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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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Krzywoń L, Lazaris A, Petrillo SK, Zlotnik O, Gao ZH, Metrakos P. Histopathological Growth Patterns Determine the Outcomes of Colorectal Cancer Liver Metastasis Following Liver Resection. Cancers (Basel) 2024; 16:3148. [PMID: 39335120 PMCID: PMC11430747 DOI: 10.3390/cancers16183148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/14/2024] [Accepted: 08/17/2024] [Indexed: 09/30/2024] Open
Abstract
INTRODUCTION Colorectal cancer liver metastasis (CRCLM) remains a lethal diagnosis, with an overall 5-year survival rate of 5-10%. Two distinct histopathological growth patterns (HGPs) of CRCLM are known to have significantly differing rates of patient survival and response to treatment. We set out to review the results of 275 patients who underwent liver resection for CRCLM at the McGill University Health Center (MUHC) and analyze their clinical outcome, mutational burden, and pattern of cancer progression in light of their HGPs, and to consider their potential effect on surgical decision making. METHODS We performed a retrospective multivariate analysis on clinical data from patients with CRCLM (n = 275) who underwent liver resection at the McGill University Health Center (MUHC). All tumors were scored using international consensus guidelines by pathologists trained in HGP scoring. RESULTS A total of 109 patients (42.2%) were classified as desmoplastic and angiogenic, whereas 149 patients (57.7%) were non-desmoplastic and vessel co-opting. The 5-year survival rates for angiogenic patients compared with vessel co-opting patients were 47.1% and 13%, respectively (p < 0.0001). Multivariate analysis showed patients with vessel co-opting CRCLM had a higher incidence of extrahepatic metastatic disease (p = 0.0215) compared with angiogenic CRCLM. Additionally, KRAS mutation status was a marker of increased likelihood of disease recurrence (p = 0.0434), as was increased number of liver tumors (p = 0.0071) and multiple sites of extrahepatic metastatic disease (p < 0.0001). CONCLUSIONS Multivariate analysis identified key clinical prognostic and molecular features correlating with the two HGPs. Determining liver tumor HGPs is essential for patient prognostication and treatment optimization.
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Affiliation(s)
- Lucyna Krzywoń
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
- Department of Experimental Surgery, McGill University, 1650 Cedar Ave., Room A7.117, Montreal, QC H4A 3J1, Canada
| | - Anthoula Lazaris
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
| | - Stephanie K Petrillo
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
| | - Oran Zlotnik
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
- Department of Experimental Surgery, McGill University, 1650 Cedar Ave., Room A7.117, Montreal, QC H4A 3J1, Canada
| | - Zu-Hua Gao
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
- Department of Pathology and Labaratory Medicine, University of British Columbia, Rm. G227-2211 Wesbrook Mall, Vancouver, BC V6T 2B5, Canada
- McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada
| | - Peter Metrakos
- Cancer Research Program, Research Institute of McGill University Health Center Glen Site, McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd Room E02.6218, Montreal, QC H4A 3J1, Canada
- McGill University Health Center, Royal Victoria Hospital-Glen Site, 1001 Decarie Blvd, Montreal, QC H4A 3J1, Canada
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3
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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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4
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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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5
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Wei T, Lu J, Xiao XL, Weiss M, Popescu I, Marques HP, Aldrighetti L, Maithel SK, Pulitano C, Bauer TW, Shen F, Poultsides GA, Soubrane O, Martel G, Koerkamp BG, Itaru E, Lv Y, Zhang XF, Pawlik TM. Classification of Intrahepatic Cholangiocarcinoma into Perihilar Versus Peripheral Subtype. Ann Surg Oncol 2024; 31:1232-1242. [PMID: 37930500 DOI: 10.1245/s10434-023-14502-3] [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: 07/27/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) constitutes a group of heterogeneous malignancies within the liver. We sought to subtype ICC based on anatomical origin of tumors, as well as propose modifications of the current classification system. METHODS Patients undergoing curative-intent resection for ICC, hilar cholangiocarcinoma (CCA), or hepatocellular carcinoma (HCC) were identified from three international multi-institutional consortia of databases. Clinicopathological characteristics and survival outcomes were assessed. RESULTS Among 1264 patients with ICC, 1066 (84.3%) were classified as ICC-peripheral subtype, whereas 198 (15.7%) were categorized as ICC-perihilar subtype. Compared with ICC-peripheral subtype, ICC-perihilar subtype was more often associated with aggressive tumor characteristics, including a higher incidence of nodal metastasis, macro- and microvascular invasion, perineural invasion, as well as worse overall survival (OS) (median: ICC-perihilar 19.8 vs. ICC-peripheral 37.1 months; p < 0.001) and disease-free survival (DFS) (median: ICC-perihilar 12.8 vs. ICC-peripheral 15.2 months; p = 0.019). ICC-perihilar subtype and hilar CCA had comparable OS (19.8 vs. 21.4 months; p = 0.581) and DFS (12.8 vs. 16.8 months; p = 0.140). ICC-peripheral subtype tumors were associated with more advanced tumor features, as well as worse survival outcomes versus HCC (OS, median: ICC-peripheral 37.1 vs. HCC 74.3 months; p < 0.001; DFS, median: ICC-peripheral 15.2 vs. HCC 45.5 months; p < 0.001). CONCLUSIONS ICC should be classified as ICC-perihilar and ICC-peripheral subtype based on distinct clinicopathological features and survival outcomes. ICC-perihilar subtype behaved more like carcinoma of the bile duct (i.e., hilar CCA), whereas ICC-peripheral subtype had features and a prognosis more akin to a primary liver malignancy.
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Affiliation(s)
- Tao Wei
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianfeng Lu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xue-Lian Xiao
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Matthew Weiss
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Irinel Popescu
- Department of Surgery, Fundeni Clinical Institute, Bucharest, Romania
| | - Hugo P Marques
- Department of Surgery, Curry Cabral Hospital, Lisbon, Portugal
| | | | | | - Carlo Pulitano
- Department of Surgery, Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia
| | - Todd W Bauer
- Department of Surgery, University of Virginia, Charlottesville, VA, USA
| | - Feng Shen
- Department of Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | | | - Oliver Soubrane
- Department of Hepatobiliopancreatic Surgery and Liver Transplantation, AP-HP, Beaujon Hospital, Clichy, France
| | - Guillaume Martel
- Division of General Surgery, Department of Surgery, University of Ottawa, Ottawa, ON, Canada
| | - Bas Groot Koerkamp
- Department of Surgery, Erasmus University Medical Centre, Rotterdam, The Netherlands
| | - Endo Itaru
- Gastroenterological Surgery Division, Yokohama City University School of Medicine, Yokohama, Japan
| | - Yi Lv
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xu-Feng Zhang
- Department of Hepatobiliary Surgery and Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Timothy M Pawlik
- Department of Surgery, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
- Department of Surgery, Oncology, Health Services Management and Policy, Wexner Medical Center, The Urban Meyer III and Shelley Meyer Chair for Cancer Research, The Ohio State University, Columbus, OH, USA.
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6
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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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7
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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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8
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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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9
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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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10
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Yonenaga Y, Yokoyama S. Isolated liver metastasis detected 11 years after the curative resection of rectal cancer: A case report. World J Clin Cases 2021; 9:8923-8931. [PMID: 34734076 PMCID: PMC8546816 DOI: 10.12998/wjcc.v9.i29.8923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 07/06/2021] [Accepted: 08/04/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The duration of surveillance after curative resection of colorectal cancer (CRC) is generally 5 years. The overall incidence of recurrence more than 5 years after surgery for CRC in Japan has been reported to be 0.6%. Moreover, it is rare for CRC to have metachronous liver metastasis more than 10 years after surgery. Here, we present a case of liver metastasis detected 11 years after the curative resection of rectal cancer.
CASE SUMMARY A 72-year-old man was referred to our hospital after a liver tumor was detected by abdominal ultrasonography at another hospital. He had undergone surgery for rectal cancer 11 years previously. Contrast-enhanced computed tomography (CT) showed a tumor with a diameter of approximately 8 cm in the posterior segment, which was weakly and gradually enhanced. 18F-fluorodeoxyglucose-positron emission tomography/CT showed an abnormally high uptake on the tumorous lesion, which showed that the tumor appeared to spread convexly along the intrahepatic bile ducts. Intrahepatic cholangiocarcinoma was therefore diagnosed, and he had an extended right posterior sectionectomy and regional lymph node dissection. Histopathological examination showed that the tumor was a moderately differentiated adenocarcinoma and showed the same pathological characteristics as the rectal cancer. Immunohistological examination showed that the cancer cells of both the liver tumor and rectal cancer were positive for cytokeratin (CK) 20 and weakly positive for CK 7. These findings were consistent with the liver metastasis from the rectal cancer.
CONCLUSION It is possible that a liver tumor is metastatic in a patient with a previous history of CRC, even if it was more than 10 years earlier.
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Affiliation(s)
- Yoshikuni Yonenaga
- Department of Surgery, Ako City Hospital, Ako 678-0232, Hyogo, Japan
- Department of Surgery, Japanese Red Cross Wakayama Medical Center, Wakayama 640-8558, Wakayama, Japan
| | - Satoshi Yokoyama
- Department of Surgery, Japanese Red Cross Wakayama Medical Center, Wakayama 640-8558, Wakayama, Japan
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11
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Boerner T, Drill E, Pak LM, Nguyen B, Sigel CS, Doussot A, Shin P, Goldman DA, Gonen M, Allen PJ, Balachandran VP, Cercek A, Harding J, Solit DB, Schultz N, Kundra R, Walch H, D’Angelica MI, DeMatteo RP, Drebin J, Kemeny NE, Kingham TP, Simpson AL, Hechtman JF, Vakiani E, Lowery MA, Ijzermans J, Buettner S, Groot Koerkamp B, Doukas M, Chandwani R, Jarnagin WR. Genetic Determinants of Outcome in Intrahepatic Cholangiocarcinoma. Hepatology 2021; 74:1429-1444. [PMID: 33765338 PMCID: PMC8713028 DOI: 10.1002/hep.31829] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 03/04/2021] [Accepted: 03/05/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM Genetic alterations in intrahepatic cholangiocarcinoma (iCCA) are increasingly well characterized, but their impact on outcome and prognosis remains unknown. APPROACH AND RESULTS This bi-institutional study of patients with confirmed iCCA (n = 412) used targeted next-generation sequencing of primary tumors to define associations among genetic alterations, clinicopathological variables, and outcome. The most common oncogenic alterations were isocitrate dehydrogenase 1 (IDH1; 20%), AT-rich interactive domain-containing protein 1A (20%), tumor protein P53 (TP53; 17%), cyclin-dependent kinase inhibitor 2A (CDKN2A; 15%), breast cancer 1-associated protein 1 (15%), FGFR2 (15%), polybromo 1 (12%), and KRAS (10%). IDH1/2 mutations (mut) were mutually exclusive with FGFR2 fusions, but neither was associated with outcome. For all patients, TP53 (P < 0.0001), KRAS (P = 0.0001), and CDKN2A (P < 0.0001) alterations predicted worse overall survival (OS). These high-risk alterations were enriched in advanced disease but adversely impacted survival across all stages, even when controlling for known correlates of outcome (multifocal disease, lymph node involvement, bile duct type, periductal infiltration). In resected patients (n = 209), TP53mut (HR, 1.82; 95% CI, 1.08-3.06; P = 0.03) and CDKN2A deletions (del; HR, 3.40; 95% CI, 1.95-5.94; P < 0.001) independently predicted shorter OS, as did high-risk clinical variables (multifocal liver disease [P < 0.001]; regional lymph node metastases [P < 0.001]), whereas KRASmut (HR, 1.69; 95% CI, 0.97-2.93; P = 0.06) trended toward statistical significance. The presence of both or neither high-risk clinical or genetic factors represented outcome extremes (median OS, 18.3 vs. 74.2 months; P < 0.001), with high-risk genetic alterations alone (median OS, 38.6 months; 95% CI, 28.8-73.5) or high-risk clinical variables alone (median OS, 37.0 months; 95% CI, 27.6-not available) associated with intermediate outcome. TP53mut, KRASmut, and CDKN2Adel similarly predicted worse outcome in patients with unresectable iCCA. CDKN2Adel tumors with high-risk clinical features were notable for limited survival and no benefit of resection over chemotherapy. CONCLUSIONS TP53, KRAS, and CDKN2A alterations were independent prognostic factors in iCCA when controlling for clinical and pathologic variables, disease stage, and treatment. Because genetic profiling can be integrated into pretreatment therapeutic decision-making, combining clinical variables with targeted tumor sequencing may identify patient subgroups with poor outcome irrespective of treatment strategy.
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Affiliation(s)
- Thomas Boerner
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Esther Drill
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Linda M. Pak
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Bastien Nguyen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Carlie S. Sigel
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alexandre Doussot
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Paul Shin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Debra A. Goldman
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mithat Gonen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Andrea Cercek
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - James Harding
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - David B. Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY;,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nikolaus Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ritika Kundra
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Henry Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY;,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | | | - Jeffrey Drebin
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nancy E. Kemeny
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - T. Peter Kingham
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Amber L. Simpson
- Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, Canada
| | - Jaclyn F. Hechtman
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Efsevia Vakiani
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - J.N.M. Ijzermans
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - S. Buettner
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - B. Groot Koerkamp
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - M. Doukas
- Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
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12
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Yang S, Lu J, Cai Y, Li B, Xiong X. Mixed adenoneuroendocrine carcinomas of stomach and ampulla of vater after curative-intent resection: a single center cases series. BMC Gastroenterol 2021; 21:329. [PMID: 34433421 PMCID: PMC8390255 DOI: 10.1186/s12876-021-01909-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 08/16/2021] [Indexed: 02/08/2023] Open
Abstract
Background Mixed adenoneuroendocrine carcinoma is a rare clinical manifestation, especially in the gastric and ampullary. The purpose of this study was to investigate the clinicopathological features and prognosis of mixed adenoneuroendocrine carcinoma in the gastric and ampullary and summarize related treatment suggestions. Methods In all, 32 cases of mixed adenoneuroendocrine carcinoma in the gastric and ampullary that were diagnosed from resected specimens were analyzed from 2009 to 2015. The corresponding demographic, clinicopathological and survival data were retrospectively reviewed. Results The 1-year, 3-year and 5-year survival rates were 78.1%, 28.1 and 9.4%, respectively, and the median overall survival was 28.0 months. In all, 75.0% (24/32) had lymph node metastasis at the time of initial diagnosis. A multivariate analysis revealed that TNM stage (HR 6.444 95%CI 1.477–28.121 P = 0.013), lymph nodes metastasis (HR10.617 95%CI 1.409–79.997 P = 0.022), vascular invasion (HR 5.855 95%CI 1.719–19.940 P = 0.005), grade of the adenocarcinoma component (HR 3.876 95%CI 1.451–10.357 P = 0.007) and CD56 positivity (HR 0.265 95%CI 0.100–0.705 P = 0.008) were independent predictors of overall survival. Conclusions Mixed adenoneuroendocrine carcinoma is an aggressive clinical entity with a poor prognosis. Taking both the neuroendocrine component and the adenocarcinoma component into consideration of optimal treatment is strongly recommended.
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Affiliation(s)
- Sishu Yang
- Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Jiong Lu
- Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Yulong Cai
- Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Bei Li
- Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China
| | - Xianze Xiong
- Department of Biliary Surgery, West China Hospital of Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, Sichuan Province, China.
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13
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Nguyen Canh H, Takahashi K, Yamamura M, Li Z, Sato Y, Yoshimura K, Kozaka K, Tanaka M, Nakanuma Y, Harada K. Diversity in cell differentiation, histology, phenotype and vasculature of mass-forming intrahepatic cholangiocarcinomas. Histopathology 2021; 79:731-750. [PMID: 34018212 DOI: 10.1111/his.14417] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 04/27/2021] [Accepted: 05/17/2021] [Indexed: 12/21/2022]
Abstract
AIMS Mass-forming intrahepatic cholangiocarcinomas (MF-iCCAs), involving small bile ducts, bile ductules or canals of Hering, remain treated as a single entity. We aimed to examine the diversity in histology, phenotype and tumour vasculature of MF-iCCAs. METHODS AND RESULTS Based on morphology and immunophenotype, we classified MF-iCCAs into small bile duct (SBD), cholangiolocarcinoma (CLC), ductal plate malformation (DPM) and hepatocellular carcinoma (HCC)-like subtypes. Genetic correlations among the histological subtypes were examined by multi-region tumour sequencing. Vasculatures and other clinicopathological features were compared among tumour groups with various proportions of the histological subtypes in 62 MF-iCCAs. Cases of pure SBD, CLC, DPM and HCC-like subtypes numbered 18 (29%), seven (11.3%), none (0%) and two (3%), respectively; the remaining 35 (56.4%) cases comprised several components. Genetic alterations, isocitrate dehydrogenase (IDH)1/2, KRAS, TP53, polybromo-1 (PBRM1) and BRCA1-associated protein 1 (BAP1), were shared among SBD, CLC, DPM and hepatoid components within a tumour. We uncovered distinct vascularisation mechanisms among SBD, CLC and DPM subtypes with a prominent vessel co-option in CLC tumours. iCCA with a DPM pattern had the highest vascular densities (mean microvascular density,140/mm2 ; arterial vessel density, 18.3/mm2 ). Increased CLC component was correlated with longer overall survival time (r = 0.44, P = 0.006). Pure SBD tumours had a lower 5-year overall survival rate compared with MF-iCCA with CLC pattern (30.5 versus 72.4%, P = 0.011). CONCLUSIONS MF-iCCAs comprise four histological subtypes. Given their sharing some driver gene alterations, indicating they can have a common cell origin, SBD, CLC and DPM subtypes, however, differ in cell differentiation, histology, phenotype or tumour vasculature.
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Affiliation(s)
- Hiep Nguyen Canh
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kenta Takahashi
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Minako Yamamura
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Zihan Li
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Yasunori Sato
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kaori Yoshimura
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Minoru Tanaka
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.,Laboratory of Stem Cell Regulation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology, Fukui Saiseikai Hospital, Fukui, Japan.,Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kenichi Harada
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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14
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Yamashita S, Morine Y, Imura S, Ikemoto T, Saito Y, Takasu C, Yamada S, Tokuda K, Okikawa S, Miyazaki K, Oya T, Tsuneyama K, Shimada M. A new pathological classification of intrahepatic cholangiocarcinoma according to protein expression of SSTR2 and Bcl2. World J Surg Oncol 2021; 19:142. [PMID: 33962620 PMCID: PMC8106133 DOI: 10.1186/s12957-021-02216-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 03/26/2021] [Indexed: 01/03/2023] Open
Abstract
Background No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group. Methods Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated. Results The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P. Conclusions This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2.
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Affiliation(s)
- Shoko Yamashita
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan.,Department of Pathology and Laboratory Medicine, Tokushima University, Tokushima, 770-8503, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan.
| | - Satoru Imura
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Tetsuya Ikemoto
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Yu Saito
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Chie Takasu
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Shinichiro Yamada
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Kazunori Tokuda
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Shohei Okikawa
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Katsuki Miyazaki
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
| | - Takeshi Oya
- Department of Molecular Pathology, Tokushima University, Tokushima, 770-8503, Japan
| | - Koichi Tsuneyama
- Department of Pathology and Laboratory Medicine, Tokushima University, Tokushima, 770-8503, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, 770-8503, Japan
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15
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Akita M, Sawada R, Komatsu M, Suleman N, Itoh T, Ajiki T, Heaton N, Fukumoto T, Zen Y. An immunostaining panel of C-reactive protein, N-cadherin, and S100 calcium binding protein P is useful for intrahepatic cholangiocarcinoma subtyping. Hum Pathol 2020; 109:45-52. [PMID: 33321161 DOI: 10.1016/j.humpath.2020.12.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 12/03/2020] [Accepted: 12/09/2020] [Indexed: 10/22/2022]
Abstract
This study aimed to establish an immunohistochemical panel useful for subclassification of intrahepatic cholangiocarcinoma (iCCA) into small- and large-duct types. Fifty surgical cases of iCCA consisting of small- (n = 31) and large-duct types (n = 19) were examined. To imitate liver needle biopsies, tissue microarrays were constructed using three tissue cores (2 mm in diameter) obtained from one representative paraffin block of each case. Immunostaining for C-reactive protein (CRP), N-cadherin, tubulin beta-III (TUBB3), neural cell adhesion molecule (NCAM), and S100 calcium binding protein P (S100P) was conducted. Most cases of small-duct iCCA were immunoreactive to CRP and N-cadherin, whereas expressions of these markers were markedly less common in large-duct iCCA (CRP, 97% vs. 5%, P < 0.001; N-cadherin, 87% vs. 16%, P < 0.001). TUBB3 and NCAM were also more frequently expressed in small-duct iCCA (65% vs. 32%, P = 0.006; 58% vs. 5%, P < 0.001), but their sensitivities were lower than those of CRP and N-cadherin. S100P was more commonly expressed in large-duct iCCA than in small-duct iCCA (95% vs. 29%, P < 0.001), and diffuse expressions were observed in 17 of 19 cases of large-duct iCCA (90%). All cases with a CRP+/S100P- immunophenotype were of small-duct type, whereas all but one case with a CRP-/S100P+ immunophenotype were of large-duct type. Of 10 cases with a double-positive or double-negative immunophenotype, 7 were appropriately classified based on immunoreactivity to N-cadherin. In conclusion, CRP, N-cadherin, and S100P form a useful immunohistochemical panel for iCCA subclassification, and correct subclassification was possible in 92% of cases based on a proposed, simple algorithm.
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Affiliation(s)
- Masayuki Akita
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan; Department of Surgery, Kakogawa Central City Hospital, Kakogawa, 675-8611, Japan
| | - Ryuichiro Sawada
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan
| | - Masato Komatsu
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Nadia Suleman
- Institute of Liver Studies, King's College Hospital & King's College London, SE5 9RS, London, UK
| | - Tomoo Itoh
- Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Tetsuo Ajiki
- Department of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, 650-0017, Japan
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital & King's College London, SE5 9RS, London, UK
| | - Takumi Fukumoto
- Department 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 & King's College London, SE5 9RS, London, UK.
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16
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Takamura H, Gabata R, Obatake Y, Nakanuma S, Hayashi H, Kozaka K, Sasaki M, Okazaki M, Yamaguchi T, Shimbashi H, Terai S, Okamoto K, Makino I, Kinoshita J, Nakamura K, Miyashita T, Tajima H, Ninomiya I, Fushida S, Kitao A, Kitahara M, Arai K, Yamashita T, Yamashita T, Ikeda H, Satoh Y, Harada K, Kaneko S, Gabata T, Kosaka T, Ohta T. Clinical features and diagnostic imaging of cholangiolocellular carcinoma compared with other primary liver cancers: a surgical perspective. Technol Cancer Res Treat 2020; 19:1533033820948141. [PMID: 33073719 PMCID: PMC7592326 DOI: 10.1177/1533033820948141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background and Objectives: Although cholangiolocellular carcinoma is considered a combined hepatocellular and cholangiocarcinoma, we feel that this classification is not appropriate. Therefore, we compared the diagnostic imaging findings, surgical prognosis, and pathological features of cholangiolocellular carcinoma with those of other combined hepatocellular and cholangiocarcinoma subtypes, hepatocellular carcinoma, and cholangiocarcinoma. Methods: The study patients included 7 with classical type combined hepatocellular and cholangiocarcinoma; 8 with stem cell feature, intermediate type combined hepatocellular and cholangiocarcinoma; 13 with cholangiolocellular carcinoma; 58 with cholangiocarcinoma; and 359 with hepatocellular carcinoma. All patients underwent hepatectomy or living-related donor liver transplantation from 2001 to 2014. Results: cholangiolocellular carcinoma could be distinguished from hepatocellular carcinom, other combined hepatocellular and cholangiocarcinoma subtypes, and cholangiocarcinoma by the presence of intratumoral Glisson’s pedicle, hepatic vein penetration, and tumor-staining pattern on angiography-assisted CT. Cholangiolocellular carcinoma was associated with a significantly lower SUV-max than that of cholangiocarcinoma on FDG-PET. Hepatocellular carcinoma, classical type, and cholangiolocellular carcinoma had significantly better prognoses than stem cell feature, intermediate type and cholangiocarcinoma. A cholangiocarcinoma component was detected in cholangiolocellular carcinoma that progressed to the hepatic hilum, and the cholangiocarcinoma component was found in perineural invasion and lymph node metastases. Conclusions: From the viewpoint of surgeon, cholangiolocellular carcinoma should be classified as a good-prognosis subtype of biliary tract carcinoma because of its tendency to differentiate into cholangiocarcinoma during its progression, and its distinctive imaging and few recurrence rates different from other combined hepatocellular and cholangiocarcinoma subtypes.
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Affiliation(s)
- Hiroyuki Takamura
- General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan.,Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Ryousuke Gabata
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yoshinao Obatake
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shinichi Nakanuma
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hironori Hayashi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kazuto Kozaka
- Radiology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Motoko Sasaki
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mitsuyoshi Okazaki
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Takahisa Yamaguchi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroyuki Shimbashi
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Shiro Terai
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Koichi Okamoto
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Isamu Makino
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Jun Kinoshita
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Keishi Nakamura
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tomoharu Miyashita
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hidehiro Tajima
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Itasu Ninomiya
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Sachio Fushida
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Azusa Kitao
- Radiology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masaaki Kitahara
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kuniaki Arai
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Taro Yamashita
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tatsuya Yamashita
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Hiroko Ikeda
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Yasunori Satoh
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Kenichi Harada
- Pathology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Syuichi Kaneko
- Gastroenterology, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
| | | | - Tateo Kosaka
- General and Digestive Surgery, 12857Kanazawa Medical University, Kahoku, Ishikawa, Japan
| | - Tetsuo Ohta
- Gastroenterologic Surgery, 12858Kanazawa University, Kanazawa, Ishikawa, Japan
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17
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Differences in 18F-FDG Uptake and Expression of Glucose Transporter Between 2 Distinct Subtypes of Mass-Forming Intrahepatic Cholangiocarcinomas. Clin Nucl Med 2020; 45:e267-e273. [PMID: 32366791 DOI: 10.1097/rlu.0000000000003055] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Recently, intrahepatic cholangiocarcinoma (iCCA) has been classified into small duct cholangiocarcinoma (SDC) and large duct cholangiocarcinoma (LDC) according to the origin of the biliary tree. Although the usefulness of F-FDG PET/CT in iCCA is well known, there are no reports evaluating differences in accumulation of F-FDG according to the recently described iCCA subtypes. The aim of this study was therefore to assess F-FDG accumulation and the expression of glucose transporters in SDC and LDC. METHODS Our institutional review board approved this retrospective study and waived the requirement for informed consent. Fourteen consecutive surgically resected mass-forming iCCA (7 SDCs, 23 ± 6.7 mm; 7 LDCs, 44 ± 26 mm) were enrolled. The SUVmax on F-FDG PET/CT and the expression of glucose transporter 1 (Glut-1), Glut-2, hexokinase 2 (HK2), and glucose-6-phosphatase by immunohistochemistry were evaluated and compared between SDC and LDC. RESULTS The SUVmax in SDC was significantly lower than that in LDC (3.2 ± 0.8 vs 7.6 ± 3.2, P < 0.01). The staining scores of Glut-1 and HK2 were significantly lower in SDC than in LDC (0 vs 3 ± 1.4, P = 0.0034; 1.6 ± 1.1 vs 3.4 ± 1.1, P = 0.014, respectively). Expression levels of Glut-2 and glucose-6-phosphatase were variable and did not show a significant difference between SDC and LDC. Overall survival was significantly worse in LDC than in SDC (P = 0.01). CONCLUSIONS F-FDG accumulation and Glut-1 and HK2 expression were significantly higher in LDC than in SDC. A low-glycolytic feature may be one of the characteristic findings of SDC.
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18
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Chung T, Rhee H, Nahm JH, Jeon Y, Yoo JE, Kim YJ, Han DH, Park YN. Clinicopathological characteristics of intrahepatic cholangiocarcinoma according to gross morphologic type: cholangiolocellular differentiation traits and inflammation- and proliferation-phenotypes. HPB (Oxford) 2020; 22:864-873. [PMID: 31735647 DOI: 10.1016/j.hpb.2019.10.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 09/05/2019] [Accepted: 10/01/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is subclassified into mass-forming (MF), periductal-infiltrative (PI), and mixed types grossly; however, their clinicopathological significance remains controversial. METHODS Clinicopathological characteristics of iCCA gross types were analysed according to histopathological type (small-duct, large-duct, indeterminate) or cholangiolocellular differentiation trait (CDT) in 108 iCCAs. The expression levels of inflammation-marker (CRP, FGB) and proliferation-marker (phospho-ERK1/2, Ki-67) were evaluated by immunohistochemistry. RESULTS There were 87 MF, 8 PI, and 13 mixed-gross type. Small-duct-type (39, 44.8%) and CDT (19, 21.8%) were found only in MF-gross type. The inflammation-marker expression was higher in MF-type than in PI- and mixed-gross types (P = 0.023). It was high in small-duct-type, middle in indeterminate-type, and low in large-duct-type (P = 0.015), and iCCAs with CDT showed higher inflammation-marker expression compared to those without (P < 0.001). Proliferation-marker expression did not differ according to gross type; however it was lower in iCCA with CDT compared to those without (P = 0.004). Subgrouping of the gross type according to histopathological type or CDT revealed that MF-type with small-duct-type or CDT had better overall survival compared to the others (P < 0.05). CONCLUSION MF-type iCCA is more heterogeneous than other gross types. High inflammation-marker/low proliferation-marker expression in MF-type with CDT or small-duct-type may be related to a good outcome.
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Affiliation(s)
- Taek Chung
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Youngsic Jeon
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Young-Joo Kim
- Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do 25451, Republic of Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
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Zhang Y, Wang S, Dudley AC. Models and molecular mechanisms of blood vessel co-option by cancer cells. Angiogenesis 2020; 23:17-25. [PMID: 31628560 PMCID: PMC7018564 DOI: 10.1007/s10456-019-09684-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/23/2019] [Indexed: 12/23/2022]
Abstract
Cancer cells have diverse mechanisms for utilizing the vasculature; they can initiate the formation of new blood vessels from preexisting ones (sprouting angiogenesis) or they can form cohesive interactions with the abluminal surface of preexisting vasculature in the absence of sprouting (co-option). The later process has received renewed attention due to the suggested role of blood vessel co-option in resistance to antiangiogenic therapies and the reported perivascular positioning and migratory patterns of cancer cells during tumor dormancy and invasion, respectively. However, only a few molecular mechanisms have been identified that contribute to the process of co-option and there has not been a formal survey of cell lines and laboratory models that can be used to study co-option in different organ microenvironments; thus, we have carried out a comprehensive literature review on this topic and have identified cell lines and described the laboratory models that are used to study blood vessel co-option in cancer. Put into practice, these models may help to shed new light on the molecular mechanisms that drive blood vessel co-option during tumor dormancy, invasion, and responses to different therapies.
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Affiliation(s)
- Yu Zhang
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Sarah Wang
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA
| | - Andrew C Dudley
- Department of Microbiology, Immunology, and Cancer Biology, The University of Virginia, Charlottesville, VA, 22908, USA.
- Emily Couric Cancer Center, The University of Virginia, Charlottesville, VA, 22908, USA.
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20
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Cholangiolocellular Carcinoma With "Ductal Plate Malformation" Pattern May Be Characterized by ARID1A Genetic Alterations. Am J Surg Pathol 2020; 43:352-360. [PMID: 30520820 DOI: 10.1097/pas.0000000000001201] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiolocellular carcinoma (CLC) is a unique subtype of primary liver carcinoma, which sometimes coexists with hepatocellular carcinoma (HCC), cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). "Ductal plate malformation" (DPM)-pattern of primary liver carcinoma, which resembles biliary lesions in Caroli disease and von Meyenburg complex, is sometimes associated with CLC. We examined genetic alterations of hTERT promoter (hTERT), IDH1 or 2 (IDH1/2), KRAS, ARID1A, PBRM1, ARID2, BAP1, p53 and their association with histologic features such as proportion of CLC and DPM-pattern in 77 patients with primary liver carcinoma diagnosed as cHCC-CCA or CLC. Primary liver carcinomas were histologically subdivided into 29 CLC-predominant (CLC component >80%), 31 with CLC (5% to 80%) and 17 without CLC (<5%). CLC-predominant group was characterized by older age, male-predominant and smaller tumor size. Genetic alterations were detected in hTERT (25%), ARID1A (21%), PBRM1 (20%), ARID2 (3%), BAP1 (1%), p53 (46%), KRAS (5%), and IDH1/2 (8%). ARID1A alteration was more frequent in CLC-predominant group, compared with other groups (P<0.05) and was correlated with the degree of DPM-pattern (P<0.01). Alterations of hTERT and p53 were less frequent in CLC-predominant group compared with "with CLC group" (P<0.05). hTERT mutation was less frequent in carcinomas with DPM-pattern (P<0.01). PBRM1 alteration was more frequent in CLC with focal HCC subgroup and without CLC group compared with other groups (P<0.05). CLC may be a distinct subgroup of primary liver carcinoma, which is different from cHCC-CCA, based on clinicopathologic and genetic alterations. ARID1A alterations may characterize CLC with DPM-pattern and could be a diagnostic immunohistochemical marker for small CLCs with DPM-pattern.
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21
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Vessel co-option and resistance to anti-angiogenic therapy. Angiogenesis 2019; 23:55-74. [PMID: 31865479 DOI: 10.1007/s10456-019-09698-6] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 11/22/2019] [Indexed: 12/20/2022]
Abstract
Vessel co-option is a non-angiogenic mechanism of tumour vascularisation in which cancer cells utilise pre-existing blood vessels instead of inducing new blood vessel formation. Vessel co-option has been observed across a range of different tumour types, in both primary cancers and metastatic disease. Importantly, vessel co-option is now implicated as a major mechanism that mediates resistance to conventional anti-angiogenic drugs and this may help to explain the limited efficacy of this therapeutic approach in certain clinical settings. This includes the use of anti-angiogenic drugs to treat advanced-stage/metastatic disease, treatment in the adjuvant setting and the treatment of primary disease. In this article, we review the available evidence linking vessel co-option with resistance to anti-angiogenic therapy in numerous tumour types, including breast, colorectal, lung and pancreatic cancer, glioblastoma, melanoma, hepatocellular carcinoma, and renal cell carcinoma. The finding that vessel co-option is a significant mechanism of resistance to anti-angiogenic therapy may have important implications for the future of anti-cancer therapy, including (a) predicting response to anti-angiogenic drugs, (b) the need to develop therapies that target both angiogenesis and vessel co-option in tumours, and (c) predicting the response to other therapeutic modalities, including immunotherapy.
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22
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Kuczynski EA, Vermeulen PB, Pezzella F, Kerbel RS, Reynolds AR. Vessel co-option in cancer. Nat Rev Clin Oncol 2019; 16:469-493. [PMID: 30816337 DOI: 10.1038/s41571-019-0181-9] [Citation(s) in RCA: 281] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
All solid tumours require a vascular supply in order to progress. Although the ability to induce angiogenesis (new blood vessel growth) has long been regarded as essential to this purpose, thus far, anti-angiogenic therapies have shown only modest efficacy in patients. Importantly, overshadowed by the literature on tumour angiogenesis is a long-standing, but continually emerging, body of research indicating that tumours can grow instead by hijacking pre-existing blood vessels of the surrounding nonmalignant tissue. This process, termed vessel co-option, is a frequently overlooked mechanism of tumour vascularization that can influence disease progression, metastasis and response to treatment. In this Review, we describe the evidence that tumours located at numerous anatomical sites can exploit vessel co-option. We also discuss the proposed molecular mechanisms involved and the multifaceted implications of vessel co-option for patient outcomes.
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Affiliation(s)
- Elizabeth A Kuczynski
- Bioscience, Oncology, IMED Biotech Unit, AstraZeneca, Cambridge, UK. .,Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.
| | - Peter B Vermeulen
- HistoGeneX, Antwerp, Belgium.,Translational Cancer Research Unit, GZA Hospitals St Augustinus, University of Antwerp, Wilrijk-Antwerp, Belgium.,Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Francesco Pezzella
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Robert S Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada.,Department of Medical Biophysics, University of Toronto, Toronto, Canada
| | - Andrew R Reynolds
- Tumour Biology Team, Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK. .,Oncology Translational Medicine Unit, IMED Biotech Unit, AstraZeneca, Cambridge, UK.
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23
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Hamaoka M, Kozaka K, Matsui O, Komori T, Matsubara T, Yoneda N, Yoshida K, Inoue D, Kitao A, Koda W, Gabata T, Kobayashi S. Early detection of intrahepatic cholangiocarcinoma. Jpn J Radiol 2019; 37:669-684. [PMID: 31372893 DOI: 10.1007/s11604-019-00860-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 07/25/2019] [Indexed: 02/07/2023]
Abstract
Cholangiocarcinoma (CC) is a malignant tumor which arises from the biliary epithelium and most cases represent adenocarcinoma. CC can be classified into intrahepatic CC (ICC), perihilar CC, and distal CC, based on the site of anatomic origin. The incidence of ICC is increasing in both Western and Eastern countries, while that of extrahepatic cholangiocarcinoma remains fairly stable. ICC infiltrates into adjacent nerves and lymphatic vessels, resulting in progressive disease with a poor prognosis; thus, early detection of ICC is critical for achieving better outcomes and providing better patient care. However, it is difficult for clinicians to detect an ICC, especially in its early stage. Different from hepatocellular carcinoma, the lack of surveillance system for the high-risk group of CC does not allow for a reliable screening examination. In this context, for early detection and diagnosis of ICC, radiologists need to know predisposing conditions that can lead to the development of ICC, such as chronic biliary or hepatic inflammation, primary sclerosing cholangitis, congenital biliary diseases, and other conditions. In this article, we discuss and illustrate the radiologic features of ICC with special attention to early disease stages and of predisposing conditions of ICC.
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Affiliation(s)
- Mami Hamaoka
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Kazuto Kozaka
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.
| | - Osamu Matsui
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Takahiro Komori
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Takashi Matsubara
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Norihide Yoneda
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Kotaro Yoshida
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Dai Inoue
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Azusa Kitao
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Wataru Koda
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medical Sciences, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Satoshi Kobayashi
- Department of Radiological Technology, School of Health Sciences, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
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24
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Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, Carpino G. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int 2019; 39 Suppl 1:7-18. [PMID: 30882996 DOI: 10.1111/liv.14093] [Citation(s) in RCA: 220] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/26/2019] [Accepted: 02/27/2019] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma constitutes a heterogeneous group of malignancies that can emerge at any point of the biliary tree. Cholangiocarcinoma is classified into intrahepatic, perihilar and distal based on its anatomical location. Histologically, conventional perihilar/distal cholangiocarcinomas are mucin-producing adenocarcinomas or papillary tumours; intrahepatic cholangiocarcinomas are more heterogeneous and can be sub-classified according to the level or size of the displayed bile duct. Cholangiocarcinoma develops through multistep carcinogenesis and is preceded by dysplastic and in situ lesions. Definition and clinical significance of precursor lesions, including biliary intraepithelial neoplasia, intraductal papillary neoplasms of the bile duct, intraductal tubulopapillary neoplasms and mucinous cystic neoplasm, are discussed in this review. A main challenge in diagnosing cholangiocarcinoma is the fact that tumour tissue for histological examination is difficult to obtain. Thus, a major clinical obstacle is the establishment of the correct diagnosis at a tumour stage that is amenable to surgery which still represents the only curable therapeutic option. Current standards, methodology and criteria for diagnosis are discussed. Cholangiocarcinoma represents a heterogeneous tumour with regard to molecular alterations. In intrahepatic subtype, mainly two distinctive morpho-molecular groups can currently be discriminated. Large-duct type intrahepatic cholangiocarcinoma shows a high mutation frequency of oncogenes and tumour suppressor genes, such as KRAS and TP53 while Isocitrate Dehydrogenase 1/2 mutations and Fibroblast Growth Factor Receptor 2-fusions are typically seen in small-duct type tumours. It is most important to ensure the separation of the given anatomical subtypes and to search for distinct subgroups within the subtypes on a molecular and morphological basis.
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Affiliation(s)
- Timothy Kendall
- Division of Pathology, University of Edinburgh, Edinburgh, UK
| | - Joanne Verheij
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Regensburg, Germany
| | - Maria Guido
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Benjamin Goeppert
- Department of Pathology, University Hospital Heidelberg and Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Rome, Italy
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25
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Kim Y, Lee K, Jeong S, Wen X, Cho NY, Kang GH. DLEC1 methylation is associated with a better clinical outcome in patients with intrahepatic cholangiocarcinoma of the small duct subtype. Virchows Arch 2019; 475:49-58. [DOI: 10.1007/s00428-018-02511-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/07/2018] [Accepted: 12/12/2018] [Indexed: 12/13/2022]
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26
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Jiang K, Al-Diffhala S, Centeno BA. Primary Liver Cancers-Part 1: Histopathology, Differential Diagnoses, and Risk Stratification. Cancer Control 2018; 25:1073274817744625. [PMID: 29350068 PMCID: PMC5933592 DOI: 10.1177/1073274817744625] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) are the 2 most common primary malignant liver tumors, with hepatocellular and bile ductular differentiation, respectively. This article reviews the key histopathological findings of these 2 primary liver cancers and includes a review of the role of ancillary testing for differential diagnosis, risk stratification according to the American Joint Committee on Cancer (AJCC) staging recommendation, and a review of precancerous lesions. A literature review was conducted to identify articles with information relevant to precancerous precursors, current histopathological classification, ancillary testing, and risk stratification of primary malignant liver tumors. The histomorphology of normal liver, preinvasive precursors, primary malignancies, and morphological variants, and the utilization of ancillary tests for the pathological diagnosis are described. Dysplastic nodules are the preinvasive precursors of HCC, and intraductal papillary neoplasms of bile ducts and biliary intraepithelial neoplasia are the preinvasive precursors of CC. Benign liver nodules including focal nodular hyperplasia and adenomas are included in this review, since some forms of adenomas progress to HCC and often they have to be differentiated from well-differentiated HCC. A number of morphological variants of HCC have been described in the literature, and it is necessary to be aware of them in order to render the correct diagnosis. Risk stratification is still dependent on the AJCC staging system. The diagnosis of primary liver carcinomas is usually straightforward. Application of the appropriate ancillary studies aids in the differential diagnosis of difficult cases. The understanding of the carcinogenesis of these malignancies has improved with the standardization of the pathological classification of preinvasive precursors and studies of the molecular pathogenesis. Risk stratification still depends on pathological staging.
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Affiliation(s)
- Kun Jiang
- 1 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
| | - Sameer Al-Diffhala
- 3 Division of Anatomic Pathology, Department of Pathology, University of Alabama School of Medicine, Birmingham, AL, USA
| | - Barbara A Centeno
- 1 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.,2 Department of Oncologic Sciences, Morsani College of Medicine at University of South Florida, Tampa, FL, USA
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27
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Intrahepatic Mass-Forming Cholangiocarcinoma: Relationship Between Computed Tomography Characteristics and Histological Subtypes. J Comput Assist Tomogr 2018; 42:340-349. [PMID: 29189405 DOI: 10.1097/rct.0000000000000695] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE The aim of this study was to determine the value of multi-detector row computed tomography (MDCT) in differentiating the small-duct (SD) and large-duct (LD) types of intrahepatic mass-forming cholangiocarcinomas (IMCCs) and predicting patient prognosis. METHODS The 4-phase MDCT image findings of 82 patients with surgically confirmed IMCCs (60 SD-type and 22 LD-type IMCCs) were compared between 2 types using univariate and multivariate analyses. Overall survival rates for 78 patients with available information were compared using the Kaplan-Meier method. RESULTS Arterial hyperenhancement, round or lobulated contour, and lack of bile duct encasement were significant MDCT features suggesting the SD type, and lymph node enlargement was significantly associated with the LD type (all P's < 0.05). The presence of those 3 SD-type-suggestive features (MDCT-suggested SD type) demonstrated high specificity (90.9% [20/22]) in differentiating the SD type. Patients of MDCT-suggested SD type without lymph node enlargement (n = 24) demonstrated significantly better overall survival than other groups. CONCLUSIONS Preoperative MDCT features of IMCCs can help differentiate the SD and LD types and predict patient prognosis.
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28
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Sasaki M, Kuo FY, Huang CC, Swanson PE, Chen CL, Chuang JH, Yeh MM. Increased expression of senescence-associated cell cycle regulators in the progression of biliary atresia: an immunohistochemical study. Histopathology 2018; 72:1164-1171. [PMID: 29392752 DOI: 10.1111/his.13476] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 12/21/2017] [Accepted: 01/24/2018] [Indexed: 01/10/2023]
Abstract
AIMS Cellular senescence plays a role in tumour suppression and in the pathogenesis of various non-neoplastic diseases, including primary biliary cholangitis and other adult cholangiopathies. Less is known about the role of cellular senescence in cholangiopathies in children. With that in mind, we examined the expression of senescence-associated cell cycle regulators in biliary atresia, the most common form of paediatric obliterative cholangiopathy. METHODS AND RESULTS The expression of senescence-associated cell cycle regulators (p16Ink4a and p21WAF1/Cip1 ) and a ductular reaction related marker (neural cell adhesion molecule: NCAM) was examined in bile ducts and bile ductules in liver samples taken from the patients with biliary atresia [n = 80; including 23 samples at the time of the Kasai procedure (KP) and 63 obtained from the explanted liver (LT) (six cases with samples at both surgical stages of disease)] and from appropriate controls (n = 17). The degree of ductular reaction and cholestasis was significantly more extensive in LT than KP (P < 0.01). The expression of p16INK4a and NCAM was significantly more extensive in bile ducts and bile ductules in ductular reaction in both KP and LT compared to controls and in LT compared to KP (P < 0.05). The expression of p21WAF1/Cip1 was significantly more extensive in bile ducts and bile ductules in KP compared to both LT and controls (P < 0.01). CONCLUSIONS Cellular senescence may play a role in the progression of bile duct loss in biliary atresia in a manner similar to that of adult cholangiopathies.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Fang-Ying Kuo
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Chao-Cheng Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Paul E Swanson
- Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA
| | - Chao-Long Chen
- Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Jiin-Haur Chuang
- Department of Pediatric Surgery, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Matthew M Yeh
- Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA.,Department of Medicine, University of Washington School of Medicine, Seattle, WA, USA
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29
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Histopathological evidence of neoplastic progression of von Meyenburg complex to intrahepatic cholangiocarcinoma. Hum Pathol 2017; 67:217-224. [PMID: 28823571 DOI: 10.1016/j.humpath.2017.08.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 08/04/2017] [Accepted: 08/10/2017] [Indexed: 12/15/2022]
Abstract
Von Meyenburg complex (VMC) is generally thought to be benign, although its preneoplastic potential for intrahepatic cholangiocarcinoma (iCC) has been a subject of contention. We retrospectively reviewed 86 hepatectomy specimens with a diagnosis of iCC. Morphologically, an association between iCC and VMC was appreciated in 35% of cases that illustrated a gradual neoplastic progression from benign VMC to dysplasia and then to iCC. Among them, 24 cases had VMC lined by epithelial cells with low-grade biliary dysplasia and 13 with high-grade biliary dysplasia. VMC-associated iCCs were smaller in size and well to moderately differentiated, with features of anastomosing glandular architecture, ductal carcinoma in situ-like growth pattern, peritumoral lymphocytic infiltrate, central fibrous scar, and complete pushing border. They often presented as T1 tumors. In contrast, non-VMC-associated iCCs were moderately to poorly differentiated with solid, cribriform or papillary growth patterns. They likely exhibited necrosis, perineural invasion, positive surgical margin, lymphovascular invasion, and high T stage. Additionally, Ki67 and p53 immunostains support the continuing neoplastic evolution from benign VMC to dysplasia and then to iCC. VMC could become neoplastic, serving as an in situ carcinoma lesion to transform to iCC. The underlying molecular alteration and clinical implication of this neoplastic transformation deserves further investigation.
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30
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Distinct Clinicopathologic and Genetic Features of 2 Histologic Subtypes of Intrahepatic Cholangiocarcinoma. Am J Surg Pathol 2017; 40:1021-30. [PMID: 27259014 DOI: 10.1097/pas.0000000000000670] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Previous studies have identified 2 clinically significant morphologic subtypes of intrahepatic cholangiocarcinoma (ICC) on the basis of anatomic location and/or histologic appearances. Recognizing that these classification schemes are not always applicable practically, this study aimed to establish a novel classification system based on mucin productivity and immunophenotype and to determine the rationale of this classification by examining the clinicopathologic and genetic characteristics of the 2 subtypes defined by this method. We retrospectively investigated 102 consecutive ICC cases and classified them on the basis of mucin productivity and immunophenotype (S100P, N-cadherin, and NCAM). We found that 42 and 56 cases were classified as type 1 and type 2 ICCs, respectively, and only 4 cases were of indeterminate type. Type 1 ICC, generally characterized by mucin production and diffuse immunoreactivity to S100P, arose less frequently in chronic liver diseases and showed higher levels of serum CEA and CA 19-9 than did type 2 ICC, which generally showed little mucin production and exhibited immunoreactivity to N-cadherin and/or NCAM. Type 1 ICC was characterized by several pathologic features, including higher frequencies of perineural invasion and lymph node metastasis. Although the log-rank test demonstrated that type 1 ICC had significantly worse survival, the multivariate Cox regression analysis showed no prognostic significance of this histologic subtype. Genetic analyses revealed that KRAS mutation was significantly more frequent in type 1 ICC, whereas IDH mutation and FGFR2 translocation were restricted to type 2 ICC. In conclusion, the present classification of ICC based on mucin productivity and immunophenotype identified 2 subtypes with clinicopathologic significance.
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Kozaka K, Matsui O, Kobayashi S, Koda W, Minami T, Kitao A, Inoue D, Yoneda N, Yoshida K, Toshima F, Nakanuma Y, Gabata T. Dynamic CT findings of cholangiolocellular carcinoma: correlation with angiography-assisted CT and histopathology. Abdom Radiol (NY) 2017; 42:861-869. [PMID: 27747442 DOI: 10.1007/s00261-016-0944-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES To elucidate the dynamic CT features of pure type of cholangiolocellular carcinoma (pure CoCC) in comparison with those of cholangiocellular carcinoma (CCC) and to analyze their bases by angiography-assisted CT with histopathologic correlation. METHODS Surgically confirmed 10 pure CoCCs, 10 CCCs and 7 mixed CoCC and CCCs from August 2001 to May 2012 were included in this study. Among them, dynamic CT features were compared. In 8 pure CoCCs, the correlative study between angiography-assisted CT and histopathological study was performed to clarify the basic mechanism of dynamic CT features. RESULTS All pure CoCCs showed early and prolonged enhancement homogeneously or inhomogeneously and 8 of 10 pure CoCCs showed early peritumoral enhancement on dynamic CT. Time-attenuation curve provided by dynamic CT showed significant higher Hounsfield unit value of pure CoCC than those of CCC at each phases (p < 0.05). The depiction of peritumoral enhancement in CoCC was nearly simultaneous to tumor stain on dynamic CT during hepatic arteriography. Pathologic analysis revealed there were abundant communications between blood sinusoids of the tumor and intra and peritumoral portal venules and surrounding hepatic sinusoids. CONCLUSION Early tumoral staining and peritumoral enhancement due to early drainage from the tumor and prolonged enhancement are characteristic findings in pure CoCCs.
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Affiliation(s)
- Kazuto Kozaka
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan.
| | - Osamu Matsui
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Satoshi Kobayashi
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Wataru Koda
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Tetsuya Minami
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Azusa Kitao
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Dai Inoue
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Norihide Yoneda
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Kotaro Yoshida
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Fumihito Toshima
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Toshifumi Gabata
- Department of Radiology, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, 920-8640, Japan
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Sasaki M, Nakanuma Y. New concept: cellular senescence in pathophysiology of cholangiocarcinoma. Expert Rev Gastroenterol Hepatol 2017; 10:625-38. [PMID: 26680649 DOI: 10.1586/17474124.2016.1133291] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Cholangiocarcinoma, a malignant tumor arising in the hepatobiliary system, presents with poor prognosis because of difficulty in its early detection/diagnosis. Recent progress revealed that cellular senescence may be involved in the pathophysiology of cholangiocarcinoma. Cellular senescence is defined as permanent growth arrest caused by several cellular injuries, such as oncogenic mutations and oxidative stress. "Oncogene-induced" and/or stress-induced senescence may occur in the process of multi-step cholangiocarcinogenesis, and overexpression of a polycomb group protein EZH2 may play a role in the escape from, and/or bypassing of, senescence. Furthermore, senescent cells may play important roles in tumor development and progression via the production of senescence-associated secretory phenotypes. Cellular senescence may be a new target for the prevention, early diagnosis, and therapy of cholangiocarcinoma in the near future.
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Affiliation(s)
- Motoko Sasaki
- a Human Pathology , Kanazawa University Graduate School of Medical Sciences , Kanzawa , Japan
| | - Yasuni Nakanuma
- b Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan
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Suzumura K, Asano Y, Hirano T, Okada T, Uyama N, Aizawa N, Iijima H, Nakasho K, Nishiguchi S, Fujimoto J. Synchronous double cancers of primary hepatocellular carcinoma and cholangiolocellular carcinoma: a case report. Surg Case Rep 2016; 2:139. [PMID: 27878570 PMCID: PMC5120164 DOI: 10.1186/s40792-016-0262-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 11/10/2016] [Indexed: 12/25/2022] Open
Abstract
Synchronous double cancers consisting of hepatocellular carcinoma (HCC) and cholangiolocellular carcinoma (CoCC) are extremely rare. We herein report a surgical case of synchronous double cancers in a patient with primary HCC and CoCC. A 45-year-old man with hepatitis B was admitted to our hospital with hepatic tumors. The level of protein induced by vitamin K antagonist (PIVKA-II) was found to be elevated. Computed tomography (CT) revealed a 23-mm tumor with early-phase enhancement and late-phase washout in the 6th segment of the liver, and a 10-mm tumor with slight early-phase enhancement and late-phase washout in the 7th segment of the liver. Magnetic resonance imaging (MRI) revealed that the two tumors in the 6th and 7th segments showed low intensity on T1-weighted images and high intensity on T2-weighted images. Based on those preoperative examinations, the liver tumors were diagnosed as multiple primary hepatocellular carcinomas. The patient underwent a posterior segmentectomy. A histopathological examination revealed that the tumor of the 6th segment of the liver was moderately differentiated HCC, and that the tumor of the 7th segment of the liver was CoCC. The postoperative course was uneventful. However, lymph node recurrence was observed 6 months later and the patient died 20 months after surgery. There are only six reported surgical cases of synchronous double primary liver cancers consisting of HCC and CoCC. We are of the opinion that curative resection may be an effective treatment for double cancer consisting of HCC and CoCC, and that it may provide long-term survival.
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Affiliation(s)
- Kazuhiro Suzumura
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Yasukane Asano
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Tadamichi Hirano
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Toshihiro Okada
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Naoki Uyama
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Nobuhiro Aizawa
- Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Hiroko Iijima
- Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Keiji Nakasho
- Department of Pathology, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Shuhei Nishiguchi
- Department of Internal Medicine, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
| | - Jiro Fujimoto
- Department of Surgery, Hyogo College of Medicine, 1-1, Mukogawa, Nishinomiya, Hyogo 663-8501 Japan
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Hoshino H, Ohta M, Ito M, Uchimura K, Sakai Y, Uehara T, Low S, Fukushima M, Kobayashi M. Apical membrane expression of distinct sulfated glycans represents a novel marker of cholangiolocellular carcinoma. J Transl Med 2016; 96:1246-1255. [PMID: 27748735 DOI: 10.1038/labinvest.2016.104] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 08/25/2016] [Accepted: 08/30/2016] [Indexed: 12/31/2022] Open
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver neoplasm, followed by hepatocellular carcinoma. ICC can be further subclassified as (i) perihilar and (ii) peripheral types, the latter histologically resembling small-sized intrahepatic bile ducts, such as interlobular bile ducts, cholangioles/ductules and the canals of Hering. Cholangiolocellular carcinoma (CoCC), now classified by the World Health Organization as a subtype of combined hepatocellular-cholangiocarcinoma, is currently regarded as a subtype of peripheral-type ICC. The present study was undertaken to determine whether sulfated glycans recognized by the MECA-79 monoclonal antibody could serve as a CoCC marker. Using immunohistochemistry, we show that MECA-79 sulfated glycans are preferentially expressed at the apical membrane of cholangiocytes found in small-sized intrahepatic bile ducts in normal liver and in canalicular structures formed in CoCC. We also report that apical membrane MECA-79 sulfated glycan expression colocalizes with that of mucin 1 (MUC1) core proteins. We also present immunoblotting of Chinese hamster ovary cells overexpressing FLAG-tagged MUC1 to show that MUC1 serves as a MECA-79 scaffold. Furthermore, we report that SSP-25 human ICC cells overexpressing N-acetylglucosamine-6-O-sulfotransferase 2 (GlcNAc6ST-2), but not GlcNAc6ST-1, exhibit membrane expression of MECA-79 sulfated glycans, suggesting that GlcNAc6ST-2 catalyzes MECA-79 epitope biosynthesis in cholangiocytes. Moreover, both wild-type and GlcNAc6ST-1 knockout mice exhibit apical membrane MECA-79 expression in small-sized intrahepatic bile ducts, namely interlobular bile ducts, whereas MECA-79 expression was completely absent in comparable tissues from GlcNAc6ST-1 and GlcNAc6ST-2 double knockout mice. These data collectively indicate that apical membrane localization of MUC1 proteins decorated with GlcNAc6ST-2-dependent MECA-79 sulfated glycans may mark cholangiocytes with cholangiolar/ductular differentiation and could serve as a useful CoCC marker.
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MESH Headings
- Animals
- Antigens, Surface/biosynthesis
- Antigens, Surface/chemistry
- Antigens, Surface/metabolism
- Antigens, Tumor-Associated, Carbohydrate/biosynthesis
- Bile Duct Neoplasms/metabolism
- Bile Duct Neoplasms/pathology
- Bile Ducts, Intrahepatic/metabolism
- Bile Ducts, Intrahepatic/pathology
- Biomarkers, Tumor/metabolism
- CHO Cells
- Cell Line, Tumor
- Cell Membrane/metabolism
- Cell Membrane/pathology
- Cell Polarity
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/pathology
- Cricetinae
- Cricetulus
- Humans
- Isoenzymes/genetics
- Isoenzymes/metabolism
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Membrane Proteins/biosynthesis
- Membrane Proteins/chemistry
- Mice, Knockout
- Mucin-1/genetics
- Mucin-1/metabolism
- Polysaccharides/biosynthesis
- Polysaccharides/metabolism
- Protein Transport
- Recombinant Proteins/metabolism
- Sulfotransferases/genetics
- Sulfotransferases/metabolism
- Sulfuric Acid Esters/metabolism
- Carbohydrate Sulfotransferases
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Affiliation(s)
- Hitomi Hoshino
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Makoto Ohta
- Department of Pathology, Fukui Red Cross Hospital, Fukui, Japan
| | - Makoto Ito
- Department of Pathology and Laboratory Medicine, Kariya Toyota General Hospital, Kariya, Japan
| | - Kenji Uchimura
- Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Sakai
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shulin Low
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
| | - Mana Fukushima
- Department of Molecular Pathology, Shinshu University Graduate School of Medicine, Matsumoto, Japan
| | - Motohiro Kobayashi
- Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
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35
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Nakanuma Y, Miyata T, Uchida T. Latest advances in the pathological understanding of cholangiocarcinomas. Expert Rev Gastroenterol Hepatol 2016; 10:113-27. [PMID: 26492529 DOI: 10.1586/17474124.2016.1104246] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cholangiocarcinomas (CCAs) are anatomically classified into intrahepatic, perihilar, and distal types. The gross pathological classification of intrahepatic CCAs divides them into mass-forming, periductal-infiltrating, and intraductal-growth types; and perihilar/distal CCAs into flat- and nodular-infiltrating and papillary types. Unique preinvasive lesions appear to precede individual gross types of CCA. Biliary intraepithelial neoplasia, a flat lesion, precedes periductal-, flat-, and nodular-infiltrating CCAs, whereas intraductal papillary neoplasm of the bile duct (IPNB) precedes the intraductal-growth and papillary type of CCAs. IPNBs are heterogeneous in their histological and pathological profiles along the biliary tree. Hepatobiliary cystadenomas/adenocarcinomas are reclassified as cystic IPNBs and hepatic mucinous cystic neoplasms. Peribiliary glands may participate in the development of CCAs. These latest findings present a new challenge for understanding the pathology of CCAs.
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Affiliation(s)
- Yasuni Nakanuma
- a Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan
| | - Takashi Miyata
- a Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan.,b Department of Hepatobiliary Pancreatic Surgery , Shizuoka Cancer Center , Shizuoka , Japan
| | - Tsuneyuki Uchida
- a Department of Diagnostic Pathology , Shizuoka Cancer Center , Shizuoka , Japan.,b Department of Hepatobiliary Pancreatic Surgery , Shizuoka Cancer Center , Shizuoka , Japan
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36
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Türkoğlu MA, Yamamoto Y, Sugiura T, Okamura Y, Ito T, Ashida R, Uemura S, Miyata T, Kakuda Y, Nakanuma Y, Uesaka K. The favorable prognosis after operative resection of hypervascular intrahepatic cholangiocarcinoma: A clinicopathologic and immunohistochemical study. Surgery 2016; 160:683-90. [DOI: 10.1016/j.surg.2016.03.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 02/22/2016] [Accepted: 03/17/2016] [Indexed: 01/14/2023]
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Ono Y, Hiratsuka Y, Murata M, Takasawa A, Fukuda R, Nojima M, Tanaka S, Osanai M, Hirata K, Sawada N. Claudins-4 and -7 might be valuable markers to distinguish hepatocellular carcinoma from cholangiocarcinoma. Virchows Arch 2016; 469:417-26. [PMID: 27444172 DOI: 10.1007/s00428-016-1984-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Revised: 04/07/2016] [Accepted: 06/30/2016] [Indexed: 12/13/2022]
Abstract
The claudin family members are the functional components of tight junctions. Expression and localization of claudins vary among organs and tumor types. In this study, we examined expression and localization of tight junction proteins (TJP) in human liver tumors, to estimate their usefulness as differential diagnostic markers. The materials used for immunohistochemical analysis were 47 liver tumor specimens including 29 cases of hepatocellular carcinoma (HCC), 15 cases of cholangiocarcinoma (CC), 3 cases of combined HCC and CC (CHC), and 3 cases of cholangiolocellular carcinoma (CoCC). Samples were examined using semiquantitative and statistical analysis of immunoreactivity. In HCC, claudin-1, occludin, tricellulin, and JAM-A were expressed on the cell membrane as well as in hepatocytes. In CC, claudins-1, -4, and -7, tricellulin, and JAM-A were expressed on the cell membrane and occludin was predominantly expressed in the apicalmost areas of the cell membrane. Significant differences in the immunohistochemical scores of claudin-4 and claudin-7 were observed when comparing HCC and CC. CHC was positive for all of the TJPs examined in this study. The expression pattern of CoCC was found to be similar to that of CC. There were differences in the distribution of intensity scores of claudins-4 and -7 and occludin between CoCC and HCC. In addition, CHC was positive for Glypican-3 and CK-19. CoCC was positive for only CK-19. The results suggest that claudins-4 and -7 might be valuable markers for distinguishing HCC and CC and that CoCC might arise from hepatic ductal cells.
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Affiliation(s)
- Yusuke Ono
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Yutaro Hiratsuka
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Masaki Murata
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan.
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Rieko Fukuda
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Masanori Nojima
- Division of Advanced Medicine Promotion, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Satoshi Tanaka
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
| | - Koichi Hirata
- Department of Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Norimasa Sawada
- Department of Pathology, Sapporo Medical University School of Medicine, S1. W17, Sapporo, 060-8556, Japan
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Yoh T, Kato T, Hirohata Y, Nakamura Y, Nakayama H, Okamura R. Cholangiolocellular carcinoma with rapid progression initially showing abnormally elevated serum alfa-fetoprotein. Clin J Gastroenterol 2016; 9:257-60. [PMID: 27363839 DOI: 10.1007/s12328-016-0667-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 06/17/2016] [Indexed: 01/17/2023]
Abstract
Cholangiolocellular carcinoma (CoCC) is a rare malignant liver tumor derived from hepatic progenitor cells, which exist in the canals of Hering. We encountered a case of CoCC with an extremely poor clinical course, initially showing abnormally elevated serum alfa-fetoprotein (AFP). A 72-year-old male presented with a liver tumor and abnormally elevated serum AFP levels (16,399 ng/ml). We preoperatively diagnosed hepatocellular carcinoma and performed extended right hepatectomy, after which the serum AFP levels remarkably decreased to 97 ng/ml. Postoperatively, the disease was pathologically diagnosed as CoCC. Furthermore, immunohistochemical pathological findings were alcian blue negative, cytokeratin (CK) 7 partially positive, CK19 positive, hepatocyte paraffin-1 negative, membranous negative for epithelial membrane antigen, and AFP negative. Fifty-five days later, intra- and extrahepatic recurrence developed, and the patient died 65 days after surgery. Although CoCCs show favorable outcomes, these characteristics of our case were not previously reported. It is necessary to accumulate more information on CoCC.
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Affiliation(s)
- Tomoaki Yoh
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-Ku, Kyoto, 606-8507, Japan.
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan.
| | - Tatsushi Kato
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan
| | - Yoshiaki Hirohata
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan
| | - Yuya Nakamura
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan
| | - Hiroyuki Nakayama
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan
| | - Ryuji Okamura
- Department of Surgery, Yamatotakada Municipal Hospital, Yamatotakada, Japan
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Tsunematsu S, Chuma M, Kamiyama T, Miyamoto N, Yabusaki S, Hatanaka K, Mitsuhashi T, Kamachi H, Yokoo H, Kakisaka T, Tsuruga Y, Orimo T, Wakayama K, Ito J, Sato F, Terashita K, Nakai M, Tsukuda Y, Sho T, Suda G, Morikawa K, Natsuizaka M, Nakanishi M, Ogawa K, Taketomi A, Matsuno Y, Sakamoto N. Intratumoral artery on contrast-enhanced computed tomography imaging: differentiating intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma. ACTA ACUST UNITED AC 2016; 40:1492-9. [PMID: 25579172 DOI: 10.1007/s00261-015-0352-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
AIM Differentiating intrahepatic cholangiocarcinoma (ICC) from poorly differentiated hepatocellular carcinoma (p-HCC) is often difficult, but it is important for providing appropriate treatments. The purpose of this study was to examine the features differentiating ICC from p-HCC on contrast-enhanced dynamic-computed tomography (CT). METHODS This study examined 42 patients with pathologically confirmed ICC (n = 19) or p-HCC (n = 23) for which contrast-enhanced dynamic CT data were available. CT images were analyzed for enhancement patterns during the arterial phase, washout pattern, delayed enhancement, satellite nodules, capsular retraction, lesion shape, and presence of an intratumoral hepatic artery, intratumoral hepatic vein, intratumoral portal vein, and bile duct dilation around the tumor, portal vein tumor thrombus, lobar atrophy, or lymphadenopathy. RESULTS Univariate analysis revealed the presence of rim enhancement (p = 0.037), lobulated shape (p = 0.004), intratumoral artery (p < 0.001), and bile duct dilation (p = 0.006) as parameters significantly favoring ICC, while a washout pattern significantly favored p-HCC (p < 0.001). Multivariate analysis revealed intratumoral artery as a significant, independent variable predictive of ICC (p = 0.037), and 15 ICCs (78.9%) showed this feature. Washout pattern was a significant, independent variable favoring p-HCC (p = 0.049), with 15 p-HCCs (65.2%) showing this feature. CONCLUSION The presence of an intratumoral artery in the arterial phase on contrast-enhanced dynamic CT was a predictable finding for ICC, and the presence of a washout pattern was a predictable finding for p-HCC, differentiating between ICC and p-HCC.
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Affiliation(s)
- Seiji Tsunematsu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, 15 Kita, 7 Nishi, Kita-ku, Sapporo, 060-8638, Japan
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40
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Clinicopathologic Characteristics of Hepatocellular Carcinoma With Reactive Ductule-like Components, a Subset of Liver Cancer Currently Classified as Combined Hepatocellular-Cholangiocarcinoma With Stem-Cell Features, Typical Subtype. Am J Surg Pathol 2016; 40:608-16. [DOI: 10.1097/pas.0000000000000579] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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41
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Zhao YJ, Chen WX, Wu DS, Zhang WY, Zheng LR. Differentiation of mass-forming intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma: based on the multivariate analysis of contrast-enhanced computed tomography findings. Abdom Radiol (NY) 2016; 41:978-89. [PMID: 27193795 DOI: 10.1007/s00261-015-0629-z] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
PURPOSE We aim to gain further insight into identifying differential radiological features of mass-forming intrahepatic cholangiocarcinoma (mICC) from poorly differentiated hepatocellular carcinoma (pHCC) on contrast-enhanced computed tomography (CT). MATERIALS AND METHODS 107 patients with pathologically confirmed mICC (n = 48) and pHCC (n = 59) who had undergone preoperative contrast-enhanced CT were enrolled. Qualitative analysis of CT images were evaluated for tumor demarcation, shape, presence of satellite nodules, capsular retraction, biliary involvement, intratumoral arteries, tortuous tumoral vessels, vascular invasion, portal vein tumor thrombus, arterial enhancement pattern, portal venous phase enhancement, and washout pattern. Quantitative analysis was performed for mean attenuation of tumor and tumor-to-liver contrast during each phase. The degree of arterial enhancement was graded based on quantitative measurements. RESULTS A lobulated shape, indistinct margin, peripheral rim enhancement in the arterial phase, and the presence of bile duct dilatation were CT features favoring mICC, whereas a round shape, partially indistinct margin, heterogeneous enhancement in the arterial phase, washout pattern and the presence of tortuous tumoral vessels were CT features favoring pHCC in the univariate analysis (P < 0.05). Tumor-to-liver contrast of pHCC was greater than that of mICC during the arterial phase (P = 0.015). In the multivariate analysis, bile duct dilatation, tortuous tumoral vessels, and a washout pattern were independent CT features for distinguishing between the two types. (P = 0.003, P = 0.003, P = 0.044, respectively). CONCLUSION The absence of a washout pattern and tortuous tumoral vessels and presence of bile duct dilatation are more indicative of mICC than of pHCC on contrast-enhanced CT.
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Affiliation(s)
- Yi-Jun Zhao
- Department of Radiology, West China Hospital of Sichuan University, NO. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
| | - Wei-Xia Chen
- Department of Radiology, West China Hospital of Sichuan University, NO. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China.
| | - Dong-Sheng Wu
- Department of Radiology, No. 4 West China Hospital of Sichuan University, NO. 18, South Renmin Road, Chengdu, Sichuan, China
| | - Wen-Yan Zhang
- Department of Pathology, West China Hospital of Sichuan University, NO. 37, Guoxue Alley, Chengdu, Sichuan, China
| | - Li-Rong Zheng
- Department of Radiology, West China Hospital of Sichuan University, NO. 37, Guoxue Alley, Chengdu, 610041, Sichuan, China
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Yang CC, Yang H, Guo MJ, Li WH, Wu YF. Contrast-enhanced CT imaging in distinguishing intrahepatic cholangiocarcinoma from poorly differentiated hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:4725-4732. [DOI: 10.11569/wcjd.v23.i29.4725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the contrast-enhanced computed tomography (CT) features in differentiating intrahepatic cholangiocarcinoma (ICC) from poorly differentiated hepatocellular carcinoma (p-HCC).
METHODS: Sixty-eight patients with pathologically confirmed ICC (n = 28) or p-HCC (n = 40) were enrolled. The clinical and imaging features were investigated retrospectively.
RESULTS: Univariate analysis showed that lobulated shape (P = 0.010), bile duct dilation (P = 0.031), intratumoral artery (P = 0.020), rim enhancement (P = 0.002), delayed enhancement (P = 0.021) and quick washout (P < 0.001) were associated with the differences between ICC and p-HCC. Multivariate logistic regression analysis revealed that intratumoral artery was a significant, independent predictive factor of ICC (P = 0.026), with 13 (46.43%) ICCs showing this feature. Quick washout significantly favored p-HCC (P = 0.015), and 25 p-HCCs (62.5%) showed this feature.
CONCLUSION: The presence of an intratumoral artery in the arterial phase on contrast-enhanced dynamic CT is an important factor for predicting ICC, while a quick washout is a predictable finding for p-HCC. Accurate imaging diagnosis between ICC and p-HCC can provide an objective basis for making reasonable, timely treatment.
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Pathologic classification of cholangiocarcinoma: New concepts. Best Pract Res Clin Gastroenterol 2015; 29:277-93. [PMID: 25966428 DOI: 10.1016/j.bpg.2015.02.006] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Revised: 01/12/2015] [Accepted: 02/07/2015] [Indexed: 02/06/2023]
Abstract
Herein, we propose a new pathologic classification of cholangiocarcinoma (CCA) based on recent progress in studies of preinvasive CCA lesions and the relationship of CCA to hepatic progenitor cells, as well as a new concept with respect to the pathologic similarities between biliary and pancreatic neoplasms. Depending on anatomical location, CCA is classifiable as intrahepatic (iCCA), perihilar (pCCA), and distal CCA (dCCA). iCCA is classifiable as the conventional type and the bile ductular type, whereas pCCA and dCCA mainly present as conventional adenocarcinoma. In addition, these three CCAs may present as the intraductal neoplasm type or rare variants. Bile ductular CCA resembles proliferating bile ductules and expressing hepatic progenitor cell phenotypes. Four types of preinvasive lesions are proposed: flat, papillary, tubular lesion, and cystic lesion. These lesions are eventually followed by invasive CCA. Interestingly, these preinvasive lesions have pancreatic counterparts. This CCA classification may introduce a new field of CCA research.
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Sasaki M, Sato H, Kakuda Y, Sato Y, Choi JH, Nakanuma Y. Clinicopathological significance of 'subtypes with stem-cell feature' in combined hepatocellular-cholangiocarcinoma. Liver Int 2015; 35:1024-35. [PMID: 24712771 DOI: 10.1111/liv.12563] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2013] [Accepted: 04/01/2014] [Indexed: 12/13/2022]
Abstract
BACKGROUNDS & AIMS Combined hepatocellular-cholangiocarcinoma (cHC-CC), a malignant liver tumour with poor prognosis, is composed of hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and diverse components with intermediate features between HCC and CC, which correspond to hepatic progenitor cells. According to the WHO classification 2010, we surveyed the prevalence and clinicopathological significance of each subtype with stem-cell features [SC subtype; typical subtype (TS), intermediate cell subtype (INT) and cholangiolocellular type (CLC)] in cHC-CC and HCC. METHODS Sixty-two patients with cHC-CC (19 women and 43 men) and 26 patients with HCC (all men) were examined. The prevalence of each component was histologically assessed with assistance of mucin and immunohistochemical stainings. RESULTS SC subtypes were observed in all cHC-CCs in various amount and combination. The prevalence of each SC subtype in cHC-CC was as follows: TS, 10 (16.1%); INT, 53 (83.9%) and CLC, 44 (71.0%). The proportion of INT was significantly correlated with gender (female-dominant) (P < 0.05), tumour size (P < 0.05), histological grading of HCC (P < 0.01) and inversely correlated with the degree of stromal fibrosis (P < 0.05). The proportion of CLC was significantly correlated with the degree of fibrosis (P < 0.01) and inflammation (P < 0.01), and inversely correlated with tumour size (P < 0.01) and histological grading of HCC (P < 0.05). The proportion of TS was significantly inversely correlated with the degree of inflammation (P < 0.01). Histological diversity score was significantly correlated with vascular invasion and the positivity for α-foetoprotein. CONCLUSION The proportion of each SC subtype was significantly associated with certain clinicopathological factors, suggesting different properties of each SC subtypes.
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Affiliation(s)
- Motoko Sasaki
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
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Ogasawara S, Akiba J, Nakayama M, Nakashima O, Torimura T, Yano H. Epithelial cell adhesion molecule-positive human hepatic neoplastic cells: development of combined hepatocellular-cholangiocarcinoma in mice. J Gastroenterol Hepatol 2015; 30:413-20. [PMID: 25087473 DOI: 10.1111/jgh.12692] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Human combined hepatocellular-cholangiocarcinoma (CHC) expresses several hepatic stem/progenitor cell (HSPC) markers, suggesting this neoplasm originates from HSPCs. We examined the significance of HSPC marker in CHC using a human CHC cell line. METHODS We used a human CHC cell line (KMCH-1) previously established in our laboratory. The original tumor was classified as CHC, showing areas of typical hepatocellular carcinoma (HCC) and cholangiocarcinoma (ChC). We examined the expression of HSPC markers and hepatocyte markers in KMCH-1 by flow cytometry (FCM) and quantitative real-time polymerase chain reaction. EpCAM(+) and EpCAM(-) KMCH-1 cells were isolated. Subsequently, their morphological features, HSPC marker expression, and biological characteristics were examined in vitro and in vivo. RESULTS FCM showed expression of EpCAM, K7, K19, and ABCG2 in KMCH-1, with various degrees. EpCAM(+) cells expressed K19 mRNA, but did not express α-fetoprotein (AFP). In contrast, EpCAM(-) cells expressed AFP mRNA, but did not express K19. EpCAM(+) cells produced both EpCAM(+) and EpCAM(-) cells, but EpCAM(-) cells produced only EpCAM(-) cells in vitro. EpCAM(+) cells showed higher tumorigenicity and formed larger tumors than EpCAM(-) cells. Inoculation of EpCAM(+) and EpCAM(-) cells produced both ChC and HCC-like component and HCC-like component only, respectively. CONCLUSION It is speculated that some CHCs may originate from EpCAM(+) neoplastic cells, and that these cells may affect malignant behavior and progression in such CHCs.
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Affiliation(s)
- Sachiko Ogasawara
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
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Abstract
Cholangiolocellular carcinoma (CoCC) is categorized as a different entity from ordinary intrahepatic cholangiocarcinoma (ICC) due to its unique clinical, radiological and histological features. The lesion is supposed to originate from cholangioles, where hepatic stem/progenitor cells exist. However, the interlobular duct is also speculated to be the origin of CoCC. According to the findings of morphometric and immunohistochemical studies, CoCC closely resembles the interlobular duct. The unique clinical and pathological features of this disease can also be explained by the interlobular duct origin theory. The malignant counterparts of cholangioles and interlobular ducts have been categorized as CoCC to date. In order to differentiate between true CoCC (cholangiole origin) and pseudo-CoCC (interlobular duct origin), assessing the size of the cancer duct, positivity for c-Kit and coexistence of an ordinary ICC component is useful.
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Affiliation(s)
- Fukuo Kondo
- Department of Pathology, Teikyo University Hospital, Japan
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Aishima S, Tanaka Y, Kubo Y, Shirabe K, Maehara Y, Oda Y. Bile duct adenoma and von Meyenburg complex-like duct arising in hepatitis and cirrhosis: pathogenesis and histological characteristics. Pathol Int 2014; 64:551-9. [PMID: 25329860 DOI: 10.1111/pin.12209] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Accepted: 09/02/2014] [Indexed: 12/15/2022]
Abstract
Morphologic features and neoplastic potentials of bile duct adenoma (BDA) and von Meyenburg complex (VMC)-like duct arising in chronic liver disease were unknown. Thirty-five BDAs and 12 VMC-like duct lesions were observed in 39 cases with chronic liver disease. BDAs were divided into the EMA-cytoplasmic type (n = 14) and EMA-luminal type (n = 21). EMA-cytoplasmic BDA composed of a proliferation of cuboidal to low-columnar cells forming an open lumen with NCAM(+)/MUC6(-), resembling an interlobular bile duct. EMA-luminal BDA showed uniform cuboidal cells with narrow lumen, and NCAM(++)/MUC6(++), resembling a ductular reaction. VMC-like duct showed positive MUC1 expression and negative MUC6. The expression of S100P, glucose transporter-1 (GLUT-1) and insulin-like growth factor II mRNA-binding protein 3 (IMP-3) were not detected in three lesions. p16 expression was higher than those of the ductular reaction, and the Ki67 and p53 indexes were very low (<1.0%). Large-sized EMA-luminal BDA shows sclerotic stroma. We classified small nodular lesions of ductal or ductular cells in chronic hepatitis and cirrhosis into the following groups: BDA, interlobular bile duct type; BDA, ductular/peribiliary gland type; and VMC-like duct. They may be reactive proliferation rather than neoplastic lesions.
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Affiliation(s)
- Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan
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Intrahepatic cholangiocarcinoma and cholangiolocellular carcinoma in cirrhosis and chronic viral hepatitis. Surg Today 2014; 45:682-7. [PMID: 25253466 DOI: 10.1007/s00595-014-1031-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2014] [Accepted: 06/15/2014] [Indexed: 12/14/2022]
Abstract
Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer. Cirrhosis and chronic viral hepatitis are known to be important risk factors for ICC, especially the mass-forming (MF) type of ICC at the periphery of the liver. Cholangiolocellular carcinoma (CoCC) is a rare type of primary liver cancer, which is thought to originate from hepatic progenitor or stem cells. CoCC often exhibits the similar MF type at the periphery of the liver, as ICC, and CoCC is also associated with cirrhosis or chronic viral hepatitis. Better survival rates after surgery have been reported for ICC patients with chronic viral hepatitis than for those without chronic viral hepatitis, although survival rates did not differ significantly in relation to cirrhosis. On the other hand, patients with CoCC had better surgical results than those with MF-type ICC. This review summarizes the clinical characteristics and surgical outcomes of ICC and CoCC associated with cirrhosis or chronic viral hepatitis.
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Aishima S, Oda Y. Pathogenesis and classification of intrahepatic cholangiocarcinoma: different characters of perihilar large duct type versus peripheral small duct type. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 22:94-100. [PMID: 25181580 DOI: 10.1002/jhbp.154] [Citation(s) in RCA: 156] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intrahepatic cholangiocarcinomas (ICCs) are made up of heterogenous carcinomas arising from different anatomical sites of the liver. Two types of candidate stem/progenitor cells of the biliary tree are postulated to exist at the peribiliary glands for large bile ducts and at the canals of Hering for small ducts and hepatocytes. According to the recent observations, ICCs can be subclassified into two types: tumors involving the large bile ducts comparable in size to the intrahepatic second branches and composed of a tubular or papillary component with tall columnar epithelium, and tumors involving the smaller duct than segmental branches and composed of small tubules with cuboidal epithelium. Perihilar large duct type ICCs can be interpreted as arising from large bile duct type ICCs, and peripheral small duct type ICCs may arise from small bile duct type or ductular type ICCs. Chronic biliary inflammation induces neoplastic change of the large bile ducts and thereby progression to the perihilar large duct type ICC, which can be grossly classified into periductal filtrating type ICC and intraductal growth type ICC, while chronic hepatitis or cirrhosis induces mass-forming peripheral small duct type ICC. The different morphological and molecular features, including stromal components and tumor vasculature, support the hypothesis that perihilar large duct type ICCs and peripheral small duct type ICCs arise from different backgrounds, have different carcinogenetic pathways, and exhibit different biologic behaviors.
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Affiliation(s)
- Shinichi Aishima
- Pathology and Microbiology, Faculty of Medicine, Saga University, 1-1 Nabeshima 5-chome, Saga 849-8501, Japan.
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Ariizumi SI, Kotera Y, Katagiri S, Nakano M, Nakanuma Y, Saito A, Yamamoto M. Long-term survival of patients with cholangiolocellular carcinoma after curative hepatectomy. Ann Surg Oncol 2014; 21 Suppl 3:S451-8. [PMID: 24633664 PMCID: PMC4024138 DOI: 10.1245/s10434-014-3582-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cholangiolocellular carcinoma (CoCC) has distinct pathological characteristics, and CoCC is considered to originate from hepatic progenitor or stem cells. However, the surgical outcome of CoCC has not been clarified in detail. METHODS We retrospectively studied 275 patients with intrahepatic cholangiocarcinoma (ICC) who underwent hepatectomy between 1990 and 2011. Surgical outcomes were compared between 29 patients with CoCC and 130 patients with mass-forming (MF) type ICC since all patients with CoCC showed MF type on macroscopic findings. RESULTS The number of patients with chronic liver disease was significantly higher in the CoCC group than in the ICC group. The number of patients with abnormal levels of CA19-9 was significantly lower in the CoCC group than in the ICC group. Portal vein invasion and intrahepatic metastasis were significantly lower in patients with CoCC group than in the ICC group. In the CoCC group, 15 of 28 patients survived for more than 5 years after curative surgery whereas 15 of 102 patients with ICC survived for more than 5 years after curative surgery. The 5-year survival rate was significantly higher in patients with CoCC (75 %) than in patients with ICC (33 %, p = 0.0005). Multivariate analysis showed CoCC, absence of portal vein invasion or hepatic vein invasion, and absence of intrahepatic metastasis to be significant independent prognostic factors for overall survival in patients with MF-type ICC and CoCC. CONCLUSIONS CoCC is rare, but patients with CoCC had special characteristics with favorable long-term survival due to its less invasive histopathologic characteristics.
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Affiliation(s)
- Shun-ichi Ariizumi
- Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Kawada 8-1, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Yoshihito Kotera
- Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Kawada 8-1, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Satoshi Katagiri
- Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Kawada 8-1, Shinjuku-ku, Tokyo, 162-8666 Japan
| | - Masayuki Nakano
- Division of Pathology, Ofuna Chuo Hospital, Kamakura, Kanagawa Japan
| | - Yasuni Nakanuma
- Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Akiko Saito
- Department of Internal Medicine, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Kawada 8-1, Shinjuku-ku, Tokyo, 162-8666 Japan
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