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Kotsifa E, Saffioti F, Mavroeidis VK. Cholangiocarcinoma: The era of liquid biopsy. World J Gastroenterol 2025; 31:104170. [PMID: 40124277 PMCID: PMC11924015 DOI: 10.3748/wjg.v31.i11.104170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/28/2025] [Accepted: 02/14/2025] [Indexed: 03/13/2025] Open
Abstract
Cholangiocarcinoma (CCA) is a highly aggressive and heterogeneous malignancy arising from the epithelial cells of the biliary tract. The limitations of the current methods in the diagnosis of CCA highlight the urgent need for new, accurate tools for early cancer detection, better prognostication and patient monitoring. Liquid biopsy (LB) is a modern and non-invasive technique comprising a diverse group of methodologies aiming to detect tumour biomarkers from body fluids. These biomarkers include circulating tumour cells, cell-free DNA, circulating tumour DNA, RNA and extracellular vesicles. The aim of this review is to explore the current and potential future applications of LB in CCA management, with a focus on diagnosis, prognostication and monitoring. We examine both its significant potential and the inevitable limitations associated with this technology. We conclude that LB holds considerable promise, but further research is necessary to fully integrate it into precision oncology for CCA.
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Affiliation(s)
- Evgenia Kotsifa
- The Second Propaedeutic Department of Surgery, National and Kapodistrian University of Athens, General Hospital of Athens “Laiko”, Athens 11527, Greece
| | - Francesca Saffioti
- Department of Gastroenterology and Hepatology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, United Kingdom
- University College London Institute for Liver and Digestive Health and Sheila Sherlock Liver Unit, Royal Free Hospital and University College London, London NW3 2QG, United Kingdom
- Division of Clinical and Molecular Hepatology, Department of Clinical and Experimental Medicine, University Hospital of Messina, Messina 98124, Italy
| | - Vasileios K Mavroeidis
- Department of Transplant Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of Gastrointestinal Surgery, North Bristol NHS Trust, Southmead Hospital, Bristol BS10 5NB, United Kingdom
- Department of HPB Surgery, Bristol Royal Infirmary, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol BS2 8HW, United Kingdom
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Cooley MA, Schneider AR, Fritcher EGB, Milosevic D, Levy MJ, Bridgeman AR, Martin JA, Petersen BT, Dayyeh BKA, Storm AC, Law RJ, Vargas EJ, Garimella V, Zemla T, Jenkins SM, Yin J, Gores GJ, Roberts LR, Kipp BR, Chandrasekhara V. Utility of methylated DNA markers for the diagnosis of malignant biliary strictures. Hepatology 2025; 81:453-464. [PMID: 38905442 PMCID: PMC11827039 DOI: 10.1097/hep.0000000000000970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 05/24/2024] [Indexed: 06/23/2024]
Abstract
BACKGROUND AND AIMS Early identification of malignant biliary strictures (MBSs) is challenging, with up to 20% classified as indeterminants after preliminary testing and tissue sampling with endoscopic retrograde cholangiopancreatography. We aimed to evaluate the use of methylated DNA markers (MDMs) from biliary brushings to enhance MBS detection in a prospective cohort. APPROACH Candidate MDMs were evaluated for their utility in MBS diagnosis through a series of discovery and validation phases. DNA was extracted from biliary brushing samples, quantified, bisulfite-converted, and then subjected to methylation-specific droplet digital polymerase chain reaction. Patients were considered to have no malignancy if the sampling was negative and there was no evidence of malignancy after 1 year or definitive negative surgical histopathology. RESULTS Fourteen candidate MDMs were evaluated in the discovery phase, with top-performing and new markers evaluated in the technical validation phase. The top 4 MDMs were TWIST1, HOXA1, VSTM2B, and CLEC11A, which individually achieved AUC values of 0.82, 0.81, 0.83, and 0.78, respectively, with sensitivities of 59.4%, 53.1%, 62.5%, and 50.0%, respectively, at high specificities for malignancy of 95.2%-95.3% for the final biologic validation phase. When combined as a panel, the AUC was 0.86, achieving 73.4% sensitivity and 92.9% specificity, which outperformed cytology and fluorescence in situ hybridization (FISH). CONCLUSIONS The selected MDMs demonstrated improved performance characteristics for the detection of MBS compared to cytology and FISH. Therefore, MDMs should be considered viable candidates for inclusion in diagnostic testing algorithms.
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Affiliation(s)
- Matthew A. Cooley
- Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota
| | - Amber R. Schneider
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Dragana Milosevic
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Michael J. Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Amber R. Bridgeman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - John A. Martin
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Bret T. Petersen
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Andrew C. Storm
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ryan J. Law
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Eric J. Vargas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vishal Garimella
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Tyler Zemla
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Sarah M. Jenkins
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Jun Yin
- Health Science Research Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Benjamin R. Kipp
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Jang SI, Nahm JH, Lee SY, Jeong S, Lee TH, Kim DU, Kwon CI, Cho JH, Sung MJ. The Catheter Flushing Method Shows a Similar Diagnostic Yield to the Conventional Method in Brushing Cytology for Biliary Strictures. J Clin Med 2024; 13:6741. [PMID: 39597885 PMCID: PMC11594799 DOI: 10.3390/jcm13226741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 10/30/2024] [Accepted: 11/07/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objectives: Endobiliary brushing is usually performed in the diagnosis of indeterminate biliary strictures; however, in this setting, brush cytology is limited by a low diagnostic yield and sensitivity. Here, we compared the catheter flushing method (CFM) with the conventional cytologic method (CCM) in terms of cellularity and diagnostic performance. Methods: Endobiliary brushings were obtained during endoscopic retrograde cholangiopancreatography (ERCP) from patients with biliary strictures enrolled at six tertiary hospitals. Additionally, the CFM was performed after brushing. Using liquid-based cytologic preparations of samples, we assessed the diagnostic performance of the CCM using Pap staining and the CFM using methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence staining. Results: From a total of 399 patients (malignant, 253; benign, 146), 374 CCM samples and 361 CFM samples contained adequate cells, with no significant difference in diagnostic yield (93.7% vs. 90.5%, respectively; p = 0.088). The sensitivity of the CFM (90.3%) was significantly higher than that of the CCM (75.1%; p < 0.001), with no significant difference in accuracy between methods (81.2% vs. 82.6%, respectively; p = 0.608). Conclusions: The diagnostic yield of the CFM was comparable to that of the CCM. Additionally, the diagnostic performance of the CFM was comparable to that of the CCM. These findings indicate that the CFM could be an additional brush cytology method for sample collection in patients with indeterminate biliary strictures. Incorporating both the CCM and CFM might be expected to improve the diagnostic yield of brush cytology in the biliary strictures. Further prospective comparative studies between the CCM and CFM using the same staining method are needed to validate these findings.
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Affiliation(s)
- Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (S.I.J.); (S.Y.L.)
| | - Ji Hae Nahm
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea;
| | - See Young Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (S.I.J.); (S.Y.L.)
| | - Seok Jeong
- Department of Internal Medicine, Inha University School of Medicine, Incheon 22332, Republic of Korea;
| | - Tae Hoon Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan 31151, Republic of Korea;
| | - Dong Uk Kim
- Department of Internal Medicine, CHA Gumi Medical Center, CHA University School of Medicine, Gumi 39295, Republic of Korea;
| | - Chang-Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea;
| | - Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea; (S.I.J.); (S.Y.L.)
| | - Min Je Sung
- Digestive Disease Center, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam 13496, Republic of Korea;
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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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Le Bourlout Y, Rehell M, Kelppe J, Rautava J, Perra E, Rantanen J, Ehnholm G, Hayward N, Nyman K, Pritzker KPH, Tarkkanen J, Atula T, Aro K, Nieminen HJ. Ultrasound-Enhanced Fine-Needle Biopsy Improves Yield in Human Epithelial and Lymphoid Tissue. ULTRASOUND IN MEDICINE & BIOLOGY 2024; 50:1247-1254. [PMID: 38834492 DOI: 10.1016/j.ultrasmedbio.2024.04.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 03/22/2024] [Accepted: 04/27/2024] [Indexed: 06/06/2024]
Abstract
OBJECTIVE Needle biopsy is a common technique used to obtain cell and tissue samples for diagnostics. Currently, two biopsy methods are widely used: (i) fine-needle aspiration biopsy (FNAB) and (ii) core needle biopsy (CNB). However, these methods have limitations. Recently, we developed ultrasound-enhanced fine-needle aspiration biopsy (USeFNAB), which employs a needle that flexurally oscillates at an ultrasonic frequency of ∼32 kHz. The needle motion contributes to increased tissue collection while preserving cells and tissue constructs for pathological assessment. Previously, USeFNAB has been investigated only in ex vivo animal tissue. The present study was aimed at determining the feasibility of using USeFNAB in human epithelial and lymphoid tissue. METHODS Needle biopsy samples were acquired using FNAB, CNB and USeFNAB on ex vivo human tonsils (N = 10). The tissue yield and quality were quantified by weight measurement and blinded pathologists' assessments. The biopsy methods were then compared. RESULTS The results revealed sample mass increases of, on average, 2.3- and 5.4-fold with USeFNAB compared with the state-of-the-art FNAB and CNB, respectively. The quality of tissue fragments collected by USeFNAB was equivalent to that collected by the state-of-the-art methods in terms of morphology and immunohistochemical stainings made from cell blocks as judged by pathologists. CONCLUSION Our study indicates that USeFNAB is a promising method that could improve tissue yield to ensure sufficient material for ancillary histochemical and molecular studies for diagnostic pathology, thereby potentially increasing diagnostic accuracy.
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Affiliation(s)
- Yohann Le Bourlout
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
| | - Minna Rehell
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland; Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jetta Kelppe
- Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jaana Rautava
- Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland
| | - Emanuele Perra
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
| | - Jouni Rantanen
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
| | - Gösta Ehnholm
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
| | - Nick Hayward
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland
| | - Kristofer Nyman
- Department of Radiology, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kenneth P H Pritzker
- Departments of Laboratory Medicine and Pathobiology and Surgery, University of Toronto, Toronto, ON, Canada
| | - Jussi Tarkkanen
- Department of Pathology, HUSLAB, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Timo Atula
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Katri Aro
- Department of Otorhinolaryngology-Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Heikki J Nieminen
- Medical Ultrasonics Laboratory (MEDUSA), Department of Neuroscience and Biomedical Engineering, Aalto University, Espoo, Finland.
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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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Affarah L, Berry P, Kotha S. Still elusive: Developments in the accurate diagnosis of indeterminate biliary strictures. World J Gastrointest Endosc 2024; 16:297-304. [PMID: 38946851 PMCID: PMC11212512 DOI: 10.4253/wjge.v16.i6.297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 04/09/2024] [Accepted: 05/07/2024] [Indexed: 06/13/2024] Open
Abstract
Indeterminate biliary strictures pose a significant diagnostic dilemma for gastroenterologists. Despite advances in endoscopic techniques and instruments, it is difficult to differentiate between benign and malignant pathology. A positive histological diagnosis is always preferred prior to high risk hepatobiliary surgery, or to inform other types of therapy. Endoscopic retrograde cholangiopancreatography with brushings has low sensitivity and despite significant improvements in instruments there is still an unacceptably high false negative rate. Other methods such as endoscopic ultrasound and cholangioscopy have improved diagnostic quality. In this review we explore the techniques available to aid accurate diagnosis of indeterminate biliary strictures and obtain accurate histology to facilitate clinical management.
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Affiliation(s)
- Lynn Affarah
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Philip Berry
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
| | - Sreelakshmi Kotha
- Department of Hepatology, Guy's and St Thomas' Hospital, London SE1 7EH, United Kingdom
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Li Z, Tabbara SO, Nwosu A, Souers RJ, Goyal A, Kurian EM, Lin X, VandenBussche C, Nguyen LN. Pancreaticobiliary Cytology Practice in 2021: Results of a College of American Pathologists Survey. Arch Pathol Lab Med 2024; 148:677-685. [PMID: 37702405 DOI: 10.5858/arpa.2023-0167-cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/03/2023] [Indexed: 09/14/2023]
Abstract
CONTEXT.— The College of American Pathologists (CAP) surveys provide national benchmarks of pathology practice. OBJECTIVE.— To investigate pancreaticobiliary cytology practice in domestic and international laboratories in 2021. DESIGN.— We analyzed data from the CAP Pancreaticobiliary Cytology Practice Supplemental Questionnaire that was distributed to laboratories participating in the 2021 CAP Nongynecologic Cytopathology Education Program. RESULTS.— Ninety-three percent (567 of 612) of respondent laboratories routinely evaluated pancreaticobiliary cytology specimens. Biliary brushing (85%) was the most common pancreaticobiliary cytology specimen evaluated, followed by pancreatic fine-needle aspiration (79%). The most used sampling methods reported by 235 laboratories were 22-gauge needle for fine-needle aspiration (62%) and SharkCore needle for fine-needle biopsy (27%). Cell block was the most used slide preparation method (76%), followed by liquid-based cytology (59%) for pancreatic cystic lesions. Up to 95% (303 of 320) of laboratories performed rapid on-site evaluation (ROSE) on pancreatic solid lesions, while 56% (180 of 320) performed ROSE for cystic lesions. Thirty-six percent (193 of 530) of laboratories used the Papanicolaou Society of Cytopathology System for Reporting Pancreaticobiliary Cytology in 2021. Among all institution types, significant differences in specimen volume, specimen type, ROSE practice, and case sign-out were identified. Additionally, significant differences in specimen type, slide preparation, and ROSE practice were found. CONCLUSIONS.— This is the first survey from the CAP to investigate pancreaticobiliary cytology practice. The findings reveal significant differences among institution types and between domestic and international laboratories. These data provide a baseline for future studies in a variety of practice settings.
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Affiliation(s)
- Zaibo Li
- From the Department of Pathology, The Ohio State University, Columbus (Li)
| | - Sana O Tabbara
- the Department of Pathology, Moffitt Cancer Center, Tampa, Florida (Tabbara)
| | - Ann Nwosu
- Biostatistics, College of American Pathologists, Northfield, Illinois (Nwosu, Souers)
| | - Rhona J Souers
- Biostatistics, College of American Pathologists, Northfield, Illinois (Nwosu, Souers)
| | - Abha Goyal
- the Department of Pathology, Weill Cornell Medicine, New York, New York (Goyal)
| | - Elizabeth M Kurian
- the Department of Pathology, University of Texas Southwestern Medical Center, Dallas (Kurian)
| | - Xiaoqi Lin
- the Department of Pathology, Northwestern University, Chicago, Illinois (Lin)
| | - Christopher VandenBussche
- the Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland (VandenBussche)
| | - Lananh N Nguyen
- the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (Nguyen)
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Lee SH, Song SY. Recent Advancement in Diagnosis of Biliary Tract Cancer through Pathological and Molecular Classifications. Cancers (Basel) 2024; 16:1761. [PMID: 38730713 PMCID: PMC11083053 DOI: 10.3390/cancers16091761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 04/24/2024] [Accepted: 04/29/2024] [Indexed: 05/13/2024] Open
Abstract
Biliary tract cancers (BTCs), including intrahepatic, perihilar, and distal cholangiocarcinomas, as well as gallbladder cancer, are a diverse group of cancers that exhibit unique molecular characteristics in each of their anatomic and pathological subtypes. The pathological classification of BTCs compromises distinct growth patterns, including mass forming, periductal infiltrating, and intraductal growing types, which can be identified through gross examination. The small-duct and large-duct types of intrahepatic cholangiocarcinoma have been recently introduced into the WHO classification. The presentation of typical clinical symptoms, as well as the extensive utilization of radiological, endoscopic, and molecular diagnostic methods, is thoroughly detailed in the description. To overcome the limitations of traditional tissue acquisition methods, new diagnostic modalities are being explored. The treatment landscape is also rapidly evolving owing to the emergence of distinct subgroups with unique molecular alterations and corresponding targeted therapies. Furthermore, we emphasize the crucial aspects of diagnosing BTC in practical clinical settings.
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Affiliation(s)
- Sang-Hoon Lee
- Department of Internal Medicine, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Republic of Korea;
| | - Si Young Song
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
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10
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Kodali S, Connor AA, Brombosz EW, Ghobrial RM. Update on the Screening, Diagnosis, and Management of Cholangiocarcinoma. Gastroenterol Hepatol (N Y) 2024; 20:151-158. [PMID: 38680168 PMCID: PMC11047158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/01/2024]
Abstract
Cholangiocarcinoma (CCA) is a neoplasm of the biliary tract that has become increasingly prevalent throughout the world. Common risk factors for developing CCA include cirrhosis, primary sclerosing cholangitis, and trematode fluke infestation, although there are no set screening guidelines in high-risk groups. Lesions are typically identified via cross-sectional imaging and/or elevated serum carbohydrate antigen 19-9 levels, often followed by cytology or brushings with fluorescence in situ hybridization for confirmation. Treatments can vary among CCA subtypes but frequently involve systemic therapies such as gemcitabine and cisplatin with durvalumab or pembrolizumab. Targeted therapies may also be effective (eg, ivosidenib, pemigatinib, infigratinib, futibatinib) depending on the molecular alterations present. Resection is the most common surgical treatment for CCA, although liver transplantation is also an option in highly selected patients with liver-limited unresectable disease. Radiotherapy may also be a treatment option, as well as transarterial radioembolization (eg, yttrium-90), which is often utilized in combination with systemic therapy. Although patients with CCA have traditionally had a poor prognosis, recent advances in treatment, including new systemic therapies and increased utilization of liver transplantation, have improved expected survival. This article reviews screening modalities, pros and cons of diagnostic techniques, and therapies that are currently available to treat patients with CCA.
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Affiliation(s)
- Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, J. C. Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
- Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, J. C. Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Weill Cornell Medical College, New York, New York
| | | | - R. Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, J. C. Walter Jr Transplant Center, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Weill Cornell Medical College, New York, New York
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11
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Sonnenday CJ. Liver Transplantation for Hilar Cholangiocarcinoma. Surg Clin North Am 2024; 104:183-196. [PMID: 37953035 DOI: 10.1016/j.suc.2023.09.004] [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] [Indexed: 11/14/2023]
Abstract
Hilar cholangiocarcinoma (hCCA) is an infiltrative disease that often presents with locally advanced and/or metastatic disease, with a minority of patients eligible for surgical resection. Select patients with unresectable hCCA, or patients with hCCA in the setting of primary sclerosing cholangitis, with tumors less than 3 cm and no evidence of extrahepatic disease, can be effectively treated with neoadjuvant chemoradiation followed by liver transplantation. Staging laparotomy documenting lack of occult metastatic disease, including a portal lymphadenectomy documenting no nodal metastases, is essential to achieve optimal outcomes. Overall 5 year survival among treated patients is approximately 60%.
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Affiliation(s)
- Christopher J Sonnenday
- Department of Surgery, University of Michigan Health, F6686 UH-South, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5296, USA.
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12
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Mohamed R, Tejaswi S, Aabakken L, Ponsioen CY, Bowlus CL, Adler DG, Forbes N, Paulsen V, Voermans RP, Urayama S, Peetermans J, Rousseau MJ, Eksteen B. Per-oral cholangioscopy in patients with primary sclerosing cholangitis: a 12-month follow-up study. Endosc Int Open 2024; 12:E237-E244. [PMID: 38362361 PMCID: PMC10869209 DOI: 10.1055/a-2236-7557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/22/2023] [Indexed: 02/17/2024] Open
Abstract
Background and study aims Patients with primary sclerosing cholangitis (PSC) have a 9% to 20% lifetime incidence of cholangiocarcinoma (CCA). Per-oral cholangioscopy (POCS) added to endoscopic retrograde cholangiography (ERC) could potentially improve detection of CCA occurrence. We prospectively assessed POCS identification of 12-month CCA incidence in PSC patients undergoing ERC. Patients and methods Consecutive patients with PSC, an indication for ERC, and no prior liver transplantation were enrolled. During the index procedure, POCS preceded planned therapeutic maneuvers. The primary endpoint was ability for POCS visualization with POCS-guided biopsy to identify CCA during 12-month follow-up. Secondary endpoints included ability of ERC/cytology to identify CCA, repeat ERC, liver transplantation, and serious adverse events (SAEs). Results Of 42 patients enrolled, 36 with successful cholangioscope advancement were analyzed. Patients had a mean age 43.5±15.6 years and 61% were male. Three patients diagnosed with CCA had POCS visualization impressions of benign/suspicious/suspicious, and respective POCS-guided biopsy findings of suspicious/positive/suspicious for malignancy at the index procedure. The three CCA cases had ERC visualization impressions of benign/benign/suspicious, and respective cytology findings of atypical/atypical/suspicious for malignancy. No additional patients were diagnosed with CCA during median 11.5-month follow-up. Twenty-three repeat ERCs (5 including POCS) were performed in 14 patients. Five patients had liver transplantation, one after CCA diagnosis and four after benign cytology at the index procedure. Three patients (7.1%) had post-ERC pancreatitis. No SAEs were POCS-related. Conclusions In PSC patients, POCS visualization/biopsy and ERC/cytology each identified three cases of CCA. Some patients had a repeat procedure and none experienced POCS-related SAEs.
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Affiliation(s)
- Rachid Mohamed
- Gastroenterology and Hepatology, University of Calgary, Calgary, Canada
| | - Sooraj Tejaswi
- Division of Gastroenterology & Hepatology, University of California Davis School of Medicine, Sacramento, United States
| | - Lars Aabakken
- Dept of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Cyriel Y Ponsioen
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, Netherlands
| | - Christopher L Bowlus
- Division of Gastroenterology & Hepatology, University of California Davis School of Medicine, Sacramento, United States
| | - Douglas G Adler
- Center for Advanced Therapeutic Endoscopy, Adventist Porter Hospital, Denver,
| | - Nauzer Forbes
- Gastroenterology and Hepatology, University of Calgary, Calgary, Canada
| | - Vemund Paulsen
- Dept of Transplantation Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway
| | - Rogier P. Voermans
- Gastroenterology and Hepatology, Amsterdam University Medical Centres, Amsterdam, Netherlands
| | - Shiro Urayama
- Division of Gastroenterology & Hepatology, University of California Davis School of Medicine, Sacramento, United States
| | - Joyce Peetermans
- Clinical Endoscopy, Boston Scientific Corporation, Marlborough, United States
| | - Matthew J Rousseau
- Clinical Endoscopy, Boston Scientific Corporation, Marlborough, United States
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13
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Saca D, Flamm SL. Cholangiocarcinoma Surveillance Recommendations in Patients with Primary Sclerosing Cholangitis. Clin Liver Dis 2024; 28:183-192. [PMID: 37945159 DOI: 10.1016/j.cld.2023.07.010] [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] [Indexed: 11/12/2023]
Abstract
Cholangiocarcinoma (CCA) is a deadly complication observed in the setting of primary sclerosing cholangitis (PSC). When symptoms develop and CCA is diagnosed, it is usually at an advanced stage. Median survival is less than 12 months. Early identification of CCA leads to improved outcomes. Although diagnostic tests have excellent specificity, they are plagued by low sensitivity. No surveillance strategies have been widely agreed upon, but most societies recommend measurement of serum carbohydrate antigen 19-9 and MRCP every 6 to 12 months in patients with PSC. Advances in understanding of the genetic factors that lead to CCA are awaited.
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Affiliation(s)
- Daniel Saca
- Rush University Medical School, 1725 West Harrison Street Suite 110, Chicago, IL 60612, USA
| | - Steven L Flamm
- Rush University Medical School, 1725 West Harrison Street Suite 110, Chicago, IL 60612, USA.
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14
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Ahmed W, Joshi D, Huggett MT, Everett SM, James M, Menon S, Oppong KW, On W, Paranandi B, Trivedi P, Webster G, Hegade VS. Update on the optimisation of endoscopic retrograde cholangiography (ERC) in patients with primary sclerosing cholangitis. Frontline Gastroenterol 2024; 15:74-83. [PMID: 38487565 PMCID: PMC10935540 DOI: 10.1136/flgastro-2023-102491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/28/2023] [Indexed: 03/17/2024] Open
Affiliation(s)
- Wafaa Ahmed
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Deepak Joshi
- Gastroenterology, King's College Hospital Liver Unit, London, UK
| | - Matthew T Huggett
- Gastroenterology, St James's University Hospital, The Leeds Teaching Hospitals NHS Foundation Trust, Leeds, UK
| | - Simon M Everett
- Gastroenterology, St James's University Hospital NHS Trust, Leeds, UK
| | - Martin James
- Gastroenterology, Nottingham University, Nottingham, UK
| | - Shyam Menon
- Department of Hepatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | | | - Wei On
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Bharat Paranandi
- Department of Gastroenterology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Palak Trivedi
- National Institute for Health Research, Centre for Liver Research, University Hospitals Birmingham, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - George Webster
- Department of Gastroenterology, University College London Hospital NHS Foundation Trust, London, UK
| | - Vinod S Hegade
- Leeds Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
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15
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Kurfurstova D, Slobodova Z, Zoundjiekpon V, Urban O. The contribution of new methods in cytology for increasing sensitivity in the diagnosis of extrahepatic bile duct lesions. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2023; 167:309-318. [PMID: 37964583 DOI: 10.5507/bp.2023.041] [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: 03/21/2023] [Accepted: 10/12/2023] [Indexed: 11/16/2023] Open
Abstract
The aim of this review is to provide a comprehensive analysis of the existing literature pertaining to cytology of extrahepatic bile ducts. A search using the keywords "biliary brush cytology" was conducted in the PubMed database, with a focus on recent articles. The inclusion criteria primarily encompassed publications addressing problematic biliary stenosis. Emphasis was placed on identifying articles that explored innovative or less-utilized examination techniques aimed at enhancing the sensitivity of cytological examination. This review presents a comprehensive overview of the various types of materials used in sampling and the corresponding sampling methods. Additionally, it explores cytological and cytogenetic techniques, such as fluorescence in situ hybridization (FISH) and genetic methods (miRNA, NGS, cfDNA). These techniques possess the potential to improve the accuracy of diagnosing bile duct tumors, although their sensitivity varies. Furthermore, their utilization can facilitate early therapy, which plays a crucial role in patient prognosis. Each examination is always dependent on the quality and quantity of material delivered. A higher sensitivity of these examinations can be achieved by combining biliary cytology and other complementary methods.
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Affiliation(s)
- Daniela Kurfurstova
- Department of Clinical and Molecular Pathology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, 779 00 Olomouc, Czech Republic
| | - Zuzana Slobodova
- Department of Clinical and Molecular Pathology, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, 779 00 Olomouc, Czech Republic
| | - Vincent Zoundjiekpon
- 2nd Department of Internal Medicine - Gastroenterology and Geriatrics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, 779 00 Olomouc, Czech Republic
| | - Ondrej Urban
- 2nd Department of Internal Medicine - Gastroenterology and Geriatrics, University Hospital Olomouc and Faculty of Medicine and Dentistry, Palacky University Olomouc, 779 00 Olomouc, Czech Republic
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17
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Ilyas SI, Affo S, Goyal L, Lamarca A, Sapisochin G, Yang JD, Gores GJ. Cholangiocarcinoma - novel biological insights and therapeutic strategies. Nat Rev Clin Oncol 2023; 20:470-486. [PMID: 37188899 PMCID: PMC10601496 DOI: 10.1038/s41571-023-00770-1] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/24/2023] [Indexed: 05/17/2023]
Abstract
In the past 5 years, important advances have been made in the scientific understanding and clinical management of cholangiocarcinoma (CCA). The cellular immune landscape of CCA has been characterized and tumour subsets with distinct immune microenvironments have been defined using molecular approaches. Among these subsets, the identification of 'immune-desert' tumours that are relatively devoid of immune cells emphasizes the need to consider the tumour immune microenvironment in the development of immunotherapy approaches. Progress has also made in identifying the complex heterogeneity and diverse functions of cancer-associated fibroblasts in this desmoplastic cancer. Assays measuring circulating cell-free DNA and cell-free tumour DNA are emerging as clinical tools for detection and monitoring of the disease. Molecularly targeted therapy for CCA has now become a reality, with three drugs targeting oncogenic fibroblast growth factor receptor 2 (FGFR2) fusions and one targeting neomorphic, gain-of-function variants of isocitrate dehydrogenase 1 (IDH1) obtaining regulatory approval. By contrast, immunotherapy using immune-checkpoint inhibitors has produced disappointing results in patients with CCA, underscoring the requirement for novel immune-based treatment strategies. Finally, liver transplantation for early stage intrahepatic CCA under research protocols is emerging as a viable therapeutic option in selected patients. This Review highlights and provides in-depth information on these advances.
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Affiliation(s)
- Sumera I Ilyas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Department of Immunology, Mayo Clinic, Rochester, MN, USA
| | - Silvia Affo
- Liver, Digestive System and Metabolism Research, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Lipika Goyal
- Department of Medicine, Mass General Cancer Center, Harvard Medical School, Boston, MA, USA
| | - Angela Lamarca
- Department of Oncology, OncoHealth Institute, Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Department of Medical Oncology, The Christie NHS Foundation, Manchester, UK
- Division of Cancer Sciences, University of Manchester, Manchester, UK
| | - Gonzalo Sapisochin
- Ajmera Transplant Program and HPB Surgical Oncology, Toronto General Hospital, University of Toronto, Toronto, Canada
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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18
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Fluorescence In Situ Hybridization in Primary Diagnosis of Biliary Strictures: A Single-Center Prospective Interventional Study. Biomedicines 2023; 11:biomedicines11030755. [PMID: 36979734 PMCID: PMC10045065 DOI: 10.3390/biomedicines11030755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/22/2023] [Accepted: 02/24/2023] [Indexed: 03/06/2023] Open
Abstract
Background and aims: Diagnosis of the biliary stricture remains a challenge. In view of the low sensitivity of brush cytology (BC), fluorescence in situ hybridization (FISH) has been reported as a useful adjunctive test in patients with biliary strictures. We aimed to determine performance characteristics of BC and FISH individually and in combination (BC + FISH) in the primary diagnosis of biliary strictures. Methods: This single-center prospective study was conducted between April 2019 and January 2021. Consecutive patients with unsampled biliary strictures undergoing first endoscopic retrograde cholangiopancreatography in our institution were included. Tissue specimens from two standardized transpapillary brushings from the strictures were examined by routine cytology and FISH. Histopathological confirmation after surgery or 12-month follow-up was regarded as the reference standard for final diagnosis. Results: Of 109 enrolled patients, six were excluded and one lost from the final analysis. In the remaining 102 patients (60.8% males, mean age 67.4, range 25–92 years), the proportions of benign and malignant strictures were 28 (27.5%) and 74 (72.5%), respectively. The proportions of proximal and distal strictures were 26 (25.5%) and 76 (74.5%), respectively. In comparison to BC alone, FISH increased the sensitivity from 36.1% to 50.7% (p = 0.076) while maintaining similar specificity (p = 0.311). Conclusions: Dual-modality tissue evaluation using BC + FISH showed an improving trend in sensitivity for the primary diagnosis of biliary strictures when compared with BC alone.
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19
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Monabbati S, Leo P, Bera K, Michael CW, Nezami BG, Harbhajanka A, Madabhushi A. Automated analysis of computerized morphological features of cell clusters associated with malignancy on bile duct brushing whole slide images. Cancer Med 2023; 12:6365-6378. [PMID: 36281473 PMCID: PMC10028025 DOI: 10.1002/cam4.5365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 06/01/2022] [Accepted: 08/07/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Bile duct brush specimens are difficult to interpret as they often present inflammatory and reactive backgrounds due to the local effects of stricture, atypical reactive changes, or previously installed stents, and often have low to intermediate cellularity. As a result, diagnosis of biliary adenocarcinomas is challenging and often results in large interobserver variability and low sensitivity OBJECTIVE: In this work, we used computational image analysis to evaluate the role of nuclear morphological and texture features of epithelial cell clusters to predict the presence of pancreatic and biliary tract adenocarcinoma on digitized brush cytology specimens. METHODS Whole slide images from 124 patients, either diagnosed as benign or malignant based on clinicopathological correlation, were collected and randomly split into training (ST , N = 58) and testing (Sv , N = 66) sets, with the exception of cases diagnosed as atypical on cytology were included in Sv . Nuclear boundaries on cell clusters extracted from each image were segmented via a watershed algorithm. A total of 536 quantitative morphometric features pertaining to nuclear shape, size, and aggregate cluster texture were extracted from within the cell clusters. The most predictive features from patients in ST were selected via rank-sum, t-test, and minimum redundancy maximum relevance (mRMR) schemes. The selected features were then used to train three machine-learning classifiers. RESULTS Malignant clusters tended to exhibit lower textural homogeneity within the nucleus, greater textural entropy around the nuclear membrane, and longer minor axis lengths. The sensitivity of cytology alone was 74% (without atypicals) and 46% (with atypicals). With machine diagnosis, the sensitivity improved to 68% from 46% when atypicals were included and treated as nonmalignant false negatives. The specificity of our model was 100% within the atypical category. CONCLUSION We achieved an area under the receiver operating characteristic curve (AUC) of 0.79 on Sv , which included atypical cytological diagnosis.
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Affiliation(s)
- Shayan Monabbati
- Department of Biomedical EngineeringCase Western Reserve UniversityClevelandOhioUSA
| | - Patrick Leo
- Department of Biomedical EngineeringCase Western Reserve UniversityClevelandOhioUSA
| | - Kaustav Bera
- Department of Biomedical EngineeringCase Western Reserve UniversityClevelandOhioUSA
| | - Claire W. Michael
- Department of PathologyCase Western Reserve University School of Medicine, University Hospitals Cleveland Medical CenterClevelandOhioUSA
| | - Behtash G. Nezami
- Department of PathologyCase Western Reserve University School of Medicine, University Hospitals Cleveland Medical CenterClevelandOhioUSA
| | - Aparna Harbhajanka
- Department of PathologyCase Western Reserve University School of Medicine, University Hospitals Cleveland Medical CenterClevelandOhioUSA
| | - Anant Madabhushi
- Department of Biomedical EngineeringCase Western Reserve UniversityClevelandOhioUSA
- Louis Stokes Cleveland Veterans Administration Medical CenterClevelandOhioUSA
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20
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Kamp EJCA, Dinjens WNM, van Velthuysen MLF, de Jonge PJF, Bruno MJ, Peppelenbosch MP, de Vries AC. Next-generation sequencing mutation analysis on biliary brush cytology for differentiation of benign and malignant strictures in primary sclerosing cholangitis. Gastrointest Endosc 2023; 97:456-465.e6. [PMID: 36252869 DOI: 10.1016/j.gie.2022.10.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 01/29/2023]
Abstract
BACKGROUND AND AIMS Differentiation of benign and malignant biliary tract strictures on brush material remains highly challenging but is essential for adequate clinical management of patients with primary sclerosing cholangitis (PSC). In this case-control study, biliary brush cytology samples from PSC patients with cholangiocarcinoma (PSC-CCA) were compared with samples from PSC patients without CCA (PSC-control subjects) using next-generation sequencing (NGS). METHODS Cells on archived slides were dissected for DNA extraction. NGS was performed using a gene panel containing 242 hotspots in 14 genes. Repeated brush samples from the same patient were analyzed to study the consistency of NGS results. In PSC-CCA cases that underwent surgical resection, molecular aberrations in brush samples were compared with NGS data from subsequent resection specimens. RESULTS Forty patients (20 PSC-CCA and 20 PSC-control subjects) were included. The gene panel detected 22 mutations in 15 of 20 PSC-CCA brush samples, including mutations in TP53 (8 brush samples), K-ras (5), G-nas (3), ERBB2 (1), APC (1), PIK3CA (1), and SMAD4 (1). One G-nas and 3 K-ras mutations were found in 3 of 20 PSC-control brush samples. The sensitivity of the NGS panel was 75% (95% confidence interval, 62%-80%) and specificity 85% (95% confidence interval, 64%-95%). Repeated brush samples showed identical mutations in 6 of 9 cases. Three repeated brush samples demonstrated additional mutations as compared with the first brush sample. In 6 of 7 patients, mutations in brush samples were identical to mutations in subsequent resection specimens. CONCLUSIONS NGS mutation analysis of PSC brush cytology detects oncogenic mutations with high sensitivity and specificity and seems to constitute a valuable adjunct to cytologic assessment of brush samples.
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Affiliation(s)
- Eline J C A Kamp
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Winand N M Dinjens
- Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | | | - Pieter Jan F de Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marco J Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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21
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Centeno BA. Cytopathology of Inflammatory Lesions of the Pancreatobiliary Tree. Arch Pathol Lab Med 2023; 147:267-282. [PMID: 36848529 DOI: 10.5858/arpa.2021-0595-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2022] [Indexed: 03/01/2023]
Abstract
CONTEXT.— A variety of inflammatory processes affect the pancreatobiliary tree. Some form mass lesions in the pancreas, mimicking pancreatic ductal adenocarcinoma, and others cause strictures in the bile ducts, mimicking cholangiocarcinoma. Acute pancreatitis, chronic pancreatitis, autoimmune pancreatitis, and paraduodenal groove pancreatitis have distinct cytopathologic features that, when correlated with clinical and imaging features, may lead to correct classification preoperatively. In biliary strictures sampled by endobiliary brushing, the uniform features are the variable presence of inflammation and reactive ductal atypia. A potential pitfall in the interpretation of pancreatobiliary fine-needle aspiration and duct brushing specimens is ductal atypia induced by the reactive process. Recognizing cytologic criteria that differentiate reactive from malignant epithelium, using ancillary testing, and correlating these features with clinical and imaging findings can lead to the correct preoperative diagnosis. OBJECTIVE.— To summarize the cytomorphologic features of inflammatory processes in the pancreas, describe the cytomorphology of atypia in pancreatobiliary specimens, and review ancillary studies applicable for the differential diagnosis of benign from malignant ductal processes for the purpose of best pathology practice. DATA SOURCES.— A PubMed review was performed. CONCLUSIONS.— Accurate preoperative diagnosis of benign and malignant processes in the pancreatobiliary tract can be achieved with application of diagnostic cytomorphologic criteria and correlation of ancillary studies with clinical and imaging findings.
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Affiliation(s)
- Barbara A Centeno
- From the Department of Pathology, Moffitt Cancer Center and Research Institution, Tampa, Florida
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22
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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: 5] [Impact Index Per Article: 2.5] [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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23
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Selvaggi SM. Diagnostic pitfalls and the value of fluorescence in situ hybridization as an adjunct to cytologic evaluation of bile duct brushings in patients with primary sclerosing cholangitis. Diagn Cytopathol 2023; 51:117-122. [PMID: 36181472 PMCID: PMC10092285 DOI: 10.1002/dc.25059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 01/04/2023]
Abstract
BACKGROUND Primary sclerosing cholangitis (PSC) can present diagnostic difficulties on bile duct brushings as cytologic features mimicking adenocarcinoma may exist. This study evaluates the role of fluorescence in-situ hybridization (FISH) as an adjunct to cytologic evaluation. METHODS From January 1, 2020, through December 31, 2021, 308 bile duct brushings were processed of which 34 (11%) were malignant, 25 (8%) were suspicious, 36 (12%) were atypical, 204 (66%) were negative and 10 (3%) were nondiagnostic. Follow-up biopsies/resections were performed in the 95 cases with diagnostic cytology (atypical/suspicious/malignant) of which 12 (13%) showed primary sclerosing cholangitis and form the basis of this study. Cytologic, histologic and FISH findings are presented and discussed. RESULTS Of the 12 bile duct brushings 4 (34%) were positive/suspicious for adenocarcinoma and 8 (66%) showed atypical epithelial cells. FISH was positive in 2/4 positive/suspicious brushings and negative in the remaining 2 brushings. Histologic findings confirmed the FISH results. The cytologic features of the 2 false positive cases overlapped those of adenocarcinoma. Two of the 8 bile duct brushings with atypical epithelial cells were positive/suspicious for adenocarcinoma on FISH analysis; findings confirmed on histologic follow-up. The remaining 8 patients underwent surveillance for the development of adenocarcinoma with repeat bile duct brushings, FISH analysis and biopsies, each of which has been negative to date. CONCLUSION FISH, as an adjunct to the cytologic evaluation of bile duct brushings from patients with PSC, plays a role in improving diagnostic accuracy and serves as a surveillance tool for the potential development of adenocarcinoma.
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Affiliation(s)
- Suzanne M Selvaggi
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
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Wadhwa V, Patel N, Grover D, Ali FS, Thosani N. Interventional gastroenterology in oncology. CA Cancer J Clin 2022; 73:286-319. [PMID: 36495087 DOI: 10.3322/caac.21766] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 10/12/2022] [Accepted: 10/17/2022] [Indexed: 12/14/2022] Open
Abstract
Cancer is one of the foremost health problems worldwide and is among the leading causes of death in the United States. Gastrointestinal tract cancers account for almost one third of the cancer-related mortality globally, making it one of the deadliest groups of cancers. Early diagnosis and prompt management are key to preventing cancer-related morbidity and mortality. With advancements in technology and endoscopic techniques, endoscopy has become the core in diagnosis and management of gastrointestinal tract cancers. In this extensive review, the authors discuss the role endoscopy plays in early detection, diagnosis, and management of esophageal, gastric, colorectal, pancreatic, ampullary, biliary tract, and small intestinal cancers.
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Affiliation(s)
- Vaibhav Wadhwa
- Center for Interventional Gastroenterology at UTHealth (iGUT), Division of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA
| | - Nicole Patel
- Center for Interventional Gastroenterology at UTHealth (iGUT), Division of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA
| | - Dheera Grover
- Center for Interventional Gastroenterology at UTHealth (iGUT), Division of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA
| | - Faisal S Ali
- Center for Interventional Gastroenterology at UTHealth (iGUT), Division of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA
| | - Nirav Thosani
- Center for Interventional Gastroenterology at UTHealth (iGUT), Division of Gastroenterology Hepatology and Nutrition, University of Texas Health Science Center, McGovern Medical School, Houston, Texas, USA
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25
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Endoscopic Evaluation and Management of Cholangiocarcinoma. Gastroenterol Clin North Am 2022; 51:519-535. [PMID: 36153108 DOI: 10.1016/j.gtc.2022.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Cholangiocarcinoma is a rare malignancy of the biliary tract with a relatively poor prognosis. As a gastroenterologist, our main role is to differentiate between benign and malignant biliary disease, help achieve a diagnosis, and palliate jaundice related to biliary obstruction. This article focuses on summarizing the various tools currently available for endoscopic evaluation and management of cholangiocarcinoma.
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26
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Hilburn CF, Pitman MB. The Cytomorphologic and Molecular Assessment of Bile Duct Brushing Specimens. Surg Pathol Clin 2022; 15:469-478. [PMID: 36049829 DOI: 10.1016/j.path.2022.05.002] [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] [Indexed: 06/15/2023]
Abstract
Biliary duct brushing cytology is the standard of care for the assessment of bile duct strictures but suffers from low sensitivity for the detection of a high-risk stricture. Pathologic diagnosis of strictures is optimized by integration of cytomorphology and molecular analysis with fluorescence in situ hybridization or next-generation sequencing. Bile duct cancers are genetically heterogeneous, requiring analysis of multiple gene panels to increase sensitivity. Using molecular analysis as an ancillary test for bile duct brushing samples aids in the identification of mutations that support the diagnosis of a high-risk stricture as well as the identification of actionable mutations for targeted therapies currently in clinical trials for the treatment of patients with bile duct cancer.
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Affiliation(s)
- Caroline F Hilburn
- Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, USA
| | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA; Harvard Medical School, Boston, USA.
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Wang J, Xia M, Jin Y, Zheng H, Shen Z, Dai W, Li X, Kang M, Wan R, Lu L, Hu B, Wan X, Cai X. More Endoscopy-Based Brushing Passes Improve the Detection of Malignant Biliary Strictures: A Multicenter Randomized Controlled Trial. Am J Gastroenterol 2022; 117:733-739. [PMID: 35108222 DOI: 10.14309/ajg.0000000000001666] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 01/20/2022] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Endoscopic biliary brushing is the most common method used for sampling in patients with malignant biliary strictures (MBSs); however, its sensitivity is relatively low. There is still no consensus on endoscopy-based biliary brushing, although brushing 10 times in 1 specimen is routinely performed. This study was designed to compare the sensitivity of brush cytology for 10, 20, or 30 brushing times of a pass in 1 specimen in patients with MBSs. METHODS In this multicenter, prospective, randomized controlled study, patients who underwent endoscopic retrograde cholangiopancreatography for suspected MBSs were enrolled. Patients were randomly assigned to receive 10, 20, and 30 brushing times of a pass. The primary outcome was to compare the sensitivity of brush cytology among the 3 groups. Patients were prospectively followed up for 6 months after endoscopic brushing for malignancy diagnosis. RESULTS A total of 443 patients were enrolled for intention-to-treat analysis (147, 148, and 148 patients in the 10-times, 20-times, and 30-time groups, respectively). The 3 groups were similar in baseline characteristics. The sensitivity of brush cytology was 38%, 47%, and 57% in the 10-times, 20-times, and 30-times groups, respectively, and the 30-times group showed significantly higher sensitivity than the 10-times group (P = 0.001). The multivariate analysis revealed that stricture length and the number of brushing passes were significant factors for the detection of biliary malignancy. No significant differences were observed in procedure-related complications among the 3 groups. DISCUSSION Brushing 30 times could increase the diagnostic sensitivity without increasing complications and seems to be preferred for the endoscopic sampling and diagnosis of MBSs (chictr.org.cn, identifier: ChiCTR1800015978).
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Affiliation(s)
- Junjun Wang
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingxing Xia
- Department of Endoscopy, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
| | - Yubiao Jin
- Department of Pathology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Haiming Zheng
- Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhenyang Shen
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiming Dai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaoman Li
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mei Kang
- Clinical Research Center, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lungen Lu
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bing Hu
- Department of Endoscopy, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China
| | - Xinjian Wan
- Department of Gastroenterology, Shanghai Sixth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaobo Cai
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Wu B, Liu YJ, Rogers J, Liu YZ, Rabinovitch PS, Small T, Swanson PE, Yeh MM. Role of DNA Flow Cytometry in the Diagnosis of Malignancy in Bile Duct Biopsies Using Paraffin-Embedded Tissue. Am J Clin Pathol 2022; 157:417-425. [PMID: 34542607 DOI: 10.1093/ajcp/aqab130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 07/02/2021] [Indexed: 01/17/2023] Open
Abstract
OBJECTIVES Histopathologic evaluation of bile biopsies for biliary strictures is frequently challenging and is affected by interobserver disagreement. Reliable ancillary tests that can help differentiate benign from malignant are not available. This study aimed to evaluate whether DNA content abnormalities detected by flow cytometry on formalin-fixed, paraffin-embedded (FFPE) tissue can help differentiate benign/reactive, dysplastic from malignant cell populations in bile duct biopsies. METHODS We performed DNA flow cytometry on 30 FFPE bile duct biopsies in 5 well-defined diagnostic categories: (1) negative for dysplasia (NED), (2) low-grade dysplasia (LGD), (3) high-grade dysplasia (HGD), (4) carcinoma (CA), and (5) indefinite for dysplasia (IND). RESULTS Abnormal DNA content was detected in 0 NED, 5 LGD (62.5%), 2 HGD (33.3%), 3 CA (60%), and 4 IND (80%) samples. As a diagnostic marker, the estimated sensitivity, specificity, positive predictive value, and negative predictive value were 63%, 100%, 100%, and 50%, respectively, for diagnosing HGD or CA. CONCLUSIONS DNA flow cytometry analysis is a useful ancillary test for the interpretation of bile duct biopsies. DNA content abnormalities, when correlated with histologic findings, will not only help confirm the morphologic impression but also identify patients who are at a higher risk of developing malignancy.
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Affiliation(s)
- Bicong Wu
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
| | - Yong-Jun Liu
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Jessica Rogers
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | | | - Thomas Small
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
| | - Paul E Swanson
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
- Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Matthew M Yeh
- Departments of Laboratory Medicine and Pathology, Seattle, WA, USA
- Medicine, University of Washington School of Medicine, Seattle, WA, USA
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Kankeu Fonkoua LA, Serrano Uson Junior PL, Mody K, Mahipal A, Borad MJ, Roberts LR. Novel and emerging targets for cholangiocarcinoma progression: therapeutic implications. Expert Opin Ther Targets 2022; 26:79-92. [PMID: 35034558 DOI: 10.1080/14728222.2022.2029412] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) is a heterogeneous group of aggressive biliary malignancies. While surgery and liver transplantation are the only potentially curative modalities for early-stage disease, limited options are available for most patients with incurable-stage disease. Survival outcomes remain dismal. Recent molecular profiling efforts have led to improved understanding of the genomic landscape of CCA and to the identification of subgroups with distinct diagnostic, prognostic, and therapeutic implications. AREAS COVERED : We provide an updated review and future perspectives on features of cholangiocarcinogenesis that can be translated into therapeutic biomarkers and targets. We highlight the critical studies that have established current systemic chemotherapy and targeted therapeutics, while elaborating on novel targeted and immunotherapeutic approaches in development. Relevant literature and clinical studies were identified by searching PubMed and www.ClinicalTrials.gov. EXPERT OPINION : While therapies targeting the various molecular subgroups of CCA are rapidly emerging and changing treatment paradigms, their success has been limited by the genetic heterogeneity of CCA and the plasticity of the targets. Novel strategies aiming to combine immunotherapy, chemotherapy, and molecularly-targeted therapeutics will be required to offer durable clinical benefit and maximize survival.
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Affiliation(s)
| | | | - Kabir Mody
- Rochester, MN, and Oncology in Jacksonville, FL, Mayo Clinic, USA
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30
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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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Jang SI, Nahm JH, Kwon NH, Jeong S, Lee TH, Cho JH, Kwon CI, Kim DU, Kim JM, Cho HD, Lee HS, Kim S, Lee DK. Clinical utility of methionyl-tRNA synthetase 1 immunostaining in cytologic brushings of indeterminate biliary strictures: a multicenter prospective study. Gastrointest Endosc 2021; 94:733-741.e4. [PMID: 33965384 DOI: 10.1016/j.gie.2021.04.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 04/27/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Endobiliary brushings are routinely used in the diagnosis, treatment, and prognostication of biliary strictures. However, standard Papanicolaou (Pap) staining has a low sensitivity in this setting, and the accuracy of brush cytology has not been established for indeterminate strictures. We therefore evaluated the diagnostic merit of methionyl-transfer RNA synthetase 1 (MARS1) immunofluorescence (IF) staining in such cytologic specimens. METHODS During ERCP, endobiliary brushings were obtained from patients with extrahepatic biliary strictures prospectively enrolled at 6 tertiary hospitals. Using liquid-based cytologic preparations of these samples, we performed Pap and MARS1 IF staining. RESULTS In total, 240 patients were eligible; of these, we compared the Pap and MARS1 IF staining results of 218 (malignant, 157; benign, 61). By conventional Pap staining, the diagnoses were distributed as follows: malignant, 55; suspicious of malignancy, 60; atypical, 45; negative for malignancy, 58. MARS1 IF staining was strongly positive in malignant biliary stricture but not so in specimens negative for malignancy. The diagnostic parameters (sensitivity, specificity, positive predictive value, negative predictive value, and accuracy) of the MARS1 IF (93.6%, 96.7%, 98.7%, 85.5%, and 94.5%, respectively) and conventional Pap (73.2%, 100%, 100%, 59.2%, and 80.7%, respectively) staining methods differed significantly (P < .0001). CONCLUSIONS The high sensitivity and accuracy of MARS1 IF staining enabled the detection of malignancy in patients with biliary strictures. Further prospective studies are needed to validate our findings. (Clinical trial registration number: NCT03708445.).
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Affiliation(s)
- Sung Ill Jang
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Ji Hae Nahm
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Nam Hoon Kwon
- Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy, Yonsei University, Incheon, Korea
| | - Seok Jeong
- Department of Internal Medicine, Inha University School of Medicine, Incheon, South Korea
| | - Tae Hoon Lee
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan, South Korea
| | - Jae Hee Cho
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Chang-Il Kwon
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Dong Uk Kim
- Department of Internal Medicine, Biomedical Research Institute, Pusan National University School of Medicine, Pusan, South Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, South Korea
| | - Hyun Deuk Cho
- Department of Pathology, Soonchunhyang University College of Medicine, Cheonan Hospital, Cheonan, South Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Sunghoon Kim
- Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea; Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Dong Ki Lee
- Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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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: 2] [Impact Index Per Article: 0.5] [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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Sanders DJ, Bomman S, Krishnamoorthi R, Kozarek RA. Endoscopic retrograde cholangiopancreatography: Current practice and future research. World J Gastrointest Endosc 2021; 13:260-274. [PMID: 34512875 PMCID: PMC8394185 DOI: 10.4253/wjge.v13.i8.260] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/18/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
Endoscopic retrograde cholangiopancreatography (ERCP) has evolved from a primarily diagnostic to therapeutic procedure in hepatobiliary and pancreatic disease. Most commonly, ERCPs are performed for choledocholithiasis with or without cholangitis, but improvements in technology and technique have allowed for management of pancreatic duct stones, benign and malignant strictures, and bile and pancreatic leaks. As an example of necessity driving innovation, the new disposable duodenoscopes have been introduced into practice. With the advantage of eliminating transmissible infections, they represent a paradigm shift in quality improvement within ERCP. With procedures becoming more complicated, the necessity for anesthesia involvement and safety of propofol use and general anesthesia has become better defined. The improvements in endoscopic ultrasound (EUS) have allowed for direct bile duct access and EUS facilitated bile duct access for ERCP. In patients with surgically altered anatomy, selective cannulation can be performed with overtube-assisted enteroscopy, laparoscopic surgery assistance, or the EUS-directed transgastric ERCP. Cholangioscopy and pancreatoscopy use has become ubiquitous with defined indications for large bile duct stones, indeterminate strictures, and hepatobiliary and pancreatic neoplasia. This review summarizes the recent advances in infection prevention, quality improvement, pancreaticobiliary access, and management of hepatobiliary and pancreatic diseases. Where appropriate, future research directions are included in each section.
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Affiliation(s)
- David J Sanders
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, United States
| | - Shivanand Bomman
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, United States
| | - Rajesh Krishnamoorthi
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, United States
| | - Richard A Kozarek
- Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA 98101, United States
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Yang JD, Ghoz H, Aboelsoud MM, Taylor WR, Yab TC, Berger CK, Cao X, Foote PH, Giama NH, Barr Fritcher EG, Mahoney DW, Moser CD, Smyrk TC, Kipp BR, Gores GJ, Roberts LR, Kisiel JB. DNA Methylation Markers for Detection of Cholangiocarcinoma: Discovery, Validation, and Clinical Testing in Biliary Brushings and Plasma. Hepatol Commun 2021; 5:1448-1459. [PMID: 34430788 PMCID: PMC8369938 DOI: 10.1002/hep4.1730] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 03/03/2021] [Accepted: 03/22/2021] [Indexed: 02/04/2023] Open
Abstract
Cholangiocarcinoma (CCA) has poor prognosis due to late-stage, symptomatic presentation. Altered DNA methylation markers may improve diagnosis of CCA. Reduced-representation bisulfite sequencing was performed on DNA extracted from frozen CCA tissues and matched to adjacent benign biliary epithelia or liver parenchyma. Methylated DNA markers (MDMs) identified from sequenced differentially methylated regions were selected for biological validation on DNA from independent formalin-fixed, paraffin-embedded CCA tumors and adjacent hepatobiliary control tissues using methylation-specific polymerase chain reaction. Selected MDMs were then blindly assayed on DNA extracted from independent archival biliary brushing specimens, including 12 perihilar cholangiocarcinoma, 4 distal cholangiocarcinoma cases, and 18 controls. Next, MDMs were blindly assayed on plasma DNA from patients with extrahepatic CCA (eCCA), including 54 perihilar CCA and 5 distal CCA cases and 95 healthy and 22 primary sclerosing cholangitis controls, balanced for age and sex. From more than 3,600 MDMs discovered in frozen tissues, 39 were tested in independent samples. In the clinical pilot of 16 MDMs on cytology brushings, methylated EMX1 (empty spiracles homeobox 1) had an area under the curve (AUC) of 0.98 (95% confidence interval [CI], 0.95-1.0). In the clinical pilot on plasma, a cross-validated recursive partitioning tree prediction model from nine MDMs was accurate for de novo eCCA (AUC, 0.88 [0.81-0.95]) but not for primary sclerosing cholangitis-associated eCCA (AUC, 0.54 [0.35-0.73]). Conclusion: Next-generation DNA sequencing yielded highly discriminant methylation markers for CCA. Confirmation of these findings in independent tissues, cytology brushings, and plasma supports further development of DNA methylation to augment diagnosis of CCA.
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Affiliation(s)
- Ju Dong Yang
- Division of Gastroenterology and HepatologyCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - Hassan Ghoz
- Division of Gastroenterology and HepatologyMayo ClinicJacksonvilleFLUSA
| | | | - William R. Taylor
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Tracy C. Yab
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Calise K. Berger
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Xiaoming Cao
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Patrick H. Foote
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Nasra H. Giama
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | | | - Douglas W. Mahoney
- Department of Biomedical Statistics and InformaticsMayo ClinicRochesterMNUSA
| | - Catherine D. Moser
- Department of Pathology and Laboratory MedicineChildren’s Healthcare of AtlantaAtlantaGAUSA
| | | | | | - Gregory J. Gores
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - Lewis R. Roberts
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
| | - John B. Kisiel
- Division of Gastroenterology and HepatologyMayo ClinicRochesterMNUSA
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Huynh R, Owers C, Pinto C, Nguyen TM, Kwok T. Endoscopic Evaluation of Biliary Strictures: Current and Emerging Techniques. Clin Endosc 2021; 54:825-832. [PMID: 34038998 PMCID: PMC8652159 DOI: 10.5946/ce.2021.048] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/17/2021] [Indexed: 11/25/2022] Open
Abstract
The diagnosis of biliary strictures in clinical practice can be challenging. Discriminating between benign and malignant biliary strictures is important to prevent the morbidity and mortality associated with incorrect diagnoses. Missing a malignant biliary stricture may delay surgery, resulting in poor prognostic outcomes. Conversely, it has been demonstrated that approximately 20% of patients who undergo surgery for suspected biliary malignancies have a benign etiology on histopathology. Traditional tissue sampling using endoscopic retrograde cholangiography does not always produce a definitive diagnosis, with a considerable proportion of cases remaining as indeterminate biliary strictures. Recent advances in endoscopic techniques have the potential to improve the diagnostic and prognostic accuracy of biliary strictures.
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Affiliation(s)
- Roy Huynh
- Department of Upper Gastrointestinal Surgery, Concord Repatriation General Hospital, Sydney, NSW, Australia.,Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Corinne Owers
- Department of Upper Gastrointestinal Surgery, Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - Christopher Pinto
- Department of Upper Gastrointestinal Surgery, Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - Thuy-My Nguyen
- Department of Upper Gastrointestinal Surgery, Concord Repatriation General Hospital, Sydney, NSW, Australia
| | - Titus Kwok
- Department of Upper Gastrointestinal Surgery, Concord Repatriation General Hospital, Sydney, NSW, Australia
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36
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Kamp EJCA, Dinjens WNM, Doukas M, Bruno MJ, de Jonge PJF, Peppelenbosch MP, de Vries AC. Optimal tissue sampling during ERCP and emerging molecular techniques for the differentiation of benign and malignant biliary strictures. Therap Adv Gastroenterol 2021; 14:17562848211002023. [PMID: 33948111 PMCID: PMC8053835 DOI: 10.1177/17562848211002023] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 02/15/2021] [Indexed: 02/04/2023] Open
Abstract
Patients with cholangiocarcinoma have poor survival since the majority of patients are diagnosed at a stage precluding surgical resection, due to locally irresectable tumors and/or metastases. Optimization of diagnostic strategies, with a principal role for tissue diagnosis, is essential to detect cancers at an earlier stage amenable to curative treatment. Current barriers for a tissue diagnosis include both insufficient tissue sampling and a difficult cyto- or histopathological assessment. During endoscopic retrograde cholangiopancreatography, optimal brush sampling includes obtaining more than one brush within an individual patient to increase its diagnostic value. Currently, no significant increase of the diagnostic accuracy for the new cytology brush devices aiming to enhance the cellularity of brushings versus standard biliary brush devices has been demonstrated. Peroral cholangioscopy with bile duct biopsies appears to be a valuable tool in the diagnostic work-up of indeterminate biliary strictures, and may overcome current technical difficulties of fluoroscopic-guided biopsies. Over the past years, molecular techniques to detect chromosomal instability, mutations and methylation profiling of tumors have revolutionized, and implementation of these techniques on biliary tissue during diagnostic work-up of biliary strictures may be awaited in the near future. Fluorescence in situ hybridization has already been implemented in routine diagnostic evaluation of biliary strictures in several centers. Next-generation sequencing is promising for standard diagnostic care in biliary strictures, and recent studies have shown adequate detection of prevalent genomic alterations in KRAS, TP53, CDKN2A, SMAD4, PIK3CA, and GNAS on biliary brush material. Detection of DNA methylation of tumor suppressor genes and microRNAs may evolve over the coming years to a valuable diagnostic tool for cholangiocarcinoma. This review summarizes optimal strategies for biliary tissue sampling during endoscopic retrograde cholangiopancreatography and focuses on the evolving molecular techniques on biliary tissue to improve the differentiation of benign and malignant biliary strictures.
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Affiliation(s)
- Eline J. C. A. Kamp
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Winand N. M. Dinjens
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Michail Doukas
- Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Marco J. Bruno
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Pieter Jan F. de Jonge
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Maikel P. Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Annemarie C. de Vries
- Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, Room Na-609, Rotterdam, 3015 GD, The Netherlands
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Fong ZV, Brownlee SA, Qadan M, Tanabe KK. The Clinical Management of Cholangiocarcinoma in the United States and Europe: A Comprehensive and Evidence-Based Comparison of Guidelines. Ann Surg Oncol 2021; 28:2660-2674. [PMID: 33646431 DOI: 10.1245/s10434-021-09671-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/18/2021] [Indexed: 12/16/2022]
Abstract
BACKGROUND The incidence of cholangiocarcinoma has doubled over the last 15 years with a similar rise in mortality, which provides the impetus for standardization of evidence-based care through the establishment of guidelines. METHODS We compared available guidelines on the clinical management of cholangiocarcinoma in the United States and Europe, which included the National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO), British Society of Gastroenterology (BSG) and the International Liver Cancer Association (ILCA) guidelines. RESULTS There is discordance in the recommendation for biopsy in patients with potentially resectable cholangiocarcinoma and in the recommendation for use of fluorodeoxyglucose positron emission tomography scans. Similarly, the recommendation for preoperative biliary drainage for extrahepatic and perihilar cholangiocarcinoma in the setting of jaundice is inconsistent across all four guidelines. The BILCAP (capecitabine) and ABC-02 trials (gemcitabine with cisplatin) have provided the strongest evidence for systemic therapy in the adjuvant and palliative settings, respectively, but all guidelines have refrained from setting them as standard of care, given heterogeneity in the study cohorts and ABC-02's negative intention-to-treat results. CONCLUSIONS Future progress in enhancing survivorship of patients with cholangiocarcinoma would likely entail improvements in diagnostic biomarkers and novel systemic therapies. Based on recent results from studies of targeted therapy, future iterations of the guidelines will likely incorporate molecular profiling.
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Affiliation(s)
- Zhi Ven Fong
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Sarah A Brownlee
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Motaz Qadan
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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Yang X, Guo JF, Sun LQ, Hu JH, Shi YJ, Zhang JY, Jin ZD. Assessment of different modalities for repeated tissue acquisition in diagnosing malignant biliary strictures: A two-center retrospective study. J Dig Dis 2021; 22:102-107. [PMID: 33247545 DOI: 10.1111/1751-2980.12964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 11/09/2020] [Accepted: 11/25/2020] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Various modalities are applied for pathological diagnosis of malignant biliary strictures (MBS), including brush cytology (BC), forceps biopsy (FB) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). We aimed to assess the value of these modalities in a repeated tissue acquisition process for biliary strictures with initially inconclusive pathological outcomes. METHODS Patients who were suspected of having MBS and underwent a BC in two large teaching hospitals were retrospectively included. The sensitivity, specificity, positive and negative predictive values, and accuracy of the initial and repeated BC, FB and EUS-FNA were analyzed. Their performances were compared to determine which modality was superior in repeated tissue acquisition. RESULTS In total, 476 patients were included. The sensitivity, specificity and accuracy in diagnosing MBS for the initial BC were 30.3%, 100% and 55.0%, respectively. Altogether 39, 27 and 44 patients underwent a repeat BC, FB and EUS-FNA, respectively. The sensitivity for repeated BC, FB and EUS-FNA was 41.2%, 61.1% and 44.4%, respectively, whereas their specificity all reached 100%. When comparing diagnostic accuracy, none of the modalities was superior (74.4% vs 74.1% vs 54.5%, P = 0.173). In the repeated process, one patient who underwent BC and two underwent FB developed mild pancreatitis. CONCLUSIONS Repeated tissue acquisition achieves a conclusive diagnosis of MBS in nearly half patients who have an initially inconclusive cytological diagnosis. None of the tissue acquisition methods is significantly superior in the repeated process.
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Affiliation(s)
- Xia Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Jie Fang Guo
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Li Qi Sun
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
| | - Jin Hua Hu
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Yong Jun Shi
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Jun Yong Zhang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China
| | - Zhen Dong Jin
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, China
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Helmy A, Saad Eldien HM, Seifeldein GS, Abu-Elfatth AM, Mohammed AA. Digital Image Analysis has an Additive Beneficial Role to Conventional Cytology in Diagnosing the Nature of Biliary Ducts Stricture. J Clin Exp Hepatol 2021; 11:209-218. [PMID: 33746446 PMCID: PMC7953004 DOI: 10.1016/j.jceh.2020.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND & AIM Conventional cytological evaluation (CCE) fails to identify nature indeterminate biliary duct stricture (IBDS) in many cases. Digital image analysis (DIA) has the ability to identify and analyze the DNA content of cells. This study assesses the role of DIA in recognizing the nature of IBDS compared to CCE. METHODS A prospective observational study was conducted at the Al-Rajhi University Hospital. Fifty patients with IBDS, based on abdominal imaging, were subjected to endoscopic retrograde cholangiopancreatography (ERCP) and brush sampling. These samples were evaluated with CCE and DIA. Follow-up for at least 9 months and cost-analysis had also been done. RESULTS Based on the final diagnosis, 32 (64.0%) patients had malignant stricture, and 39 (78.0%) had distal stricture. DIA had 84.40% (95% CI; 67.20-94.70) sensitivity and 94.40% (95% CI; 72.70-99.90) specificity in identifying nature of IBDS, whereas CCE had 19.0% (95% CI; 7.20-36.40) sensitivity and 89.0% (95% CI; 65.30-98.60) specificity. Combination of both modalities had 84.40% (95% CI; 67.20-94.70) sensitivity and 83.30% (95% CI; 58.60-96.40) specificity in identification nature of IBDS. Based on CCE alone, only 6/32 (18.80%) of malignant stricture were diagnosed, and 26/32 (81.20%) were missed. However, DIA alone was able to diagnose 27/32 (84.40%) of malignant stricture, and only 5 cases were missed. Both procedures had detection rate of malignant stricture as DIA alone. Benign stricture was correctly diagnosed in 16/18 (88.80%), 17/18 (94.40%), and 15/18 (83.30%) using CCE alone, DIA alone, and both procedures together, respectively. Cost per detection additional one malignant stricture using DIA required 99.4$. CONCLUSION DIA is substantially better than CCE in diagnosing the nature of IBDS but at an increase cost and thus suggests its application in a wider role in clinical practice. CLINICAL TRIAL NUMBER NCT04112030.
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Affiliation(s)
- Ahmed Helmy
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Heba Mohamed Saad Eldien
- Department of Histology and Cell Biology, Faculty of Medicine, Assiut University, Assiut, Egypt,Tissue Culture and Molecular Biology Center, Assiut University, Egypt,Department of Anatomy College of Medicine, Jouf University, KSA
| | - Gehan Sayed Seifeldein
- Department of Diagnostic and Interventional Radiology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Ahmed Mohammed Abu-Elfatth
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt,Address for correspondence: Ahmed Mohammed Abu-Elfatth, Departments of Tropical Medicine and Gastroenterology, 7th Floor, Al-Rajhi Liver University Hospital & Faculty of Medicine, Assiut University, Assiut 71111, Egypt.
| | - Adnan Ahmed Mohammed
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
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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: 8] [Impact Index Per Article: 1.6] [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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Liu YJ, Rogers J, Liu YZ, Gui X, Jalikis F, Koch L, Swanson PE, Truong CD, Yeh MM. Interobserver agreement in pathologic evaluation of bile duct biopsies. Hum Pathol 2020; 107:29-38. [PMID: 33129823 DOI: 10.1016/j.humpath.2020.10.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Revised: 10/07/2020] [Accepted: 10/12/2020] [Indexed: 12/20/2022]
Abstract
Intraductal biopsy is commonly used for preoperative evaluation of the etiology of biliary strictures. Interpretation of intraductal biopsies is frequently challenging. The diagnosis often suffers from interobserver disagreement, which has not been studied in the literature. We sought to assess interobserver concordance in the interpretation of intraductal biopsies. Eighty-five biopsies were retrieved, falling into five diagnostic categories: negative for dysplasia (NED), indefinite for dysplasia (IND), low-grade dysplasia (LGD), high-grade dysplasia (HGD), and carcinoma (CA). Eight gastrointestinal pathologists blindly reviewed all the slides. Agreement among pathologists was analyzed using Fleiss κ and weighted concordance coefficient S∗. A face-to-face consensus/training session was held to discuss the classification criteria, followed by a second round review. The overall interobserver agreement was fair in the first round review (κ = 0.39; S∗ = 0.56) and improved to moderate in the second round review (κ = 0.48; S∗ = 0.69). The agreement before and after consensus meeting was substantial to nearly perfect for CA (κ = 0.65, S∗ = 0.83; and κ = 0.80, S∗ = 0.91), fair for HGD (κ = 0.28, S∗ = 0.69; and κ = 0.40, S∗ = 0.63), and moderate for NED (κ = 0.47, S∗ = 0.50; and κ = 0.47, S∗ = 0.53). Agreement improved from fair to moderate for LGD (κ = 0.36, S∗ = 0.61; and κ = 0.49, S∗ = 0.71) and slight to fair for IND (κ = 0.16, S∗ = 0.51; and κ = 0.33, S∗ = 0.50). Compared with Hollande's fixed specimens, the agreement was higher in almost all diagnostic categories in formalin-fixed biopsies. Overall, interobserver concordance was improved after a consensus/training session. Interobserver reproducibility was high at the end of the diagnostic spectrum (CA) but fair to moderate for other diagnostic categories.
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Affiliation(s)
- Yong-Jun Liu
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, WI, 53705, USA
| | - Jessica Rogers
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, LA, 70112, USA
| | - Xianyong Gui
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Florencia Jalikis
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Lisa Koch
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Paul E Swanson
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Camtu D Truong
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA.
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Azad AI, Rosen CB, Taner T, Heimbach JK, Gores GJ. Selected Patients with Unresectable Perihilar Cholangiocarcinoma (pCCA) Derive Long-Term Benefit from Liver Transplantation. Cancers (Basel) 2020; 12:E3157. [PMID: 33121179 PMCID: PMC7693604 DOI: 10.3390/cancers12113157] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 10/21/2020] [Indexed: 02/07/2023] Open
Abstract
Selected patients with unresectable perihilar cholangiocarcinoma (pCCA) derive long-term benefits from liver transplantation. Between 1993-2019, our group at Mayo Clinic performed 237 transplants for pCCA. With this experience, we note that two distinct patient populations comprise this group of pCCA patients: those with underlying primary sclerosing cholangitis (PSC) and those without identifiable risk factors termed sporadic or de novo pCCA. Long-term survival after transplant is better in PSC patients (74% five-year survival) than in those with de novo pCCA (58% five-year survival). Herein, we review the likely clinical factors contributing to the divergence in outcomes for these two patient populations. We also offer our insights on how further advances may improve patient selection and survival, focusing on the de novo pCCA patient population.
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Affiliation(s)
- Adiba I. Azad
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA;
| | - Charles B. Rosen
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN 55905, USA; (C.B.R.); (T.T.); (J.K.H.)
| | - Timucin Taner
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN 55905, USA; (C.B.R.); (T.T.); (J.K.H.)
| | - Julie K. Heimbach
- Division of Transplantation Surgery, Mayo Clinic, Rochester, MN 55905, USA; (C.B.R.); (T.T.); (J.K.H.)
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, USA;
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Harbhajanka A, Michael CW, Janaki N, Gokozan HN, Wasman J, Bomeisl P, Yoest J, Sadri N. Tiny but mighty: use of next generation sequencing on discarded cytocentrifuged bile duct brushing specimens to increase sensitivity of cytological diagnosis. Mod Pathol 2020; 33:2019-2025. [PMID: 32457409 DOI: 10.1038/s41379-020-0577-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/15/2020] [Accepted: 05/15/2020] [Indexed: 12/12/2022]
Abstract
Bile duct brushing (BDB) is used to evaluate pancreatobiliary lesions as it widely samples lesions with a low complication rate. Cytological evaluation of BDB is a specific but insensitive test. There is limited literature on the use of post-cytocentrifuged (PCC) samples, which are usually discarded, for next-generation sequencing (NGS) as an adjunct to cytological diagnosis of BDB. In this study we investigate whether molecular analysis by NGS of PCC specimens improves the sensitivity of diagnosis. PCC samples from 100 consecutive BDB specimens spanning 93 unique patients were retained. DNA was extracted and mutational analysis was performed agnostic of morphologic or clinical findings. Each BDB specimen was characterized as negative, atypical or positive based on morphological analysis by trained cytopathologists. Performance characteristics for mutational profiling and morphological analysis were calculated on the basis of clinicopathologic follow-up. There was sufficient clinicopathologic follow-up to classify 94 of 100 cases as either malignant (n = 43) or benign (n = 51). Based on morphologic analysis of cytology, these 94 cases were classified as either benign (n = 55), atypical (n = 18), or as at least suspicious or positive for malignancy (n = 21). Morphologic analysis of cytology showed a sensitivity of 49% and a specificity of 100% if atypical cases were considered negative. NGS revealed oncogenic alterations in 40/43 (93%) of malignant cases based on clinicopathologic follow-up. The most common alterations were in KRAS and TP53, observed in 77% and 49% of malignant cases respectively. No alterations were observed in the 51 benign cases classified based on clinicopathologic follow-up. Supplementing cytomorphologic analysis with molecular profiling of PCC by targeted NGS analysis increased the sensitivity to 93% and maintained specificity at 100%. This study provides evidence for the utility of NGS molecular profiling of PCC specimens to increase the sensitivity of BDB cytology samples, although studies with larger cohorts are needed to verify these findings.
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Affiliation(s)
- Aparna Harbhajanka
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Claire W Michael
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Nafiseh Janaki
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School Boston, Boston, MA, USA
| | - Hamza N Gokozan
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jay Wasman
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Philip Bomeisl
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Jennifer Yoest
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Navid Sadri
- Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
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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: 52] [Impact Index Per Article: 10.4] [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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45
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Wang L, Yang Z, Wu Z, He J, Xu S, Li D, Zou Q, Yuan Y. Increased expression of cystathionine beta-synthase and chemokine ligand 21 is closely associated with poor prognosis in extrahepatic cholangiocarcinoma. Medicine (Baltimore) 2020; 99:e22255. [PMID: 32957374 PMCID: PMC7505348 DOI: 10.1097/md.0000000000022255] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
The expression of Cystathionine beta-synthase (CBS) and Chemokine ligand 21 (CCL21) is associated with the tumorigenesis and progression of a variety of tumors, but whether alterations in their expression levels correlates with the carcinogenesis and progression of EHCC is still unknown. This study investigated the clinicopathological significance of CBS and CCL21 expression in EHCC.We investigated the correlations between the expression of CBS and CCL21 and clinicopathological characteristics in EHCC using EnVision immunohistochemistry.The expression of CBS and CCL21 was significantly higher in EHCC tumors than in nontumor tissues (P < .05 and P < .01). EHCC patients with CBS and CCL21 expression combined with lymph node metastasis, tumor cell invasion, and TNM III/IV stage had more severe conditions than those with no lymph node metastasis, distant invasion and TNM I/II stage (P < .01). Kaplan-Meier survival analysis showed that the overall survival rates for EHCC patients with negative CBS or CCL21 reaction were significantly higher than those for patients with positive CBS or CCL21 reaction((P < .01). CBS or CCL21 expression was revealed as an independent poor prognostic factor for EHCC patients by Cox multivariate analysis.The present study indicates that CBS and CCL21 expression is closely associated with the pathogenesis of clinical, pathological and biological behaviors and poor prognosis in EHCC.
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Affiliation(s)
- Lingxiang Wang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery
| | - Zhulin Yang
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery
| | - Zhengchun Wu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery
| | - Jun He
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery
| | - Shu Xu
- Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Department of General Surgery
| | - Daiqiang Li
- Department of Pathology, Second Xiangya Hospital
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
| | - Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan, PR China
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Furnari M, Telese A, Hann A, Lisotti A, Boškoski I, Eusebi LH. New Devices for Endoscopic Treatments in Gastroenterology: A Narrative Review. Curr Drug Metab 2020; 21:850-865. [PMID: 32703127 DOI: 10.2174/1389200221666200722145727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/04/2020] [Accepted: 06/02/2020] [Indexed: 12/07/2022]
Abstract
Endoscopy is in a period of continuous innovations in terms of image quality, endoscopes, post-processing software and lastly, application of Artificial Intelligence. Therapeutic boundaries have expanded, widening the grey zone between endoscopy and surgery, and increasing endoscopic approaches in clinical scenarios where, until a few years ago, surgery was the only option. New scopes and accessories have made it easier to access critical areas such as the biliary tree and the small bowel intestine. In the field of hepato-pancreato-biliary endoscopy (HPB), it is now possible to directly access the biliary ducts or cystic lesions though dedicated stents and scopes, rather than having to rely only on fluoroscopy and ultrasound, increasing the diagnostic and therapeutic options by applying a three-dimensional approach. This narrative review will give an overview of some of the most relevant emerging fields in luminal and HPB endoscopy, highlighting advantages and main limitations of the techniques, and providing considerations for future development.
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Affiliation(s)
- Manuele Furnari
- Department of Internal Medicine, Gastroenterology Unit, Policlinico IRCCS "San Martino", University of Genoa, Genoa, Italy
| | - Andrea Telese
- Department of Gastroenterology, University College Hospital NHS Foundation Trust, London, United Kingdom
| | - Alexander Hann
- Interventional and Experimental Endoscopy (InExEn), Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Andrea Lisotti
- Gastroenterology Unit, Hospital of Imola, University of Bologna, Bologna, Italy
| | - Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCSS, Rome, Italy
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Rosenbaum MW, Arpin R, Limbocker J, Casey B, Le L, Dudley J, Iafrate AJ, Pitman MB. Cytomorphologic characteristics of next-generation sequencing-positive bile duct brushing specimens. J Am Soc Cytopathol 2020; 9:520-527. [PMID: 32839152 DOI: 10.1016/j.jasc.2020.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/26/2020] [Accepted: 06/18/2020] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Cytology of bile duct brushings (BDBs) is a specific, but insensitive, test for malignancy. Next-generation sequencing (NGS) of BDBs has recently been shown to improve sensitivity. We analyzed the cytologic features of NGS-positive (NGS+) and NGS-negative (NGS-) BDBs and correlated the morphology with the presence of mutations. MATERIALS AND METHODS A total of 96 BDBs were analyzed for 29 cytologic features by 2 pathologists who were unaware of the original diagnosis and NGS results. Clinicopathologic follow-up was used to determine the patient outcomes (ie, benign, low-grade neoplasm, malignant [carcinoma/high-grade dysplasia]). RESULTS We analyzed 74 NGS+ BDBs from 66 patients and 22 NGS- BDBs from 22 patients. During follow-up, 58 of 66 NGS+ patients (88%) had malignancy compared with 0% of NGS- patients (P < 0.001). Fewer than 50% of the malignant cases had been interpreted as malignant on cytology; however, 100% had demonstrated mutations using NGS. Within the NGS+ cases, 53% showed late mutations (TP53, SMAD4, and CDKN2A) supportive of a high-risk stricture. Significant morphologic differences were seen in the background appearance, presence of single cells, architectural disarray, nucleomegaly, anisonucleosis, irregular nuclear borders, increased nuclear/cytoplasmic ratio, nuclear hyperchromasia, nucleoli, abnormal groups, clusters, and/or single cells, and overall impression. Naked nuclei, nucleomegaly, anisonucleosis, and coarse chromatin were more common in BDBs with late mutations than in those with KRAS/GNAS (Kirsten rat sarcoma viral oncogene homolog/guanine nucleotide binding protein, α-stimulating complex locus) mutations only. Cytology had a sensitivity of 16% and a specificity of 100% for malignancy. In contrast, NGS had a sensitivity of 100% and a specificity of 73%. Late mutations were 100% specific for malignancy compared with mutations in KRAS/GNAS only, of which 69% were malignant. CONCLUSIONS We found significant overlap in the cytomorphologic features between neoplastic and non-neoplastic BDBs, and more than one half of cancer cases had been interpreted as "nonmalignant" on cytology. NGS showing late mutations was 100% specific for malignancy. Adding genetic testing to BDB cytology would be a valuable ancillary test for the detection of malignancy, and reflex testing should be considered.
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Affiliation(s)
- Matthew W Rosenbaum
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts.
| | - Ronald Arpin
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Jessica Limbocker
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Brenna Casey
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts
| | - Long Le
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Jonathan Dudley
- Department of Pathology, Johns Hopkins Hospital, Baltimore, Maryland
| | - A John Iafrate
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
| | - Martha B Pitman
- Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts
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48
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Vedeld HM, Folseraas T, Lind GE. Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis - The promise of DNA methylation and molecular biomarkers. JHEP Rep 2020; 2:100143. [PMID: 32939446 PMCID: PMC7479288 DOI: 10.1016/j.jhepr.2020.100143] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/25/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a highly fatal malignancy of the bile ducts that arises in up to 20% of patients with primary sclerosing cholangitis (PSC). Current detection methods for CCA display suboptimal sensitivity and/or specificity, and there is no evidence-based screening strategy for CCA in patients with PSC. Consequently, CCA is often detected too late for surgical resection, contributing to the high mortality associated with this malignancy. Recently, biomarkers have emerged with potential to complement current detection methods, and/or be used for cancer surveillance in high-risk patient groups, including patients with PSC. Aberrant DNA methylation patterns represent promising biomarkers with great potential for CCA detection. Such aberrations are frequent in CCA, often occur early, and can be detected in liquid biopsies, including blood, bile and urine. This review summarises and highlights the most promising DNA methylation biomarkers identified for CCA detection so far, focusing on patients with PSC. Other promising molecular biomarkers for detection of PSC-associated CCA in liquid biopsies will also be briefly covered.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
| | - Trine Folseraas
- Norwegian PSC Research Center, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway.,Section of Gastroenterology, Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway
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Singhi AD, Nikiforova MN, Chennat J, Papachristou GI, Khalid A, Rabinovitz M, Das R, Sarkaria S, Ayasso MS, Wald AI, Monaco SE, Nalesnik M, Ohori NP, Geller D, Tsung A, Zureikat AH, Zeh H, Marsh JW, Hogg M, Lee K, Bartlett DL, Pingpank JF, Humar A, Bahary N, Dasyam AK, Brand R, Fasanella KE, McGrath K, Slivka A. Integrating next-generation sequencing to endoscopic retrograde cholangiopancreatography (ERCP)-obtained biliary specimens improves the detection and management of patients with malignant bile duct strictures. Gut 2020; 69:52-61. [PMID: 30971436 PMCID: PMC6943248 DOI: 10.1136/gutjnl-2018-317817] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 03/25/2019] [Accepted: 03/27/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Despite improvements in imaging, serum CA19-9 and pathological evaluation, differentiating between benign and malignant bile duct strictures remains a diagnostic conundrum. Recent developments in next-generation sequencing (NGS) have opened new opportunities for early detection and management of cancers but, to date, have not been rigorously applied to biliary specimens. DESIGN We prospectively evaluated a 28-gene NGS panel (BiliSeq) using endoscopic retrograde cholangiopancreatography-obtained biliary specimens from patients with bile duct strictures. The diagnostic performance of serum CA19-9, pathological evaluation and BiliSeq was assessed on 252 patients (57 trainings and 195 validations) with 346 biliary specimens. RESULTS The sensitivity and specificity of BiliSeq for malignant strictures was 73% and 100%, respectively. In comparison, an elevated serum CA19-9 and pathological evaluation had sensitivities of 76% and 48%, and specificities of 69% and 99%, respectively. The combination of BiliSeq and pathological evaluation increased the sensitivity to 83% and maintained a specificity of 99%. BiliSeq improved the sensitivity of pathological evaluation for malignancy from 35% to 77% for biliary brushings and from 52% to 83% for biliary biopsies. Among patients with primary sclerosing cholangitis (PSC), BiliSeq had an 83% sensitivity as compared with pathological evaluation with an 8% sensitivity. Therapeutically relevant genomic alterations were identified in 20 (8%) patients. Two patients with ERBB2-amplified cholangiocarcinoma received a trastuzumab-based regimen and had measurable clinicoradiographic response. CONCLUSIONS The combination of BiliSeq and pathological evaluation of biliary specimens increased the detection of malignant strictures, particularly in patients with PSC. Additionally, BiliSeq identified alterations that may stratify patients for specific anticancer therapies.
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Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
| | - Jennifer Chennat
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Asif Khalid
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Rohit Das
- Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Savreet Sarkaria
- Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - M Samir Ayasso
- Department of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
| | - Sara E Monaco
- Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
| | - Michael Nalesnik
- Department of Pathology, Division of Transplant Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - N Paul Ohori
- Department of Pathology, University of Pittsburgh Medical Center Health System, Pittsburgh, Pennsylvania, USA
| | - David Geller
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Herbert Zeh
- Department of Clinical Sciences, Surgery, University of Texas Southwestern, Dallas, Texas, USA
| | - J Wallis Marsh
- Department of Surgery, West Virginia University Health Sciences Center, Morgantown, West Virginia, USA
| | - Melissa Hogg
- Department of Surgery, NorthShore University Health System, Evanston, Illinois, USA
| | - Kenneth Lee
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - David L Bartlett
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - James F Pingpank
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Abhinav Humar
- Department of Transplant, Thomas E Starzl Transplant Instiute University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Nathan Bahary
- Division of Hematology and Oncology, UPMC Cancer Centers, Pittsburgh, Pennsylvania, USA
| | - Anil K Dasyam
- Department of Radiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Randall Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kenneth E Fasanella
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Kevin McGrath
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Adam Slivka
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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50
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Yang X, Sun L, Guo J, Gao L, Qin C, Jin Z. The value of DNA image cytometry combined with brush routine cytology in diagnosing indeterminate biliary strictures: A large sample size retrospective study. J Gastroenterol Hepatol 2019; 34:2036-2042. [PMID: 30963609 DOI: 10.1111/jgh.14681] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 03/09/2019] [Accepted: 03/31/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM Brush cytology is widely applied to diagnosis indeterminate biliary stricture but suffer from low sensitivity. Changes in DNA content are a character of malignant cell and can be detected by DNA image cytometry (DNA-ICM). The study aimed to estimate the value of routine cytology (RC), DNA-ICM, and their combination in diagnosing indeterminate biliary strictures. METHODS A total of 362 patients who underwent both RC and DNA-ICM tests were analysed. Their results were retrospectively applied to final diagnoses. Diagnostic values were compared among RC, DNA-ICM, and their combination based on the location of strictures. RESULTS The DNA-ICM and combination of two methods had higher diagnostic accuracy than RC in all strictures (63.3% vs 42.3%, P < 0.001, 64.36% vs 42.3%, P < 0.001) and in distal strictures (65.36% vs 42.81%, P < 0.001, 66.01% vs 42.81%, P < 0.001). But in proximal strictures, DNA-ICM showed no superior (51.8% vs 42.81%, P = 0.184). Combination of two methods was not fully significant superior to RC in proximal strictures (55.36% vs 39.29%, P = 0.089). After classification of "suspicious for malignancy" as positive for malignancy, the diagnostic accuracy of DNA-ICM was still higher than that of RC in all strictures (63.3% vs 51.9%, P = 0.002) and in distal strictures (65.36% vs 52.29%, P = 0.001). Combination of two methods was no superior to DNA-ICM alone (64.36% vs 63.3%, P = 0.757). The utilization of DNA-ICM was more accurate in distal strictures than in proximal strictures (65.36% vs 51.8%, P = 0.017). CONCLUSION DNA-ICM is an objective and effective addition tool with RC, especially in distal strictures. The combination of DNA-ICM and RC showed no superior to DNA-ICM alone but could improve diagnostic accuracy to RC in proximal strictures although not fully significant.
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Affiliation(s)
- Xia Yang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, China
| | - Liqi Sun
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Jiefang Guo
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Li Gao
- Department of Pathology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
| | - Chengyong Qin
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, China
| | - Zhendong Jin
- Department of Gastroenterology, Changhai Hospital, Second Military Medical University/Naval Medical University, Shanghai, China
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