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Akabane M, Imaoka Y, Kawashima J, Pawlik TM. Advancing precision medicine in hepatocellular carcinoma: current challenges and future directions in liquid biopsy, immune microenvironment, single nucleotide polymorphisms, and conversion therapy. Hepat Oncol 2025; 12:2493457. [PMID: 40260687 PMCID: PMC12026093 DOI: 10.1080/20450923.2025.2493457] [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: 01/31/2025] [Accepted: 04/11/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular carcinoma (HCC) remains a health concern characterized by heterogeneity and high mortality. Surgical resection, radiofrequency ablation, trans-arterial chemoembolization, and liver transplantation offer potentially curative treatments for early-stage disease, but recurrence remains high. Most patients present with advanced-stage HCC, where locoregional therapies are less effective, and systemic treatments-primarily multi-kinase inhibitors and immune checkpoint inhibitors-often yield limited responses. Precision medicine aims to tailor therapy to molecular and genetic profiles, yet its adoption in HCC is hindered by inter-/intra-tumoral heterogeneity and limited biopsy availability. Advances in molecular diagnostics support reintroducing tissue sampling to better characterize genetic, epigenetic, and immunological features. Liquid biopsy offers a minimally invasive method for capturing real-time tumor evolution, overcoming spatial and temporal heterogeneity. Artificial intelligence and machine learning are revolutionizing biomarker discovery, risk stratification, and treatment planning by integrating multi-omics data. Immunological factors such as tumor-infiltrating lymphocytes, natural killer cells, macrophages, and fibroblasts have emerged as determinants of HCC progression and treatment response. Conversion therapy-combining systemic agents with locoregional treatments-has showndemonstrated promise in downstaging unresectable HCC. Ongoing efforts to refine biomarker-driven approaches and optimize multi-modality regimens underscore precision medicine's potential to improve outcomes. PubMed (January 2002-February 2025) was searched for relevant studies.
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Affiliation(s)
- Miho Akabane
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Yuki Imaoka
- Division of Abdominal Transplant, Department of Surgery, Stanford University, CA, USA
| | - Jun Kawashima
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
| | - Timothy M. Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center and James Comprehensive Cancer Center, Columbus, OH, USA
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Aoki T, Nishida N, Minami Y, Kudo M. The Impact of Normal Hepatobiliary Cell Zonation Programs on the Phenotypes and Functions of Primary Liver Tumors. Liver Cancer 2025; 14:92-103. [PMID: 40144466 PMCID: PMC11936443 DOI: 10.1159/000541077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 08/21/2024] [Indexed: 03/28/2025] Open
Abstract
Background Traditional tumor classifications have relied on cellular origin, pathological morphological features, gene expression profiles, and more recently, the tumor immune microenvironment. While these classifications provide valuable insights, incorporating physiological classifications focusing on liver metabolic functions may lead to new discoveries. Summary We proposed to reclassify benign and malignant hepatocellular neoplasms based on their physiological functions such as albumin production, bile acid production, glycolysis, glycogenesis, and adipogenesis. We further demonstrated the homology between signal pathways activated by the differentiation program of the normal hepatobiliary cells and those activated by genetic abnormalities in tumors. Specifically, Wnt/β-catenin, RAS, NOTCH, and TGF-β signaling not only contribute to cell differentiation via activation of liver-enriched transcription factors but also determine the tumor traits. Examining the distinctions between hepatocellular carcinomas (HCCs) that maintain or lose metabolic functions can yield valuable insights into the drivers of biological malignancy and tumor plasticity. Key Messages To confirm the homology between the differentiation programs of normal hepatobiliary cells, hepatocellular adenomas (HCA), and HCC we identify liver-specific functions such as catabolism and anabolism within tumors. HCCs and HCAs that have lost these metabolic functions exhibit characteristics such as dedifferentiation, resemblance to biliary cells, or increased glycolysis. Focusing on this underexplored area will likely stimulate active research into new tumor characteristics.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Yasunori Minami
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan
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Liu K, Tian F, Chen X, Liu B, Tian S, Hou Y, Wang L, Han M, Peng S, Tan Y, Pan Y, Chu Z, Li J, Che L, Chen D, Wen L, Qin Z, Li X, Xiang J, Bian X, Liu Q, Ye X, Wang T, Wang B. Stabilization of TGF-β Receptor 1 by a Receptor-Associated Adaptor Dictates Feedback Activation of the TGF-β Signaling Pathway to Maintain Liver Cancer Stemness and Drug Resistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2402327. [PMID: 38981014 PMCID: PMC11425868 DOI: 10.1002/advs.202402327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/16/2024] [Indexed: 07/11/2024]
Abstract
Dysregulation of the transforming growth factor-β (TGF-β) signaling pathway regulates cancer stem cells (CSCs) and drug sensitivity, whereas it remains largely unknown how feedback regulatory mechanisms are hijacked to fuel drug-resistant CSCs. Through a genome-wide CRISPR activation screen utilizing stem-like drug-resistant properties as a readout, the TGF-β receptor-associated binding protein 1 (TGFBRAP1) is identified as a TGF-β-inducible positive feedback regulator that governs sensitivity to tyrosine kinase inhibitors (TKIs) and promotes liver cancer stemness. By interacting with and stabilizing the TGF-β receptor type 1 (TGFBR1), TGFBRAP1 plays an important role in potentiating TGF-β signaling. Mechanistically, TGFBRAP1 competes with E3 ubiquitin ligases Smurf1/2 for binding to TGFΒR1, leading to impaired receptor poly-ubiquitination and proteasomal degradation. Moreover, hyperactive TGF-β signaling in turn up-regulates TGFBRAP1 expression in drug-resistant CSC-like cells, thereby constituting a previously uncharacterized feedback mechanism to amplify TGF-β signaling. As such, TGFBRAP1 expression is correlated with TGFΒR1 levels and TGF-β signaling activity in hepatocellular carcinoma (HCC) tissues, as well as overall survival and disease recurrence in multiple HCC cohorts. Therapeutically, blocking TGFBRAP1-mediated stabilization of TGFBR1 by selective inhibitors alleviates Regorafenib resistance via reducing CSCs. Collectively, targeting feedback machinery of TGF-β signaling pathway may be an actionable approach to mitigate drug resistance and liver cancer stemness.
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Affiliation(s)
- Kewei Liu
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life SciencesSouthwest UniversityChongqing400715P. R. China
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Fanxuan Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Xu Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- School of MedicineChongqing UniversityChongqing400044P. R. China
| | - Biyin Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Shuoran Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Yongying Hou
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- Department of PathologyDaping Hospital, Army Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Lei Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Mengyi Han
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Shiying Peng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- School of MedicineChongqing UniversityChongqing400044P. R. China
| | - Yuting Tan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- School of MedicineChongqing UniversityChongqing400044P. R. China
| | - Yuwei Pan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- School of MedicineChongqing UniversityChongqing400044P. R. China
| | - Zhaole Chu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Jinyang Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Linrong Che
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Liangzhi Wen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Zhongyi Qin
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Xianfeng Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Junyu Xiang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Xiu‐wu Bian
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038P. R. China
| | - Qin Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- School of MedicineChongqing UniversityChongqing400044P. R. China
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038P. R. China
| | - Xiaoli Ye
- Engineering Research Center of Coptis Development and Utilization (Ministry of Education), School of Life SciencesSouthwest UniversityChongqing400715P. R. China
| | - Tao Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
| | - Bin Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping HospitalArmy Medical University (Third Military Medical University)Chongqing400042P. R. China
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest HospitalArmy Medical University (Third Military Medical University)Chongqing400038P. R. China
- Jinfeng LaboratoryChongqing401329P. R. China
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Soon GST, Callea F, Burt AD, Cook S, Terracciano L, Ercan C, Dienes HP, Goodman ZD, Roberts EA, Clouston AD, Gouw ASH, Kleiner DE, Park YN, Chung T, Schirmacher P, Tiniakos D, Dimopoulou K, Weber A, Endhardt K, Torbenson M. Steatohepatitic hepatocellular Carcinoma:A new approach to classifying morphological subtypes of hepatocellular carcinoma. Hum Pathol 2024; 149:55-65. [PMID: 38876199 DOI: 10.1016/j.humpath.2024.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/16/2024]
Abstract
Histological subtyping of hepatocellular carcinoma (HCC) is challenging in the presence of histological heterogeneity, where distinctly different morphological patterns are present within the same tumor. Current approaches rely on percent cut-offs. We hypothesized that morphologic intratumor heterogeneity is a non-random biological feature and that incorporating recurrent patterns would improve histological subtyping of HCC. Resected HCC were studied and the overall frequency of morphologic intratumor heterogeneity was 45% in 242 specimens. Steatohepatitic HCC (SH-HCC) had the highest frequency of morphologic intratumor heterogeneity (91%); this was confirmed in additional cohorts of SH-HCC from different medical centers (overall frequency of 78% in SH-HCC). Morphologic intratumor heterogeneity in SH-HCC showed distinct and recurrent patterns that could be classified as early, intermediate, and advanced. Incorporating these patterns into the definition of SH-HCC allowed successful resolution of several persistent challenges: the problem of the best cut-off for subtyping SH-HCC, the problem of the relationship between SH-HCC and scirrhous HCC, and the classification for HCC with abundant microvesicular steatosis. This approach also clarified the relationship between SH-HCC and CTNNB1 mutations, showing that CTNNB1 mutations occur late in a subset of SH-HCC. In summary, there is a high frequency of morphologic intratumor heterogeneity in HCC. Incorporating this finding into histological subtyping resolved several persistent problems with the SH-HCC subtype.
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Affiliation(s)
- Gwyneth S T Soon
- Department of Pathology, National University Hospital, Singapore
| | | | - Alastair D Burt
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Sam Cook
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom
| | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Caner Ercan
- Institute of Pathology and Medical Genetics, University Hospital Basel, Basel, Switzerland
| | - Hans-Peter Dienes
- Institute of Pathology, Meduniwien, Medical University of Vienna, 1090 Wien, Austria
| | - Zachary D Goodman
- Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA 22042, USA
| | - Eve A Roberts
- Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario M5G1X8, Canada
| | - Andrew D Clouston
- Centre for Liver Disease Research, School of Medicine (Southern), University of Queensland, Princess Alexandra Hospital, Ipswich Rd Woolloongabba 4109, Australia
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, 9700 RB Groningen, the Netherlands
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, USA
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul Korea
| | - Taek Chung
- Department of Pathology, Yonsei University College of Medicine, Seoul Korea.
| | - Peter Schirmacher
- Institute of Pathology, University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom; Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Konstantina Dimopoulou
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Achim Weber
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Katharina Endhardt
- Department of Pathology and Molecular Pathology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - Michael Torbenson
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
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5
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Nishikawa Y. Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors. Pathol Int 2024; 74:361-378. [PMID: 38837539 PMCID: PMC11551836 DOI: 10.1111/pin.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024]
Abstract
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
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Affiliation(s)
- Yuji Nishikawa
- President's OfficeAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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Heo S, Kang HJ, Choi SH, Kim S, Yoo Y, Choi WM, Kim SY, Lee SS. Proliferative hepatocellular carcinomas in cirrhosis: patient outcomes of LI-RADS category 4/5 and category M. Eur Radiol 2024; 34:2974-2985. [PMID: 37848775 DOI: 10.1007/s00330-023-10305-y] [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: 02/06/2023] [Revised: 07/15/2023] [Accepted: 08/10/2023] [Indexed: 10/19/2023]
Abstract
OBJECTIVES We aimed to compare Liver Imaging Reporting and Data System (LI-RADS) category 4/5 and category M (LR-M) of proliferative hepatocellular carcinomas (HCCs) in cirrhotic patients and evaluate their impacts on prognosis. METHODS This retrospective multi-reader study included cirrhotic patients with single treatment-naïve HCC ≤ 5.0 cm who underwent contrast-enhanced CT, MRI, and subsequent hepatic resection within 2 months. The percentages of CT/MRI LR-4/5 and LR-M in proliferative and non-proliferative HCCs were compared. Univariable and multivariable Cox proportional hazards regression analyses were performed to assess the association of LI-RADS categories (LR-4/5 vs. LR-M) and pathologic classification (proliferative vs. non-proliferative) with overall survival (OS) and recurrence-free survival (RFS). Subgroups of patients with proliferative and non-proliferative HCCs were analyzed to compare OS and RFS between LR-4/5 and LR-M. RESULTS Of the 204 included patients, 38 were classified as having proliferative HCC. The percentages of LR-M were higher in proliferative than non-proliferative HCC on both CT (15.8% vs. 3.0%, p = 0.007) and MRI (26.3% vs. 9.6%, p = 0.016). Independent of pathologic classification, CT and MRI LR-M were significantly associated with poorer OS (hazard ratio (HR) = 4.58, p = 0.013, and HR = 6.45, p < 0.001) and RFS (HR = 3.66, p = 0.005, and HR = 6.44, p < 0.001) than LR-4/5. MRI LR-M was associated with significantly poorer OS (p ≤ 0.003) and RFS (p < 0.001) than MRI LR-4/5 in both proliferative and non-proliferative HCCs. CONCLUSIONS This multi-reader study showed that the percentages of LR-M were significantly higher in proliferative than non-proliferative HCCs. CT/MRI LR-M was significantly associated with poor OS and RFS, independent of the pathologic classification of proliferative versus non-proliferative HCCs. CLINICAL RELEVANCE STATEMENT CT and MRI LI-RADS category M can be clinically useful in predicting poor outcomes in patients with proliferative and non-proliferative hepatocellular carcinomas. KEY POINTS • The percentages of LR-M tumors on both CT and MRI were significantly higher in proliferative than non-proliferative hepatocellular carcinomas. • Independent of pathologic classification, CT/MRI LR-M categories were correlated with poor overall survival and recurrence-free survival. • Patients with both proliferative and non-proliferative hepatocellular carcinomas categorized as MRI LR-M had significantly poorer overall survival and recurrence-free survival than those categorized as MRI LR-4/5.
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Affiliation(s)
- Subin Heo
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Hyo Jeong Kang
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Sang Hyun Choi
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
| | - Sehee Kim
- Department of Clinical Epidemiology and Biostatistics, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Youngeun Yoo
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Seung Soo Lee
- Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
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Cao J, Srinivas-Rao S, Mroueh N, Anand R, Kongboonvijit S, Sertic M, Shenoy-Bhangle AS, Kambadakone A. Cholangiocarcinoma imaging: from diagnosis to response assessment. Abdom Radiol (NY) 2024; 49:1699-1715. [PMID: 38578323 DOI: 10.1007/s00261-024-04267-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 04/06/2024]
Abstract
Cholangiocarcinoma (CCA), a highly aggressive primary liver cancer arising from the bile duct epithelium, represents a substantial proportion of hepatobiliary malignancies, posing formidable challenges in diagnosis and treatment. Notably, the global incidence of intrahepatic CCA has seen a rise, necessitating a critical examination of diagnostic and management strategies, especially due to presence of close imaging mimics such as hepatocellular carcinoma (HCC) and combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA). Hence, it is imperative to understand the role of various imaging modalities such as ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI), elucidating their strengths, and limitations in diagnostic precision and staging accuracy. Beyond conventional approaches, there is emerging significance of functional imaging tools including positron emission tomography (PET)-CT and diffusion-weighted (DW)-MRI, providing pivotal insights into diagnosis, therapeutic assessment, and prognostic evaluation. This comprehensive review explores the risk factors, classification, clinical features, and role of imaging in the holistic spectrum of diagnosis, staging, management, and restaging for CCA, hence serving as a valuable resource for radiologists evaluating CCA.
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Affiliation(s)
- Jinjin Cao
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Shravya Srinivas-Rao
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Nayla Mroueh
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Roshni Anand
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Sasiprang Kongboonvijit
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
- Department of Radiology, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Madeleine Sertic
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Anuradha S Shenoy-Bhangle
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA
| | - Avinash Kambadakone
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, White 270, Boston, MA, 02114-2696, USA.
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Ding F, Huang M, Ren P, Zhang J, Lin Z, Sun Y, Liang C, Zhao X. Quantitative information from gadobenate dimeglumine-enhanced MRI can predict proliferative subtype of solitary hepatocellular carcinoma: a multicenter retrospective study. Eur Radiol 2024; 34:2445-2456. [PMID: 37691080 DOI: 10.1007/s00330-023-10227-9] [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: 12/07/2022] [Revised: 06/18/2023] [Accepted: 07/15/2023] [Indexed: 09/12/2023]
Abstract
OBJECTIVES To investigate the value of quantitative parameters derived from gadobenate dimeglumine-enhanced magnetic resonance imaging (MRI) for predicting molecular subtype of hepatocellular carcinoma (HCC) and overall survival. METHODS This multicenter retrospective study included 218 solitary HCC patients who underwent gadobenate dimeglumine-enhanced MRI. All HCC lesions were resected and pathologically confirmed. The lesion-to-liver contrast enhancement ratio (LLCER) and lesion-to-liver contrast (LLC) were measured in the hepatobiliary phase. Potential risk factors for proliferative HCC were assessed by logistic regression. The ability of LLCER and LLC to predict proliferative HCC was assessed by the receiver operating characteristic (ROC) curve. Prognostic factors were evaluated using the Cox proportional hazards regression model for survival outcomes. RESULTS LLCER was an independent predictor of proliferative HCC (odds ratio, 0.015; 95% confidence interval [CI], 0.008-0.022; p < 0.001). The area under the ROC curve was 0.812 (95% CI, 0.748-0.877), higher than that of LLC, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement (all p ≤ 0.001). HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%. During the follow-up period, LLCER was an independent predictor of overall survival (hazard ratio, 0.070; 95% CI, 0.015-0.324; p = 0.001) in HCC patients. CONCLUSIONS Gadobenate dimeglumine-enhanced quantitative parameter in the hepatobiliary phase can predict the proliferative subtype of solitary HCC with a moderately high accuracy. CLINICAL RELEVANCE STATEMENT Quantitative information from gadobenate dimeglumine-enhanced MRI can provide crucial information on hepatocellular carcinoma subtypes. It might be valuable to design novel therapeutic strategies, such as targeted therapies or immunotherapy. KEY POINTS • The lesion-to-liver contrast enhancement ratio (LLCER) is an independent predictor of proliferative hepatocellular carcinoma (HCC). • The ability of LLCER to predict proliferative HCC outperformed lesion-to-liver contrast, alpha-fetoprotein > 100 ng/ml, satellite nodules, and rim arterial phase hyperenhancement. • HCC patients with LLCER < -4.59% had a significantly higher incidence of proliferative HCC than those with the LLCER ≥ -4.59%.
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Affiliation(s)
- Feier Ding
- Department of Radiology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong Province, China
| | - Min Huang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong Province, China
| | - Ping Ren
- Department of Radiology, Central Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong Province, China
| | - Junlei Zhang
- Department of Radiology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong Province, China
| | - Zhengyu Lin
- Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350000, Fujian Province, China
| | - Yan Sun
- Department of Radiology, The First Affiliated Hospital of Shandong First Medical University, Jinan, 250021, Shandong Province, China
| | - Changhu Liang
- Department of Radiology, Shandong Provincial Hospital, Shandong University, Jinan, 250021, Shandong Province, China.
| | - Xinya Zhao
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong Province, China.
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9
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Chen S, Liao C, Hu H, Liao J, Chen Z, Li S, Zeng X, Peng B, Shen S, Li D, Li S, Lai J, Peng S, Xie Y, Kuang M. Hypoxia-driven tumor stromal remodeling and immunosuppressive microenvironment in scirrhous HCC. Hepatology 2024; 79:780-797. [PMID: 37725755 DOI: 10.1097/hep.0000000000000599] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 07/26/2023] [Indexed: 09/21/2023]
Abstract
BACKGROUND AND AIMS Scirrhous HCC (SHCC) is one of the unique subtypes of HCC, characterized by abundant fibrous stroma in the tumor microenvironment. However, the molecular traits of SHCC remain unclear, which is essential to develop specialized therapeutic approaches for SHCC. APPROACH AND RESULTS We presented an integrative analysis containing single-cell RNA-sequencing, whole-exome sequencing, and bulk RNA-sequencing in SHCC and usual HCC samples from 134 patients to delineate genomic features, transcriptomic profiles, and stromal immune microenvironment of SHCC. Multiplexed immunofluorescence staining, flow cytometry, and functional experiments were performed for validation. Here, we identified SHCC presented with less genomic heterogeneity while possessing a unique transcriptomic profile different from usual HCC. Insulin-like growth factor 2 was significantly upregulated in SHCC tumor cells compared to usual HCC, and could serve as a potential diagnostic biomarker for SHCC. Significant tumor stromal remodeling and hypoxia were observed in SHCC with enrichment of matrix cancer-associated fibroblasts and upregulation of hypoxic pathways. Insulin-like growth factor 2 was identified as a key mediator in shaping the hypoxic stromal microenvironment of SHCC. Under this microenvironment, SHCC exhibited an immunosuppressive niche correlated to enhanced VEGFA signaling activity, where CD4 + T cells and CD8 + T cells were dysfunctional. Furthermore, we found that another hypoxic-related molecule SPP1 from SHCC tumor cells suppressed the function of dendritic cells via the SPP1-CD44 axis, which also probably hindered the activation of T cells. CONCLUSION We uncovered the genomic characteristics of SHCC, and revealed a hypoxia-driven tumor stroma remodeling and immunosuppressive microenvironment in SHCC.
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Affiliation(s)
- Shuling Chen
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Changyi Liao
- Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Huanjing Hu
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Junbin Liao
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Zebin Chen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shuang Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Xuezhen Zeng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Bo Peng
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shunli Shen
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Dongming Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Shaoqiang Li
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Jiaming Lai
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Sui Peng
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Yubin Xie
- Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
| | - Ming Kuang
- Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
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10
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-Like Lesions. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:842-946. [DOI: 10.1016/b978-0-7020-8228-3.00013-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Adhoute X, Pietri O, Pénaranda G, Wolf T, Beaurain P, Monnet O, Laquière A, Bonomini J, Neumann F, Levrel O, Buono JP, Hanna X, Castellani P, Perrier H, Bourliere M, Anty R. Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis. J Clin Transl Hepatol 2023; 11:1106-1117. [PMID: 37577232 PMCID: PMC10412698 DOI: 10.14218/jcth.2022.00141] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 03/16/2023] [Accepted: 03/23/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses. Methods This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed. Results HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients. Conclusions In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.
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Affiliation(s)
- Xavier Adhoute
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Olivia Pietri
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Guillaume Pénaranda
- Department of Biostatistics, AlphaBio-Biogroup Laboratory, Marseille, France
| | - Thomas Wolf
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Patrick Beaurain
- Department of Radiology, Hôpital Saint-Joseph, Marseille, France
| | - Olivier Monnet
- Department of Radiology, Hôpital Saint-Joseph, Marseille, France
| | - Arthur Laquière
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Justine Bonomini
- Department of Clinical Research, Hôpital Saint-Joseph, Marseille, France
| | | | | | | | - Xavier Hanna
- Department of Hepatobiliary Surgery, Hôpital Saint-Joseph, Marseille, France
| | - Paul Castellani
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Hervé Perrier
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Marc Bourliere
- Department of Gastroenterology and Hepatology, Hôpital Saint-Joseph, Marseille, France
| | - Rodolphe Anty
- Department of Gastroenterology and Hepatology, Hôpital Universitaire de l’Archet, Nice, France
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12
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Xu D, Wei L, Zeng L, Mukiibi R, Xin H, Zhang F. An integrated mRNA-lncRNA signature for overall survival prediction in cholangiocarcinoma. Medicine (Baltimore) 2023; 102:e35348. [PMID: 37773863 PMCID: PMC10545162 DOI: 10.1097/md.0000000000035348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/01/2023] [Indexed: 10/01/2023] Open
Abstract
The combination of mRNA and lncRNA profiles for establishing an integrated mRNA-lncRNA prognostic signature has remained unexplored in cholangiocarcinoma (CCA) patients. We utilized a training dataset of 36 samples from The Cancer Genome Atlas dataset and a validation cohort (GSE107943) of 30 samples from Gene Expression Omnibus. Two mRNAs (CFHR3 and PIWIL4) and 2 lncRNAs (AC007285.1 and AC134682.1) were identified to construct the integrated signature through a univariate Cox regression (P-value = 1.35E-02) and a multivariable Cox analysis (P-value = 3.07E-02). Kaplan-Meier curve showed that patients with low risk scores had notably prolonged overall survival than those with high risk scores (P-value = 4.61E-03). Subsequently, the signature was validated in GSE107943 cohort with an area under the curve of 0.750 at 1-year and 0.729 at 3-year. The signature was not only independent from diverse clinical features (P-value = 3.07E-02), but also surpassed other clinical characteristics as prognostic biomarkers with area under the curve of 0.781 at 3-year. Moreover, the weighted gene co-expression network analysis and gene enrichment analyses found that the integrated signature were associated with metabolic-related biological process and lipid metabolism pathway, which has been implicated in the pathogenesis of CCA. Taken together, we developed an integrated mRNA-lncRNA signature that had an independent prognostic value in the risk stratification of patients with CCA.
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Affiliation(s)
- Derong Xu
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, The Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Lili Wei
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Liping Zeng
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, The Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Robert Mukiibi
- The Roslin Institute, University of Edinburgh, Midlothian, United Kingdom
| | - Hongbo Xin
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, The Institute of Translational Medicine, Nanchang University, Nanchang, China
| | - Feng Zhang
- The National Engineering Research Center for Bioengineering Drugs and the Technologies, The Institute of Translational Medicine, Nanchang University, Nanchang, China
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Choi JH, Thung SN. Advances in Histological and Molecular Classification of Hepatocellular Carcinoma. Biomedicines 2023; 11:2582. [PMID: 37761023 PMCID: PMC10526317 DOI: 10.3390/biomedicines11092582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 09/06/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary liver cancer characterized by hepatocellular differentiation. HCC is molecularly heterogeneous with a wide spectrum of histopathology. The prognosis of patients with HCC is generally poor, especially in those with advanced stages. HCC remains a diagnostic challenge for pathologists because of its morphological and phenotypic diversity. However, recent advances have enhanced our understanding of the molecular genetics and histological subtypes of HCC. Accurate diagnosis of HCC is important for patient management and prognosis. This review provides an update on HCC pathology, focusing on molecular genetics, 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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14
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Spârchez Z, Crăciun R, Nenu I, Mocan LP, Spârchez M, Mocan T. Refining Liver Biopsy in Hepatocellular Carcinoma: An In-Depth Exploration of Shifting Diagnostic and Therapeutic Applications. Biomedicines 2023; 11:2324. [PMID: 37626820 PMCID: PMC10452389 DOI: 10.3390/biomedicines11082324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 08/17/2023] [Accepted: 08/19/2023] [Indexed: 08/27/2023] Open
Abstract
The field of hepatocellular carcinoma (HCC) has faced significant change on multiple levels in the past few years. The increasing emphasis on the various HCC phenotypes and the emergence of novel, specific therapies have slowly paved the way for a personalized approach to primary liver cancer. In this light, the role of percutaneous liver biopsy of focal lesions has shifted from a purely confirmatory method to a technique capable of providing an in-depth characterization of any nodule. Cancer subtype, gene expression, the mutational profile, and tissue biomarkers might soon become widely available through biopsy. However, indications, expectations, and techniques might suffer changes as the aim of the biopsy evolves from providing minimal proof of the disease to high-quality specimens for extensive analysis. Consequently, a revamped position of tissue biopsy is expected in HCC, following the reign of non-invasive imaging-only diagnosis. Moreover, given the advances in techniques that have recently reached the spotlight, such as liquid biopsy, concomitant use of all the available methods might gather just enough data to improve therapy selection and, ultimately, outcomes. The current review aims to discuss the changing role of liver biopsy and provide an evidence-based rationale for its use in the era of precision medicine in HCC.
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Affiliation(s)
- Zeno Spârchez
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Rareș Crăciun
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Internal Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400162 Cluj-Napoca, Romania
| | - Iuliana Nenu
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- Department of Physiology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400006 Cluj-Napoca, Romania
| | - Lavinia Patricia Mocan
- Department of Histology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania;
| | - Mihaela Spârchez
- 2nd Pediatric Department, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400124 Cluj-Napoca, Romania;
| | - Tudor Mocan
- Department of Gastroenterology, “Prof. Dr. O. Fodor” Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania; (Z.S.); (I.N.); (T.M.)
- UBBMed Department, Babeș-Bolyai University, 400349 Cluj-Napoca, Romania
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15
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Brunese MC, Fantozzi MR, Fusco R, De Muzio F, Gabelloni M, Danti G, Borgheresi A, Palumbo P, Bruno F, Gandolfo N, Giovagnoni A, Miele V, Barile A, Granata V. Update on the Applications of Radiomics in Diagnosis, Staging, and Recurrence of Intrahepatic Cholangiocarcinoma. Diagnostics (Basel) 2023; 13:diagnostics13081488. [PMID: 37189589 DOI: 10.3390/diagnostics13081488] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 04/14/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND This paper offers an assessment of radiomics tools in the evaluation of intrahepatic cholangiocarcinoma. METHODS The PubMed database was searched for papers published in the English language no earlier than October 2022. RESULTS We found 236 studies, and 37 satisfied our research criteria. Several studies addressed multidisciplinary topics, especially diagnosis, prognosis, response to therapy, and prediction of staging (TNM) or pathomorphological patterns. In this review, we have covered diagnostic tools developed through machine learning, deep learning, and neural network for the recurrence and prediction of biological characteristics. The majority of the studies were retrospective. CONCLUSIONS It is possible to conclude that many performing models have been developed to make differential diagnosis easier for radiologists to predict recurrence and genomic patterns. However, all the studies were retrospective, lacking further external validation in prospective and multicentric cohorts. Furthermore, the radiomics models and the expression of results should be standardized and automatized to be applicable in clinical practice.
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Affiliation(s)
- Maria Chiara Brunese
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, 86100 Campobasso, Italy
| | | | - Roberta Fusco
- Medical Oncology Division, Igea SpA, 80013 Naples, Italy
| | - Federica De Muzio
- Department of Medicine and Health Sciences "V. Tiberio", University of Molise, 86100 Campobasso, Italy
| | - Michela Gabelloni
- Nuclear Medicine Unit, Department of Translational Research, University of Pisa, 56126 Pisa, Italy
| | - Ginevra Danti
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Via della Signora 2, 20122 Milan, Italy
- Department of Emergency Radiology, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy
| | - Alessandra Borgheresi
- Department of Radiology, University Hospital "Azienda Ospedaliera Universitaria delle Marche", 60121 Ancona, Italy
- Department of Clinical, Special and Dental Sciences, Università Politecnica delle Marche, 60121 Ancona, Italy
| | - Pierpaolo Palumbo
- Department of Diagnostic Imaging, Area of Cardiovascular and Interventional Imaging, Abruzzo Health Unit 1, 67100 L'Aquila, Italy
| | - Federico Bruno
- Department of Diagnostic Imaging, Area of Cardiovascular and Interventional Imaging, Abruzzo Health Unit 1, 67100 L'Aquila, Italy
| | - Nicoletta Gandolfo
- Diagnostic Imaging Department, Villa Scassi Hospital-ASL 3, 16149 Genoa, Italy
| | - Andrea Giovagnoni
- Department of Radiology, University Hospital "Azienda Ospedaliera Universitaria delle Marche", 60121 Ancona, Italy
- Department of Clinical, Special and Dental Sciences, Università Politecnica delle Marche, 60121 Ancona, Italy
| | - Vittorio Miele
- Italian Society of Medical and Interventional Radiology (SIRM), SIRM Foundation, Via della Signora 2, 20122 Milan, Italy
- Department of Emergency Radiology, Careggi University Hospital, Largo Brambilla 3, 50134 Florence, Italy
| | - Antonio Barile
- Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, 67100 L'Aquila, Italy
| | - Vincenza Granata
- Division of Radiology, Istituto Nazionale Tumori IRCCS Fondazione Pascale-IRCCS di Napoli, 80131 Naples, Italy
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16
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Jeon Y, Kwon SM, Rhee H, Yoo JE, Chung T, Woo HG, Park YN. Molecular and radiopathologic spectrum between HCC and intrahepatic cholangiocarcinoma. Hepatology 2023; 77:92-108. [PMID: 35124821 DOI: 10.1002/hep.32397] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Primary liver cancers (LCs), including HCC and intrahepatic cholangiocarcinoma (iCCA), are derived from a common developmental lineage, conferring a molecular spectrum between them. To elucidate the molecular spectrum, we performed an integrative analysis of transcriptome profiles associated with patients' radiopathologic features. APPROACH AND RESULTS We identified four LC subtypes (LC1-LC4) from RNA-sequencing profiles, revealing intermediate subtypes between HCC and iCCA. LC1 is a typical HCC characterized by active bile acid metabolism, telomerase reverse transcriptase promoter mutations, and high uptake of gadoxetic acid in MRI. LC2 is an iCCA-like HCC characterized by expression of the progenitor cell-like trait, tumor protein p53 mutations, and rim arterial-phase hyperenhancement in MRI. LC3 is an HCC-like iCCA, mainly small duct (SD) type, associated with HCC-related etiologic factors. LC4 is further subclassified into LC4-SD and LC4-large duct iCCAs according to the pathological features, which exhibited distinct genetic variations (e.g., KRAS , isocitrate dehydrogenase 1/2 mutation, and FGF receptor 2 fusion), stromal type, and prognostic outcomes. CONCLUSIONS Our integrated view of the molecular spectrum of LCs can identify subtypes associated with transcriptomic, genomic, and radiopathologic features, providing mechanistic insights into heterogeneous LC progression.
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Affiliation(s)
- Youngsic Jeon
- Department of Pathology , Graduate School of Medical Science , Brain Korea 21 Project , Yonsei University College of Medicine , Seoul , Republic of Korea
- Natural Products Research Center , Korea Institute of Science and Technology , Gangneung , Republic of Korea
| | - So Mee Kwon
- Department of Physiology , Ajou University School of Medicine , Suwon , Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology , Yonsei University College of Medicine , Seoul , Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology , Graduate School of Medical Science , Brain Korea 21 Project , Yonsei University College of Medicine , Seoul , Republic of Korea
| | - Taek Chung
- Department of Biomedical Systems Informatics , Yonsei University College of Medicine , Seoul , Republic of Korea
| | - Hyun Goo Woo
- Department of Physiology , Ajou University School of Medicine , Suwon , Republic of Korea
- Department of Biomedical Science , Graduate School , Ajou University , Suwon , Republic of Korea
| | - Young Nyun Park
- Department of Pathology , Graduate School of Medical Science , Brain Korea 21 Project , Yonsei University College of Medicine , Seoul , Republic of Korea
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Shen H, Bai X, Liu J, Liu P, Zhang T. Screening potential biomarkers of cholangiocarcinoma based on gene chip meta-analysis and small-sample experimental research. Front Oncol 2022; 12:1001400. [PMID: 36300097 PMCID: PMC9590411 DOI: 10.3389/fonc.2022.1001400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Cholangiocarcinoma (CCA) is a rare malignant tumor associated with poor prognosis. This study aimed to identify CCA biomarkers by investigating differentially expressed genes (DEGs) between CCA patients and healthy subjects obtained from the Gene Expression Omnibus database. Bioinformatics tools, including the Illumina BaseSpace Correlation Engine (BSCE) and Gene Expression Profiling Interactive Analysis (GEPIA), were used. The initial DEGs from GSE26566, GSE31370, and GSE77984 were analyzed using GEO2R and Venn, and protein–protein interaction networks were constructed using STRING. The BSCE was applied to assess curated CCA studies to select additional DEGs and them DEGs across the 10 biosets, which was supported by findings in the literature. The final 18 DEGs with clinical significance for CCA were further verified using GEPIA. These included CEACAM6, EPCAM, LAMC2, MMP11, KRT7, KRT17, KRT19, SFN, and SOX9, which were upregulated, and ADH1A, ALDOB, AOX1, CTH, FGA, FGB, FGG, GSTA1, and OTC, which were downregulated in CCA patients. Among these 18 genes, 56 groups of genes (two in each group) were significantly related, and none were independently and differentially expressed. The hub genes FGA, OTC, CTH, and MMP11, which were most correlated with the 18 DEGs, were screened using STRING. The significantly low expression of FGA, OTC, and CTH and significantly high expression of MMP11 were verified by immunohistochemical analysis. Overall, four CCA biomarkers were identified that might regulate the occurrence and development of this disease and affect the patient survival rate, and they have the potential to become diagnostic and therapeutic targets for patients with CCA.
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Affiliation(s)
- Hengyan Shen
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Xinyu Bai
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Jie Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
| | - Ping Liu
- Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, China
- *Correspondence: Tao Zhang, ; Ping Liu,
| | - Tao Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- *Correspondence: Tao Zhang, ; Ping Liu,
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Wei H, Yang T, Chen J, Duan T, Jiang H, Song B. Prognostic implications of CT/MRI LI-RADS in hepatocellular carcinoma: State of the art and future directions. Liver Int 2022; 42:2131-2144. [PMID: 35808845 DOI: 10.1111/liv.15362] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/13/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fourth most lethal malignancy with an increasing incidence worldwide. Management of HCC has followed several clinical staging systems that rely on tumour morphologic characteristics and clinical variables. However, these algorithms are unlikely to profile the full landscape of tumour aggressiveness and allow accurate prognosis stratification. Noninvasive imaging biomarkers on computed tomography (CT) or magnetic resonance imaging (MRI) exhibit a promising prospect to refine the prognostication of HCC. The Liver Imaging Reporting and Data System (LI-RADS) is a comprehensive system for standardizing the terminology, techniques, interpretation, reporting and data collection of liver imaging. At present, it has been widely accepted as an effective diagnostic system for HCC in at-risk patients. Emerging data have provided new insights into the potential of CT/MRI LI-RADS in HCC prognostication, which may help refine the prognostic paradigm of HCC that promises to direct individualized management and improve patient outcomes. Therefore, this review aims to summarize several prognostic imaging features at CT/MRI for patients with HCC; the available evidence regarding the use of LI-RDAS for evaluation of tumour biology and clinical outcomes, pitfalls of current literature, and future directions for LI-RADS in the management of HCC.
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Affiliation(s)
- Hong Wei
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Yang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Chen
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Ting Duan
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Hanyu Jiang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Bin Song
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
- Department of Radiology, Sanya People's Hospital, Sanya, China
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Low Complement Factor H-Related 3 (CFHR3) Expression Indicates Poor Prognosis and Immune Regulation in Cholangiocarcinoma. JOURNAL OF ONCOLOGY 2022; 2022:1752827. [PMID: 36213819 PMCID: PMC9546675 DOI: 10.1155/2022/1752827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/06/2022] [Accepted: 09/12/2022] [Indexed: 11/17/2022]
Abstract
Background Cholangiocarcinoma (CCA) is a cancerous tumor that leads to a high rate of morbidity and death. Complement factor H-related 3 (CFHR3) is a gene belonging to the CFHR gene family. In this study, we investigated the usefulness of CFHR3 in the diagnostic stage and CCA prognosis prediction. In the interim, we looked at its coexpressed genes and their roles. The correlation between CFHR3 and immunological infiltration was also investigated. Methods The expression of the genes data and the clinical information were obtained from the databases of The Cancer Genome Atlas (TCGA) together with the Gene Expression Omnibus (GEO). The crucial gene was found to be the overlapping gene in the two databases. The area under the curve (AUC) and the Kaplan-Meier survival curve were used to describe the usefulness of the predictive prognosis of CCA patients. Univariate regression analysis and multivariate survival analysis were performed to find the independent prognosis factors. The PPI network was constructed based on the STRING database, and the coexpression approach was utilized in predicting the coexpression genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed to identify the related functions. Additionally, the probable mechanism of the important gene was examined using gene set enrichment analysis (GSEA). The correlation between CFHR3 and immune infiltration was discovered using TIMER. The LncACTdb 3.0 database was used to analyze the location of CFHR3 in the cell. The cBioPortal database was used to find the mutation in CFHR3. Results TCGA datasets and GEO datasets revealed an elevated expression level of CFHR3 in normal tissues as well as a lower expression level in cholangiocarcinoma tissues in the present research. The low expression level of CFHR3 was related to an unfavorable prognosis. Using CFHR3 expression in diagnosis and predicting the patient prognosis (AUC = 1.000) is valuable. Using the CFHR3 gene and a time-lapse prediction, we could estimate survival rates over 1, 2, and 3 years. The AUC values were more than 0.6(AUC = 0.808; 0.760; 0.711). Functional enrichment analysis revealed a substantial correlation between this signature and complement and coagulation cascades. The same outcomes from GSEA were achieved. We found the key gene widely exists in the nucleus, exosomes, and cytoplasm of normal cells using the LncACTdb 3.0 database. In immune regulation analysis, we identified that the expression level of CFHR3 had a positive correlation with infiltrating levels of B cells, neutrophils, and macrophages, but correlated negatively with cholangiocarcinoma cells, CD8+ T cells, and monocytes.
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The immunosuppressive tumor microenvironment in hepatocellular carcinoma-current situation and outlook. Mol Immunol 2022; 151:218-230. [PMID: 36179604 DOI: 10.1016/j.molimm.2022.09.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/05/2022] [Accepted: 09/20/2022] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the most severe malignant tumors that threaten human health, and its incidence is still on the rise recently. In spite of the current emerging treatment strategies, the overall prognosis of liver cancer remains worrying. Currently, immunotherapy has become a new research-active spot. The emergence of immune checkpoints and targeted immune cell therapy can significantly improve the prognosis of HCC. To a large extent, the effect of this immunotherapy depends on the tumor immune microenvironment (TME), an intricate system in which cancer cells and other non-cancer cells display various interactions. Understanding the immunosuppressive situation of these cells, along with the malignant behavior of cancer cells, can assist us to design new therapeutic approaches against tumors. Therefore, it is necessary to clarify the TME of HCC for further improvement of clinical treatment. This review discussed the functions of several immunosuppressive cells and exosomes in the latest research progress of HCC, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils (TANs) interacted actively to facilitate tumor progression. It further describes the treatment methods targeting them and the potential that needs to be explored in the future.
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Sweed D, Sweed E, Moaz I, Mosbeh A, Fayed Y, Elhamed SMA, Sweed E, Macshut M, Abdelsattar S, Kilany S, Saied SA, Badr R, Abdallah MS, Ehsan N. The clinicopathological and prognostic factors of hepatocellular carcinoma: a 10-year tertiary center experience in Egypt. World J Surg Oncol 2022; 20:298. [PMID: 36117166 PMCID: PMC9484175 DOI: 10.1186/s12957-022-02764-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 09/06/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains a major health problem despite the emergence of several preventive and therapeutic modalities. HCC has heterogeneous and wide morpho-molecular patterns, resulting in unique clinical and prognostic criteria. Therefore, we aimed to study the clinical and pathological criteria of HCC to update the morpho-molecular classifications and provide a guide to the diagnosis of this disease. METHODS Five hundred thirty pathologically analyzed HCC cases were included in this study. The clinical and survival data of these cases were collected. RESULTS Hepatitis C virus is still the dominant cause of HCC in Egypt. Post-direct-acting antiviral agent HCC showed an aggressive course compared to interferon-related HCC. Old age, male gender, elevated alpha-fetoprotein level, tumor size, and background liver were important prognostic parameters. Special HCC variants have characteristic clinical, laboratory, radiological, prognostic, and survival data. Tumor-infiltrating lymphocytes rather than neutrophil-rich HCC have an excellent prognosis. CONCLUSIONS HCC is a heterogenous tumor with diverse clinical, pathological, and prognostic parameters. Incorporating the clinicopathological profile per specific subtype is essential in the treatment decision of patients with HCC. TRIAL REGISTRATION This was a retrospective study that included 530 HCC cases eligible for analysis. The cases were obtained from the archives of the Pathology Department, during the period between January 2010 and December 2019. Clinical and survival data were collected from the patients' medical records after approval by the institutional review board (IRB No. 246/2021) of Liver National Institute, Menoufia University. The research followed the guidelines outlined in the Declaration of Helsinki and registered on ClinicalTrials.gov (NCT05047146).
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Affiliation(s)
- Dina Sweed
- Pathology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Enas Sweed
- Radiology Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Inas Moaz
- Epidemiology, and Preventive Medicine Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Asmaa Mosbeh
- Pathology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Yahya Fayed
- Hepatopancreatobiliary Surgery Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Sara Mohamed Abd Elhamed
- Pathology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Eman Sweed
- Clinical Pharmacology Department, Faculty of Medicine, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Mahmoud Macshut
- Hepatopancreatobiliary Surgery Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Shimaa Abdelsattar
- Clinical Biochemistry and Molecular Diagnostics Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Shimaa Kilany
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Sara A. Saied
- Clinical Pathology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Reda Badr
- Hepatology and Gastroenterology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
| | - Mahmoud S. Abdallah
- Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufia Egypt
| | - Nermine Ehsan
- Pathology Department, National Liver Institute, Menoufia University, Shebin Elkom, Menoufia Egypt
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Loy LM, Low HM, Choi JY, Rhee H, Wong CF, Tan CH. Variant Hepatocellular Carcinoma Subtypes According to the 2019 WHO Classification: An Imaging-Focused Review. AJR Am J Roentgenol 2022; 219:212-223. [PMID: 35170359 DOI: 10.2214/ajr.21.26982] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The 2019 5th edition of the WHO classification of digestive system tumors estimates that up to 35% of hepatocellular carcinomas (HCCs) can be classified as one of eight subtypes defined by molecular characteristics: steatohepatitic, clear cell, macrotrabecular-massive, scirrhous, chromophobe, fibrolamellar, neutrophil-rich, and lymphocyte-rich HCCs. Due to their distinct cellular and architectural characteristics, these subtypes may not display arterial phase hyperenhancement and washout appearance, which are the classic MRI features of HCC, creating challenges in noninvasively diagnosing such lesions as HCC. Moreover, certain subtypes with atypical imaging features have a worse prognosis than other HCCs. A range of distinguishing imaging features may help raise suspicion that a liver lesion represents one of these HCC subtypes. In this review, we describe the MRI features that have been reported in association with various HCC subtypes according to the 2019 WHO classification, with attention given to the current understanding of these subtypes' pathologic and molecular bases and relevance to clinical practice. Imaging findings that differentiate the subtypes from benign liver lesions and non-HCC malignancies are highlighted. Familiarity with these sub-types and their imaging features may allow the radiologist to suggest their presence, though histologic analysis remains needed to establish the diagnosis.
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Affiliation(s)
- Liang Meng Loy
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
| | - Hsien Min Low
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
| | - Jin-Young Choi
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology, Severance Hospital, Research Institute of Radiological Science and Center for Clinical Imaging Data Science, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Chin Fong Wong
- Department of Pathology, Tan Tock Seng Hospital, Singapore, Singapore
| | - Cher Heng Tan
- Department of Diagnostic Radiology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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MRI features of histologic subtypes of hepatocellular carcinoma: correlation with histologic, genetic, and molecular biologic classification. Eur Radiol 2022; 32:5119-5133. [PMID: 35258675 DOI: 10.1007/s00330-022-08643-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 01/31/2022] [Accepted: 02/11/2022] [Indexed: 02/07/2023]
Abstract
HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression. Advancements in imaging techniques have allowed imaging diagnosis to become a critical part of managing HCC in the clinical setting, even without pathologic diagnosis. With the identification of many HCC subtypes, there is increasing correlative evidence between imaging phenotypes and histologic, molecular, and genetic characteristics of various HCC subtypes. In this review, current knowledge of histologic heterogeneity of HCC correlated to features on gadolinium-enhanced dynamic liver MRI will be discussed. In addition, HCC subtype classification according to transcriptomic profiles will be outlined with descriptions of histologic, genetic, and molecular characteristics of some relatively well-established morphologic subtypes, namely the low proliferation class (steatohepatitic HCC and CTNNB1-mutated HCC) and the high proliferation class (macrotrabecular-massive HCC (MTM-HCC), scirrhous HCC, and CK19-positive HCC). Characteristics of sarcomatoid HCC and fibrolamellar HCC will also be discussed. Further research on radiological characteristics of HCC subtypes may ultimately enable non-invasive diagnosis and serve as a biomarker in predicting prognosis, molecular characteristics, and therapeutic response. In the era of precision medicine, a multidisciplinary effort to develop an integrated radiologic and clinical diagnostic system of various HCC subtypes is necessary. KEY POINTS: • HCC is a heterogeneous group of tumors in terms of histology, genetic aberration, and protein expression, which can be divided into many subtypes according to transcriptome profiles. • There is increasing evidence of a correlation between imaging phenotypes and histologic, genetic, and molecular biologic characteristics of various HCC subtypes. • Imaging characteristics may ultimately enable non-invasive diagnosis and subtype characterization, serving as a biomarker for predicting prognosis, molecular characteristics, and therapeutic response.
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24
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Katabathina VS, Khanna L, Surabhi VR, Minervini M, Shanbhogue K, Dasyam AK, Prasad SR. Morphomolecular Classification Update on Hepatocellular Adenoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma. Radiographics 2022; 42:1338-1357. [PMID: 35776676 DOI: 10.1148/rg.210206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Hepatocellular adenomas (HCAs), hepatocellular carcinomas (HCCs), and intrahepatic cholangiocarcinomas (iCCAs) are a highly heterogeneous group of liver tumors with diverse pathomolecular features and prognoses. High-throughput gene sequencing techniques have allowed discovery of distinct genetic and molecular underpinnings of these tumors and identified distinct subtypes that demonstrate varied clinicobiologic behaviors, imaging findings, and complications. The combination of histopathologic findings and molecular profiling form the basis for the morphomolecular classification of liver tumors. Distinct HCA subtypes with characteristic imaging findings and complications include HNF1A-inactivated, inflammatory, β-catenin-activated, β-catenin-activated inflammatory, and sonic hedgehog HCAs. HCCs can be grouped into proliferative and nonproliferative subtypes. Proliferative HCCs include macrotrabecular-massive, TP53-mutated, scirrhous, clear cell, fibrolamellar, and sarcomatoid HCCs and combined HCC-cholangiocarcinoma. Steatohepatitic and β-catenin-mutated HCCs constitute the nonproliferative subtypes. iCCAs are classified as small-duct and large-duct types on the basis of the level of bile duct involvement, with significant differences in pathogenesis, molecular signatures, imaging findings, and biologic behaviors. Cross-sectional imaging modalities, including multiphase CT and multiparametric MRI, play an essential role in diagnosis, staging, treatment response assessment, and surveillance. Select imaging phenotypes can be correlated with genetic abnormalities, and identification of surrogate imaging markers may help avoid genetic testing. Improved understanding of morphomolecular features of liver tumors has opened new areas of research in the targeted therapeutics and management guidelines. The purpose of this article is to review imaging findings of select morphomolecular subtypes of HCAs, HCCs, and iCCAs and discuss therapeutic and prognostic implications. Online supplemental material is available for this article. ©RSNA, 2022.
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Affiliation(s)
- Venkata S Katabathina
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Lokesh Khanna
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Venkateswar R Surabhi
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Marta Minervini
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Krishna Shanbhogue
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Anil K Dasyam
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
| | - Srinivasa R Prasad
- From the Department of Radiology, University of Texas Health at San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229 (V.S.K., L.K.); Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, Tex (V.R.S., S.R.P.); Departments of Pathology (M.M.) and Radiology (A.K.D.), University of Pittsburgh Medical Center, Pittsburgh, Pa; and Department of Radiology, NYU Medical Center, New York, NY (K.S.)
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Yuan RH, Hsu CL, Jhuang YL, Liu YR, Hsieh TH, Jeng YM. Tumor-matrix interaction induces phenotypic switching in liver cancer cells. Hepatol Int 2022; 16:562-576. [PMID: 35525880 DOI: 10.1007/s12072-022-10315-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Accepted: 02/13/2022] [Indexed: 01/16/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (ICC) is characterized by fibrous stroma and clinical behavior more aggressive than that of hepatocellular carcinoma (HCC). Scirrhous HCC is a subtype of HCC with fibrous stroma, frequently has partial cholangiocytic differentiation, and is more likely to have an aggressive behavior. This study explored the interaction of liver cancer cells with the extracellular matrix. METHODS AND RESULTS Liver cancer cells grown on collagen 1-coated plates showed upregulation of cholangiocytic marker expression but downregulation of hepatocytic marker expression. Three-dimensional sphere culture and Boyden chamber assay showed enhanced invasion and migration ability in collagen 1-conditioned liver cancer cells. Interaction with collagen 1 reduced liver cancer cell proliferation. RNA sequencing showed that in the liver cancer cells, collagen 1 upregulated cell cycle inhibitor expression and cell-matrix interaction, tumor migration, and angiogenesis pathways, but downregulated liver metabolic function pathways. Cholangiocytic differentiation and invasiveness induced by collagen 1 was mediated by the mitogen-activated protein kinase (MAPK) pathway, which was regulated by cell-matrix interaction-induced Src activation. Analysis of the Cancer Genome Atlas cohort showed that collagen 1 induced and suppressed genes were highly enriched in ICC and HCC, respectively. In HCC samples, collagen 1-regulated genes were strongly coexpressed and correlated with COL1A1 expression. CONCLUSIONS Liver cancer cell-matrix interaction induces cholangiocytic differentiation and switches liver cancer cells from a proliferative to an invasive phenotype through the Src/MAPK pathway, which may partly explain the differences in the behaviors of HCC and ICC.
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Affiliation(s)
- Ray-Hwang Yuan
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
- Department of Surgery, Hsinchu Branch, National Taiwan University Hospital, Hsinchu, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-Lin Jhuang
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yun-Ru Liu
- Joint Biobank Office of Human Research, Taipei Medical University, Taipei, Taiwan
| | - Tsung-Han Hsieh
- Joint Biobank Office of Human Research, Taipei Medical University, Taipei, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan.
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
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Chen Q, Xiao H, Gu Y, Weng Z, Wei L, Li B, Liao B, Li J, Lin J, Hei M, Peng S, Wang W, Kuang M, Chen S. Deep learning for evaluation of microvascular invasion in hepatocellular carcinoma from tumor areas of histology images. Hepatol Int 2022; 16:590-602. [PMID: 35349075 PMCID: PMC9174315 DOI: 10.1007/s12072-022-10323-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 02/16/2022] [Indexed: 11/23/2022]
Abstract
BACKGROUND Microvascular invasion (MVI) is essential for the management of hepatocellular carcinoma (HCC). However, MVI is hard to evaluate in patients without sufficient peri-tumoral tissue samples, which account for over a half of HCC patients. METHODS We established an MVI deep-learning (MVI-DL) model with a weakly supervised multiple-instance learning framework, to evaluate MVI status using only tumor tissues from the histological whole slide images (WSIs). A total of 350 HCC patients (2917 WSIs) from the First Affiliated Hospital of Sun Yat-sen University (FAHSYSU cohort) were divided into a training and test set. One hundred and twenty patients (504 WSIs) from Dongguan People's Hospital and Shunde Hospital of Southern Medical University (DG-SD cohort) formed an external test set. Unsupervised clustering and class activation mapping were applied to visualize the key histological features. RESULTS In the FAHSYSU and DG-SD test set, the MVI-DL model achieved an AUC of 0.904 (95% CI 0.888-0.920) and 0.871 (95% CI 0.837-0.905), respectively. Visualization results showed that macrotrabecular architecture with rich blood sinus, rich tumor stroma and high intratumor heterogeneity were identified as the key features associated with MVI ( +), whereas severe immune infiltration and highly differentiated tumor cells were associated with MVI (-). In the simulation of patients with only one WSI or biopsies only, the AUC of the MVI-DL model reached 0.875 (95% CI 0.855-0.895) and 0.879 (95% CI 0.853-0.906), respectively. CONCLUSION The effective, interpretable MVI-DL model has potential as an important tool with practical clinical applicability in evaluating MVI status from the tumor areas on the histological slides.
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Affiliation(s)
- Qiaofeng Chen
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Han Xiao
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China
| | - Yunquan Gu
- Clinical Trials Unit, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zongpeng Weng
- Clinical Trials Unit, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Lihong Wei
- Department of Pathology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bin Li
- Clinical Trials Unit, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Bing Liao
- Department of Pathology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Jiali Li
- Department of Liver and Pancreatobiliary Surgery, Dongguan People's Hospital, Dongguan, Guangdong, China
| | - Jie Lin
- Department of Liver and Pancreatobiliary Surgery, Shunde Hospital of Southern Medical University, Shunde, Guangdong, China
| | - Mengying Hei
- Department of Pathology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Sui Peng
- Department of Gastroenterology, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
- Clinical Trials Unit, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Wei Wang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
| | - Ming Kuang
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
- Department of Liver Surgery, Cancer Center, Institute of Precision Medicine, the First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
| | - Shuling Chen
- Department of Medical Ultrasonics, Institute of Diagnostic and Interventional Ultrasound, the First Affiliated Hospital of Sun Yat-Sen University, No. 58, Zhongshan 2nd Road, Guangzhou, 510080, Guangdong, China.
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27
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Aoki T, Nishida N, Kudo M. Clinical Significance of the Duality of Wnt/β-Catenin Signaling in Human Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14020444. [PMID: 35053606 PMCID: PMC8773595 DOI: 10.3390/cancers14020444] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/13/2022] [Accepted: 01/14/2022] [Indexed: 12/24/2022] Open
Abstract
Combination therapy with immune checkpoint inhibitors (ICIs) and vascular endothelial growth factor inhibitors has been approved as a first-line treatment for unresectable hepatocellular carcinoma (HCC), indicating a critical role of ICIs in the treatment of HCC. However, 20% of patients do not respond effectively to ICIs; mutations in the activation of the Wnt/β-catenin pathway are known to contribute to primary resistance to ICIs. From this point of view, non-invasive detection of Wnt/β-catenin activation should be informative for the management of advanced HCC. Wnt/β-catenin mutations in HCC have a dual aspect, which results in two distinct tumor phenotypes. HCC with minimal vascular invasion, metastasis, and good prognosis is named the “Jekyll phenotype”, while the poorly differentiated HCC subset with frequent vascular invasion and metastasis, cancer stem cell features, and high serum Alpha fetoprotein levels, is named the “Hyde phenotype”. To differentiate these two HCC phenotypes, a combination of the hepatobiliary phase of gadolinium-ethoxybenzyl-diethylenetriamine (Gd-EOB-DTPA)-enhanced magnetic resonance imaging and fluoro-2-deoxy-D-glucose-PET/CT may be useful. The former is applicable for the detection of the Jekyll phenotype, as nodules present higher enhancement on the hepatobiliary phase, while the latter is likely to be informative for the detection of the Hyde phenotype by showing an increased glucose uptake.
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Affiliation(s)
| | - Naoshi Nishida
- Correspondence: ; Tel.: +81-72-366-0221 (ext. 3149); Fax: +81-72-367-2880
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28
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Woo HY, Rhee H, Yoo JE, Kim SH, Choi GH, Kim DY, Woo HG, Lee HS, Park YN. Lung and lymph node metastases from hepatocellular carcinoma: Comparison of pathological aspects. Liver Int 2022; 42:199-209. [PMID: 34490997 DOI: 10.1111/liv.15051] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 07/30/2021] [Accepted: 08/27/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Extrahepatic metastasis from hepatocellular carcinoma (HCC) is a catastrophic event, yet organ-specific pathological characteristics of metastatic HCC remain unclear. We aimed to characterize the pathological aspects of HCC metastases to various organs. METHODS We collected intrahepatic HCC (cohort 1, n = 322) and extrahepatic metastatic HCC (cohort 2, n = 130) samples. Clinicopathological evaluation and immunostaining for K19, CD34, αSMA, fibroblast-associated protein (FAP), CAIX, VEGF, PD-L1, CD3, CD8, Foxp3, CD163 and epithelial-mesenchymal transition (EMT)-related markers were performed. RESULTS Independent factors for extrahepatic metastasis included BCLC stage B-C, microvascular invasion (MVI), vessels encapsulating tumour clusters (VETC)-HCC, K19 and FAP expression, and CD163+ macrophage infiltration (cohort 1, P < .05 for all). Lung metastases (n = 63) had the highest proportion of VETC-HCC and macrotrabecular-massive (MTM)-HCC. Lymph node metastases (n = 19) showed significantly high rates of EMT-high features, K19 expression, fibrous tumour stroma with αSMA and FAP expression, high immune cell infiltration, PD-L1 expression (combined positive score), CD3+, CD8+, Foxp3+ T cell and CD163+ macrophage infiltration (adjusted P < .05 for all). In both cohorts, EMT-high HCCs showed higher rates of K19 expression, fibrous tumour stroma, high immune cell infiltration, PD-L1 expression and CD3+ T cell infiltration, whereas EMT-low HCCs were more frequent among VETC-HCCs (P < .05 for all). Overall phenotypic features were not significantly different between paired primary-metastatic HCCs (n = 32). CONCLUSIONS Metastatic HCCs to various organs showed different pathological features. VETC and MTM subtypes were related to lung metastasis, whereas K19 expression, EMT-high features with fibrous tumour stroma and high immune cell infiltration were related to lymph node metastasis.
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Affiliation(s)
- Ha Young Woo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Department of Pathology, National Cancer Center, Goyang, Republic of Korea
| | - Hyungjin Rhee
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Se Hoon Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hye Sun Lee
- Biostatistics Collaboration Unit, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Republic of Korea
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29
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Aoki T, Nishida N, Kudo M. Current Perspectives on the Immunosuppressive Niche and Role of Fibrosis in Hepatocellular Carcinoma and the Development of Antitumor Immunity. J Histochem Cytochem 2022; 70:53-81. [PMID: 34751050 PMCID: PMC8721576 DOI: 10.1369/00221554211056853] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Immune checkpoint inhibitors have become the mainstay of treatment for hepatocellular carcinoma (HCC). However, they are ineffective in some cases. Previous studies have reported that genetic alterations in oncogenic pathways such as Wnt/β-catenin are the important triggers in HCC for primary refractoriness. T-cell exhaustion has been reported in various tumors and is likely to play a prominent role in the emergence of HCC due to chronic inflammation and cirrhosis-associated immune dysfunction. Immunosuppressive cells including regulatory T-cells and tumor-associated macrophages infiltrating the tumor are associated with hyperprogressive disease in the early stages of immune checkpoint inhibitor treatment. In addition, stellate cells and tumor-associated fibroblasts create an abundant desmoplastic environment by producing extracellular matrix. This strongly contributes to epithelial to mesenchymal transition via signaling activities including transforming growth factor beta, Wnt/β-catenin, and Hippo pathway. The abundant desmoplastic environment has been demonstrated in pancreatic ductal adenocarcinoma and cholangiocarcinoma to suppress cytotoxic T-cell infiltration, PD-L1 expression, and neoantigen expression, resulting in a highly immunosuppressive niche. It is possible that a similar immunosuppressive environment is created in HCC with advanced fibrosis in the background liver. Although sufficient understanding is required for the establishment of immune therapies of HCC, further investigations are still required in this field.
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Affiliation(s)
- Tomoko Aoki
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
| | - Naoshi Nishida
- Naoshi Nishida, Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, 377-2 Ohno-higashi, Osaka-Sayama 589-8511, Japan. E-mail:
| | - Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka-Sayama, Japan
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30
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Castro-Gil MP, Torres-Mena JE, Salgado RM, Muñoz-Montero SA, Martínez-Garcés JM, López-Torres CD, Mendoza-Vargas A, Gabiño-López NB, Villa-Treviño S, Del Pozo-Yauner L, Arellanes-Robledo J, Krötzsch E, Pérez-Carreón JI. The transcriptome of early GGT/KRT19-positive hepatocellular carcinoma reveals a downregulated gene expression profile associated with fatty acid metabolism. Genomics 2021; 114:72-83. [PMID: 34861383 DOI: 10.1016/j.ygeno.2021.11.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 11/05/2021] [Accepted: 11/26/2021] [Indexed: 01/14/2023]
Abstract
Hepatocellular carcinoma expressing hepatobiliary progenitor markers, is considered of poor prognosis. By using a hepatocarcinogenesis model, laser capture microdissection, and RNA-Sequencing analysis, we identified an expression profile in GGT/KRT19-positive experimental tumors; 438 differentially expressed genes were found in early and late nodules along with increased collagen deposition. Dysregulated genes were involved in Fatty Acid Metabolism, RXR function, and Hepatic Stellate Cells Activation. Downregulation of Slc27a5, Acsl1, and Cyp2e1, demonstrated that Retinoid X Receptor α (RXRα) function is compromised in GGT/KRT19-positive nodules. Since RXRα controls NRF2 pathway activation, we determined the expression of NRF2 targeted genes; Akr1b8, Akr7a3, Gstp1, Abcc3, Ptgr1, and Txnrd1 were upregulated, indicating NRF2 pathway activation. A comparative analysis in human HCC showed that SLC27A5, ACSL1, CYP2E1, and RXRα gene expression is mutually exclusive with KRT19 gene expression. Our results indicate that the downregulation of Slc27a5, Acsl1, Rxrα, and Cyp2e1 genes is an early event within GGT/KRT19-positive HCC.
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Affiliation(s)
| | | | - Rosa M Salgado
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
| | - Said A Muñoz-Montero
- Department of Computational Genomics, National Institute of Genomic Medicine, CDMX, Mexico
| | | | | | | | | | - Saúl Villa-Treviño
- Department of Cell Biology, Center for Research and Advanced Studies of the National Polytechnic Institute, CDMX, Mexico
| | - Luis Del Pozo-Yauner
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Jaime Arellanes-Robledo
- Laboratory of Liver Diseases, National Institute of Genomic Medicine, CDMX, Mexico; Directorate of Cátedras, National Council of Science and Technology, CDMX, Mexico
| | - Edgar Krötzsch
- Laboratory of Connective Tissue, Centro Nacional de Investigación y Atención de Quemados, Instituto Nacional de Rehabilitación "Luis Guillermo Ibarra Ibarra", CDMX, Mexico
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31
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Nahm JH, Park YN. [Up-to-date Knowledge on the Pathological Diagnosis of Hepatocellular Carcinoma]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2021; 78:268-283. [PMID: 34824185 DOI: 10.4166/kjg.2021.140] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 10/21/2021] [Accepted: 10/22/2021] [Indexed: 11/09/2022]
Abstract
Hepatocellular carcinoma (HCC) has heterogeneous molecular and pathological features and biological behavior. Large-scale genetic studies of HCC were accumulated, and a pathological-molecular classification of HCC was proposed. Approximately 35% of HCCs can be classified into distinct histopathological subtypes according to their molecular characteristics. Among recently identified subtypes, macrotrabecular massive HCC, neutrophil-rich HCC, vessels encapsulating tumor clusters HCC, and progenitor phenotype HCC (HCC with CK19 expression) are associated with a poor prognosis, whereas the lymphocyte-rich HCC subtype is related to a better prognosis. This review provides up-to-date knowledge on the pathological diagnosis of HCC according to the updated World Health Organization Classification of Digestive System Tumors 5th ed.
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Affiliation(s)
- Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Korea.,Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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32
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Renne SL, Sarcognato S, Sacchi D, Guido M, Roncalli M, Terracciano L, Di Tommaso L. Hepatocellular carcinoma: a clinical and pathological overview. Pathologica 2021; 113:203-217. [PMID: 34294938 PMCID: PMC8299323 DOI: 10.32074/1591-951x-295] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
HCC incidence rates have been rising in the past 3 decades and by 2025 > 1 million individuals will be affected annually. High-throughput sequencing technologies led to the identification of several molecular HCC subclasses that can be broadly grouped into 2 major subgroups, each characterized by specific morphological and phenotypical features. It is likely that this increasing knowledge and a more appropriate characterization of HCC at the pathological level will impact HCC patient management.
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Affiliation(s)
- Salvatore Lorenzo Renne
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Samantha Sarcognato
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Diana Sacchi
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Maria Guido
- Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
- Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Massimo Roncalli
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luigi Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Luca Di Tommaso
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
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33
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Gonzalez RS, Raza A, Propst R, Adeyi O, Bateman J, Sopha SC, Shaw J, Auerbach A. Recent Advances in Digestive Tract Tumors: Updates From the 5th Edition of the World Health Organization "Blue Book". Arch Pathol Lab Med 2021; 145:607-626. [PMID: 32886739 DOI: 10.5858/arpa.2020-0047-ra] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/12/2020] [Indexed: 11/06/2022]
Abstract
CONTEXT.— The World Health Organization Classification of Tumours: Digestive System Tumors, 5th edition, was published in 2019 and shows several impactful changes as compared with the 4th edition published in 2010. Changes include a revised nomenclature of serrated lesions and revamping the classification of neuroendocrine neoplasms. Appendiceal goblet cell adenocarcinoma is heavily revised, and intrahepatic cholangiocarcinoma is split into 2 subtypes. New subtypes of colorectal carcinoma and hepatocellular carcinoma are described. Precursor lesions are emphasized with their own entries, and both dysplastic and invasive lesions are generally recommended to be graded using a 2-tier system. Hematolymphoid tumors, mesenchymal tumors, and genetic tumor syndromes each have their own sections in the 5th edition. New hematolymphoid lesions include monomorphic epitheliotropic intestinal T-cell lymphoma; duodenal-type follicular lymphoma; intestinal T-cell lymphoma, not otherwise specified; and indolent T-cell lymphoproliferative disorder of the gastrointestinal tract. This paper will provide an in-depth look at the changes in the 5th edition as compared with the 4th edition. OBJECTIVE.— To provide a comprehensive, in-depth update on the World Health Organization classification of digestive tumors, including changes to nomenclature, updated diagnostic criteria, and newly described entities. DATA SOURCES.— The 5th edition of the World Health Organization Classification of Tumours: Digestive System Tumours, as well as the 4th edition. CONCLUSIONS.— The World Health Organization has made many key changes in its newest update on tumors of the digestive system. Pathologists should be aware of these changes and incorporate them into their practice as able or necessary.
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Affiliation(s)
- Raul S Gonzalez
- The Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts (Gonzalez)
| | - Anwar Raza
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Robert Propst
- The Department of Pathology and Human Anatomy, Loma Linda University, Loma Linda, California (Raza, Propst)
| | - Oyedele Adeyi
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Justin Bateman
- The Department of Pathology, University of Minnesota, Minneapolis (Adeyi, Bateman)
| | - Sabrina C Sopha
- The Department of Pathology, University of Maryland Baltimore Washington Medical Center, Glen Burnie (Sopha)
| | - Janet Shaw
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
| | - Aaron Auerbach
- The Joint Pathology Center, Silver Spring, Maryland (Shaw, Auerbach)
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34
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Samdanci ET, Akatli AN, Soylu NK. Clinicopathological Features of Two Extremely Rare Hepatocellular Carcinoma Variants: a Brief Review of Fibrolamellar and Scirrhous Hepatocellular Carcinoma. J Gastrointest Cancer 2021; 51:1187-1192. [PMID: 32860202 DOI: 10.1007/s12029-020-00500-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE We aimed to distinguish between fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma histopathologically. METHODS AND RESULTS In this review, fibrolamellar hepatocellular carcinoma and scirrhous hepatocellular carcinoma two specific and rare variants of hepatocellular carcinoma, which are difficult to diagnose histopathologically are discussed. CONCLUSION The clinical, radiological, gross, histopathological, immunohistochemical, and molecular features of these two tumors, which are defined by the World Health Organization (WHO), are mentioned.
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Affiliation(s)
- Emine Turkmen Samdanci
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey.
| | - Ayse Nur Akatli
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey
| | - Nese Karadag Soylu
- Liver Institute, Pathology Department, Inonu University, School of Medicine, Malatya, Turkey
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35
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Vij M, Calderaro J. Pathologic and molecular features of hepatocellular carcinoma: An update. World J Hepatol 2021; 13:393-410. [PMID: 33959223 PMCID: PMC8080551 DOI: 10.4254/wjh.v13.i4.393] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/27/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Morphological diversity and several new distinct pathologic subtypes of hepatocellular carcinoma (HCC) are now well-recognized. Recent advances in tumor genomics and transcriptomics have identified several recurrent somatic/genetic alterations that are closely related with histomorphological subtypes and have therefore, greatly improved our understanding of HCC pathogenesis. Pathologic subtyping allows for a diagnosis which is clinically helpful and can have important implication in patient prognostication as some of these subtypes are extremely aggressive with vascular invasion, early recurrence, and worst outcomes. Several targeted treatments are now being considered in HCC, and the reporting of subtypes may be quite useful for personalized therapeutic purpose. This manuscript reviews the recently identified histomorphological subtypes and molecular alterations in HCC.
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Affiliation(s)
- Mukul Vij
- Department ofPathology, Dr Rela Institute and Medical Center, Chennai 600044, Tamil Nadu, India.
| | - Julien Calderaro
- Department of Pathology, Groupe Hospitalier Henri Mondor, Creteil F-94010, France
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36
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Park H, Lee Y, Lee K, Lee H, Yoo JE, Ahn S, Park YN, Kim H. The Clinicopathological Significance of YAP/TAZ Expression in Hepatocellular Carcinoma with Relation to Hypoxia and Stemness. Pathol Oncol Res 2021; 27:604600. [PMID: 34257565 PMCID: PMC8262240 DOI: 10.3389/pore.2021.604600] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 01/12/2021] [Indexed: 12/30/2022]
Abstract
Background/Aims: Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) activation has been implicated in hepatocarcinogenesis and hepatic progenitor cell differentiation, and hypoxia has been shown to induce nuclear translocation of YAP in cancer cells. Here, we aimed to investigate the relationship between hypoxia, YAP and TAZ expression and stemness-related marker expression in human hepatocellular carcinomas (HCCs) and its clinical implications. Methods: Immunohistochemical stains were performed on tissue microarrays from 305 surgically resected HCCs, and the expression status of YAP and TAZ were correlated with CAIX, stemness markers (K19, EpCAM) and epithelial-mesenchymal transition (EMT)-related markers (uPAR, ezrin). The clinicopathological significance of YAP/TAZ expression was analyzed with relation to CAIX expression status. Results: YAP and TAZ expression were seen in 13.4 and 4.3% of HCCs, respectively. YAP/TAZ-positive HCCs frequently demonstrated higher serum AFP levels, microvascular invasion, advanced tumor stage, increased proliferative activity and expression of stemness- and EMT-related markers, CAIX, p53 and Smad2/3 (p < 0.05, all). Interestingly, YAP/TAZ-positivity was associated with microvascular invasion, higher serum AFP levels, stemness and EMT-related marker expression only in tumors expressing CAIX (p < 0.05, all), while these associations were not seen in CAIX-negative HCCs. Conclusions: YAP/TAZ expression is associated with vascular invasion, stemness and EMT in HCCs with hypoxia marker expression. The effect of Hippo signaling pathway deregulation in HCC may depend on the presence or absence of a hypoxic microenvironment, and hypoxia marker expression status should be taken into account when considering the use of YAP/TAZ as markers of aggressive biologic behavior in HCC.
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Affiliation(s)
- Hyunjin Park
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Yangkyu Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Kiryang Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
| | - Hyejung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.,Department of Pathology, Seoul National University Hospital, Seoul, Korea
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37
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Huang SC, Liao SH, Su TH, Jeng YM, Kao JH. Clinical manifestations and outcomes of patients with scirrhous hepatocellular carcinoma. Hepatol Int 2021; 15:472-481. [PMID: 33544314 DOI: 10.1007/s12072-021-10146-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Accepted: 01/17/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND The scirrhous hepatocellular carcinoma (HCC) is a rare subtype characterized by prominent fibrous stroma separating nests of tumor cells histologically. The clinical characteristics of scirrhous HCC have not been clearly elucidated due to limited literatures. We aimed to investigate the clinical manifestations and outcomes of patients with scirrhous HCC. METHODS A total of 4012 patients with histologically proven HCC from the Cancer Registry Database (2004-2016) of the National Taiwan University Hospital (NTUH) were enrolled; whereas, 30 patients with scirrhous HCC were identified from the pathology database of NTUH. We matched 120 patients with non-scirrhous HCC through propensity score according to sex, age, Barcelona Clinic Liver Cancer stage and initial treatment modality for comparison. RESULTS No significant difference in baseline characteristics and presentations was observed between the patients with scirrhous and non-scirrhous HCC except baseline alpha-fetoprotein level. The overall survival was comparable in these two groups. For the patients undergoing curative therapy, the risk of recurrence in the patients with scirrhous HCC was significantly higher within 24 months after curative therapy (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.43-5.80, p value, 0.003) as compared with those with non-scirrhous HCC. The overall recurrence rate was comparable in these two groups. CONCLUSIONS Using propensity score matching, the risk of recurrence in the patients with scirrhous HCC was significantly higher in the first 2 years after curative therapy as compared to those with non-scirrhous HCC. An individualized post-curative treatment monitoring strategy should be considered for the patients with scirrhous HCC.
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Affiliation(s)
- Shang-Chin Huang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Sih-Han Liao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medicine, National Taiwan University Cancer Center, Taipei, Taiwan
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tung-Hung Su
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jia-Horng Kao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
- Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, 1 Chang-Te St., Taipei, 10002, Taiwan.
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Park C, Kim JH, Kim PH, Kim SY, Gwon DI, Chu HH, Park M, Hur J, Kim JY, Kim DJ. Imaging Predictors of Survival in Patients with Single Small Hepatocellular Carcinoma Treated with Transarterial Chemoembolization. Korean J Radiol 2021; 22:213-224. [PMID: 32901464 PMCID: PMC7817628 DOI: 10.3348/kjr.2020.0325] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 05/19/2020] [Accepted: 05/24/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE Clinical outcomes of patients who undergo transarterial chemoembolization (TACE) for single small hepatocellular carcinoma (HCC) are not consistent, and may differ based on certain imaging findings. This retrospective study was aimed at determining the efficacy of pre-TACE CT or MR imaging findings in predicting survival outcomes in patients with small HCC upon being treated with TACE. Besides, the study proposed to build a risk prediction model for these patients. MATERIALS AND METHODS Altogether, 750 patients with functionally good hepatic reserve who received TACE as the first-line treatment for single small HCC between 2004 and 2014 were included in the study. These patients were randomly assigned into training (n = 525) and validation (n = 225) sets. RESULTS According to the results of a multivariable Cox analysis, three pre-TACE imaging findings (tumor margin, tumor location, enhancement pattern) and two clinical factors (age, serum albumin level) were selected and scored to create predictive models for overall, local tumor progression (LTP)-free, and progression-free survival in the training set. The median overall survival time in the validation set were 137.5 months, 76.1 months, and 44.0 months for low-, intermediate-, and high-risk groups, respectively (p < 0.001). Time-dependent receiver operating characteristic curves of the predictive models for overall, LTP-free, and progression-free survival applied to the validation cohort showed acceptable areas under the curve values (0.734, 0.802, and 0.775 for overall survival; 0.738, 0.789, and 0.791 for LTP-free survival; and 0.671, 0.733, and 0.694 for progression-free survival at 3, 5, and 10 years, respectively). CONCLUSION Pre-TACE CT or MR imaging findings could predict survival outcomes in patients with small HCC upon treatment with TACE. Our predictive models including three imaging predictors could be helpful in prognostication, identification, and selection of suitable candidates for TACE in patients with single small HCC.
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Affiliation(s)
- Chan Park
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Hyoung Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
| | - Pyeong Hwa Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - So Yeon Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Il Gwon
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Ho Chu
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Minho Park
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joonho Hur
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Young Kim
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Joon Kim
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Kang X, Bai L, QI X, Wang J. Screening and identification of key genes between liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) by bioinformatic analysis. Medicine (Baltimore) 2020; 99:e23563. [PMID: 33327311 PMCID: PMC7738106 DOI: 10.1097/md.0000000000023563] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 10/27/2020] [Accepted: 11/05/2020] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Liver hepatocellular carcinoma (LIHC) and cholangiocarcinoma (CHOL) are common primary liver cancers worldwide. Liver stem cells have biopotential to differentiate into either hepatocytes and cholangiocytes, the phenotypic overlap between LIHC and CHOL has been acceptable as a continuous liver cancer spectrum. However, few studies directly investigated the underlying molecular mechanisms between LIHC and CHOL. METHOD To identify the candidate genes between LIHC and CHOL, three data series including GSE31370, GSE15765 and GSE40367 were downloaded from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were identified, and function enrichment analyses were performed. The protein-protein interaction network (PPI) was constructed and the module analysis was performed using STRING and Cytoscape. RESULTS A total of 171 DEGs were identified, consisting of 49 downregulated genes and 122 upregulated genes. Compared with CHOL, the enriched functions of the DEGs mainly included steroid metabolic process, acute inflammatory response, coagulation. Meanwhile, the pathway of KEGG enrichment analyses showed that the upregulated gene(s) were mainly enriched complement and coagulation cascades, cholesterol metabolism and PPAR signaling pathway, while the downregulated gene(s) were mainly enriched in ECM-receptor interaction, focal adhesion, bile secretion. Similarly, the most significant module was identified and biological process analysis revealed that these genes were mainly enriched in regulation of blood coagulation, acute inflammatory response, complement and coagulation cascades. Finally, two (ITIH2 and APOA2) of 10 hub genes had been screened out to help differential diagnosis. CONCLUSION 171 DEGs and two (ITIH2 and APOA2) of 10 hub genes identified in the present study help us understand the different molecular mechanisms between LIHC and CHOL, and provide candidate targets for differential diagnosis.
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Affiliation(s)
- Xindan Kang
- Department of Oncology, The First Medical Center of Chinese People's Liberation Army General Hospital
- Department of Graduate Administration, Chinese PLA General Hospital/Medical School of Chinese PLA, Beijing, China
| | - Li Bai
- Department of Oncology, The First Medical Center of Chinese People's Liberation Army General Hospital
| | - Xiaoguang QI
- Department of Oncology, The First Medical Center of Chinese People's Liberation Army General Hospital
| | - Jing Wang
- Department of Graduate Administration, Chinese PLA General Hospital/Medical School of Chinese PLA, Beijing, China
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Rhee H, Kim H, Park YN. Clinico-Radio-Pathological and Molecular Features of Hepatocellular Carcinomas with Keratin 19 Expression. Liver Cancer 2020; 9:663-681. [PMID: 33442539 PMCID: PMC7768132 DOI: 10.1159/000510522] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/28/2020] [Indexed: 02/04/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a heterogeneous neoplasm, both from the molecular and histomorphological aspects. One example of heterogeneity is the expression of keratin 19 (K19) in a subset (4-28%) of HCCs. The presence of K19 expression in HCCs has important clinical implications, as K19-positive HCCs have been associated with aggressive tumor biology and poor prognosis. Histomorphologically, K19-positive HCCs demonstrate a more infiltrative appearance, poor histological differentiation, more frequent vascular invasion, and more intratumoral fibrous stroma than K19-negative conventional HCCs. From the molecular aspect, K19-positive HCCs have been matched with various gene signatures that have been associated with stemness and poor prognosis, including the G1-3 groups, S2 class, cluster A, proliferation signature, and vascular invasion signature. K19-positive HCCs also show upregulated signatures related to transforming growth factor-β pathway and epithelial-to-mesenchymal transition. The main regulators of K19 expression include hepatocyte growth factor-MET paracrine signaling by cancer-associated fibroblast, epidermal growth factor-epidermal growth factor receptor signaling, laminin, and DNA methylation. Clinically, higher serum alpha-fetoprotein levels, frequent association with chronic hepatitis B, more invasive growth, and lymph node metastasis have been shown to be characteristics of K19-positive HCCs. Radiologic features including atypical enhancement patterns, absence of tumor capsules, and irregular tumor margins can be a clue for K19-positive HCCs. From a therapeutic standpoint, K19-positive HCCs have been associated with poor outcomes after curative resection or liver transplantation, and resistance to systemic chemotherapy and locoregional treatment, including transarterial chemoembolization and radiofrequency ablation. In this review, we summarize the currently available knowledge on the clinico-radio-pathological and molecular features of K19-expressing HCCs, including a detailed discussion on the regulation mechanism of these tumors.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea,*Young Nyun Park, Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-Ro, Seodaemun-gu, Seoul 03722 (Republic of Korea),
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Pavlović N, Calitz C, Thanapirom K, Mazza G, Rombouts K, Gerwins P, Heindryckx F. Inhibiting IRE1α-endonuclease activity decreases tumor burden in a mouse model for hepatocellular carcinoma. eLife 2020; 9:e55865. [PMID: 33103995 PMCID: PMC7661042 DOI: 10.7554/elife.55865] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1α-inhibitor 4μ8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IREα in stellate cells, thereby contributing to their activation. Inhibiting IRE1α blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1α in tumor cells.
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Affiliation(s)
- Nataša Pavlović
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Carlemi Calitz
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
| | - Kess Thanapirom
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Guiseppe Mazza
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Krista Rombouts
- Regenerative Medicine & Fibrosis Group, Institute for Liver and Digestive Health, University College LondonLondonUnited Kingdom
| | - Pär Gerwins
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
- Department of Radiology, Uppsala University HospitalUppsalaSweden
| | - Femke Heindryckx
- Department of Medical Cell Biology, Uppsala UniversityUppsalaSweden
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Kim YJ, Jang H, Lee K, Park S, Min SG, Hong C, Park JH, Lee K, Kim J, Hong W, Jung H, Liu Y, Rajkumar H, Khened M, Krishnamurthi G, Yang S, Wang X, Han CH, Kwak JT, Ma J, Tang Z, Marami B, Zeineh J, Zhao Z, Heng PA, Schmitz R, Madesta F, Rösch T, Werner R, Tian J, Puybareau E, Bovio M, Zhang X, Zhu Y, Chun SY, Jeong WK, Park P, Choi J. PAIP 2019: Liver cancer segmentation challenge. Med Image Anal 2020; 67:101854. [PMID: 33091742 DOI: 10.1016/j.media.2020.101854] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 07/06/2020] [Accepted: 09/03/2020] [Indexed: 01/22/2023]
Abstract
Pathology Artificial Intelligence Platform (PAIP) is a free research platform in support of pathological artificial intelligence (AI). The main goal of the platform is to construct a high-quality pathology learning data set that will allow greater accessibility. The PAIP Liver Cancer Segmentation Challenge, organized in conjunction with the Medical Image Computing and Computer Assisted Intervention Society (MICCAI 2019), is the first image analysis challenge to apply PAIP datasets. The goal of the challenge was to evaluate new and existing algorithms for automated detection of liver cancer in whole-slide images (WSIs). Additionally, the PAIP of this year attempted to address potential future problems of AI applicability in clinical settings. In the challenge, participants were asked to use analytical data and statistical metrics to evaluate the performance of automated algorithms in two different tasks. The participants were given the two different tasks: Task 1 involved investigating Liver Cancer Segmentation and Task 2 involved investigating Viable Tumor Burden Estimation. There was a strong correlation between high performance of teams on both tasks, in which teams that performed well on Task 1 also performed well on Task 2. After evaluation, we summarized the top 11 team's algorithms. We then gave pathological implications on the easily predicted images for cancer segmentation and the challenging images for viable tumor burden estimation. Out of the 231 participants of the PAIP challenge datasets, a total of 64 were submitted from 28 team participants. The submitted algorithms predicted the automatic segmentation on the liver cancer with WSIs to an accuracy of a score estimation of 0.78. The PAIP challenge was created in an effort to combat the lack of research that has been done to address Liver cancer using digital pathology. It remains unclear of how the applicability of AI algorithms created during the challenge can affect clinical diagnoses. However, the results of this dataset and evaluation metric provided has the potential to aid the development and benchmarking of cancer diagnosis and segmentation.
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Affiliation(s)
- Yoo Jung Kim
- Department of Biomedical Engineering, Seoul National University Hospital, Seoul, South Korea.
| | - Hyungjoon Jang
- School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea.
| | - Kyoungbun Lee
- Department of Pathology, Seoul National University Hospital, Seoul, South Korea.
| | - Seongkeun Park
- Department of Biomedical Engineering, Seoul National University Hospital, Seoul, South Korea
| | - Sung-Gyu Min
- Department of Pathology, Seoul National University Hospital, Seoul, South Korea
| | - Choyeon Hong
- Department of Pathology, Seoul National University Hospital, Seoul, South Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul Metropolitan Government-Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Kanggeun Lee
- School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Jisoo Kim
- School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Wonjae Hong
- School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea
| | - Hyun Jung
- Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
| | - Yanling Liu
- Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States
| | - Haran Rajkumar
- Department of Engineering Design, Indian Institute Of Technology Madras, Chennai, Tamil Nadu, India
| | - Mahendra Khened
- Department of Engineering Design, Indian Institute Of Technology Madras, Chennai, Tamil Nadu, India
| | - Ganapathy Krishnamurthi
- Department of Engineering Design, Indian Institute Of Technology Madras, Chennai, Tamil Nadu, India
| | - Sen Yang
- Sichuan University and Tencent AI Lab, Chengdu, Sichuan, China
| | - Xiyue Wang
- College of Computer Science, Sichuan University, Chengdu, Sichuan, China
| | - Chang Hee Han
- Department of Computer Science and Engineering, Sejong University, Seoul, South Korea
| | - Jin Tae Kwak
- Department of Computer Science and Engineering, Sejong University, Seoul, South Korea
| | | | | | - Bahram Marami
- The Center for Computational and Systems Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Jack Zeineh
- The Center for Computational and Systems Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Zixu Zhao
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong
| | - Pheng-Ann Heng
- Department of Computer Science and Engineering, The Chinese University of Hong Kong, Hong Kong
| | - Rüdiger Schmitz
- Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DAISYlabs, Forschungszentrum Medizintechnik Hamburg, Hamburg, Germany
| | - Frederic Madesta
- Instutute of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DAISYlabs, Forschungszentrum Medizintechnik Hamburg, Hamburg, Germany
| | - Thomas Rösch
- Department for Interdisciplinary Endoscopy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rene Werner
- Instutute of Computational Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; DAISYlabs, Forschungszentrum Medizintechnik Hamburg, Hamburg, Germany
| | - Jie Tian
- Shanghai JiaoTong University, Shanghai, China
| | | | | | | | - Yifeng Zhu
- University of Maine, Orono, ME, United States
| | - Se Young Chun
- School of Electrical and Computer Engineering, Ulsan National Institute of Science and Technology, Ulsan, South Korea.
| | - Won-Ki Jeong
- Department of Computer Science and Engineering, College of Informatics, Korea University, Seoul, 02841, Korea.
| | | | - Jinwook Choi
- Department of Biomedical Engineering, Seoul National University Hospital, Seoul, South Korea.
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Kim JH, Joo I, Lee JM. Atypical Appearance of Hepatocellular Carcinoma and Its Mimickers: How to Solve Challenging Cases Using Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging. Korean J Radiol 2020; 20:1019-1041. [PMID: 31270973 PMCID: PMC6609440 DOI: 10.3348/kjr.2018.0636] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 03/17/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) can be diagnosed noninvasively with contrast-enhanced dynamic computed tomography, magnetic resonance imaging, or ultrasonography on the basis of its hallmark imaging features of arterial phase hyperenhancement and washout on portal or delayed phase images. However, approximately 40% of HCCs show atypical imaging features, posing a significant diagnostic challenge for radiologists. Another challenge for radiologists in clinical practice is the presentation of many HCC mimickers such as intrahepatic cholangiocarcinoma, combined HCC-cholangiocarcinoma, arterioportal shunt, and hemangioma in the cirrhotic liver. The differentiation of HCCs from these mimickers on preoperative imaging studies is of critical importance. Hence, we will review the typical and atypical imaging features of HCCs and the imaging features of its common mimickers. In addition, we will discuss how to solve these challenges in practice.
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Affiliation(s)
- Jae Hyun Kim
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Min Lee
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea.,Institute of Radiation Medicine, Seoul National University Medical Research Center, Seoul, Korea.
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Wang G, Wang Q, Liang N, Xue H, Yang T, Chen X, Qiu Z, Zeng C, Sun T, Yuan W, Liu C, Chen Z, He X. Oncogenic driver genes and tumor microenvironment determine the type of liver cancer. Cell Death Dis 2020; 11:313. [PMID: 32366840 PMCID: PMC7198508 DOI: 10.1038/s41419-020-2509-x] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 04/10/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Primary liver cancer (PLC) may be mainly classified as the following four types: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), hepatoblastoma (HB), and combined hepatocellular carcinoma and intrahepatic cholangiocarcinoma (cHCC-ICC). The majority of PLC develops in the background of tumor microenvironment, such as inflammatory microenvironments caused by viral hepatitis, alcoholic or nonalcoholic steatohepatitis, carbon tetrachloride (CCl4), 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), and necroptosis-associated hepatic cytokine microenvironment caused by necroptosis of hepatocytes. However, the impact of different types of microenvironments on the phenotypes of PLC generated by distinct oncogenes is still unclear. In addition, the cell origin of different liver cancers have not been clarified, as far as we know. Recent researches show that mature hepatocytes retain phenotypic plasticity to differentiate into cholangiocytes. More importantly, our results initially demonstrated that HCC, ICC, and cHCC-ICC could originate from mature hepatocytes rather than liver progenitor cells (LPCs), hepatic stellate cells (HSCs) and cholangiocytes in AKT-driven, AKT/NICD-driven and AKT/CAT-driven mouse PLC models respectively by using hydrodynamic transfection methodology. Therefore, liver tumors originated from mature hepatocytes embody a wide spectrum of phenotypes from HCC to CC, possibly including cHCC-ICC and HB. However, the underlying mechanism determining the cancer phenotype of liver tumors has yet to be delineated. In this review, we will provide a summary of the possible mechanisms for directing the cancer phenotype of liver tumors (i.e., ICC, HCC, and cHCC-ICC) in terms of oncogenic driver genes and tumor microenvironment. Moreover, this study initially revealed the cell origin of different types of liver cancer.
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Affiliation(s)
- Gang Wang
- Department of General Surgery, The 74th Group Army Hospital, Guangzhou, 510220, China.,Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China
| | - Qian Wang
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.,Department of Anorectal Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China
| | - Ning Liang
- Department of General Surgery, The 75th Group Army Hospital, Dali, 671000, China
| | - Hongyuan Xue
- Department of General Surgery, Huashan North Hospital, Fudan University, Shanghai, 201907, China
| | - Tao Yang
- Department of Pain Treatment, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shanxi, China
| | - Xuguang Chen
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Guangzhou, 510091, China
| | - Zhaoyan Qiu
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Chao Zeng
- Department of Cardiology, The 74th Group Army Hospital, Guangzhou, 510318, China
| | - Tao Sun
- Departmentof Neurosurgery, First Affiliated Hospital, Zhengzhou University, Zheng zhou, 450052, China
| | - Weitang Yuan
- Department of Anorectal Surgery, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China
| | - Chaoxu Liu
- Department of General Surgery, Huashan North Hospital, Fudan University, Shanghai, 201907, China. .,Department of Anorectal Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310003, China.
| | - Zhangqian Chen
- Department of Infectious Diseases, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China. .,State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
| | - Xianli He
- Department of General Surgery, Tangdu Hospital, Air Force Military Medical University, Xi'an, 710032, Shaanxi, China.
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Maehara J, Masugi Y, Abe T, Tsujikawa H, Kurebayashi Y, Ueno A, Ojima H, Okuda S, Jinzaki M, Shinoda M, Kitagawa Y, Oda Y, Honda H, Sakamoto M. Quantification of intratumoral collagen and elastin fibers within hepatocellular carcinoma tissues finds correlations with clinico-patho-radiological features. Hepatol Res 2020; 50:607-619. [PMID: 31886596 DOI: 10.1111/hepr.13484] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/24/2019] [Accepted: 12/26/2019] [Indexed: 02/08/2023]
Abstract
AIM Emerging evidence suggests a promising role for tumor stromal factors in characterizing patients with various types of malignancies, including hepatocellular carcinoma (HCC). We quantified the amount of collagen and elastin fibers in HCC samples with the aim of clarifying the clinico-patho-radiological significance of fiber deposition in HCC. METHODS We computed the amount of collagen and elastin fibers using digital image analysis of whole-slide images of Elastica van Gieson-stained tissues from 156 surgically resected HCCs. Furthermore, we assessed the correlations between the fiber content of HCC samples and clinical, pathological, and radiological features, including immunohistochemistry-based molecular subtypes and immunosubtypes. RESULTS The intratumoral area ratio of collagen in HCC tissues (median 3.4%, range 0.1-22.2%) was more than threefold that of elastin (median 0.9%, range 0.1-9.0%); there was a strong positive correlation between the amounts of collagen and elastin. Higher levels of combined collagen and elastin were significantly associated with the confluent multinodular macroscopic tumor type, the absence of a fibrous capsule, intratumoral steatosis, scirrhous tumor stroma, dense inflammatory-cell infiltrates, and the biliary/stem cell markers-positive HCC subtype. The associations of higher collagen levels with radiological findings, including heterogeneous enhancement and persistent enhancement on dynamic computed tomography, were significant. In contrast, the associations of radiological findings with elastin fibers were not significant. Intratumoral fibrous stroma in HCC comprised septum-like and perisinusoidal fibrosis; these two forms represented distinct distribution patterns of fibers and fibroblasts. CONCLUSION Quantitative analysis suggested that stromal fiber-rich HCCs likely represent a distinct clinico-patho-radiological entity.
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Affiliation(s)
- Junki Maehara
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan.,Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Tokiya Abe
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Akihisa Ueno
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Shigeo Okuda
- Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Jinzaki
- Department of Diagnostic Radiology, Keio University School of Medicine, Tokyo, Japan
| | - Masahiro Shinoda
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hiroshi Honda
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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Kim H, Jang M, Park YN. Histopathological Variants of Hepatocellular Carcinomas: an Update According to the 5th Edition of the WHO Classification of Digestive System Tumors. ACTA ACUST UNITED AC 2020. [DOI: 10.17998/jlc.20.1.17] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Rhee H, Chung T, Yoo JE, Nahm JH, Woo HY, Choi GH, Han DH, Park YN. Gross type of hepatocellular carcinoma reflects the tumor hypoxia, fibrosis, and stemness-related marker expression. Hepatol Int 2020; 14:239-248. [PMID: 31993941 DOI: 10.1007/s12072-020-10012-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Accepted: 01/07/2020] [Indexed: 01/13/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is subclassified into five gross types, namely, vaguely nodular (VN), single nodular (SN), single nodular with extranodular growth (SNEG), confluent multinodular (CM), and infiltrative (INF) type. However, the pathological background underlying differences in biological behavior of different gross types of HCC remains unclear. METHODS The histopathological features, clinical outcomes of HCC gross types, and their relationships with stemness-related marker status and fibrotic/hypoxic tumor microenvironment (TME) were evaluated in 266 resected HCCs. The stemness-related markers (CD24, CD44, CD133, SALL4, YAP1, K19 and EpCAM), fibrous tumor stroma (αSMA), and hypoxia (CAIX) were evaluated with immunohistochemistry. RESULTS Poorer differentiation, reduced capsule formation, higher microvascular invasion, larger tumor size and larger area of necrosis were observed in order of VN-SN-SNEG-CM-INF type (p = 0.005 for all, linear-by-linear association). The expression of summed stemness-related markers and hypoxic/fibrotic TME showed an increasing trend in order of VN-SN-SNEG-CM-INF type (p < 0.005), and their expression well correlated with each other. INF type was found only in HCCs with hypoxic/fibrotic TME or high expression of stemness-related markers. CAIX expression and tumor necrosis ≥ 30% were independent prognostic markers for disease-specific survival. Early recurrence-free survival showed a significant difference based on gross types, revealing best outcome with VN type and worst outcome with INF type. CONCLUSION The marker expression of stemness-related and hypoxic/fibrotic TME of HCC showed an increasing trend in order of VN-SN-SNEG-CM-INF gross types, and their cross-talk may be involved in the determination of various gross-morphological features and their distinct biological behavior.
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Affiliation(s)
- Hyungjin Rhee
- Department of Radiology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Taek Chung
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.,Department of Biomedical Systems Informatics, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Jeong Eun Yoo
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Ji Hae Nahm
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Ha Young Woo
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Gi Hong Choi
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Dai Hoon Han
- Department of Surgery, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Young Nyun Park
- Department of Pathology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. .,BK21 PLUS Project for Medical Science, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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Kaur H, Dhall A, Kumar R, Raghava GPS. Identification of Platform-Independent Diagnostic Biomarker Panel for Hepatocellular Carcinoma Using Large-Scale Transcriptomics Data. Front Genet 2020; 10:1306. [PMID: 31998366 PMCID: PMC6967266 DOI: 10.3389/fgene.2019.01306] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 11/26/2019] [Indexed: 12/20/2022] Open
Abstract
The high mortality rate of hepatocellular carcinoma (HCC) is primarily due to its late diagnosis. In the past, numerous attempts have been made to design genetic biomarkers for the identification of HCC; unfortunately, most of the studies are based on small datasets obtained from a specific platform or lack reasonable validation performance on the external datasets. In order to identify a universal expression-based diagnostic biomarker panel for HCC that can be applicable across multiple platforms, we have employed large-scale transcriptomic profiling datasets containing a total of 2,316 HCC and 1,665 non-tumorous tissue samples. These samples were obtained from 30 studies generated by mainly four types of profiling techniques (Affymetrix, Illumina, Agilent, and High-throughput sequencing), which are implemented in a wide range of platforms. Firstly, we scrutinized overlapping 26 genes that are differentially expressed in numerous datasets. Subsequently, we identified a panel of three genes (FCN3, CLEC1B, and PRC1) as HCC biomarker using different feature selection techniques. Three-genes-based HCC biomarker identified HCC samples in training/validation datasets with an accuracy between 93 and 98%, Area Under Receiver Operating Characteristic curve (AUROC) in a range of 0.97 to 1.0. A reasonable performance, i.e., AUROC 0.91–0.96 achieved on validation dataset containing peripheral blood mononuclear cells, concurred their non-invasive utility. Furthermore, the prognostic potential of these genes was evaluated on TCGA-LIHC and GSE14520 cohorts using univariate survival analysis. This analysis revealed that these genes are prognostic indicators for various types of the survivals of HCC patients (e.g., Overall Survival, Progression-Free Survival, Disease-Free Survival). These genes significantly stratified high-risk and low-risk HCC patients (p-value <0.05). In conclusion, we identified a universal platform-independent three-genes-based biomarker that can predict HCC patients with high precision and also possess significant prognostic potential. Eventually, we developed a web server HCCpred based on the above study to facilitate scientific community (http://webs.iiitd.edu.in/raghava/hccpred/).
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Affiliation(s)
- Harpreet Kaur
- Bioinformatics Center, CSIR-Institute of Microbial Technology, Chandigarh, India.,Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Anjali Dhall
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Rajesh Kumar
- Bioinformatics Center, CSIR-Institute of Microbial Technology, Chandigarh, India.,Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
| | - Gajendra P S Raghava
- Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India
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Ueno A, Masugi Y, Yamazaki K, Kurebayashi Y, Tsujikawa H, Effendi K, Ojima H, Sakamoto M. Precision pathology analysis of the development and progression of hepatocellular carcinoma: Implication for precision diagnosis of hepatocellular carcinoma. Pathol Int 2020; 70:140-154. [PMID: 31908112 DOI: 10.1111/pin.12895] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 12/11/2019] [Indexed: 12/25/2022]
Abstract
Outcomes for patients with hepatocellular carcinoma (HCC) remain poor because the condition is often unresponsive to the available treatments. Consequently, the early and precise diagnosis of HCC is crucial to achieve improvements in prognosis. For patients with chronic liver disease, the assessment of liver fibrosis is also important to ascertain both the staging of fibrosis and the risk of HCC occurrence. Early HCC was first described in 1991 in Japan and was defined internationally in 2009. As the concept of early HCC spread, the multistage hepatocarcinogenesis process became accepted. Consequently, improvements in imaging technology made the early diagnosis of HCC possible. At present, the most appropriate therapeutic strategy for HCC is determined using an integrated staging system that assesses the tumor burden, the degree of liver dysfunction and the patient performance status; however, pathological and molecular features are not taken into account. The recent introduction of several new therapeutic agents will change the treatment strategy for HCC. Against this background, HCC subclassification based on tumor cellular and microenvironmental characteristics will become increasingly important. In this review, we give an overview of how pathological analysis contributes to understanding the development and progression of HCC and establishing a precision diagnosis of HCC.
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Affiliation(s)
- Akihisa Ueno
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Ken Yamazaki
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Yutaka Kurebayashi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hanako Tsujikawa
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Kathryn Effendi
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Hidenori Ojima
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Michiie Sakamoto
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
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50
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Pez F, Gifu P, Degli-Esposti D, Fares N, Lopez A, Lefrançois L, Michelet M, Rivoire M, Bancel B, Sylla BS, Herceg Z, Merle P, Caron de Fromentel C. In vitro transformation of primary human hepatocytes: Epigenetic changes and stemness properties. Exp Cell Res 2019; 384:111643. [PMID: 31557464 DOI: 10.1016/j.yexcr.2019.111643] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Revised: 09/19/2019] [Accepted: 09/21/2019] [Indexed: 02/07/2023]
Abstract
Human hepatocarcinogenesis is a complex process with many unresolved issues, including the cell of origin (differentiated and/or progenitor/stem cells) and the initial steps leading to tumor development. With the aim of providing new tools for studying hepatocellular carcinoma initiation and progression, we developed an innovative model based on primary human hepatocytes (PHHs) lentivirus-transduced with SV40LT+ST, HRASV12 with or without hTERT. The differentiation status of these transduced-PHHs was characterized by RNA sequencing (including lncRNAs), and the expression of some differentiation markers confirmed by RT-qPCR and immunofluorescence. In addition, their transformation capacity was assessed by colony formation in soft agar and tumorigenicity evaluated in immune-deficient mice. The co-expression of SV40LT+ST and HRASV12 in PHHs, in association or not with hTERT, led to the emergence of transformed clones. These clones exhibited a poorly differentiated cell phenotype with expression of stemness and mesenchymal-epithelial transition markers and gave rise to cancer stem cell subpopulations. In vivo, they resulted in poorly differentiated hepatocellular carcinomas with a reactivation of endogenous hTERT. These experiments demonstrate for the first time that non-cycling human mature hepatocytes can be permissive to in vitro transformation. This cellular tool provides the first comprehensive in vitro model for identifying genetic/epigenetic changes driving human hepatocarcinogenesis.
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Affiliation(s)
- Floriane Pez
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Patricia Gifu
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Davide Degli-Esposti
- Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Nadim Fares
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Anaïs Lopez
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Lydie Lefrançois
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Maud Michelet
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Michel Rivoire
- Département de Chirurgie et Institut de Chirurgie Expérimentale, Centre Léon Bérard, Lyon, France
| | - Brigitte Bancel
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Hospices Civils de Lyon, Service d'Anatomopathologie, Groupement Hospitalier Lyon Nord, France
| | - Bakary S Sylla
- Infections and Cancer Biology Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Zdenko Herceg
- Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France
| | - Philippe Merle
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Hospices Civils de Lyon, Service d'Hépatologie et Gastroentérologie, Groupement Hospitalier Lyon Nord, France
| | - Claude Caron de Fromentel
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
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