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Gong R, Chen ZE, Matsukuma K. Morphologic and immunohistochemical characterization of small and large duct cholangiocarcinomas in a Western cohort: A panel of pCEA, CRP, N-cadherin, and albumin in situ hybridization aids in subclassification. Ann Diagn Pathol 2025; 75:152437. [PMID: 39832462 DOI: 10.1016/j.anndiagpath.2025.152437] [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: 10/22/2024] [Revised: 01/07/2025] [Accepted: 01/09/2025] [Indexed: 01/22/2025]
Abstract
Two morphologic subtypes of intrahepatic cholangiocarcinoma (iCCA), small duct and large duct, are now recognized, and importantly, these subtypes are associated with distinct molecular pathways and therapeutic options. Initial studies demonstrated the feasibility of morphologic subclassification and helped characterize the immunoprofile of the subtypes. However, few studies have been undertaken in Western countries where incidence of the subtypes is likely distinct from that in the East. To address this, 48 tumors from a North American cohort, consisting of 29 iCCAs, 18 extrahepatic CCAs (eCCAs), and 1 tumor of unclear origin (liver vs. gallbladder growing into liver) were classified by morphologic criteria as large duct (19 tumors), small duct (13 tumors), or indeterminate (13 tumors; all iCCAs). Notably, only 3 iCCAs were classified as large duct. Additionally, we evaluated the utility of common biomarkers to aid in subclassification, given that a significant portion of iCCAs were challenging to classify (e.g., indeterminate morphology). Tumors were screened for expression of mucicarmine, epithelial membrane antigen (EMA), monoclonal (mCEA), polyclonal CEA (pCEA), N-cadherin, CD56, and albumin by in situ hybridization (ALB-ISH). Of these, pCEA, CRP, N-cadherin, and ALB-ISH showed statistically significant differences between large and small duct types (P < 0.0028), with high specificity (≥88 %) and at least moderate sensitivity (≥60 %). Eleven of the 13 morphologically indeterminate tumors could be classified based on their expression of these 4 markers. Four additional large duct iCCAs were subsequently obtained from a second North American institution and assessed for pCEA, N-cadherin, and albumin expression. Combining these data with the initial cohort of large duct iCCAs (total of 7 large duct iCCAs) showed similar biomarker associations. In conclusion, in this Western cohort, 55 % of iCCAs (16 of 29) could be subclassified as large or small duct type based on morphology alone. With the aid of the 4-marker panel, 93 % of iCCAs (27 of 29) could be classified. Unlike in East Asian cohorts, the vast majority of iCCAs (88 %) was small duct type, and hepatolithiasis was not observed. CRP, N-cadherin, and ALB-ISH were found to be specific for small duct iCCA, whereas diffuse, strong expression of pCEA showed specificity for large duct tumors. This is the first report to highlight the utility of pCEA to subclassify iCCAs. Additionally, in cases in which the primary site (within the biliary tract) was unclear, CRP, ALB-ISH, N-cadherin, and pCEA were helpful in distinguishing iCCA from eCCA.
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Affiliation(s)
- Raymond Gong
- University of California Davis School of Medicine, Department of Pathology and Laboratory Medicine, 4400 V Street, Sacramento, CA 95817, USA.
| | - Zongming E Chen
- Mayo Clinic, Department of Lab Medicine and Pathology, Rochester, MN, USA.
| | - Karen Matsukuma
- University of California Davis School of Medicine, Department of Pathology and Laboratory Medicine, 4400 V Street, Sacramento, CA 95817, USA.
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2
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De Santis A, Zhu L, Tao J, Reißfelder C, Schölch S. Molecular subtypes of intrahepatic cholangiocarcinoma. Trends Mol Med 2025:S1471-4914(25)00008-5. [PMID: 39955217 DOI: 10.1016/j.molmed.2025.01.008] [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: 10/30/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/17/2025]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small duct (SD-iCCA). These subtypes exhibit significant molecular, genetic, and histopathological differences that impact patient prognosis and treatment responsiveness. This review advocates for a subtype-specific approach to iCCA research and clinical management, including tailored therapeutic strategies that consider distinct genetic profiles and tumor microenvironments. Current therapeutic approaches hold promise, yet efficacy varies by subtype. Additionally, subtype-specific molecular diagnostics, including DNA methylation-based classifiers and transcriptomic sequencing, have shown potential in refining iCCA subclassification, thereby guiding precision medicine efforts. This article outlines existing clinical trials, key research trajectories, and future directions for developing more effective subtype-adapted therapies for iCCA.
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Affiliation(s)
- Alessandro De Santis
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), Heidelberg, Germany; DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Biology and Biotechnology Charles Darwin, Sapienza University of Rome, Rome, Italy
| | - Lei Zhu
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), Heidelberg, Germany; DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
| | - Jianxin Tao
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), Heidelberg, Germany; DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Reißfelder
- DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Sebastian Schölch
- JCCU Translational Surgical Oncology (A430), German Cancer Research Center (DKFZ), Heidelberg, Germany; DKFZ-Hector Cancer Institute, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
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3
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Akita M, Yanagimoto H, Tsugawa D, Zen Y, Fukumoto T. Surgical interpretation of the WHO subclassification of intrahepatic cholangiocarcinoma: a narrative review. Surg Today 2025; 55:1-9. [PMID: 38563999 DOI: 10.1007/s00595-024-02825-x] [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: 10/02/2023] [Accepted: 02/14/2024] [Indexed: 04/04/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) has been subclassified by its gross morphology into the mass-forming (MF), periductal-infiltrating (PI), and intraductal growth (IG) types and their combinations. This classification correlates well with clinical features; for example, MF-iCCA has less lymph-node metastasis and a better prognosis than PI-iCCA. According to the recently accumulated evidence from histological investigations, the WHO classification endorsed a subclassification scheme in which iCCA cases are classified into small- and large-duct types. Small-duct iCCA is considered to originate from septal or smaller bile ducts and is characterized by less frequent lymph-node metastasis, a favorable prognosis, and an MF appearance. Large-duct iCCA arises around the second branch of the biliary tree and has more aggressive biology and distinct genetic abnormalities. According to the practice guidelines for iCCA from the Liver Cancer Study Group of Japan and the National Comprehensive Cancer Network, upfront surgery is recommended for iCCA without distant metastasis regardless of the morphological subtype, based on clinical experience. In consideration of the biological heterogeneity of iCCA, the treatment strategy for iCCA needs to be reconsidered based on the WHO subtypes.
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Affiliation(s)
- Masayuki Akita
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Hiroaki Yanagimoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan.
| | - Daisuke Tsugawa
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Yoh Zen
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Takumi Fukumoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
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4
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Goeppert B, Zen Y, Valle J, Klimstra D, Deshpande V. Cholangiocarcinoma classification: current approach, relevance and challenges. J Clin Pathol 2024:jcp-2024-209708. [PMID: 39674584 DOI: 10.1136/jcp-2024-209708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 11/26/2024] [Indexed: 12/16/2024]
Affiliation(s)
- Benjamin Goeppert
- Institute of Pathology, Regionale Kliniken Holding RKH GmbH, Ludwigsburg, Germany
- Institute of Pathology, Heidelberg University, Heidelberg, Germany
| | - Yoh Zen
- Liver Institute, King's College Hospital, London, UK
| | - Juan Valle
- Research Department, Cholangiocarcinoma Foundation, Herriman, Utah, USA
| | - David Klimstra
- Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Vikram Deshpande
- Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Zhang R, Tan Y, Liu M, Wang L. Lymph node metastasis of intrahepatic cholangiocarcinoma: the present and prospect of detection and dissection. Eur J Gastroenterol Hepatol 2024; 36:1359-1369. [PMID: 39475782 PMCID: PMC11527382 DOI: 10.1097/meg.0000000000002856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 09/06/2024] [Indexed: 11/02/2024]
Abstract
Intrahepatic cholangiocarcinoma (ICC) ranks as the second most primary liver cancer that often goes unnoticed with a high mortality rate. Hepatectomy is the main treatment for ICC, but only 15% of patients are suitable for surgery. Despite advancements in therapeutic approaches, ICC has an unfavorable prognosis, largely due to lymph node metastasis (LNM) that is closely linked to the elevated recurrence rates. Consequently, the identification of precise and suitable techniques for the detection and staging of LNM assumes paramount importance for ICC therapy. While preoperative imaging plays a crucial role in ICC diagnosis, its efficacy in accurately diagnosing LNM remains unsatisfactory. The inclusion of lymph node dissection as part of the hepatectomy procedures is significant for the accurate pathological diagnosis of LNM, although it continues to be a topic of debate. The concept of sentinel lymph node in ICC has presented a novel and potentially valuable approach for diagnosing LNM. This review aims to explore the current state and prospects of LNM in ICC, offering a promising avenue for enhancing the clinical diagnosis and treatment of ICC to improve patient prognosis.
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Affiliation(s)
- Ruoyu Zhang
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
| | - Yunfei Tan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Unit III, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute
| | - Mei Liu
- Laboratory of Cell and Molecular Biology & State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
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6
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Toriyama K, Uehara T, Iwakoshi A, Kawashima H, Hosoda W. HNF6 and HNF4α expression in adenocarcinomas of the liver, pancreaticobiliary tract, and gastrointestinal tract: an immunohistochemical study of 480 adenocarcinomas of the digestive system. Pathology 2024; 56:804-813. [PMID: 38926048 DOI: 10.1016/j.pathol.2024.03.010] [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] [Received: 11/27/2023] [Revised: 03/05/2024] [Accepted: 03/20/2024] [Indexed: 06/28/2024]
Abstract
Hepatocyte nuclear factors (HNF) 6 and 4α are master transcriptional regulators of development and maintenance of the liver and pancreaticobiliary tract in mice and humans. However, little is known about the prevalence of HNF6 and HNF4α expression in carcinomas of the hepatobiliary tract and pancreas. We aimed to reveal the diagnostic utility of HNF6 and HNF4α immunolabelling in adenocarcinomas of these organs. We investigated HNF6 and HNF4α expression by immunohistochemistry using a total of 480 adenocarcinomas of the digestive system, including 282 of the hepatobiliary tract and pancreas and 198 of the gastrointestinal tract. HNF6 expression was primarily restricted to intrahepatic cholangiocarcinomas (CCs) (63%, n=80) and gallbladder adenocarcinomas (43%, n=88), among others. Notably, small duct intrahepatic CCs almost invariably expressed HNF6 (90%, n=42), showing stark contrast to a low prevalence in large duct intrahepatic CCs (10%, n=21; p<0.0001). HNF6 expression was infrequent in extrahepatic CCs (9%, n=55) and pancreatic ductal adenocarcinomas (7%, n=58), and it was rare in adenocarcinomas of the gastrointestinal tract [oesophagus/oesophagogastric junction (EGJ) (2%, n=45), stomach (2%, n=86), duodenum (0%, n=25), and colorectum (0%, n=42)]. In contrast, HNF4α was widely expressed among adenocarcinomas of the digestive system, including intrahepatic CCs (88%), extrahepatic CCs (94%), adenocarcinomas of the gallbladder (98%), pancreas (98%), oesophagus/EGJ (96%), stomach (98%), duodenum (80%), and colorectum (100%). HNF6 was frequently expressed in and almost restricted to intrahepatic CCs of small duct type and gallbladder adenocarcinomas, while HNF4α was expressed throughout adenocarcinomas of the digestive system. HNF6 immunolabelling may be useful in distinguishing small duct intrahepatic CCs from other types of CC as well as metastatic gastrointestinal adenocarcinomas.
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Affiliation(s)
- Kazuhiro Toriyama
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akari Iwakoshi
- Department of Pathology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan
| | - Hiroki Kawashima
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Waki Hosoda
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan.
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7
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Guest RV, Goeppert B, Nault JC, Sia D. Morphomolecular Pathology and Genomic Insights into the Cells of Origin of Cholangiocarcinoma and Combined Hepatocellular-Cholangiocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 195:S0002-9440(24)00357-2. [PMID: 39341365 PMCID: PMC11841493 DOI: 10.1016/j.ajpath.2024.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 08/14/2024] [Accepted: 08/21/2024] [Indexed: 10/01/2024]
Abstract
Cholangiocarcinomas are a highly heterogeneous group of malignancies that, despite recent progress in the understanding of their molecular pathogenesis and clinical management, continue to pose a major challenge to public health. The traditional view posits that cholangiocarcinomas derive from the neoplastic transformation of cholangiocytes lining the biliary tree. However, increasing genetic and experimental evidence has recently pointed to a more complex, and nuanced, scenario for the potential cell of origin of cholangiocarcinomas. Hepatocytes as well as hepatic stem/progenitor cells are being considered as additional potential sources, depending on microenvironmental contexts, including liver injury. The hypothesis of potentially diverse cells of origin for cholangiocarcinoma, albeit controversial, is certainly not surprising given the plasticity of the cells populating the liver as well as the existence of liver cancer subtypes with mixed histologic and molecular features. This review carefully examines the current pathologic, genomic, and experimental evidence supporting the existence of multiple cells of origin of liver and biliary tract cancers, with particular focus on cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma.
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Affiliation(s)
- Rachel V Guest
- Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Benjamin Goeppert
- Institute of Pathology, RKH Klinikum Ludwigsburg, Ludwigsburg, Germany; Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université Paris Cité, Team "Functional Genomics of Solid Tumors", Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France; Liver Unit, Avicenne Hospital, APHP, University Sorbonne Paris Nord, Bobigny, France
| | - Daniela Sia
- Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Liver Cancer Program, Icahn School of Medicine at Mount Sinai, New York, New York.
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8
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Li Z, Nguyen Canh H, Takahashi K, Le Thanh D, Nguyen Thi Q, Yang R, Yoshimura K, Sato Y, Nguyen Thi K, Nakata H, Ikeda H, Kozaka K, Kobayashi S, Yagi S, Harada K. Histopathological growth pattern and vessel co-option in intrahepatic cholangiocarcinoma. Med Mol Morphol 2024; 57:200-217. [PMID: 38960952 PMCID: PMC11343874 DOI: 10.1007/s00795-024-00392-1] [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: 05/28/2024] [Accepted: 06/17/2024] [Indexed: 07/05/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) exhibits different blood imaging features and prognosis depending on histology. To clarity histopathological growth patterns (HGPs) and vascularization processes of iCCA, we collected 145 surgical specimens and histologically classified them into large bile duct (LBD) (20 cases), small bile duct (SBD) (54), cholangiolocarcinoma (CLC) (35), combined SBD-CLC (cSBD-CLC) (26), and ductal plate malformation (DPM) (10) (sub)types. According to the invasive pattern at the interface between tumor and adjacent background liver, HGPs were classified into desmoplastic, pushing, and replacing HGPs. Desmoplastic HGP predominated in LBD type (55.5%), while replacing HGP was common in CLC (82.9%) and cSBD-CLC (84.6%) subtypes. Desmoplastic HGP reflected angiogenesis, while replacing HGP showed vessel co-option in addition to angiogenesis. By evaluating microvessel density (MVD) using vascular markers, ELTD1 identified vessel co-option and angiogenesis, and ELTD1-positive MVD at invasive margin in replacing HGP was significantly higher than those in desmoplastic and pushing HGPs. REDD1, an angiogenesis-related marker, demonstrated preferably higher MVD in the tumor center than in other areas. iCCA (sub)types and HGPs were closely related to vessel co-option and immune-related factors (lymphatic vessels, lymphocytes, and neutrophils). In conclusion, HGPs and vascular mechanisms characterize iCCA (sub)types and vessel co-option linked to the immune microenvironment.
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Affiliation(s)
- Zihan Li
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Hiep Nguyen Canh
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Kenta Takahashi
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Dong Le Thanh
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Quynh Nguyen Thi
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Rui Yang
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Kaori Yoshimura
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan
| | - Khuyen Nguyen Thi
- Center of Pathology and Molecular Biology, National Cancer Hospital, Hanoi, Vietnam
| | - Hiroki Nakata
- Department of Clinical Engineering, Faculty of Health Sciences, Komatsu University, Komatsu, Japan
- Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Hiroko Ikeda
- Department of Diagnostic Pathology, Kanazawa University Hospital, Kanazawa, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan
| | - Satoshi Kobayashi
- Department of Radiology, Kanazawa University Hospital, Kanazawa, Japan
| | - Shintaro Yagi
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, 920-8640, Japan.
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Chen Z, Gao J, Li Z, Ma D, Wang Y, Cheng Q, Zhu J, Li Z. Integrative analysis reveals different feature of intrahepatic cholangiocarcinoma subtypes. Liver Int 2024; 44:2477-2493. [PMID: 38924592 DOI: 10.1111/liv.16015] [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: 12/16/2023] [Revised: 06/04/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024]
Abstract
BACKGROUND & AIMS Intrahepatic cholangiocarcinoma (iCCA) has two main histological subtypes: large and small duct-type iCCA, which are characterized by different clinicopathological features. This study was conducted with the purpose of expanding our understanding of their differences in molecular features and immune microenvironment. METHODS We selected 132 patients who underwent radical surgery at our department between 2015 and 2021 for clinical and survival analyses. Whole-exome sequencing was performed to analyse mutational landscapes. Bulk RNA sequencing and single-cell RNA sequencing data were used for pathway enrichment and immune infiltration analyses based on differentially expressed genes. The function of PPP1R1B was analysed both in vitro and in vivo and the gene mechanism was further investigated. RESULTS We found that large duct-type iCCA had worse overall survival and recurrence-free survival rates than small duct-type iCCA. Mutations in ARID1A, DOT1L and ELF3 usually occur in large duct-type iCCA, whereas mutations in IDH1 and BAP1 occur in small duct-type iCCA. Among the differentially expressed genes, we found that PPP1R1B was highly expressed in large duct-type iCCA tumour tissues. Expression of PPP1R1B promoted cell proliferation, migration and invasion and indicated a worse prognosis. A combination of USF2 with the promoter of PPP1R1B can enhance gene expression in iCCA, which may further affect the expression of genes such as AHNAK, C4BPA and activating the PI3K/AKT pathway. CONCLUSIONS Our findings extend our understanding of large and small duct-type iCCA. In addition, PPP1R1B may serve as a potential marker and therapeutic target for large duct-type iCCA.
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Affiliation(s)
- Zhuomiaoyu Chen
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
| | - Jie Gao
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
| | - Zuyin Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
| | - Delin Ma
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
| | - Yang Wang
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
| | - Qian Cheng
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
| | - Jiye Zhu
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
| | - Zhao Li
- Department of Hepatobiliary Surgery, Peking University People's Hospital, Beijing, China
- Beijing Key Laboratory of HCC and Liver Cirrhosis, Peking University People's Hospital, Beijing, China
- Peking University Center of Liver Cancer Diagnosis and Treatment, Peking University People's Hospital, Beijing, China
- Peking University Institute of Organ Transplantation, Peking University People's Hospital, Beijing, China
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10
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Li MY, Liu YH, Wei F, Zhang P, Sun XD, Wang M, Du XH, Ye JF, Qiu W, Shi XJ, Ji B, Wang YC, Jiang C, Chai WG, Huang B, Liu XK, Chen QM, Fu Y, Hu XT, Chen LG, He JX, Chai KY, Gou ZM, Yang T, Wang GY, Jiang YF, Fan ZQ, Lv GY. Identification of prognostic biomarkers for cholangiocarcinoma by combined analysis of molecular characteristics of clinical MVI subtypes and molecular subtypes. Genomics 2024; 116:110889. [PMID: 38901654 DOI: 10.1016/j.ygeno.2024.110889] [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: 03/18/2024] [Revised: 05/27/2024] [Accepted: 06/15/2024] [Indexed: 06/22/2024]
Abstract
Cholangiocarcinoma (CCA) is widely noted for its high degree of malignancy, rapid progression, and limited therapeutic options. This study was carried out on transcriptome data of 417 CCA samples from different anatomical locations. The effects of lipid metabolism related genes and immune related genes as CCA classifiers were compared. Key genes were derived from MVI subtypes and better molecular subtypes. Pathways such as epithelial mesenchymal transition (EMT) and cell cycle were significantly activated in MVI-positive group. CCA patients were classified into three (four) subtypes based on lipid metabolism (immune) related genes, with better prognosis observed in lipid metabolism-C1, immune-C2, and immune-C4. IPTW analysis found that the prognosis of lipid metabolism-C1 was significantly better than that of lipid metabolism-C2 + C3 before and after correction. KRT16 was finally selected as the key gene. And knockdown of KRT16 inhibited proliferation, migration and invasion of CCA cells.
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Affiliation(s)
- Ming-Yue Li
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ya-Hui Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Feng Wei
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ping Zhang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiao-Dong Sun
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Meng Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiao-Hong Du
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jun-Feng Ye
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wei Qiu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xiao-Ju Shi
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Bai Ji
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Ying-Chao Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Chao Jiang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Wen-Gang Chai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Bo Huang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xing-Kai Liu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Qing-Min Chen
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yu Fu
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Xin-Tong Hu
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Li-Guo Chen
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Jia-Xue He
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Kai-Yuan Chai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhao-Ming Gou
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Tian Yang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China
| | - Guang-Yi Wang
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China
| | - Yan-Fang Jiang
- Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Center, First Hospital of Jilin University, Changchun, Jilin, China.
| | - Zhong-Qi Fan
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China.
| | - Guo-Yue Lv
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Changchun, Jilin, China.
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11
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Bernatz S, Schulze F, Bein J, Bankov K, Mahmoudi S, Grünewald LD, Koch V, Stehle A, Schnitzbauer AA, Walter D, Finkelmeier F, Zeuzem S, Vogl TJ, Wild PJ, Kinzler MN. Small duct and large duct type intrahepatic cholangiocarcinoma reveal distinct patterns of immune signatures. J Cancer Res Clin Oncol 2024; 150:357. [PMID: 39034327 PMCID: PMC11271402 DOI: 10.1007/s00432-024-05888-y] [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: 05/27/2024] [Accepted: 07/11/2024] [Indexed: 07/23/2024]
Abstract
PURPOSE Dedicated gene signatures in small (SD-iCCA) and large (LD-iCCA) duct type intrahepatic cholangiocarcinoma remain unknown. We performed immune profiling in SD- and LD-iCCA to identify novel biomarker candidates for personalized medicine. METHODS Retrospectively, 19 iCCA patients with either SD-iCCA (n = 10, median age, 63.1 years (45-86); men, 4) or LD-iCCA (n = 9, median age, 69.7 years (62-85); men, 5)) were included. All patients were diagnosed and histologically confirmed between 04/2009 and 01/2021. Tumor tissue samples were processed for differential expression profiling using NanoString nCounter® PanCancer Immune Profiling Panel. RESULTS With the exception of complement signatures, immune-related pathways were broadly downregulated in SD-iCCA vs. LD-iCCA. A total of 20 immune-related genes were strongly downregulated in SD-iCCA with DMBT1 (log2fc = -5.39, p = 0.01) and CEACAM6 (log2fc = -6.38, p = 0.01) showing the strongest downregulation. Among 7 strongly (log2fc > 2, p ≤ 0.02) upregulated genes, CRP (log2fc = 5.06, p = 0.02) ranked first, and four others were associated with complement (C5, C4BPA, C8A, C8B). Total tumor-infiltrating lymphocytes (TIL) signature was decreased in SD-iCCA with elevated ratios of exhausted-CD8/TILs, NK/TILs, and cytotoxic cells/TILs while having decreased ratios of B-cells/TILs, mast cells/TILs and dendritic cells/TILs. The immune profiling signatures in SD-iCCA revealed downregulation in chemokine signaling pathways inclulding JAK2/3 and ERK1/2 as well as nearly all cytokine-cytokine receptor interaction pathways with the exception of the CXCL1/CXCR1-axis. CONCLUSION Immune patterns differed in SD-iCCA versus LD-iCCA. We identified potential biomarker candidate genes, including CRP, CEACAM6, DMBT1, and various complement factors that could be explored for augmented diagnostics and treatment decision-making.
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Affiliation(s)
- Simon Bernatz
- Department of Diagnostic and Interventional Radiology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- University Cancer Center Frankfurt (UCT), University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Falko Schulze
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Julia Bein
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Katrin Bankov
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Department of Pediatric Oncology and Hematology, Charité, Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Scherwin Mahmoudi
- Department of Diagnostic and Interventional Radiology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Leon D Grünewald
- Department of Diagnostic and Interventional Radiology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Vitali Koch
- Department of Diagnostic and Interventional Radiology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Angelika Stehle
- Medical Clinic 1, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Andreas A Schnitzbauer
- Department of General, Visceral, Transplant and Thoracic Surgery, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Dirk Walter
- Medical Clinic 1, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Fabian Finkelmeier
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Medical Clinic 1, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Medical Clinic 1, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Thomas J Vogl
- Department of Diagnostic and Interventional Radiology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
| | - Peter J Wild
- Dr. Senckenberg Institute for Pathology, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany
- Frankfurt Institute for Advanced Studies (FIAS), Frankfurt am Main, Germany
| | - Maximilian N Kinzler
- Medical Clinic 1, University Hospital, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
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12
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Yoshizawa T, Uehara T, Iwaya M, Nakajima T, Shimizu A, Kubota K, Notake T, Kitagawa N, Masuo H, Sakai H, Hayashi H, Tomida H, Yamazaki S, Hirano S, Ota H, Soejima Y. An Immunohistochemical Analysis of Osteopontin and S100 Calcium-binding Protein P is Useful for Subclassifying Large- and Small-duct Type Intrahepatic Cholangiocarcinomas. Am J Surg Pathol 2024; 48:751-760. [PMID: 38584480 DOI: 10.1097/pas.0000000000002224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) has been newly subclassified into two different subtypes: large-duct (LD) type and small-duct (SD) type. However, many cases are difficult to subclassify, and there is no consensus regarding subclassification criteria. LD type expresses the highly sensitive diagnostic marker S100 calcium-binding protein P (S100P), while SD type lacks sensitive markers. We identified osteopontin (OPN) as a highly sensitive marker for SD type. This study aimed to develop new subclassification criteria for LD-type and SD-type iCCA. We retrospectively investigated 74 patients with iCCA and subclassified them based on whole-section immunostaining of S100P and OPN. Of the 74 cases, 41 were subclassified as LD type, 32 as SD type, and one was indeterminate. Notably, all S100P-negative cases had OPN positivity. Seventy-three of the 74 cases (98.6%) were clearly and easily subclassified as LD or SD type using only these 2 markers. We also determined the value of immunohistochemistry in cases that were difficult to diagnose based on hematoxylin-eosin and Alcian blue-periodic acid-Schiff staining. Furthermore, we analyzed the clinicopathological characteristics and prognoses of these 2 subtypes. LD type was a poor prognostic factor on univariate analysis; it had significantly worse overall survival ( P = 0.007) and recurrence-free survival ( P < 0.001) than the SD type. In conclusion, we propose new subclassification criteria for iCCA based on immunostaining of S100P and OPN. These criteria may help pathologists to diagnose subtypes of iCCA, supporting future clinical trials and the development of medications for these 2 subtypes as distinct cancers.
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Affiliation(s)
- Takahiro Yoshizawa
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Mai Iwaya
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tomoyuki Nakajima
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Akira Shimizu
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Koji Kubota
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Tsuyoshi Notake
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Noriyuki Kitagawa
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Hitoshi Masuo
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Hiroki Sakai
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Hikaru Hayashi
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Hidenori Tomida
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Shiori Yamazaki
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Shohei Hirano
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
| | - Hiroyoshi Ota
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
- Department of Biomedical Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Soejima
- Department of Surgery, Division of Gastroenterological, Hepato-Biliary-Pancreatic, Transplantation and Pediatric Surgery, Shinshu University School of Medicine, Matsumoto Japan
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13
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Zhu MR, Zhao CK, Sun YK, Li XL, Yin HH, Lu D, Ye X, Hu XY, Wang X, Xia HS, Han H, Zhou BY, Xu HX, Wang LF. Subtype prediction of intrahepatic cholangiocarcinoma using dynamic contrast-enhanced ultrasound. Insights Imaging 2024; 15:119. [PMID: 38755299 PMCID: PMC11098973 DOI: 10.1186/s13244-024-01683-y] [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: 07/02/2023] [Accepted: 03/30/2024] [Indexed: 05/18/2024] Open
Abstract
OBJECTIVE The study aimed to investigate the predictive value of dynamic contrast-enhanced ultrasound (DCE-US) in differentiating small-duct (SD) and large-duct (LD) types of intrahepatic cholangiocarcinoma (ICC). METHODS This study retrospectively enrolled 110 patients with pathologically confirmed ICC lesions who were subject to preoperative contrast-enhanced ultrasound (CEUS) examinations between January 2022 and February 2023. Patients were further classified according to the subtype: SD-type and LD-type, and an optimal predictive model was established and validated using the above pilot cohort. The test cohort, consisting of 48 patients prospectively enrolled from March 2023 to September 2023, was evaluated. RESULTS In the pilot cohort, compared with SD-type ICCs, more LD-type ICCs showed elevated carcinoembryonic antigen (p < 0.001), carbohydrate antigen 19-9 (p = 0.004), ill-defined margin (p = 0.018), intrahepatic bile duct dilation (p < 0.001). Among DCE-US quantitative parameters, the wash-out area under the curve (WoAUC), wash-in and wash-out area under the curve (WiWoAUC), and fall time (FT) at the margin of lesions were higher in the SD-type group (all p < 0.05). Meanwhile, the mean transit time (mTT) and wash-out rate (WoR) at the margin of the lesion were higher in the LD-type group (p = 0.041 and 0.007, respectively). Logistic regression analysis showed that intrahepatic bile duct dilation, mTT, and WoR were significant predictive factors for predicting ICC subtypes, and the AUC of the predictive model achieved 0.833 in the test cohort. CONCLUSIONS Preoperative DCE-US has the potential to become a novel complementary method for predicting the pathological subtype of ICC. CRITICAL RELEVANCE STATEMENT DCE-US has the potential to assess the subtypes of ICC lesions quantitatively and preoperatively, which allows for more accurate and objective differential diagnoses, and more appropriate treatments and follow-up or additional examination strategies for the two subtypes. KEY POINTS Preoperative determination of intrahepatic cholangiocarcinoma (ICC) subtype aids in surgical decision-making. Quantitative parameters from dynamic contrast-enhanced US (DCE-US) allow for the prediction of the ICC subtype. DCE-US-based imaging has the potential to become a novel complementary method for predicting ICC subtypes.
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Affiliation(s)
- Ming-Rui Zhu
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Chong-Ke Zhao
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Yi-Kang Sun
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Xiao-Long Li
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Hao-Hao Yin
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Dan Lu
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Xin Ye
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Xin-Yuan Hu
- School of Medicine, Anhui University of Science and Technology, 232000, Anhui, China
| | - Xi Wang
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Han-Sheng Xia
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Hong Han
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China
- Shanghai Institute of Medical Imaging, 200032, Shanghai, China
| | - Bo-Yang Zhou
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
| | - Hui-Xiong Xu
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
| | - Li-Fan Wang
- Department of Ultrasound, Institute of Ultrasound in Medicine and Engineering, Zhongshan Hospital, Fudan University, 200032, Shanghai, China.
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14
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Kinzler MN, Schulze F, Jeroch J, Schmitt C, Ebner S, Gretser S, Bein J, Finkelmeier F, Trojan J, Zeuzem S, Schnitzbauer AA, Demes MC, Reis H, Wild PJ, Walter D. Heterogeneity of small duct- and large duct-type intrahepatic cholangiocarcinoma. Histopathology 2024; 84:1061-1067. [PMID: 38409827 DOI: 10.1111/his.15162] [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: 10/16/2023] [Revised: 01/29/2024] [Accepted: 02/09/2024] [Indexed: 02/28/2024]
Abstract
AIMS The histological subtype of intrahepatic cholangiocarcinoma (iCCA) is associated with different mutational characteristics that impact clinical management. So far, data are lacking on the presence of small duct iCCA (SD-iCCA) and large duct iCCA (LD-iCCA) in a single patient. The aim of the current study was to determine the presence and degree of intratumoural heterogeneity of SD- and LD-iCCA features in different tumour regions. METHODS AND RESULTS All patients treated with surgically resected iCCA at Frankfurt University Hospital between December 2005 and March 2023 were retrospectively analysed. Histomorphological features of SD- and LD-iCCA were evaluated by an expert hepatobiliary pathologist. Tissue samples suspicious for subtype heterogeneity were further investigated. Immunohistochemistry for N-cadherin, S100P, MUC5AC, MUC6, TFF1 and AGR2 and mutational profiling with the Illumina TruSight Oncology 500 (TSO500) assay were performed separately for the SD- and LD-iCCA regions. Of 129 patients with surgically resected iCCA, features of either SD- or LD-iCCA were present in 67.4% (n = 87) and 24.8% of the patients (n = 32), respectively; 7.8% (n = 10) had histomorphological features of both SD- and LD-iCCA, seven patients (5.4%) of which had sufficient formalin-fixed, paraffin-embedded tissue for further analysis. Heterogeneity of both subtypes could be confirmed with immunohistochemistry. In five of seven (71.4%) patients, molecular profiling revealed intratumoural differences in genetic alterations between the SD- and LD-iCCA region. In one patient, a BRAF mutation (p.V600E) was found in the SD-iCCA but not in the LD-iCCA region of the tumour. CONCLUSIONS A marked portion of patients with iCCA exhibits both SD- and LD-iCCA in different tumour regions. In case of the presence of histopathological heterogeneity, mutational profiling should be considered to avoid missing therapeutically relevant genetic alterations.
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Affiliation(s)
- Maximilian N Kinzler
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt am Main, Germany
| | - Falko Schulze
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Jan Jeroch
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Christina Schmitt
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Silvana Ebner
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Steffen Gretser
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Julia Bein
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Fabian Finkelmeier
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Jörg Trojan
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt am Main, Germany
| | - Andreas A Schnitzbauer
- Department of General, Visceral, Transplant and Thoracic Surgery, Goethe University Frankfurt, University Hospital, Frankfurt am Main, Germany
| | - Melanie C Demes
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Henning Reis
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
| | - Peter J Wild
- Goethe University Frankfurt, University Hospital, Dr Senckenberg Institute of Pathology, Frankfurt am Main, Germany
- Frankfurt Cancer Institute (FCI), Goethe University Frankfurt, Frankfurt am Main, Germany
- Frankfurt Institute for Advanced Studies (FIAS), Frankfurt am Main, Germany
| | - Dirk Walter
- Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt am Main, Germany
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15
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Sugita H, Nakanuma S, Gabata R, Tokoro T, Takei R, Okazaki M, Kato K, Takada S, Makino I, Kozaka K, Harada K, Yagi S. Clinicopathological features of cholangiolocarcinoma and impact of tumor heterogeneity on prognosis: A single institution retrospective study. Oncol Lett 2024; 27:213. [PMID: 38572060 PMCID: PMC10988194 DOI: 10.3892/ol.2024.14346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 02/16/2024] [Indexed: 04/05/2024] Open
Abstract
Cholangiolocarcinoma (CLC) is an extremely rare tumor classified as a subtype of small duct-type intrahepatic cholangiocarcinoma (iCCA). There are few detailed reports on CLC and the prognostic impact of tumor heterogeneity is not clear. Between April 2006 and June 2022, of the 774 primary liver cancer resection cases who presented at Kanazawa University Hospital, 14 patients were pathologically diagnosed with CLC through immunohistochemical analysis of their molecular and biological features. Clinicopathological features and prognoses were evaluated retrospectively. Additionally, tumor heterogeneity was assessed and tumors were classified into pure and partial types according to the CLC component proportion in a single tumor. Chronic liver disease was observed in nine patients (64.3%). All tumors were mass-forming, and pathological R0 resection was achieved in 11 patients (78.6%). Tumor heterogeneity was classified as pure in 11 (78.6%) and partial in three (21.4%) patients. The median follow-up was 59.5 months (12-114 months). There was no difference in the 5-year disease-specific survival rates between the pure and partial (90.0% vs. 100.0%; P=0.200) types, but rates were significantly higher in the R0 resection group compared with those in the R1 resection group (100.0% vs. 50.0%; P=0.025). In conclusion, these results suggest that it is important for CLC patients to achieve curative resection, and CLC may have a good prognosis regardless of the proportion of CLC components in a single tumor.
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Affiliation(s)
- Hiroaki Sugita
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Shinichi Nakanuma
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Ryosuke Gabata
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Tomokazu Tokoro
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Ryohei Takei
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Mitsuyoshi Okazaki
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Kaichiro Kato
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Satoshi Takada
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Isamu Makino
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Ishikawa 920-8640, Japan
| | - Shintaro Yagi
- Department of Hepato-Biliary-Pancreatic Surgery and Transplantation, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan
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16
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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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17
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Choi JH, Thung SN. Recent Advances in Pathology of Intrahepatic Cholangiocarcinoma. Cancers (Basel) 2024; 16:1537. [PMID: 38672619 PMCID: PMC11048541 DOI: 10.3390/cancers16081537] [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: 02/29/2024] [Revised: 04/10/2024] [Accepted: 04/16/2024] [Indexed: 04/28/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (ICCA) is a malignant epithelial neoplasm characterized by biliary differentiation within the liver. ICCA is molecularly heterogeneous and exhibits a broad spectrum of histopathological features. It is a highly aggressive carcinoma with high mortality and poor survival rates. ICCAs are classified into two main subtypes: the small-duct type and large-duct types. These two tumor types have different cell origins and clinicopathological features. ICCAs are characterized by numerous molecular alterations, including mutations in KRAS, TP53, IDH1/2, ARID1A, BAP1, BRAF, SAMD4, and EGFR, and FGFR2 fusion. Two main molecular subtypes-inflammation and proliferation-have been proposed. Recent advances in high-throughput assays using next-generation sequencing have improved our understanding of ICCA pathogenesis and molecular genetics. The diagnosis of ICCA poses a significant challenge for pathologists because of its varied morphologies and phenotypes. Accurate diagnosis of ICCA is essential for effective patient management and prognostic determination. This article provides an updated overview of ICCA pathology, focusing particularly on molecular features, histological subtypes, and diagnostic approaches.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea
| | - Swan N. Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA;
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18
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Li R, Chen B, Chen Z, Su Q, He Q, Yang J, Xu P, Hu J, Jin Y, Bo Z. Impact of sarcopenia on the short-term and long-term outcomes of intrahepatic cholangiocarcinoma undergoing hepatectomy: A multi-center study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108246. [PMID: 38484491 DOI: 10.1016/j.ejso.2024.108246] [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: 11/28/2023] [Revised: 02/25/2024] [Accepted: 03/02/2024] [Indexed: 04/02/2024]
Abstract
BACKGROUND Sarcopenia is associated with adverse prognosis of intrahepatic cholangiocarcinoma (iCCA) after surgery. METHODS 321 patients with iCCA undergoing surgery were retrospectively recruited and assigned to training and validation cohort. Skeletal muscle index (SMI) was assessed to define sarcopenia. Logistic regression and cox regression analysis were used to identify risk factors. A novel sarcopenia-based nomogram was constructed and validated by ROC curves, calibration curves, and DCA curves. RESULTS 260 patients were included for analysis. The median age was 63.0 years and 161 patients (61.9%) were diagnosed with sarcopenia. Patients with sarcopenia exhibited a higher rate of postoperative complications, a worse OS and RFS than patients without sarcopenia. Sarcopenia, low albumin and intraoperative blood transfusion were independent risk factors of postoperative complications, while sarcopenia and low albumin were risk factors of high CCI≥26.2. Sarcopenia, high PS score, low-undifferentiated differentiation, perineural invasion, TNM stage III-IV were risk factors of OS, and a novel nomogram based on these five factors was built to predict the 12-, 24-, and 36-months OS, with the mean AUC > 0.6. CONCLUSION Sarcopenia is negatively associated with both postoperative complications and survival prognosis of iCCA undergoing hepatectomy.
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Affiliation(s)
- Rizhao Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Bo Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Ziyan Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Qing Su
- Department of Epidemiology and Biostatistics, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
| | - Qikuan He
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jinhuan Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Shandong, China
| | - Puchuang Xu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jiawei Hu
- Department of Hepatobiliary Surgery, Shaoxing People's Hospital, Shaoxing, Zhejiang, China.
| | - Yuepeng Jin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
| | - Zhiyuan Bo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
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19
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Kinoshita M, Sato Y, Shinkawa H, Kimura K, Ohira G, Nishio K, Tanaka R, Kurihara S, Kushiyama S, Tani N, Kawaguchi T, Yamamoto A, Ishizawa T, Kubo S. Impact of Tumor Subclassifications for Identifying an Appropriate Surgical Strategy in Patients with Intrahepatic Cholangiocarcinoma. Ann Surg Oncol 2024; 31:2579-2590. [PMID: 38180706 DOI: 10.1245/s10434-023-14833-1] [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: 09/14/2023] [Accepted: 12/08/2023] [Indexed: 01/06/2024]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. The impact of these subclassifications for identifying appropriate surgical strategies remains unclear. PATIENTS AND METHODS This study included 118 patients with ICC who underwent liver resection. Based on the pathological examination results, the participants were divided into the small duct-type ICC group (n = 64) and large duct-type ICC group (n = 54). The clinicopathological features and postoperative outcomes were compared between the two groups to investigate the impact of subclassification for selecting appropriate surgical strategies. RESULTS Ten patients in the small duct-type ICC group had synchronous or metachronous hepatocellular carcinoma. The large duct-type ICC group had higher proportions of patients who underwent major hepatectomy, extrahepatic bile duct resection, portal vein resection, and lymph node sampling or dissection than the small duct-type ICC group. The large duct-type ICC group had significantly higher incidences of lymph node metastasis/recurrence and pathological major vessel invasion than the other. The small duct-type ICC group exhibited significantly higher recurrence-free and overall survival rates than the large duct-type ICC group. Further, the large duct-type ICC group had a significantly higher incidence of lymph node metastasis/recurrence than the small duct-type ICC at the perihilar region group. CONCLUSIONS Suitable surgical strategies may differ between the small and large duct-type ICCs. In patients with large duct-type ICCs, hepatectomy with lymph node dissection and/or biliary reconstruction should be considered, whereas hepatectomy without these advanced procedures can be suggested for patients with small duct-type ICCs.
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Affiliation(s)
- Masahiko Kinoshita
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Hiroji Shinkawa
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kenjiro Kimura
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Go Ohira
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kohei Nishio
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Ryota Tanaka
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shigeaki Kurihara
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Kushiyama
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Naoki Tani
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takahito Kawaguchi
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Akira Yamamoto
- Department of Radiology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takeaki Ishizawa
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Health Education Course, Department of Education, Faculty of Education, Shitennoji University, Habikino, Osaka, Japan
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20
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Komuta M. Intrahepatic cholangiocarcinoma: histological diversity and the role of the pathologist. JOURNAL OF LIVER CANCER 2024; 24:17-22. [PMID: 38171533 PMCID: PMC10990672 DOI: 10.17998/jlc.2023.12.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 12/11/2023] [Indexed: 01/05/2024]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is one of the primary liver cancers and presents with tumor heterogeneity. About 50% of iCCAs comprise actionable mutations, which completely change patient management. In addition, the precise diagnosis of iCCA, including subtype, has become crucial, and pathologists play an important role in this regard. This review focuses on iCCA heterogeneity; looking at different perspectives to guide diagnosis and optimal treatment choice.
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Affiliation(s)
- Mina Komuta
- Department of Pathology, International University of Health and Welfare School of Medicine, IUHW Narita Hospital, Chiba, Japan
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21
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Bragazzi MC, Venere R, Ribichini E, Covotta F, Cardinale V, Alvaro D. Intrahepatic cholangiocarcinoma: Evolving strategies in management and treatment. Dig Liver Dis 2024; 56:383-393. [PMID: 37722960 DOI: 10.1016/j.dld.2023.08.052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/07/2023] [Accepted: 08/21/2023] [Indexed: 09/20/2023]
Abstract
Intrahepatic cholangiocarcinoma is the second most frequent primary liver cancer after hepatocellular carcinoma. According to International Classification of Diseases-11 (ICD-11), intrahepatic cholangiocarcinoma is identified by a specific diagnostic code, different with respect to perihilar-CCA or distal-CCA. Intrahepatic cholangiocarcinoma originates from intrahepatic small or large bile ducts including the second-order bile ducts and has a silent presentation that combined with the highly aggressive nature and refractoriness to chemotherapy contributes to the alarming increasing incidence and mortality. Indeed, at the moment of the diagnosis, less than 40% of intrahepatic cholangiocarcinoma are suitable of curative surgical therapy, that is so far the only effective treatment. The main goals of clinicians and researchers are to make an early diagnosis, and to carry out molecular characterization to provide the patient with personalized treatment. Unfortunately, these goals are not easily achievable because of the heterogeneity of this tumor from anatomical, molecular, biological, and clinical perspectives. However, recent progress has been made in molecular characterization, surgical treatment, and management of intrahepatic cholangiocarcinoma and, this article deals with these advances.
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Affiliation(s)
- Maria Consiglia Bragazzi
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy.
| | - Rosanna Venere
- Department of Medical-Surgical Sciences and Biotechnology, Sapienza University of Rome Polo Pontino, Italy
| | - Emanuela Ribichini
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Francesco Covotta
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Vincenzo Cardinale
- Department Translational and Precision, Sapienza University of Rome, Italy
| | - Domenico Alvaro
- Department Translational and Precision, Sapienza University of Rome, Italy
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22
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Khosla D, Misra S, Chu PL, Guan P, Nada R, Gupta R, Kaewnarin K, Ko TK, Heng HL, Srinivasalu VK, Kapoor R, Singh D, Klanrit P, Sampattavanich S, Tan J, Kongpetch S, Jusakul A, Teh BT, Chan JY, Hong JH. Cholangiocarcinoma: Recent Advances in Molecular Pathobiology and Therapeutic Approaches. Cancers (Basel) 2024; 16:801. [PMID: 38398194 PMCID: PMC10887007 DOI: 10.3390/cancers16040801] [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: 01/11/2024] [Revised: 02/05/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024] Open
Abstract
Cholangiocarcinomas (CCA) pose a complex challenge in oncology due to diverse etiologies, necessitating tailored therapeutic approaches. This review discusses the risk factors, molecular pathology, and current therapeutic options for CCA and explores the emerging strategies encompassing targeted therapies, immunotherapy, novel compounds from natural sources, and modulation of gut microbiota. CCA are driven by an intricate landscape of genetic mutations, epigenetic dysregulation, and post-transcriptional modification, which differs based on geography (e.g., for liver fluke versus non-liver fluke-driven CCA) and exposure to environmental carcinogens (e.g., exposure to aristolochic acid). Liquid biopsy, including circulating cell-free DNA, is a potential diagnostic tool for CCA, which warrants further investigations. Currently, surgical resection is the primary curative treatment for CCA despite the technical challenges. Adjuvant chemotherapy, including cisplatin and gemcitabine, is standard for advanced, unresectable, or recurrent CCA. Second-line therapy options, such as FOLFOX (oxaliplatin and 5-FU), and the significance of radiation therapy in adjuvant, neoadjuvant, and palliative settings are also discussed. This review underscores the need for personalized therapies and demonstrates the shift towards precision medicine in CCA treatment. The development of targeted therapies, including FDA-approved drugs inhibiting FGFR2 gene fusions and IDH1 mutations, is of major research focus. Investigations into immune checkpoint inhibitors have also revealed potential clinical benefits, although improvements in survival remain elusive, especially across patient demographics. Novel compounds from natural sources exhibit anti-CCA activity, while microbiota dysbiosis emerges as a potential contributor to CCA progression, necessitating further exploration of their direct impact and mechanisms through in-depth research and clinical studies. In the future, extensive translational research efforts are imperative to bridge existing gaps and optimize therapeutic strategies to improve therapeutic outcomes for this complex malignancy.
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Affiliation(s)
- Divya Khosla
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Shagun Misra
- Department of Radiotherapy and Oncology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Pek Lim Chu
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
| | - Peiyong Guan
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
| | - Ritambhra Nada
- Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Rajesh Gupta
- Department of GI Surgery, HPB, and Liver Transplantation, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Khwanta Kaewnarin
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Tun Kiat Ko
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Hong Lee Heng
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
| | - Vijay Kumar Srinivasalu
- Department of Medical Oncology, Mazumdar Shaw Medical Center, NH Health City Campus, Bommasandra, Bangalore 560099, India
| | - Rakesh Kapoor
- Department of Radiotherapy and Oncology, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Deepika Singh
- SingHealth Duke-NUS Institute of Biodiversity Medicine, Singapore 168583, Singapore
| | - Poramate Klanrit
- Cholangiocarcinoma Screening and Care Program (CASCAP), Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Somponnat Sampattavanich
- Siriraj Center of Research Excellence for Systems Pharmacology, Department of Pharmacology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok 73170, Thailand
| | - Jing Tan
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center of Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Sarinya Kongpetch
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Apinya Jusakul
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen 40002, Thailand
- Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Bin Tean Teh
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
- Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore 138672, Singapore
- Laboratory of Cancer Epigenome, Division of Medical Science, National Cancer Center Singapore, Singapore 168583, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore
| | - Jason Yongsheng Chan
- Cancer Discovery Hub, National Cancer Center Singapore, Singapore 168583, Singapore
- Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore 169857, Singapore
- Division of Medical Oncology, National Cancer Center, Singapore 168583, Singapore
| | - Jing Han Hong
- Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, Singapore 169857, Singapore
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23
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Fassan M, Angerilli V, Normanno N, Pruneri G, Marchetti A, Grillo F, Tonini G, Scarpa A, Rimassa L. Practical guidelines for molecular testing of cholangiocarcinoma in clinical practice: Italian experts' position paper. Crit Rev Oncol Hematol 2024; 194:104224. [PMID: 38211900 DOI: 10.1016/j.critrevonc.2023.104224] [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: 10/04/2023] [Revised: 11/20/2023] [Accepted: 11/26/2023] [Indexed: 01/13/2024] Open
Abstract
Biliary tract cancers (BTCs) represent a spectrum of malignancies associated with a dismal prognosis. Recent genomic profiling studies have provided a deeper understanding of the complex and heterogenous molecular landscape of BTCs, identifying several actionable genetic alterations, and expanding treatment options. Due to the high number and complexity of genetic alterations which require testing, next-generation sequencing (NGS) is currently the preferred approach over conventional methods (i.e., immunohistochemistry, fluorescence in-situ hybridization and PCR) for molecular profiling of BTCs and should be performed upfront in all BTC patients. However, BTC sampling often yields low tumor cellularity tissue, hampering NGS analysis. Future perspectives to overcome this obstacle include liquid biopsy and optimization of biopsy protocols. In this position paper, the authors discuss the current histopathologic, molecular, and therapeutic landscape of BTCs, provide a critical overview of the available testing methods for molecular diagnostics, and propose a practical diagnostic algorithm for molecular testing of BTC samples.
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Affiliation(s)
- Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | | | - Nicola Normanno
- Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy
| | - Giancarlo Pruneri
- Pathology Unit 2, Department of Innovation Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; University of Milan, School of Medicine, Milan, Italy
| | - Antonio Marchetti
- Department of Medical, Oral and Biotechnological Sciences, Centre for Advanced Studies and Technology (CAST), University of Chieti, Chieti, Italy
| | - Federica Grillo
- Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, Italy; IRCCS-Ospedale Policlinico San Martino, Genoa, Italy.
| | - Giuseppe Tonini
- Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Roma, Italy; Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Roma, Italy
| | - Aldo Scarpa
- Section of Pathology, Department of Diagnostic and Public Health, University of Verona, Verona, Italy
| | - Lorenza Rimassa
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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24
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Wang H, Chen J, Zhang X, Sheng X, Chang XY, Chen J, Chen MS, Dong H, Duan GJ, Hu HP, Huang ZY, Jia WD, Jiang XQ, Kuang D, Li SS, Li ZS, Lu CL, Qin SK, Qiu XS, Qu LJ, Shao CK, Shen F, Shi GM, Shi SS, Shi YJ, Sun HC, Teng XD, Wang B, Wang ZB, Wen TF, Yang JM, Yang QQ, Ye SL, Yin HF, Yuan ZG, Yun JP, Zang FL, Zhang HQ, Zhang LH, Zhao JM, Zhou J, Zhou WX, Fan J, Chen XP, Lau WY, Ji Y, Cong WM. Expert Consensus on Pathological Diagnosis of Intrahepatic Cholangiocarcinoma (2022 version). J Clin Transl Hepatol 2023; 11:1553-1564. [PMID: 38161496 PMCID: PMC10752808 DOI: 10.14218/jcth.2023.00118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/09/2023] [Accepted: 05/26/2023] [Indexed: 01/03/2024] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) can originate from the large bile duct group (segment bile ducts and area bile ducts), small bile duct group (septal bile ducts and interlobular bile ducts), and terminal bile duct group (bile ductules and canals of Hering) of the intrahepatic biliary tree, which can be histopathological corresponding to large duct type iCCA, small duct type iCCA and iCCA with ductal plate malformation pattern, and cholangiolocarcinoma, respectively. The challenge in pathological diagnosis of above subtypes of iCCA falls in the distinction of cellular morphologies, tissue structures, growth patterns, invasive behaviors, immunophenotypes, molecular mutations, and surgical prognoses. For these reasons, this expert consensus provides nine recommendations as a reference for standardizing and refining the diagnosis of pathological subtypes of iCCA, mainly based on the 5th edition of the World Health Organization Classification of Tumours of the Digestive System.
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Affiliation(s)
- Han Wang
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jun Chen
- Department of Pathology, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xin Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xia Sheng
- Department of Pathology, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiao-Yan Chang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Min-Shan Chen
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Hui Dong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Guang-Jie Duan
- Department of Pathology, The First Affiliated Hospital, Army Medical University, Chongqing, China
| | - He-Ping Hu
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Zhi-Yong Huang
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wei-Dong Jia
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xiao-Qing Jiang
- Department of Biliary Surgery I, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Dong Kuang
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shan-Shan Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
| | - Zeng-Shan Li
- Department of Pathology, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China
| | - Chang-Li Lu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shu-Kui Qin
- Cancer Center of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Xue-Shan Qiu
- Department of Pathology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
| | - Li-Juan Qu
- Department of Pathology, The 900 Hospital of the Chinese People′s Liberation Army Joint Logistics Team, Fuzhou, Fujian, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Feng Shen
- Department of Hepatic Surgery IV, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Guo-Ming Shi
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Su-Sheng Shi
- Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Jun Shi
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Hui-Chuan Sun
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Dong Teng
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Bin Wang
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhan-Bo Wang
- Department of Pathology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Tian-Fu Wen
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jia-Mei Yang
- Department of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Qiao-Qiao Yang
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng-Long Ye
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hong-Fang Yin
- Department of Pathology, Beijing Tsinghua Changgung Hospital, Beijing, China
| | - Zhen-Gang Yuan
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
| | - Feng-Lin Zang
- Department of Pathology, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Hong-Qi Zhang
- Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Li-Hong Zhang
- Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jing-Min Zhao
- Department of Pathology and Hepatology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei-Xun Zhou
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Ping Chen
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Wan Yee Lau
- Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chinese Society of Liver Cancer of Chinese Anti-Cancer Association; Digestive Disease Group of Chinese Society of Pathology, Chinese Medical Association; Chinese Society of Pathology of Chinese Anti-Cancer Association; Hepatic Surgery Group of Chinese Society of Surgery, Chinese Medical Association; Biliary Tract Tumor Committee of China Anti-Cancer Association; Chinese Society of Clinical Oncology
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Pathology, the Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Pathology, Minhang Hospital, Fudan University, Shanghai, China
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Liver Surgery, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Pathology, The First Affiliated Hospital, Army Medical University, Chongqing, China
- Department of Hepatobiliary Medicine, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of General Surgery, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Department of Biliary Surgery I, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China
- Department of Pathology, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Cancer Center of Jinling Hospital, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
- Department of Pathology, The First Affiliated Hospital, China Medical University, Shenyang, Liaoning, China
- Department of Pathology, The 900 Hospital of the Chinese People′s Liberation Army Joint Logistics Team, Fuzhou, Fujian, China
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, China
- Department of Hepatic Surgery IV, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Pathology, Cancer Hospital, Chinese Academy of Medical Sciences, Beijing, China
- Institute of Clinical Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Pathology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Pathology, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Department of Pathology, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Department of Liver Surgery & Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of Special Medical Care, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Pathology, Beijing Tsinghua Changgung Hospital, Beijing, China
- Department of Oncology, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong, China
- Department of Pathology, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
- Department of Anatomy, Histology and Embryology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Pathology and Hepatology, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, China
- Faculty of Medicine, Chinese University of Hong Kong, Hong Kong, China
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25
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Rushbrook SM, Kendall TJ, Zen Y, Albazaz R, Manoharan P, Pereira SP, Sturgess R, Davidson BR, Malik HZ, Manas D, Heaton N, Prasad KR, Bridgewater J, Valle JW, Goody R, Hawkins M, Prentice W, Morement H, Walmsley M, Khan SA. British Society of Gastroenterology guidelines for the diagnosis and management of cholangiocarcinoma. Gut 2023; 73:16-46. [PMID: 37770126 PMCID: PMC10715509 DOI: 10.1136/gutjnl-2023-330029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 09/05/2023] [Indexed: 10/03/2023]
Abstract
These guidelines for the diagnosis and management of cholangiocarcinoma (CCA) were commissioned by the British Society of Gastroenterology liver section. The guideline writing committee included a multidisciplinary team of experts from various specialties involved in the management of CCA, as well as patient/public representatives from AMMF (the Cholangiocarcinoma Charity) and PSC Support. Quality of evidence is presented using the Appraisal of Guidelines for Research and Evaluation (AGREE II) format. The recommendations arising are to be used as guidance rather than as a strict protocol-based reference, as the management of patients with CCA is often complex and always requires individual patient-centred considerations.
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Affiliation(s)
- Simon M Rushbrook
- Department of Hepatology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, UK
| | - Timothy James Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
- University of Edinburgh MRC Centre for Inflammation Research, Edinburgh, UK
| | - Yoh Zen
- Department of Pathology, King's College London, London, UK
| | - Raneem Albazaz
- Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | | | | | - Richard Sturgess
- Digestive Diseases Unit, Aintree University Hospitals NHS Foundation Trust, Liverpool, UK
| | - Brian R Davidson
- Department of Surgery, Royal Free Campus, UCL Medical School, London, UK
| | - Hassan Z Malik
- Department of Surgery, University Hospital Aintree, Liverpool, UK
| | - Derek Manas
- Department of Surgery, Newcastle University, Newcastle upon Tyne, Tyne and Wear, UK
| | - Nigel Heaton
- Department of Hepatobiliary and Pancreatic Surgery, King's College London, London, UK
| | - K Raj Prasad
- John Goligher Colorectal Unit, St. James University Hospital, Leeds, UK
| | - John Bridgewater
- Department of Oncology, UCL Cancer Institute, University College London, London, UK
| | - Juan W Valle
- Department of Medical Oncology, The Christie NHS Foundation Trust/University of Manchester, Manchester, UK
| | - Rebecca Goody
- Department of Oncology, St James's University Hospital, Leeds, UK
| | - Maria Hawkins
- Department of Medical Physics and Biomedical Engineering, University College London, London, UK
| | - Wendy Prentice
- King's College Hospital NHS Foundation Trust, London, UK
| | | | | | - Shahid A Khan
- Hepatology and Gastroenterology Section, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Imperial College Healthcare NHS Trust, London, UK
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26
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Li Z, Huang N, Du Q, Huang W, Wang B, Wang B, Shen G, Zhang H, Shi S, Wang L. Role of immunophenotypic characterisation in prognostic subtyping of intrahepatic cholangiocarcinoma. Pathology 2023; 55:979-988. [PMID: 37858435 DOI: 10.1016/j.pathol.2023.07.008] [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: 01/17/2023] [Revised: 06/07/2023] [Accepted: 07/23/2023] [Indexed: 10/21/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is classified by the 5th WHO classification of tumours of the digestive system as large duct type (LDT) and small duct type (SDT), based on the anatomical location, morphological appearances, immunophenotype, and gene events. We evaluated the subtyping system using real-world data and established a supplementary method using immunohistochemical (IHC) detection. We retrospectively investigated 190 cases of surgically resected iCCA and classified them according to histological evaluations and gene detection. The prognostic value of the IHC markers were evaluated according to the relapse-free survival (RFS) and overall survival (OS). Basic histological classification was insufficient, with 61 cases classified as uncertain. This method showed no prognostic value for RFS or OS. The four-marker IHC detection, including EMA, S100P, N-cadherin, and CRP, which classified 68 cases as LDT, 108 cases as SDT, and 14 cases as uncertain, was highly efficient in subtyping and prognosis. The seven-marker method, including CD56, MUC5AC and MUC6, was consistent with the four-marker method. FGFR2 gene fusion was exclusively detected in 20 cases of SDT iCCA, according to the four- and seven-marker IHC detection. This novel method of iCCA classification exhibited diagnostic, prognostic and therapeutic value in clinical practice.
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Affiliation(s)
- Zhuo Li
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ning Huang
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Du
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wenting Huang
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Bingzhi Wang
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bingning Wang
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guihua Shen
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Haifeng Zhang
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Susheng Shi
- Department of Pathology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Liming Wang
- Department of Hepatobiliary Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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27
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Zou Y, Zhu K, Pang Y, Han J, Zhang X, Jiang Z, Huang Y, Gu W, Ji Y. Molecular Detection of FGFR2 Rearrangements in Resected Intrahepatic Cholangiocarcinomas: FISH Could Be An Ideal Method in Patients with Histological Small Duct Subtype. J Clin Transl Hepatol 2023; 11:1355-1367. [PMID: 37719957 PMCID: PMC10500298 DOI: 10.14218/jcth.2022.00060s] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 03/17/2023] [Accepted: 04/18/2023] [Indexed: 09/19/2023] Open
Abstract
Background and Aims Intrahepatic cholangiocarcinoma (ICC) is a subtype of primary liver cancer for which effective therapeutic agents are lacking. Fibroblast growth factor receptor 2 (FGFR2) has become a promising therapeutic target in ICC; however, its incidence and optimum testing method have not been fully assessed. This study investigated the rearrangement of FGFR2 in intrahepatic cholangiocarcinoma using multiple molecular detection methods. Methods The samples and clinical data of 167 patients who underwent surgical resection of intrahepatic cholangiocarcinoma in Zhongshan hospital, Fudan university were collected. The presence of FGFR2 gene rearrangement was confirmed using fluorescence in situ hybridization (FISH) and targeted next-generation sequencing (NGS). FGFR2 protein expression was determined using immunohistochemistry (IHC). The concordance between the methods was statistically compared. PD-L1 expression was also assessed in this cohort. The clinicopathological characteristics and genomic profile related to FGFR2 rearrangements were also analyzed to assist candidate-screening for targeted therapies. Results FGFR2 rearrangement was detected in 21 of the 167 ICC cases (12.5%) using FISH. NGS analysis revealed that FGFR2 rearrangement was present in 16 of the 20 FISH-positive cases, which was consistent with the FISH results (kappa value=0.696, p<0.01). IHC showed that 80 of the 167 cases (48%) were positive for FGFR2 expression, which was discordant with both FISH and NGS results. By comparison, FGFR2-positivity tended to correlate with unique clinicopathological subgroups, featuring early clinical stage, histologically small duct subtype, and reduced mucus production (P<0.05), with improved overall survival (p<0.05). FGFR2-positivity was not associated with PD-L1 expression in ICCs. In genome research, we identified eight partner genes fused with FGFR2, among which FGFR2-BICC1 was the most common fusion type. BAP1, CDKN2A, and CDKN2B were the most common concomitant genetic alterations of FGFR2, whereas KRAS and IDH1 mutations were mutually exclusive to FGFR2 rearrangements. Conclusions FISH achieved satisfactory concordance with NGS, has potential value for FGFR2 screening for targeted therapies. FGFR2 detection should be prioritized for unique clinical subgroups in ICC, which features a histological small duct subtype, early clinical stage, and reduced mucus production.
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Affiliation(s)
- Yining Zou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Pathology, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China
| | - Kun Zhu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Pathology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yanrui Pang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Jing Han
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Xin Zhang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Zhengzeng Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Yufeng Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Wenyi Gu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
- Fudan University, Shanghai, China
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28
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Pu X, Qi L, Yan JW, Ai Z, Wu P, Yang F, Fu Y, Li X, Zhang M, Sun B, Yue S, Chen J. Oncogenic activation revealed by FGFR2 genetic alterations in intrahepatic cholangiocarcinomas. Cell Biosci 2023; 13:208. [PMID: 37964396 PMCID: PMC10644541 DOI: 10.1186/s13578-023-01156-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 10/26/2023] [Indexed: 11/16/2023] Open
Abstract
BACKGROUND Except for gene fusions, FGFR2 genetic alterations in intrahepatic cholangiocarcinomas (ICCs) have received limited attention, leaving patients harboring activating FGFR2 gene mutations with inadequate access to targeted therapies. EXPERIMENTAL DESIGN We sought to survey FGFR2 genetic alterations in ICC and pan-cancers using fluorescence in situ hybridization and next-generation sequencing. We conducted an analysis of the clinical and pathological features of ICCs with different FGFR2 alterations, compared FGFR2 lesion spectrum through public databases and multicenter data, and performed cellular experiments to investigate the oncogenic potential of different FGFR2 mutants. RESULTS FGFR2 gene fusions were identified in 30 out of 474 ICC samples, while five FGFR2 genetic alterations aside from fusion were present in 290 ICCs. The tumors containing FGFR2 translocations exhibited unique features, which we designated as the "FGFR2 fusion subtypes of ICC". Molecular analysis revealed that FGFR2 fusions were not mutually exclusive with other oncogenic driver genes/mutations, whereas FGFR2 in-frame deletions and site mutations often co-occurred with TP53 mutations. Multicenter and pan-cancer studies demonstrated that FGFR2 in-frame deletions were more prevalent in ICCs (0.62%) than in other cancers, and were not limited to the extracellular domain. We selected representative FGFR2 genetic alterations, including in-frame deletions, point mutations, and frameshift mutations, to analyze their oncogenic activity and responsiveness to targeted drugs. Cellular experiments revealed that different FGFR2 genetic alterations promoted ICC tumor growth, invasion, and metastasis but responded differently to FGFR-selective small molecule kinase inhibitors (SMKIs). CONCLUSIONS FGFR2 oncogenic alterations have different clinicopathological features and respond differently to SMKIs.
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Affiliation(s)
- Xiaohong Pu
- Department of Pathology, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Liang Qi
- Department of Radiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Jia Wu Yan
- Department of Hepatobiliary Surgery, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Zihe Ai
- Department of Medical Genetics, Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Ping Wu
- Department of Medical Genetics, Nanjing Medical University, Nanjing, 210008, Jiangsu, China
| | - Fei Yang
- Department of Hepatobiliary Surgery, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Yao Fu
- Department of Pathology, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China
| | - Xing Li
- Shanghai Origimed Limited Company, Shanghai, 20000, China
| | - Min Zhang
- Beijing Gene Plus Limited Company, Beijing, 10000, China
| | - Beicheng Sun
- Department of Hepatobiliary Surgery, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China.
| | - Shen Yue
- Department of Medical Genetics, Nanjing Medical University, Nanjing, 210008, Jiangsu, China.
| | - Jun Chen
- Department of Pathology, Drum Tower Hospital, Affiliated Hospital of Medical School,Nanjing University, Nanjing, 210008, Jiangsu, China.
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29
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El Jabbour T, Molnar A, Lagana SM. Challenges in Diagnosing and Reporting Cholangiocarcinoma. Surg Pathol Clin 2023; 16:599-608. [PMID: 37536891 DOI: 10.1016/j.path.2023.04.012] [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: 08/05/2023]
Abstract
Intrahepatic cholangiocarcinoma is a challenge to the practicing surgical pathologist for several reasons. It is rare in many parts of the world, and thus practical exposure may be limited. Related to the fact of its rarity is the fact that more common tumors which frequently metastasize to the liver can be morphologically indistinguishable (eg, pancreatic ductal adenocarcinoma). Immunohistochemical testing is generally non-contributory in this context. Other difficulties arise from the protean morphologic manifestations of cholangiocarcinoma (ie, small duct vs. large duct) and the existence of combined cholangiocarcinoma and hepatocellular carcinoma. These, and other issues of concern to the practicing diagnostic pathologist are discussed herein.
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Affiliation(s)
| | - Attila Molnar
- Mount Sinai Morningside and Mount Sinai West, Department of Pathology, 1000 Tenth Avenue, First floor, Room G183, New York, NY 10019, USA
| | - Stephen M Lagana
- New York-Presbyterian /Columbia University, Irving Medical Center, 622 W168th St, Vc14-209, New York, NY 10032, USA.
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30
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Sakata M, Kitada K, Omote R, Sonobe H, Utsumi M, Tokunaga N, Fushimi T, Nagao R, Sakata T, Kaneyoshi T, Toyokawa T, Inagaki M. Synchronous Double Primary Combined Hepatocellular-cholangiocarcinoma and Cholangiolocarcinoma in a Cirrhotic Liver. J Clin Transl Hepatol 2023; 11:991-997. [PMID: 37408806 PMCID: PMC10318272 DOI: 10.14218/jcth.2022.00382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2022] [Revised: 10/09/2022] [Accepted: 01/04/2023] [Indexed: 07/07/2023] Open
Abstract
Both combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and cholangiolocarcinoma are rare primary liver cancers. cHCC-CCA is believed to originate from transformed hepatocellular carcinoma or liver stem/progenitor cells. Cholangiolocarcinoma is characterized by ductular reaction-like anastomosing cords and glands resembling cholangioles or canals containing hepatocellular carcinoma components and adenocarcinoma cells. According to the 2019 revision of the World Health Organization criteria, a subtype with stem cell features as a subclassification of cHCC-CCA was abolished for lack of conclusive evidence of the stem cell origin theory. That led to the classification of cholangiolocarcinoma with hepatocytic differentiation as cHCC-CCA. Consequently, cholangiolocarcinoma without hepatocytic differentiation is classified as a subtype of small-duct cholangiocarcinoma and is assumed to originate from the bile duct. Herein, we report the first case of double primary cHCC-CCA and cholangiolocarcinoma without hepatocytic differentiation in different hepatic segments of a cirrhotic liver. We believe this case supports the validity of the new World Health Organization criteria because the pathological finding of cHCC-CCA in this case shows the transformation of hepatocellular carcinoma to cholangiocarcinoma. Furthermore, this case may demonstrate that immature ductular cell stemness and mature hepatocyte cell stemness in hepatocarcinogenesis can coexist in the same environment. The results provide valuable insights into the mechanisms of growth, differentiation, and regulation of liver cancers.
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Affiliation(s)
- Masahiro Sakata
- Department of Gastroenterology and Hepatology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Koji Kitada
- Department of Surgery, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Rika Omote
- Department of Laboratory and Pathology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Hiroshi Sonobe
- Department of Laboratory and Pathology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Masashi Utsumi
- Department of Surgery, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Naoyuki Tokunaga
- Department of Surgery, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Takashi Fushimi
- Department of Gastroenterology and Hepatology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Ryota Nagao
- Department of Radiology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Tatsuro Sakata
- Department of Gastroenterology and Hepatology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Toshihiko Kaneyoshi
- Department of Gastroenterology and Hepatology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Tatsuya Toyokawa
- Department of Gastroenterology and Hepatology, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
| | - Masaru Inagaki
- Department of Surgery, National Hospital Organization, Fukuyama Medical Center, Fukuyama, Hiroshima, Japan
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31
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Alvaro D, Gores GJ, Walicki J, Hassan C, Sapisochin G, Komuta M, Forner A, Valle JW, Laghi A, Ilyas SI, Park JW, Kelley RK, Reig M, Sangro B. EASL-ILCA Clinical Practice Guidelines on the management of intrahepatic cholangiocarcinoma. J Hepatol 2023; 79:181-208. [PMID: 37084797 DOI: 10.1016/j.jhep.2023.03.010] [Citation(s) in RCA: 81] [Impact Index Per Article: 40.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Accepted: 03/10/2023] [Indexed: 04/23/2023]
Abstract
Intrahepatic cholangiocarcinoma (iCCA) develops inside the liver, between bile ductules and the second-order bile ducts. It is the second most frequent primary liver cancer after hepatocellular carcinoma, and its global incidence is increasing. It is associated with an alarming mortality rate owing to its silent presentation (often leading to late diagnosis), highly aggressive nature and resistance to treatment. Early diagnosis, molecular characterisation, accurate staging and personalised multidisciplinary treatments represent current challenges for researchers and physicians. Unfortunately, these challenges are beset by the high heterogeneity of iCCA at the clinical, genomic, epigenetic and molecular levels, very often precluding successful management. Nonetheless, in the last few years, progress has been made in molecular characterisation, surgical management, and targeted therapy. Recent advances together with the awareness that iCCA represents a distinct entity amongst the CCA family, led the ILCA and EASL governing boards to commission international experts to draft dedicated evidence-based guidelines for physicians involved in the diagnostic, prognostic, and therapeutic management of iCCA.
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32
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Chen W, Xu D, Liu Q, Wu Y, Wang Y, Yang J. Unraveling the heterogeneity of cholangiocarcinoma and identifying biomarkers and therapeutic strategies with single-cell sequencing technology. Biomed Pharmacother 2023; 162:114697. [PMID: 37060660 DOI: 10.1016/j.biopha.2023.114697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/06/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023] Open
Abstract
Cholangiocarcinoma (CCA) is a common malignant tumor of the biliary tract that carries a high burden of morbidity and a poor prognosis. Due to the lack of precise diagnostic methods, many patients are often diagnosed at advanced stages of the disease. The current treatment options available are of varying efficacy, underscoring the urgency for the discovery of more effective biomarkers for early diagnosis and improved treatment. Recently, single-cell sequencing (SCS) technology has gained popularity in cancer research. This technology has the ability to analyze tumor tissues at the single-cell level, thus providing insights into the genomics and epigenetics of tumor cells. It also serves as a practical approach to study the mechanisms of cancer progression and to explore therapeutic strategies. In this review, we aim to assess the heterogeneity of CCA using single-cell sequencing technology, with the ultimate goal of identifying possible biomarkers and potential treatment targets.
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Affiliation(s)
- Wangyang Chen
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province 310003, China
| | - Dongchao Xu
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province 310003, China
| | - Qiang Liu
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province 310003, China
| | - Yirong Wu
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China
| | - Yu Wang
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province 310003, China.
| | - Jianfeng Yang
- Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Hangzhou Institute of Digestive Diseases, Hangzhou, Zhejiang Province 310003, China; Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, Zhejiang Province 310003, China; Zhejiang Provincial Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research, Hangzhou, Zhejiang Province 310003, China.
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Xiao Y, Zhou C, Ni X, Huang P, Wu F, Yang C, Zeng M. Preoperative subcategorization based on magnetic resonance imaging in intrahepatic cholangiocarcinoma. Cancer Imaging 2023; 23:15. [PMID: 36782276 PMCID: PMC9926776 DOI: 10.1186/s40644-023-00533-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Appropriate preoperative identification of iCCA subtype is essential for personalized management, so the aim of this study is to investigate the role of MR imaging features in preoperatively differentiating the iCCA subtype. METHODS Ninety-three patients with mass-forming intrahepatic cholangiocarcinoma (iCCA, 63 small duct type and 30 large duct type) were retrospectively enrolled according to the latest 5th WHO classification (mean age, males vs. females: 60.66 ± 10.53 vs. 61.88 ± 12.82, 50 men). Significant imaging features for differentiating large duct iCCA and small duct iCCA were identified using univariate and multivariate logistic regression analyses, and a regression-based predictive model was then generated. Furthermore, diagnostic performance parameters of single significant imaging features and the predictive model were obtained, and corresponding receiver operating characteristic (ROC) curves were subsequently presented. RESULTS The univariate analysis showed that tumor in vein, arterial phase hypoenhancement, intrahepatic duct dilatation, lack of targetoid restriction and lack of targetoid appearance in T2 were predictors of large duct type iCCA. Arterial phase hypoenhancement, intrahepatic duct dilatation and lack of targetoid restriction were independent predictors for large duct type iCCA in multivariate analysis. The regression-based predictive model has achieved the best preoperative prediction performance in iCCA subcategorization so far. The area under the ROC curve of the regression-based predictive model was up to 0.91 (95% CI: 0.85, 0.98), and it was significantly higher than every single significant imaging feature. CONCLUSIONS Arterial phase hypoenhancement, intrahepatic duct dilatation and lack of targetoid restriction could be considered reliable MR imaging indicators of large duct type iCCA. MR imaging features can facilitate noninvasive prediction of iCCA subtype with satisfactory predictive performance.
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Affiliation(s)
- Yuyao Xiao
- grid.8547.e0000 0001 0125 2443Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
| | - Changwu Zhou
- grid.8547.e0000 0001 0125 2443Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China ,grid.413087.90000 0004 1755 3939Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
| | - Xiaoyan Ni
- grid.8547.e0000 0001 0125 2443Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
| | - Peng Huang
- grid.8547.e0000 0001 0125 2443Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
| | - Fei Wu
- grid.8547.e0000 0001 0125 2443Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032 China
| | - Chun Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China.
| | - Mengsu Zeng
- Department of Radiology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China. .,Shanghai Institute of Medical Imaging, No. 180 Fenglin Road, Xuhui District, Shanghai, 200032, China. .,Department of Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China.
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Zen Y. Intrahepatic cholangiocarcinoma: typical features, uncommon variants, and controversial related entities. Hum Pathol 2023; 132:197-207. [PMID: 35697170 DOI: 10.1016/j.humpath.2022.06.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/02/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023]
Abstract
Pathologists play a central role in the diagnosis and classification of intrahepatic cholangiocarcinoma (iCCA). iCCA is currently classified into small- and large-duct types. Small-duct iCCA is characterized by a mass-forming gross appearance, mucus-poor ductule-like histology, and frequent association with chronic parenchymal liver diseases (eg, cirrhosis). Large-duct iCCA is an infiltrative duct-forming adenocarcinoma with a fibrotic stroma, similar to perihilar cholangiocarcinoma. Chronic cholangiopathies (eg, primary sclerosing cholangitis, liver flukes) are associated with an increased risk of large-duct iCCA. Alterations in IDH1/2, BAP1, or FGFR2 are characteristic molecular features of small-duct iCCA, whereas mutations in KRAS and SMAD4 and the amplification of MDM2 are mainly observed in large-duct iCCA. C-reactive protein and N-cadherin are commonly expressed in small-duct iCCA, and S100P is a good marker for large-duct iCCA. In addition to well-known subtypes (eg, cholangiolocellular carcinoma), uncommon variants are recognized. A tubulocystic variant is often misinterpreted as a benign neoplasm. Mucoepidermoid and enteroblastic variants are under-recognized and pose a diagnostic challenge. Cholangioblastic cholangiocarcinoma characterized by inhibin-A expression was recently found to have an NIPBL-NACC1 gene fusion. Despite significant advances in hepatobiliary pathology, there are still controversial premalignant entities that require large comprehensive studies. There are morphological overlaps between biliary adenofibroma and the tubulocystic variant of iCCA. Type 2 intraductal papillary neoplasm of the bile duct (IPNB) is typically associated with invasive malignancy at the initial presentation and lacks unique molecular features. Therefore, some pathologists prefer the term "papillary cholangiocarcinoma" over type 2 IPNB.
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Affiliation(s)
- Yoh Zen
- Institute of Liver Studies, King's College Hospital, London SE5 9RS, UK.
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35
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Chung YS, Jeon Y, Yoo JE, Chung T, Ryu HJ, Kim H, Rhee H, Park YN. Albumin, filamin-A and cytokeratin 19 help distinguish intrahepatic cholangiocarcinoma from extrahepatic adenocarcinoma. Hepatol Int 2023; 17:77-85. [PMID: 36253584 DOI: 10.1007/s12072-022-10428-2] [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: 06/02/2022] [Accepted: 09/17/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The differential diagnosis of intrahepatic cholangiocarcinomas (iCCAs) from metastatic adenocarcinomas from organs adjacent to the liver (gallbladder, pancreas, and stomach) is difficult due to histopathological similarity and a lack of specific markers. This study aimed to develop a method to differentiate iCCA and adenocarcinomas originated from extrahepatic organs adjacent to the liver. METHODS We retrospectively enrolled surgically resected iCCA (n = 181) and adenocarcinomas from extrahepatic organs (n = 30, n = 28, and n = 38 from gallbladder, pancreas, and stomach, respectively) between 2007 and 2013. The albumin mRNA in situ hybridization (ISH) and immunohistochemistry (IHC) of filamin-A and cytokeratin 19 (CK19) were performed using tissue microarray. Using logistic regression analysis of three markers, iCCA-score was developed, and its diagnostic performance was evaluated. RESULTS The iCCAs were more frequently positive for albumin ISH (23.2% vs. 0%), filamin-A IHC (47.5% vs. 12.5%) and CK19 (68.5% vs. 40.6%) than extrahepatic adenocarcinomas (p < 0.001 for all). The iCCA-score consisting of these three markers was developed, and it showed higher diagnostic performance (area under the curve [AUC], 0.798 vs. 0.616, p < 0.001). Taking an iCCA-score of 2 or higher as the threshold for iCCA, the sensitivity was substantially higher than albumin ISH alone (45.9% and 23.2%, respectively; p < 0.001), but maintained high specificity (94.8% and 100%, respectively). CONCLUSION Albumin ISH and IHC staining for filamin-A and CK19 showed distinct expression patterns between iCCA and extrahepatic adenocarcinomas from gallbladder, pancreas, and stomach. We developed iCCA-score that consisted of those three markers, and it showed better diagnostic performance than albumin ISH alone.
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Affiliation(s)
- Yeon Seung Chung
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Youngsic Jeon
- Natural Products Research Center, Korea Institute of Science and Technology (KIST), Gangneung-si, Gangwon-do, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
| | - Taek Chung
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, Korea
| | - Hyang Joo Ryu
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunki Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
| | - Young Nyun Park
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea. .,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea.
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36
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Liu Y, Yeh MM. Bile duct dysplasia and associated invasive carcinoma: clinicopathological features, diagnosis, and practical challenges. Hum Pathol 2023; 132:158-168. [PMID: 35714833 DOI: 10.1016/j.humpath.2022.06.012] [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: 05/31/2022] [Accepted: 06/08/2022] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma represents the second most frequent type of primary liver cancer that develops through a multistep histopathologic sequence. Dysplasia in the biliary tract epithelium is a precursor lesion of cholangiocarcinoma. This review provides a practical overview of bile duct dysplasia in relation to invasive carcinoma, covering clinicopathological features, diagnostic criteria, differential diagnosis, useful testing modalities, and challenges in daily practice. The key features of biliary intraepithelial neoplasia, intraductal papillary neoplasm, intraductal tubulopapillary neoplasm, and mucinous cystic neoplasm are described. Important differential diagnoses are included. Common pitfalls in histopathologic interpretation of bile duct biopsies and frozen sections are discussed.
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Affiliation(s)
- Yongjun Liu
- Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, WI, 53792, USA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, 98115, USA; Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA.
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Integrative analysis of multiple genomic data from intrahepatic cholangiocarcinoma organoids enables tumor subtyping. Nat Commun 2023; 14:237. [PMID: 36646721 PMCID: PMC9842736 DOI: 10.1038/s41467-023-35896-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023] Open
Abstract
As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. Here, we verify the recently suggested two subgroups of ICC in the organoids model, compare the characteristics between types. ICC patients are subclassified into small-duct (SD) and large-duct (LD) subtype according to histological characteristics. ICC organoids are established, and unsupervised principal component analysis clustering separates each type of ICC. Differential gene expression reveals enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type (P < 0.05). Gene set enrichment analysis demonstrates that the cholangiocarcinoma class 2 signature, defined by Andersen et al., is enriched in the LD-type (enrichment Score = 2.19, P < 0.001). A protein-protein interaction network analysis identifies ZNF217 as a significant hub protein (odds ratio = 4.96, P = 0.0105). We perform prospective modeling of histological subtype using patient-derived organoids. Moreover, gene expression profiling of ICC organoids enables identification of type-specific targetable pathways.
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38
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Park HJ, Kim KW, Lee SS. Artificial intelligence in radiology and its application in liver disease. ARTIFICIAL INTELLIGENCE, MACHINE LEARNING, AND DEEP LEARNING IN PRECISION MEDICINE IN LIVER DISEASES 2023:53-79. [DOI: 10.1016/b978-0-323-99136-0.00002-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Testa U, Pelosi E, Castelli G. Cholangiocarcinoma: Molecular Abnormalities and Cells of Origin. Technol Cancer Res Treat 2023; 22:15330338221128689. [PMID: 36872875 PMCID: PMC9989414 DOI: 10.1177/15330338221128689] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 09/01/2022] [Accepted: 09/07/2022] [Indexed: 03/07/2023] Open
Abstract
Cholangiocarcinomas (CCAs) are a group of heterogeneous epithelial malignancies that can originate at the level of any location of the biliary tree. These tumors are relatively rare but associated with a high rate of mortality. CCAs are morphologically and molecularly heterogeneous and for their location can be distinguished as intracellular and extracellular, subdivided into perihilar and distal. Recent epidemiological, molecular, and cellular studies have supported that the consistent heterogeneity observed for CCAs may result from the convergence of various key elements mainly represented by risk factors, heterogeneity of the associated molecular abnormalities at genetic and epigenetic levels and by different potential cells of origin. These studies have consistently contributed to better defining the pathogenesis of CCAs and to identify in some instances new therapeutic targets. Although the therapeutic progress were still limited, these observations suggest that a better understanding of the molecular mechanisms underlying CCA in the future will help to develop more efficacious treatment strategies.
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Affiliation(s)
- Ugo Testa
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Elvira Pelosi
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
| | - Germana Castelli
- Department of Oncology, Istituto Supeirore di Sanità, Rome, Italy
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40
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Connor AA, Kodali S, Abdelrahim M, Javle MM, Brombosz EW, Ghobrial RM. Intrahepatic cholangiocarcinoma: The role of liver transplantation, adjunctive treatments, and prognostic biomarkers. Front Oncol 2022; 12:996710. [PMID: 36479082 PMCID: PMC9719919 DOI: 10.3389/fonc.2022.996710] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 10/31/2022] [Indexed: 08/01/2023] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a primary epithelial cell malignancy of the liver with rising incidence rate globally. Its insidious presentation, heterogeneous and aggressive biology, and recalcitrance to current therapies results in unacceptably high morbidity and mortality. This has spurred research efforts in the last decade to better characterize it molecularly with translation to improved diagnostic tools and treatments. Much of this has been driven by patient advocacy. This has renewed interest in orthotopic liver transplantation (LT) with adjunctive therapies for iCCA, which was historically disparaged due to poor recipient outcomes and donor organ scarcity. However, the optimal use of LT as a treatment for iCCA care remains unclear. Here, we review the epidemiology of iCCA, the history of LT as a treatment modality, alternative approaches to iCCA local control, the evidence for peri-operative systemic therapies, and the potential roles of biomarkers and targeted agents. In doing so, we hope to prioritize areas for continued research and identify areas where multidisciplinary care can improve outcomes.
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Affiliation(s)
- Ashton A. Connor
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
| | - Sudha Kodali
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
| | - Maen Abdelrahim
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
- Section of Gastrointestinal Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
- Cockrell Center Phase 1 Unit, Cockrell Center for Advanced Therapeutics, Houston Methodist Hospital, Houston, TX, United States
| | - Milind M. Javle
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, United States
| | | | - R. Mark Ghobrial
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, JC Walter Jr Transplant Center, Houston Methodist Hospital, Houston, TX, United States
- Department of Surgery, Houston Methodist Hospital, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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Tanaka M, Kunita A, Yamagishi M, Katoh H, Ishikawa S, Yamamoto H, Abe J, Arita J, Hasegawa K, Shibata T, Ushiku T. KRAS mutation in intrahepatic cholangiocarcinoma: Linkage with metastasis-free survival and reduced E-cadherin expression. Liver Int 2022; 42:2329-2340. [PMID: 35833881 DOI: 10.1111/liv.15366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 06/21/2022] [Accepted: 07/11/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Although KRAS mutations are the major driver of intrahepatic cholangiocarcinoma (ICC), their role remains unexplored. This study aimed to elucidate the prognostic effects, association with clinicopathologic characteristics and potent functions of KRAS mutations in ICC. METHODS A hundred and seven resected stage I-III ICCs were analysed for KRAS mutation status and its link with clinicopathological features. An independent validation cohort (n = 138) was included. In vitro analyses using KRAS-mutant ICC cell lines were performed. RESULTS KRAS mutation was significantly associated with worse overall survival in stage I-III ICCs, which was validated in an independent cohort. Recurrence-free survival did not significantly differ between cases with and without KRAS mutations, but if limited to recurrence with extrahepatic metastasis, KRAS-mutant cases showed significantly worse distant metastasis-free survival than KRAS-wild cases showed. KRAS mutations were associated with frequent tumour budding with reduced E-cadherin expression. In vitro, KRAS depletion caused marked inhibition of cell growth and migration together with E-cadherin upregulation in KRAS-mutant ICC cells. The RNA-sequencing assay revealed that KRAS depletion caused MYC pathway downregulation and interferon pathway upregulation. CONCLUSIONS Our observations suggest that KRAS mutations are associated with aggressive behaviour of ICC, especially the development of extrahepatic metastasis. Mutant KRAS is likely to change the adhesive status of ICC cells, affect the responsiveness of tumour cells to interferon immune signals, and consequently promote extrahepatic metastasis. KRAS mutation status, which predicts the prognoses of patients with ICC after surgical resection, is expected to help stratify patients better for individual postoperative treatment strategies.
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Affiliation(s)
- Mariko Tanaka
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Akiko Kunita
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Makoto Yamagishi
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan
| | - Hiroto Katoh
- Department of Preventive Medicine, The University of Tokyo, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Preventive Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Yamamoto
- AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan
| | - Jun Abe
- Department of Oncology, Microbiology and Immunology, University of Fribourg, Fribourg, Switzerland
| | - Junichi Arita
- Department of Surgery, Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Department of Surgery, Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
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Kinzler MN, Schulze F, Bankov K, Gretser S, Becker N, Leichner R, Stehle A, Abedin N, Trojan J, Zeuzem S, Schnitzbauer AA, Wild PJ, Walter D. Impact of small duct- and large duct type on survival in patients with intrahepatic cholangiocarcinoma: Results from a German tertiary center. Pathol Res Pract 2022; 238:154126. [PMID: 36137398 DOI: 10.1016/j.prp.2022.154126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Revised: 09/09/2022] [Accepted: 09/13/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND & AIMS In recent years, histopathological characterization of intrahepatic cholangiocarcinoma revealed small duct type (SD-iCCA) and large duct type (LD-iCCA). Data on the prevalence of the subtypes are limited and highly varying. The aim of this study was to assess the prevalence of SD-iCCA and LD-iCCA and their impact on survival for the first time in a European cohort. MATERIALS AND METHODS All patients with surgically resected iCCA diagnosed between December 2005 and December 2021 at the University Hospital Frankfurt were analyzed by an expert hepatobiliary pathologist. For overall survival (OS) and progression-free survival (PFS), Kaplan-Meier curves and Cox-regression analyses were performed. RESULTS In total, 116 patients with surgically resected iCCA treated in our tertiary hospital were classified as SD-iCCA (73.3%, n = 85) and LD-iCCA (26.7%, n = 31). Subgroup analyses revealed median OS of 54.4 months (95% CI = 38.3 - 70.4 months) and 25.4 months (95% CI = 15.1 - 35.7 months) for SD-iCCA and LD-iCCA, respectively (p = 0.027). The median PFS for patients receiving gemcitabine-based chemotherapy with SD- and LD-iCCA was 8.4 months (95% CI = 4.7 - 12 months) and 3.3 months (95% CI = 1.8 - 4.7 months), respectively (p = 0.011). While LD-iCCA was as a significant risk factor of OS (HR = 1.7, 95% CI = 1 - 2.8, p = 0.031) in univariate analysis, it was not significant in multivariate analysis. CONCLUSION In contrast to data from Asia, SD-iCCA is more prevalent than LD-iCCA in our cohort. LD-iCCA is associated with impaired OS after surgical resection and decreased PFS for patients receiving chemotherapy. These findings may suggest including the histological subtype in clinical routine diagnostics.
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Affiliation(s)
- Maximilian N Kinzler
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany.
| | - Falko Schulze
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Katrin Bankov
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Steffen Gretser
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Nina Becker
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany; University Cancer Center (UCT) Frankfurt, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
| | - Regina Leichner
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Frankfurt, Germany
| | - Angelika Stehle
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Nada Abedin
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Jörg Trojan
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Andreas A Schnitzbauer
- Department of General, Visceral, Transplant and Thoracic Surgery, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
| | - Peter J Wild
- Dr. Senckenberg Institute of Pathology, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany; Frankfurt Institute for Advanced Studies (FIAS), Frankfurt am Main, Germany; Wildlab, University Hospital Frankfurt MVZ GmbH, Frankfurt am Main, Germany
| | - Dirk Walter
- Department of Internal Medicine I, University Hospital Frankfurt, Goethe University Frankfurt am Main, Germany
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Abdelrahim M, Al-Rawi H, Esmail A, Xu J, Umoru G, Ibnshamsah F, Abudayyeh A, Victor D, Saharia A, McMillan R, Al Najjar E, Bugazia D, Al-Rawi M, Ghobrial RM. Gemcitabine and Cisplatin as Neo-Adjuvant for Cholangiocarcinoma Patients Prior to Liver Transplantation: Case-Series. Curr Oncol 2022; 29:3585-3594. [PMID: 35621680 PMCID: PMC9139862 DOI: 10.3390/curroncol29050290] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/01/2022] [Accepted: 05/06/2022] [Indexed: 01/04/2023] Open
Abstract
Background: The management of cholangiocarcinoma is continually reviewed on a current evidence basis to develop practice guidelines and consensus statements. However, the standardized treatment guidelines are still unclear for cholangiocarcinoma patients who are listed for liver transplantation. We aimed to validate and evaluate the potential efficacy of chemotherapy combination of Gemcitabine and Cisplatin as a neo-adjuvant treatment for cholangiocarcinoma patients before liver transplantation. Methods: In this prospective case series, patients with locally advanced, unresectable, hilar, or intrahepatic cholangiocarcinoma with no evidence of extrahepatic disease or vascular involvement were treated with a combination of neoadjuvant gemcitabine and cisplatin with no radiation. All patients included received chemotherapy prior to being listed for liver transplantation at a single cancer center according to an open-labeled, and center-approved clinical management protocol. The primary endpoints were the overall survival and recurrence-free survival after liver transplantation. Results: Between 1 March 2016, and 15 March 2022, 10 patients (8 males and 2 females) with a median age of 62.71(interquartile range: 60.02–71.87) had a confirmed diagnosis of intrahepatic or hilar cholangiocarcinoma and underwent liver transplantation. Median days of neoadjuvant therapy for a given combination of gemcitabine and cisplatin were 181 (IRQ: 120–250). Nine patients (90%) were reported with no recurrence or metastasis, and only 1 patient had confirmed metastasis (10%); days for metastasis after transplantation were 612 for this patient. All patients received a combination of gemcitabine and cisplatin as neo-adjuvant while awaiting liver transplantation. The median days of follow-up were 851 (813–967). Overall survival was 100% (95% CI 100–100%) at both years one and two; 75% (95% CI 13–96%) at years three to five. One patient died at eight hundred and eighty-five days. No adverse events were reported after liver transplantation including the patient who was confirmed with recurrence. Conclusions: Our finding demonstrated that neo-adjuvant gemcitabine and cisplatin with no radiation prior to liver transplantation resulted in excellent outcomes for patients with cholangiocarcinoma.
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Affiliation(s)
- Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- Correspondence:
| | - Hadeel Al-Rawi
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA; (H.A.-R.); (A.E.)
- Cancer Clinical Trials, Houston Methodist Research Institute, Houston, TX 77030, USA
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Jiaqiong Xu
- Center for Outcomes Research, Houston Methodist Research Institute, Houston, TX 77030, USA;
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Cancer Center, Houston, TX 77030, USA;
| | - Fahad Ibnshamsah
- Medical Oncology, King Fahd Specialist Hospital, Buraydah 52366, Saudi Arabia;
- Faculty of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - David Victor
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ashish Saharia
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Robert McMillan
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
| | - Ebtesam Al Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sanaa 15201, Yemen;
| | - Doaa Bugazia
- Faculty of Medicine, University of Tripoli, Tripoli 22131, Libya;
| | - Maryam Al-Rawi
- Faculty of Medicine, University of Jordan, Amman 11942, Jordan;
| | - Rafik M. Ghobrial
- Weill Cornell Medical College, New York, NY 14853, USA; (A.S.); (R.M.); (R.M.G.)
- JC Walter Jr Center for Transplantation and Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston, TX 77030, USA;
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Association between Immunohistochemistry Markers and Tumor Features and Their Diagnostic and Prognostic Values in Intrahepatic Cholangiocarcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:8367395. [PMID: 35529254 PMCID: PMC9071873 DOI: 10.1155/2022/8367395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Revised: 02/14/2022] [Accepted: 02/22/2022] [Indexed: 12/28/2022]
Abstract
This study investigated the expression of some frequently used immunohistochemistry (IHC) markers. Besides, we evaluated their correlations with the clinical features and outcomes of intrahepatic cholangiocarcinoma (ICC). Patients who underwent surgical removal of the ICC tumors were followed up for 4 years. The paraffin-embedded sections were used to obtain different markers, including CK7, CK19, CK20, CDX2, Glypican3, Hepa1, Ki-67, Villin, and SATB1. Overall survival in relation to IHC marker expression patterns and other clinical characteristics was evaluated by Kaplan-Meier survival curve and log-rank test, followed by the Cox proportional hazard model (to evaluate the relationship between multiple factors and the overall postoperative survival). A total of 122 ICC patients (67 males and 55 females, averagely aged 57.75) were included in this study. There were 44 cases with vascular invasion, 46 cases with lymphatic metastasis, and 13 cases with distant metastasis. CK7 was negatively correlated with lymphatic metastasis; and in distant-metastasis cases, the positive ratio of SATB1 was lower. Interestingly, SATB1 expression indicated a poorer survival, while Villin expression was associated with a better survival. The COX regression analysis showed that female was a protective factor versus male, Villin expression was a strong protective factor, and Ki-67 expression was correlated with a poor survival. Together, IHC markers are associated with tumor features and postoperative survival, especially for SATB1 as a risk factor and Villin as a protective marker, and female ICC patients may have better survival than males.
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45
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Rhee H, Choi SH, Park JH, Cho ES, Yeom SK, Park S, Han K, Lee SS, Park MS. Preoperative magnetic resonance imaging-based prognostic model for mass-forming intrahepatic cholangiocarcinoma. Liver Int 2022; 42:930-941. [PMID: 35152534 DOI: 10.1111/liv.15196] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS As most staging systems for intrahepatic cholangiocarcinoma (iCCA) are based on pathological results, preoperative prognostic prediction is limited. This study aimed to develop and validate a prognostic model for the overall survival of patients with mass-forming iCCA (MF-iCCA) using preoperative magnetic resonance imaging (MRI) and clinical findings. METHODS We enrolled a total of 316 patients who underwent preoperative MRI and surgical resection for treatment-naive MF-iCCA from six institutions, between January 2009 and December 2015. The subjects were randomly assigned to a training set (n = 208) or validation set (n = 108). The MRIs were independently reviewed by three abdominal radiologists. Using MRI and clinical findings, an MRI prognostic score was established. We compared the discrimination performance of MRI prognostic scores with those of conventional pathological staging systems. RESULTS We developed an MRI prognostic score consisting of serum CA19-9 and three MRI findings (tumour multiplicity, lymph node metastasis and bile duct invasion). The MRI prognostic score demonstrated good discrimination performance in both the training set (C-index, 0.738; 95% confidence interval [CI], 0.698-0.780) and validation set (C-index, 0.605; 95% CI, 0.526-0.680). In the validation set, MRI prognostic score showed no significant difference with AJCC 8th TNM stage, MEGNA score and Nathan's stage. CONCLUSIONS Our MRI prognostic score for overall survival of MF-iCCA showed comparable discriminatory performance with pathological staging systems and might be used to determine an optimal treatment strategy.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Ji Hoon Park
- Department of Radiology, Seoul National University Bundang Hospital, Seoul, Republic of Korea
| | - Eun-Suk Cho
- Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine Seoul, Seoul, Republic of Korea
| | - Suk-Keu Yeom
- Department of Radiology, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea
| | - Sumi Park
- Department of Radiology, National Health Insurance Service Ilsan Hospital, Goyang, Republic of Korea
| | - Kyunghwa Han
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, College of Medicine, Yonsei University, Seoul, South Korea
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Mi-Suk Park
- Department of Radiology, Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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46
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Chung T, Park YN. Up-to-Date Pathologic Classification and Molecular Characteristics of Intrahepatic Cholangiocarcinoma. Front Med (Lausanne) 2022; 9:857140. [PMID: 35433771 PMCID: PMC9008308 DOI: 10.3389/fmed.2022.857140] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/07/2022] [Indexed: 12/26/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is an aggressive primary liver malignancy with an increasing incidence worldwide. Recently, histopathologic classification of small duct type and large duct type iCCA has been introduced. Both these types of tumors exhibit differences in clinicopathological features, mutational profiles, and prognosis. Small duct type iCCA is composed of non-mucin-producing cuboidal cells, whereas large duct type iCCA is composed of mucin-producing columnar cells, reflecting different cells of origin. Large duct type iCCA shows more invasive growth and poorer prognosis than small duct type iCCA. The background liver of small duct type iCCA often shows chronic liver disease related to hepatitis B or C viral infection, or alcoholic or non-alcoholic fatty liver disease/steatohepatitis, in contrast to large duct type iCCA that is often related to hepatolithiasis and liver fluke infection. Cholangiolocarcinoma is a variant of small duct type iCCA composed of naïve-looking cuboidal cells forming cords or ductule-like structures, and shows better prognosis than the conventional small duct type. Fibrous tumor stroma, one of the characteristic features of iCCA, contains activated fibroblasts intermixed with innate and adaptive immune cells. The types of stroma (mature versus immature) are related to tumor behavior and prognosis. Low tumor-infiltrating lymphocyte density, KRAS alteration, and chromosomal instability are related to immune-suppressive tumor microenvironments with resistance to programmed death 1/ programmed death ligand 1 blockade. Data from recent large-scale exome analyses have revealed the heterogeneity in the molecular profiles of iCCA, showing that small duct type iCCA exhibit frequent BAP1, IDH1/2 hotspot mutations and FGFR2 fusion, in contrast to frequent mutations in KRAS, TP53, and SMAD4 observed in large duct type iCCA. Multi-omics analyses have proposed several molecular classifications of iCCA, including inflammation class and proliferation class. The inflammation class is enriched in inflammatory signaling pathways and expression of cytokines, while the proliferation class has activated oncogenic growth signaling pathways. Diverse pathologic features of iCCA and its associated multi-omics characteristics are currently under active investigation, thereby providing insights into precision therapeutics for patients with iCCA. This review provides the latest knowledge on the histopathologic classification of iCCA and its associated molecular features, ranging from tumor microenvironment to genomic and transcriptomic research.
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Affiliation(s)
- Taek Chung
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul, South Korea
| | - Young Nyun Park
- Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, South Korea
- *Correspondence: Young Nyun Park,
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47
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Song G, Shi Y, Meng L, Ma J, Huang S, Zhang J, Wu Y, Li J, Lin Y, Yang S, Rao D, Cheng Y, Lin J, Ji S, Liu Y, Jiang S, Wang X, Zhang S, Ke A, Wang X, Cao Y, Ji Y, Zhou J, Fan J, Zhang X, Xi R, Gao Q. Single-cell transcriptomic analysis suggests two molecularly subtypes of intrahepatic cholangiocarcinoma. Nat Commun 2022; 13:1642. [PMID: 35347134 PMCID: PMC8960779 DOI: 10.1038/s41467-022-29164-0] [Citation(s) in RCA: 64] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Accepted: 02/25/2022] [Indexed: 12/12/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1− iCCAphl has significantly reduced levels of infiltrating CD4+ T cells, CD56+ NK cells, and increased CCL18+ macrophages and PD1+CD8+ T cells compared to S100P-SPP1 + iCCApps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCApps has significantly more SPP1+ macrophage infiltration, less aggressiveness and better survival than S100P + SPP1− iCCAphl. Moreover, S100P-SPP1 + iCCApps harbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA. The molecular classification and tumour microenvironment in intrahepatic cholangiocarcinoma (iCCA) need further characterisation. Here, the authors perform single cell RNA-sequencing from 14 pairs of iCCA tumours and non-tumour liver tissues and propose S100P and SPP1 as markers for patient classification.
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Affiliation(s)
- Guohe Song
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yang Shi
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China
| | - Lu Meng
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Jiaqiang Ma
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.,Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Siyuan Huang
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Juan Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yingcheng Wu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Jiaxin Li
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | - Youpei Lin
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Shuaixi Yang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Dongning Rao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Yifei Cheng
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Jian Lin
- Department of Cancer Center, Jin Shan Hospital, Fudan University, Shanghai, China
| | - Shuyi Ji
- Department of Cancer Center, Jin Shan Hospital, Fudan University, Shanghai, China
| | - Yuming Liu
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Shan Jiang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoliang Wang
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Shu Zhang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Aiwu Ke
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Xiaoying Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jian Zhou
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.,Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Jia Fan
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China. .,Key Laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
| | - Xiaoming Zhang
- Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
| | - Ruibin Xi
- School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China.
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Fudan University, Shanghai, China.
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Vij M, Puri Y, Rammohan A, G G, Rajalingam R, Kaliamoorthy I, Rela M. Pathological, molecular, and clinical characteristics of cholangiocarcinoma: A comprehensive review. World J Gastrointest Oncol 2022; 14:607-627. [PMID: 35321284 PMCID: PMC8919011 DOI: 10.4251/wjgo.v14.i3.607] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/13/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Cholangiocarcinomas are a heterogeneous group of highly aggressive cancers that may arise anywhere within the biliary tree. There is a wide geographical variation with regards to its incidence, and risk-factor associations which may include liver fluke infection, primary sclerosing cholangitis, and hepatolithiasis amongst others. These tumours are classified into intrahepatic, perihilar and distal based on their anatomical location. Morphologically, intrahepatic cholangiocarcinomas are further sub-classified into small and large duct variants. Perihilar and distal cholangiocarcinomas are usually mucin-producing tubular adenocarcinomas. Cholangiocarcinomas develop through a multistep carcinogenesis and are preceded by dysplastic and in situ lesions. While clinical characteristics and management of these tumours have been extensively elucidated in literature, their ultra-structure and tumour biology remain relatively unknown. This review focuses on the current knowledge of pathological characteristics, molecular alterations of cholangiocarcinoma, and its precursor lesions (including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm).
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Affiliation(s)
- Mukul Vij
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Yogesh Puri
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ashwin Rammohan
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Gowripriya G
- Department of Pathology, Dr Rela Institute and Medical center, Chennai 600044, Tamil Nadu, India
| | - Rajesh Rajalingam
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Ilankumaran Kaliamoorthy
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
| | - Mohamed Rela
- Institute of Liver Disease and Transplantation, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India
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49
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Meta-analysis on prognostic value of KRAS mutation in resected mass-forming cholangiocarcinoma. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1455-1463. [PMID: 35317947 DOI: 10.1016/j.ejso.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 02/14/2022] [Accepted: 03/08/2022] [Indexed: 11/22/2022]
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50
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Kovač JD, Janković A, Đikić-Rom A, Grubor N, Antić A, Dugalić V. Imaging Spectrum of Intrahepatic Mass-Forming Cholangiocarcinoma and Its Mimickers: How to Differentiate Them Using MRI. Curr Oncol 2022; 29:698-723. [PMID: 35200560 PMCID: PMC8870737 DOI: 10.3390/curroncol29020061] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/23/2022] [Accepted: 01/29/2022] [Indexed: 12/14/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary hepatic malignancy, with mass-forming growth pattern being the most common. The typical imaging appearance of mass-forming ICC (mICC) consists of irregular ring enhancement in the arterial phase followed by the progressive central enhancement on portal venous and delayed phases. However, atypical imaging presentation in the form of hypervascular mICC might also be seen, which can be attributed to distinct pathological characteristics. Ancillary imaging features such as lobular shape, capsular retraction, segmental biliary dilatation, and vascular encasement favor the diagnosis of mICC. Nevertheless, these radiological findings may also be present in certain benign conditions such as focal confluent fibrosis, sclerosing hemangioma, organizing hepatic abscess, or the pseudosolid form of hydatid disease. In addition, a few malignant lesions including primary liver lymphoma, hemangioendothelioma, solitary hypovascular liver metastases, and atypical forms of hepatocellular carcinoma (HCC), such as scirrhous HCC, infiltrative HCC, and poorly differentiated HCC, may also pose a diagnostic dilemma by simulating mICC in imaging studies. Diffusion-weighted imaging and the use of hepatobiliary contrast agents might be helpful for differential diagnosis in certain cases. The aim of this manuscript is to provide a comprehensive overview of mICC imaging features and to describe useful tips for differential diagnosis with its potential mimickers.
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Affiliation(s)
- Jelena Djokic Kovač
- Center for Radiology and Magnetic Resonance Imaging, University Clinical Centre of Serbia, Pasterova No. 2, 11000 Belgrade, Serbia;
- Faculty of Medicine, University of Belgrade, Dr Subotica No. 8, 11000 Belgrade, Serbia; (N.G.); (A.A.); (V.D.)
- Correspondence: ; Tel.: +381-65-8270-290
| | - Aleksandra Janković
- Center for Radiology and Magnetic Resonance Imaging, University Clinical Centre of Serbia, Pasterova No. 2, 11000 Belgrade, Serbia;
| | - Aleksandra Đikić-Rom
- Department of Pathology, University Clinical Centre of Serbia, Pasterova No.2, 11000 Belgrade, Serbia;
| | - Nikica Grubor
- Faculty of Medicine, University of Belgrade, Dr Subotica No. 8, 11000 Belgrade, Serbia; (N.G.); (A.A.); (V.D.)
- Clinic for Digestive Surgery, University Clinical Centre of Serbia, Koste Todorovica Street, No. 6, 11000 Belgrade, Serbia
| | - Andrija Antić
- Faculty of Medicine, University of Belgrade, Dr Subotica No. 8, 11000 Belgrade, Serbia; (N.G.); (A.A.); (V.D.)
- Clinic for Digestive Surgery, University Clinical Centre of Serbia, Koste Todorovica Street, No. 6, 11000 Belgrade, Serbia
| | - Vladimir Dugalić
- Faculty of Medicine, University of Belgrade, Dr Subotica No. 8, 11000 Belgrade, Serbia; (N.G.); (A.A.); (V.D.)
- Clinic for Digestive Surgery, University Clinical Centre of Serbia, Koste Todorovica Street, No. 6, 11000 Belgrade, Serbia
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