patients may progress to liver cirrhosis; CCA most commonly occurs between the ages of 30 and 45 years when cirrhosis has not yet developed. Therefore, CCA in patients with PSC occurs earlier than in patients without PSC. Expert commentary: Despite improvement in diagnostic methods and devices, the dilemma of diagnosing CCA in patients with PSC has not been solved yet and needs further investigation.
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Affiliation(s)
- Seyed Alireza Taghavi
- a Gastroenterohepatology Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Ahad Eshraghian
- a Gastroenterohepatology Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Ramin Niknam
- a Gastroenterohepatology Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Gholam Reza Sivandzadeh
- a Gastroenterohepatology Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
| | - Kamran Bagheri Lankarani
- a Gastroenterohepatology Research Center , Shiraz University of Medical Sciences , Shiraz , Iran
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30
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Rizvi S, Eaton J, Yang JD, Chandrasekhara V, Gores GJ. Emerging Technologies for the Diagnosis of Perihilar Cholangiocarcinoma. Semin Liver Dis 2018; 38:160-169. [PMID: 29871021 PMCID: PMC6463495 DOI: 10.1055/s-0038-1655775] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The diagnosis of malignant biliary strictures remains problematic, especially in the perihilar region and in primary sclerosing cholangitis (PSC). Conventional cytology obtained during endoscopic retrograde cholangiography (ERC)-guided brushings of biliary strictures is suboptimal due to limited sensitivity, albeit it remains the gold standard with a high specificity. Emerging technologies are being developed and validated to address this pressing unmet patient need. Such technologies include enhanced visualization of the biliary tree by cholangioscopy, intraductal ultrasound, and confocal laser endomicroscopy. Conventional cytology can be aided by employing complementary and advanced cytologic techniques such as fluorescent in situ hybridization (FISH), and this technique should be widely adapted. Interrogation of bile and serum by examining extracellular vesicle number and cargo, and exploiting next-generation sequencing and proteomic technologies, is also being explored. Examination of circulating cell-free deoxyribonucleic acid (cfDNA) for differentially methylated regions is a promising test which is being rigorously validated. The special expertise required for these analyses has to date hampered their validation and adaptation. Herein, we will review these emerging technologies to inform the reader of the progress made and encourage further studies, as well as adaptation of validated approaches.
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Affiliation(s)
- Sumera Rizvi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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31
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Sandrasegaran K, Menias CO. Imaging and Screening of Cancer of the Gallbladder and Bile Ducts. Radiol Clin North Am 2017; 55:1211-1222. [DOI: 10.1016/j.rcl.2017.06.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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32
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Schramm C, Eaton J, Ringe KI, Venkatesh S, Yamamura J. Recommendations on the use of magnetic resonance imaging in PSC-A position statement from the International PSC Study Group. Hepatology 2017; 66:1675-1688. [PMID: 28555945 DOI: 10.1002/hep.29293] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Revised: 04/14/2017] [Accepted: 05/24/2017] [Indexed: 12/15/2022]
Abstract
UNLABELLED Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disorder characterized by inflammation and fibrosis of the intra- and/or extrahepatic bile ducts. Magnetic resonance imaging (MRI) is a noninvasive imaging modality that can be used to diagnose PSC and detect disease related complications. Quantitative MRI technologies also have the potential to provide valuable prognostic information. Despite the potential of this imaging technology, the clinical application of MRI in the care of PSC patients and imaging standards vary across institutions. Moreover, a unified position statement about the role of MRI in the care of PSC patients, quality imaging standards, and its potential as a research tool is lacking. CONCLUSION Members of the International PSC Study Group and radiologists from North America and Europe have compiled the following position statement to provide guidance regarding the application of MRI in the care of PSC patients, minimum imaging standards, and future areas of research. (Hepatology 2017;66:1675-1688).
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Affiliation(s)
- Christoph Schramm
- 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - John Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Kristina I Ringe
- Department of Diagnostic and Interventional Radiology, Hannover Medical School, Hannover, Germany
| | | | - Jin Yamamura
- Department of Diagnostic and Interventional Radiology and Nuclear Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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33
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Berretta M, Cavaliere C, Alessandrini L, Stanzione B, Facchini G, Balestreri L, Perin T, Canzonieri V. Serum and tissue markers in hepatocellular carcinoma and cholangiocarcinoma: clinical and prognostic implications. Oncotarget 2017; 8:14192-14220. [PMID: 28077782 PMCID: PMC5355172 DOI: 10.18632/oncotarget.13929] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022] Open
Abstract
HCC represents the sixth most common cancer worldwide and the second leading cause of cancer-related death. Despite the high incidence, treatment options for advanced HCC remain limited and unsuccessful, resulting in a poor prognosis. Despite the major advances achieved in the diagnostic management of HCC, only one third of the newly diagnosed patients are presently eligible for curative treatments. Advances in technology and an increased understanding of HCC biology have led to the discovery of novel biomarkers. Improving our knowledge about serum and tissutal markers could ultimately lead to an early diagnosis and better and early treatment strategies for this deadly disease. Serum biomarkers are striking potential tools for surveillance and early diagnosis of HCC thanks to the non-invasive, objective, and reproducible assessments they potentially enable. To date, many biomarkers have been proposed in the diagnosis of HCC. Cholangiocarcinoma (CCA) is an aggressive malignancy, characterized by early lymph node involvement and distant metastasis, with 5-year survival rates of 5%-10%. The identification of new biomarkers with diagnostic, prognostic or predictive value is especially important as resection (by surgery or combined with a liver transplant) has shown promising results and novel therapies are emerging. However, the relatively low incidence of CCA, high frequency of co-existing cholestasis or cholangitis (primary sclerosing cholangitis –PSC- above all), and difficulties with obtaining adequate samples, despite advances in sampling techniques and in endoscopic visualization of the bile ducts, have complicated the search for accurate biomarkers. In this review, we attempt to analyze the existing literature on this argument.
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Affiliation(s)
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto Taranto, Italy
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
| | - Brigida Stanzione
- Department of Medical Oncology, National Cancer Institute, Aviano (PN), Italy
| | - Gaetano Facchini
- Department of Medical Oncology, National Cancer Institute, "G. Pascale" Foundation, Naples, Italy
| | - Luca Balestreri
- Department of Radiology, National Cancer Institute, Aviano (PN), Italy
| | - Tiziana Perin
- Division of Pathology, National Cancer Institute, Aviano (PN), Italy
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34
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Horsley-Silva JL, Rodriguez EA, Franco DL, Lindor KD. An update on cancer risk and surveillance in primary sclerosing cholangitis. Liver Int 2017; 37:1103-1109. [PMID: 28028930 DOI: 10.1111/liv.13354] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 12/20/2016] [Indexed: 02/13/2023]
Abstract
Malignancy represents substantial morbidity and mortality in patients with primary sclerosing cholangitis (PSC). This subset of patients has been proven to be at increased risk for developing cholangiocarcinoma, gallbladder carcinoma and colorectal cancer in those with overlapping inflammatory bowel disease. Herein, we review the prevalence of these malignancies and recommend screening tools and current knowledge to reduce the disease burden in this population. Cholangiocarcinoma is the most dominant malignancy affecting PSC patients, with a lifetime risk ranging from 5% to 20%. We advocate for serial US or MRI/MRCP and CA 19-9 to screen for cholangiocarcinoma. Gallbladder cancer has a lifetime risk around 2% in this population and we agree with annual imaging for lesions as recommended by national guidelines. Patients with PSC and concomitant IBD are at increased risk of colorectal carcinoma from time of diagnosis and therefore should likely undergo annual surveillance. The low rates of hepatocellular cancer and pancreatic cancer indicate surveillance for these malignancies is less advantageous.
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Affiliation(s)
| | | | - Diana L Franco
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA
| | - Keith D Lindor
- Division of Gastroenterology and Hepatology, Mayo Clinic, Phoenix, AZ, USA.,College of Health Solutions, Arizona State University, Phoenix, AZ, USA
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35
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Larson L, James M, Gossard A. Cholestatic Liver Injury: Care of Patients With Primary Biliary Cholangitis or Primary Sclerosing Cholangitis. AACN Adv Crit Care 2017; 27:441-452. [PMID: 27959300 DOI: 10.4037/aacnacc2016202] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
The most common causes of chronic cholestatic liver disease are primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). Both disease processes are characterized by a destruction of intrahepatic and/or extrahepatic biliary ducts. The etiology is not entirely clear; however, there is an underlying autoimmune component contributing to both disease processes. Although PBC and PSC are often diagnosed and managed in the outpatient setting, in some instances, a patient may have jaundice, fatigue, and pruritus requiring evaluation and determination of the cholestatic cause. Patients with PSC should be monitored for evidence of cholangiocarcinoma, colon cancer, and gallbladder polyps as they are at an increased risk of malignant neoplasms. Liver transplant has the potential for improving quality of life, although disease recurrence is a risk.
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Affiliation(s)
- Laurie Larson
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Michelle James
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Andrea Gossard
- Laurie Larson is Nurse Practitioner, Hepatology, 406 Harvard St SE, MMC 36, University of Minnesota, Minneapolis, MN 55455 . Michelle James is Clinical Director of Transplant Services, University of Minnesota, Minneapolis, Minnesota. Andrea Gossard is Nurse Practitioner, Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
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36
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Varadarajulu S, Bang JY, Hasan MK, Navaneethan U, Hawes R, Hebert-Magee S. Improving the diagnostic yield of single-operator cholangioscopy-guided biopsy of indeterminate biliary strictures: ROSE to the rescue? (with video). Gastrointest Endosc 2016; 84:681-7. [PMID: 27048973 DOI: 10.1016/j.gie.2016.03.1497] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 03/26/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Tissue diagnosis, regardless of technique or endoscope used, can be challenging in patients with indeterminate biliary strictures (IDBSs). This exploratory study evaluated the utility and role of rapid onsite evaluation of touch imprint cytology (ROSE-TIC) when single-operator cholangioscopy (SOC)-guided biopsies of IDBSs are performed. METHODS Patients with IDBSs were evaluated by intraprocedural ROSE-TIC during SOC-guided biopsy procedures. Final diagnosis was established by long-term patient follow-up in conjunction with off-site findings or surgical histology. The main outcome measure was to evaluate the utility of ROSE-TIC by determination of its operating characteristics and comparison with off-site histologic assessment. RESULTS Of 31 patients with IDBSs, tissue diagnosis was indeterminate at prior ERCP-guided brush and/or biopsy in 14, prior EUS-guided FNA (EUS-FNA) in 6, and a mass could not be identified at EUS in 11. The mean number of biopsies performed was 3.3 (range 1-8), and diagnostic interpretation by ROSE-TIC was diagnostic and/or suspicious for carcinoma in 15, benign in 13, atypical-reactive in 2, and bile duct intraductal papillary mucinous neoplasm in 1. Final diagnosis by surgical histology (n = 4), death by disease (n = 10), and patient follow-up (n = 17) showed that the overall sensitivity of ROSE-TIC for diagnosing malignancy was 100%, specificity 88.9%, positive predictive value 86.7%, negative predictive value 100%, and diagnostic accuracy 93.5%. CONCLUSIONS Preliminary data suggest that the diagnostic outcomes of SOC-guided biopsies in IDBSs can be significantly improved by using ROSE-TIC. This technique also may benefit centers that rely mainly on fluoroscopy-guided intraductal biopsies.
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Affiliation(s)
- Shyam Varadarajulu
- Center for Interventional Endoscopy, Florida Hospital, Orlando, Florida, USA
| | - Ji Young Bang
- Divison of Gastroenterology-Hepatology, Indiana University, Indianapolis, Indiana, USA
| | - Muhammad K Hasan
- Center for Interventional Endoscopy, Florida Hospital, Orlando, Florida, USA
| | | | - Robert Hawes
- Center for Interventional Endoscopy, Florida Hospital, Orlando, Florida, USA
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Coelho-Prabhu N, Martin JA. Dilation of Strictures in Patients with Inflammatory Bowel Disease: Who, When and How. Gastrointest Endosc Clin N Am 2016; 26:739-59. [PMID: 27633600 DOI: 10.1016/j.giec.2016.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Stricture formation occurs in up to 40% of patients with inflammatory bowel disease (IBD). Patients are often symptomatic, resulting in significant morbidity, hospitalizations, and loss of productivity. Strictures can be managed endoscopically in addition to traditional surgical management (sphincteroplasty or resection of the affected bowel segments). About 3% to 5% patients with IBD develop primary sclerosing cholangitis (PSC), which results in stricture formation in the biliary tree, managed for the most part by endoscopic therapies. In this article, we discuss endoscopic management of strictures both in the alimentary tract and biliary tree in patients with IBD and/or PSC.
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Affiliation(s)
- Nayantara Coelho-Prabhu
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA
| | - John A Martin
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905, USA.
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38
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Risk and Surveillance of Cancers in Primary Biliary Tract Disease. Gastroenterol Res Pract 2016; 2016:3432640. [PMID: 27413366 PMCID: PMC4930812 DOI: 10.1155/2016/3432640] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/14/2016] [Accepted: 05/18/2016] [Indexed: 12/20/2022] Open
Abstract
Primary biliary diseases have been associated in several studies with various malignancies. Understanding the risk and optimizing surveillance strategy of these malignancies in this specific subset of patients are an important facet of clinical care. For instance, primary sclerosing cholangitis is associated with an increased risk for cholangiocarcinoma (which is very challenging to diagnose) and when IBD is present for colorectal cancer. On the other hand, primary biliary cirrhosis patients with cirrhosis or not responding to 12 months of ursodeoxycholic acid therapy are at increased risk of hepatocellular carcinoma. In this review we will discuss in detail the risks and optimal surveillance strategies for patients with primary biliary diseases.
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39
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Viterbo D, Gausman V, Gonda T. Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy. World J Gastrointest Endosc 2016; 8:128-142. [PMID: 26862363 PMCID: PMC4734972 DOI: 10.4253/wjge.v8.i3.128] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 10/17/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) and cholangiocarcinoma (CCA) are two malignancies that carry significant morbidity and mortality. The poor prognoses of these cancers are strongly related to lack of effective screening modalities as well as few therapeutic options. In this review, we highlight novel biomarkers that have the potential to be used as diagnostic, prognostic and predictive markers. The focus of this review is biomarkers that can be evaluated on endoscopically-obtained biopsies or brush specimens in the pre-operative setting. We also provide an overview of novel serum based markers in the early diagnosis of both PDAC and CCA. In pancreatic cancer, the emphasis is placed on prognostic and theranostic markers, whereas in CCA the utility of molecular markers in diagnosis and prognosis are highlighted.
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40
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Abstract
Primary sclerosing cholangitis (PSC) is a chronic, progressive disease characterized by inflammatory and fibrosing strictures of the biliary tree. PSC is associated with a high lifetime risk of hepatobiliary and colorectal cancers. The nature of the carcinogenic process in PSC is not well established. The lack of diagnostic methods for early detection and the limited therapeutic options for cholangiocarcinoma constitute a major challenge in the current handling of PSC patients. The article reviews the risk for cancer development in PSC and discusses surveillance strategies for PSC-associated cancers.
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Affiliation(s)
- Trine Folseraas
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Oslo, Norway
| | - Kirsten Muri Boberg
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Oslo, Norway.
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41
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Tabibian JH, Visrodia KH, Levy MJ, Gostout CJ. Advanced endoscopic imaging of indeterminate biliary strictures. World J Gastrointest Endosc 2015; 7:1268-1278. [PMID: 26675379 PMCID: PMC4673389 DOI: 10.4253/wjge.v7.i18.1268] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 08/05/2015] [Accepted: 10/27/2015] [Indexed: 02/05/2023] Open
Abstract
Endoscopic evaluation of indeterminate biliary strictures (IDBSs) has evolved considerably since the development of flexible fiberoptic endoscopes over 50 years ago. Endoscopic retrograde cholangiography pancreatography (ERCP) was introduced nearly a decade later and has since become the mainstay of therapy for relieving obstruction of the biliary tract. However, longstanding methods of ERCP-guided tissue acquisition (i.e., biliary brushings for cytology and intraductal forceps biopsy for histology) have demonstrated disappointing performance characteristics in distinguishing malignant from benign etiologies of IDBSs. The limitations of these methods have thus helped drive the search for novel techniques to enhance the evaluation of IDBSs and thereby improve diagnosis and clinical care. These modalities include, but are not limited to, endoscopic ultrasound, intraductal ultrasound, cholangioscopy, confocal endomicroscopy, and optical coherence tomography. In this review, we discuss established and emerging options in the evaluation of IDBSs.
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Barr Fritcher EG, Voss JS, Brankley SM, Campion MB, Jenkins SM, Keeney ME, Henry MR, Kerr SM, Chaiteerakij R, Pestova EV, Clayton AC, Zhang J, Roberts LR, Gores GJ, Halling KC, Kipp BR. An Optimized Set of Fluorescence In Situ Hybridization Probes for Detection of Pancreatobiliary Tract Cancer in Cytology Brush Samples. Gastroenterology 2015; 149:1813-1824.e1. [PMID: 26327129 DOI: 10.1053/j.gastro.2015.08.046] [Citation(s) in RCA: 94] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 07/23/2015] [Accepted: 08/21/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Pancreatobiliary cancer is detected by fluorescence in situ hybridization (FISH) of pancreatobiliary brush samples with UroVysion probes, originally designed to detect bladder cancer. We designed a set of new probes to detect pancreatobiliary cancer and compared its performance with that of UroVysion and routine cytology analysis. METHODS We tested a set of FISH probes on tumor tissues (cholangiocarcinoma or pancreatic carcinoma) and non-tumor tissues from 29 patients. We identified 4 probes that had high specificity for tumor vs non-tumor tissues; we called this set of probes pancreatobiliary FISH. We performed a retrospective analysis of brush samples from 272 patients who underwent endoscopic retrograde cholangiopancreatography for evaluation of malignancy at the Mayo Clinic; results were available from routine cytology and FISH with UroVysion probes. Archived residual specimens were retrieved and used to evaluate the pancreatobiliary FISH probes. Cutoff values for FISH with the pancreatobiliary probes were determined using 89 samples and validated in the remaining 183 samples. Clinical and pathologic evidence of malignancy in the pancreatobiliary tract within 2 years of brush sample collection was used as the standard; samples from patients without malignancies were used as negative controls. The validation cohort included 85 patients with malignancies (46.4%) and 114 patients with primary sclerosing cholangitis (62.3%). Samples containing cells above the cutoff for polysomy (copy number gain of ≥2 probes) were classified as positive in FISH with the UroVysion and pancreatobiliary probes. Multivariable logistic regression was used to estimate associations between clinical and pathology findings and results from FISH. RESULTS The combination of FISH probes 1q21, 7p12, 8q24, and 9p21 identified cancer cells with 93% sensitivity and 100% specificity in pancreatobiliary tissue samples and were therefore included in the pancreatobiliary probe set. In the validation cohort of brush samples, pancreatobiliary FISH identified samples from patients with malignancy with a significantly higher level of sensitivity (64.7%) than the UroVysion probes (45.9%) (P < .001) or routine cytology analysis (18.8%) (P < .001), but similar specificity (92.9%, 90.8%, and 100.0% respectively). Factors significantly associated with detection of carcinoma, in adjusted analyses, included detection of polysomy by pancreatobiliary FISH (P < .001), a mass by cross-sectional imaging (P < .001), cancer cells by routine cytology (overall P = .003), as well as absence of primary sclerosing cholangitis (P = .011). CONCLUSIONS We identified a set of FISH probes that detects cancer cells in pancreatobiliary brush samples from patients with and without primary sclerosing cholangitis with higher levels of sensitivity than UroVysion probes. Cytologic brushing test results and clinical features were independently associated with detection of cancer and might be used to identify patients with pancreatobiliary cancers.
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Affiliation(s)
- Emily G Barr Fritcher
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Jesse S Voss
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Shannon M Brankley
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Michael B Campion
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Sarah M Jenkins
- Division of Biomedical Statistics and Informatics, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Matthew E Keeney
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Michael R Henry
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Sarah M Kerr
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota; Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | | | - Amy C Clayton
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Jun Zhang
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Kevin C Halling
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota
| | - Benjamin R Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Foundation, Rochester, Minnesota.
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Ilyas SI, Eaton JE, Gores GJ. Primary Sclerosing Cholangitis as a Premalignant Biliary Tract Disease: Surveillance and Management. Clin Gastroenterol Hepatol 2015; 13:2152-65. [PMID: 26051390 PMCID: PMC4618039 DOI: 10.1016/j.cgh.2015.05.035] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Revised: 05/20/2015] [Accepted: 05/22/2015] [Indexed: 02/07/2023]
Abstract
Primary sclerosing cholangitis (PSC) is a premalignant biliary tract disease that confers a significant risk for the development of cholangiocarcinoma (CCA). The chronic biliary tract inflammation of PSC promotes pro-oncogenic processes such as cellular proliferation, induction of DNA damage, alterations of the extracellular matrix, and cholestasis. The diagnosis of malignancy in PSC can be challenging because inflammation-related changes in PSC may produce dominant biliary tract strictures mimicking CCA. Biomarkers such as detection of methylated genes in biliary specimens represent noninvasive techniques that may discriminate malignant biliary ductal changes from PSC strictures. However, conventional cytology and advanced cytologic techniques such as fluorescence in situ hybridization for polysomy remain the practice standard for diagnosing CCA in PSC. Curative treatment options of malignancy arising in PSC are limited. For a subset of patients selected by using stringent criteria, liver transplantation after neoadjuvant chemoradiation is a potential curative therapy. However, most patients have advanced malignancy at the time of diagnosis. Advances directed at identifying high-risk patients, early cancer detection, and development of chemopreventive strategies will be essential to better manage the cancer risk in this premalignant disease. A better understanding of dysplasia definition and especially its natural history is also needed in this disease. Herein, we review recent developments in our understanding of the risk factors, pathogenic mechanisms of PSC associated with CCA, as well as advances in early detection and therapies.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - John E Eaton
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Sclair SN, Little E, Levy C. Current Concepts in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis. Clin Transl Gastroenterol 2015; 6:e109. [PMID: 26312413 PMCID: PMC4816277 DOI: 10.1038/ctg.2015.33] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Accepted: 07/23/2015] [Indexed: 12/15/2022] Open
Abstract
Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are chronic, cholestatic diseases of the liver with common clinical manifestations. Early diagnosis and treatment of PBC slows progression and decreases the need for transplant. However, one-third of patients will progress regardless of treatment. Bilirubin <1.0 and alkaline phosphatase <2.0 x the upper limit of normal at 1 year after treatment appear to predict 10-year survival. Ursodeoxycholic acid (UDCA) is the recommended treatment for PBC, and recent studies with obeticholic acid showed promising results for UDCA non-responders. Unlike PBC, no therapy has been shown to alter the natural history of PSC. The recommended initial diagnostic test for PSC is magnetic resonance cholangiopancreatography, typically showing bile duct wall thickening, focal bile duct dilatation, and saccular dilatation of the intra- and/or extrahepatic bile ducts. Immunoglobulin 4-associated cholangitis must be excluded when considering the diagnosis of PSC, to allow for proper treatment, and monitoring of disease progression. In addition to the lack of therapy, PSC is a pre-malignant condition and close surveillance is indicated.
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Affiliation(s)
- Seth N Sclair
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ester Little
- Banner University Medical Center, Phoenix, Arizona, USA
| | - Cynthia Levy
- Schiff Center for Liver Diseases, University of Miami Miller School of Medicine, Miami, Florida, USA
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