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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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Nagae G, Yamamoto S, Fujita M, Fujita T, Nonaka A, Umeda T, Fukuda S, Tatsuno K, Maejima K, Hayashi A, Kurihara S, Kojima M, Hishiki T, Watanabe K, Ida K, Yano M, Hiyama Y, Tanaka Y, Inoue T, Ueda H, Nakagawa H, Aburatani H, Hiyama E. Genetic and epigenetic basis of hepatoblastoma diversity. Nat Commun 2021; 12:5423. [PMID: 34538872 PMCID: PMC8450290 DOI: 10.1038/s41467-021-25430-9] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 08/06/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. Here, we perform an integrative genomic profiling of 163 pediatric liver tumors (154 HBs and nine hepatocellular carcinomas) based on the data acquired from a cohort study (JPLT-2). The total number of somatic mutations is precious low (0.52/Mb on exonic regions) but correlated with age at diagnosis. Telomerase reverse transcriptase (TERT) promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling reveals that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their "cell of origin" derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach for understanding the epigenetic drivers of hepatoblast carcinogenesis and deriving clues for risk stratification.
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Affiliation(s)
- Genta Nagae
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Shogo Yamamoto
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Masashi Fujita
- grid.509459.40000 0004 0472 0267Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Takanori Fujita
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Aya Nonaka
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Takayoshi Umeda
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Shiro Fukuda
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Kazuhiro Maejima
- grid.509459.40000 0004 0472 0267Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Akimasa Hayashi
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan ,grid.411205.30000 0000 9340 2869Department of Pathology, Kyorin University Faculty of Medicine, Tokyo, Japan
| | - Sho Kurihara
- grid.470097.d0000 0004 0618 7953Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Masato Kojima
- grid.470097.d0000 0004 0618 7953Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan
| | - Tomoro Hishiki
- grid.136304.30000 0004 0370 1101Chiba University Graduate School of Medicine, Chiba, Japan
| | - Kenichiro Watanabe
- grid.415798.60000 0004 0378 1551Shizuoka Children’s Hospital, Shizuoka, Japan
| | - Kohmei Ida
- grid.412305.10000 0004 1769 1397Department of Pediatrics, Teikyo University Mizonokuchi Hospital, Kawasaki, Japan
| | - Michihiro Yano
- grid.411403.30000 0004 0631 7850Department of Pediatrics, Akita University Hospital, Akita, Japan
| | - Yoko Hiyama
- grid.257022.00000 0000 8711 3200Department of Biomedical Science, Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan 734-8551, 1-2-3, Kasumi, Minami-ku, Hiroshima
| | - Yukichi Tanaka
- grid.414947.b0000 0004 0377 7528Department of Pathology, Kanagawa Children’s Medical Center, Yokohama, Japan
| | - Takeshi Inoue
- grid.416948.60000 0004 1764 9308Department of Pathology, Osaka City General Hospital, Osaka, Japan
| | - Hiroki Ueda
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Hidewaki Nakagawa
- grid.509459.40000 0004 0472 0267Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Hiroyuki Aburatani
- grid.26999.3d0000 0001 2151 536XGenome Science Laboratory, Research Center for Advanced Science and Technology (RCAST), the University of Tokyo, Tokyo, Japan
| | - Eiso Hiyama
- grid.470097.d0000 0004 0618 7953Department of Pediatric Surgery, Hiroshima University Hospital, Hiroshima, Japan ,grid.257022.00000 0000 8711 3200Department of Biomedical Science, Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan 734-8551, 1-2-3, Kasumi, Minami-ku, Hiroshima
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Ferrell LD, Kakar S, Terracciano LM, Wee A. Tumours and Tumour-like Lesions of the Liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:780-879. [DOI: 10.1016/b978-0-7020-6697-9.00013-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Sousa CMN, Gadelha PMM, Cartaxo RDS, Pedrosa GWH, Honorio RS, Lima JMDC, Coelho GR, Coelho CR. Hepatocyte Nuclear Factor 1α-Mutated Hepatocellular Adenomas: An Atypical Presentation. Case Rep Gastroenterol 2017; 11:637-642. [PMID: 29282384 PMCID: PMC5731146 DOI: 10.1159/000480376] [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: 07/05/2017] [Accepted: 08/15/2017] [Indexed: 11/19/2022] Open
Abstract
Hepatocellular adenomas (HCAs) are rare benign monoclonal hepatic tumors that commonly occur in females (3-4 per 100,000 women) due to the use of oral contraceptives, its primary risk factor. Recently, HCAs have been classified into 4 distinct subtypes according to genotypic and phenotypic characteristics and clinical features: inflammatory HCA (40-50%), which are hypervascular with marked peliosis and a tendency to bleed; hepatocyte nuclear factor 1α (HNF1A)-mutated HCA (H-HCA, 30-40%) that are diffusely steatotic and rarely undergo malignant transformation; β-catenin activated HCA (10-15%), which frequently undergo malignant transformation and may seem hepatocellular carcinoma on imaging; and unclassified HCA (10-25%). In this study, we report the case of a 23-year-old female oral contraceptive user with H-HCA. Usually, H-HCA is considered to be nonsevere in most cases and often requires outpatient follow-up. However, in this case, the injury had substantially increased in volume and evolved with a major bleeding frame, which was an unusual finding for this subtype of adenoma. The therapeutic used for this patient was a laparoscopic left hepatic segmentectomy. Thus, the choice of treatment to be performed in a patient with H-HCA can depend on the tumor size (>5 cm), the outcome of previous bleeding, and the risk of bleeding recurrence.
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Affiliation(s)
| | | | | | | | | | | | - Gustavo Rêgo Coelho
- Department of Surgery, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil
| | - Clovis Rêgo Coelho
- São Carlos Institute of Education and Research, Farias Brito Faculty, Fortaleza, Brazil
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Yoneda N, Matsui O, Kitao A, Kozaka K, Kobayashi S, Sasaki M, Yoshida K, Inoue D, Minami T, Gabata T. Benign Hepatocellular Nodules: Hepatobiliary Phase of Gadoxetic Acid-enhanced MR Imaging Based on Molecular Background. Radiographics 2016; 36:2010-2027. [PMID: 27740898 DOI: 10.1148/rg.2016160037] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Gadoxetic acid is a contrast agent for magnetic resonance (MR) imaging with hepatocyte-specific properties and is becoming increasingly important in detection and characterization of hepatocellular carcinoma and benign hepatocellular nodules, including focal nodular hyperplasia (FNH), nodular regenerative hyperplasia (NRH), hepatocellular adenoma (HCA), and dysplastic nodule. In these hepatocellular nodules, a positive correlation between the grade of membranous uptake transporter organic anion-transporting polypeptide (OATP) 1B3 expression and signal intensity in the hepatobiliary (HB) phase has been verified. In addition, it has been clarified that OATP1B3 expression is regulated by activation of β-catenin and/or hepatocyte nuclear factor 4α. On the other hand, recent studies have also revealed some of the background molecular mechanisms of benign hepatocellular nodules. FNH commonly shows iso- or hyperintensity in the HB phase with equal or stronger OATP1B3 expression, with map-like distribution of glutamine synthetase (a target of Wnt/β-catenin signaling) and OATP1B3 expression. NRH shows doughnut-like enhancement with hypointensity in the central portion in the HB phase with OATP1B3 expression. The majority of HCAs show hypointensity in the HB phase, but β-catenin-activated HCA exclusively demonstrates iso- or hyperintensity with increased expression of nuclear β-catenin, glutamine synthetase, and OATP1B3. Dysplastic nodule commonly shows iso- or hyperintensity in the HB phase with similar to increased OATP1B3 expression, but one-third of high-grade dysplastic nodules can be demonstrated as a hypointense nodule with decreased OATP1B3 expression. Knowledge of these background molecular mechanisms of gadoxetic acid-enhanced MR imaging is important not only for precise imaging diagnosis but also understanding of the pathogenesis of benign hepatocellular nodules. ©RSNA, 2016.
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Affiliation(s)
- Norihide Yoneda
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Osamu Matsui
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Azusa Kitao
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Kazuto Kozaka
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Satoshi Kobayashi
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Motoko Sasaki
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Kotaro Yoshida
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Dai Inoue
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Tetsuya Minami
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
| | - Toshifumi Gabata
- From the Departments of Radiology (N.Y., O.M., A.K., K.K., K.Y., D.I., T.M., T.G.), Quantum Medical Imaging (S.K.), and Human Pathology (M.S.), Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8640, Japan
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Cho SJ, Ferrell LD, Gill RM. Expression of liver fatty acid binding protein in hepatocellular carcinoma. Hum Pathol 2015; 50:135-9. [PMID: 26997447 DOI: 10.1016/j.humpath.2015.12.002] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2015] [Revised: 11/28/2015] [Accepted: 12/05/2015] [Indexed: 11/28/2022]
Abstract
Loss of expression of liver fatty acid binding protein (LFABP) by immunohistochemistry has been shown to be characteristic of a subset of hepatocellular adenomas (HCAs) in which HNF1A is inactivated. Transformation to hepatocellular carcinoma is thought to be a very rare phenomenon in the HNF1A-inactivated variant of HCA. However, we recently observed 2 cases at our institution, 1 definite hepatocellular carcinoma and 1 possible hepatocellular carcinoma, with loss of LFABP staining, raising the possibility that LFABP down-regulation may be associated with hepatocellular carcinogenesis. Our aim was to evaluate hepatocellular carcinomas arising in various backgrounds and with varying degrees of differentiation for loss of LFABP staining. Twenty total cases of hepatocellular carcinoma were examined. Thirteen cases arose in a background of cirrhosis due to hepatitis C (n = 8) or steatohepatitis (n = 5); 7 cases arose in a noncirrhotic background, with 2 cases arising within HNF1A-inactivated variant HCA and 2 cases arising within inflammatory variant HCA. Complete loss of expression of LFABP was seen in 6 of 20 cases, including 2 cases of hepatocellular carcinoma arising within HNF1A-inactivated variant HCA. Thus, loss of staining for LFABP appears to be common in hepatocellular carcinoma and may be seen in well-differentiated hepatocellular carcinoma. Therefore, LFABP loss should not be interpreted as evidence for hepatocellular adenoma over carcinoma, when other features support a diagnosis of hepatocellular carcinoma. The findings raise consideration for a role of HNF1A inactivation in hepatocellular carcinogenesis, particularly in less differentiated tumors.
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Affiliation(s)
- Soo-Jin Cho
- Department of Pathology, University of California, San Francisco, CA 94143
| | - Linda D Ferrell
- Department of Pathology, University of California, San Francisco, CA 94143
| | - Ryan M Gill
- Department of Pathology, University of California, San Francisco, CA 94143.
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Current updates on the molecular genetics and magnetic resonance imaging of focal nodular hyperplasia and hepatocellular adenoma. Insights Imaging 2015; 6:347-62. [PMID: 25790815 PMCID: PMC4444792 DOI: 10.1007/s13244-015-0399-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/29/2015] [Accepted: 02/04/2015] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCAs) constitute benign hepatic neoplasms in adults. HCAs are monoclonal neoplasms characterised by an increased predilection to haemorrhage and also malignant transformation. On the other hand, FNH is a polyclonal tumour-like lesion that occurs in response to increased perfusion and has an uneventful clinical course. Recent advances in molecular genetics and genotype-phenotype correlation in these hepatocellular neoplasms have enabled a new classification system. FNHs are classified into the typical and atypical types based on histomorphological and imaging features. HCAs have been categorised into four subtypes: (1) HCAs with HNF-1α mutations are diffusely steatotic, do not undergo malignant transformation, and are associated with familial diabetes or adenomatosis. (2) Inflammatory HCAs are hypervascular with marked peliosis and a tendency to bleed. They are associated with obesity, alcohol and hepatic steatosis. (3) HCAs with β-catenin mutations are associated with male hormone administration and glycogen storage disease, frequently undergo malignant transformation and may simulate hepatocellular carcinoma on imaging. (4) The final type is unclassified HCAs. Each of these except the unclassified subtype has a few distinct imaging features, often enabling reasonably accurate diagnosis. Biopsy with immunohistochemical analysis is helpful in difficult cases and has strong implications for patient management. TEACHING POINTS • FNHs are benign polyclonal neoplasms with no risk of haemorrhage or malignancy. • HCAs are benign monoclonal neoplasms classified into four subtypes based on immunohistochemistry. • Inflammatory HCAs show an atoll sign with a risk of bleeding and malignant transformation. • HNF-1α HCAs are steatotic HCAs with minimal complications and the best prognosis. • β-Catenin HCA shows variable MRI features and a high risk of malignancy.
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Nasser F, Affonso BB, Galastri FL, Odisio BC, Garcia RG. Minimally invasive treatment of hepatic adenoma in special cases. EINSTEIN-SAO PAULO 2014; 11:524-7. [PMID: 24488396 PMCID: PMC4880394 DOI: 10.1590/s1679-45082013000400021] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Accepted: 10/09/2013] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular adenoma is a rare benign tumor that was increasingly diagnosed in the 1980s and 1990s. This increase has been attributed to the widespread use of oral hormonal contraceptives and the broader availability and advances of radiological tests. We report two cases of patients with large hepatic adenomas who were subjected to minimally invasive treatment using arterial embolization. One case underwent elective embolization due to the presence of multiple adenomas and recent bleeding in one of the nodules. The second case was a victim of blunt abdominal trauma with rupture of a hepatic adenoma and clinical signs of hemodynamic shock secondary to intra-abdominal hemorrhage, which required urgent treatment. The development of minimally invasive locoregional treatments, such as arterial embolization, introduced novel approaches for the treatment of individuals with hepatic adenoma. The mortality rate of emergency resection of ruptured hepatic adenomas varies from 5 to 10%, but this rate decreases to 1% when resection is elective. Arterial embolization of hepatic adenomas in the presence of bleeding is a subject of debate. This observation suggests a role for transarterial embolization in the treatment of ruptured and non-ruptured adenomas, which might reduce the indication for surgery in selected cases and decrease morbidity and mortality. Magnetic resonance imaging showed a reduction of the embolized lesions and significant avascular component 30 days after treatment in the two cases in this report. No novel lesions were observed, and a reduction in the embolized lesions was demonstrated upon radiological assessment at a 12-month follow-up examination.
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Pérez Rojas J, Guarín Corredor MJ, Artes Martinez MJ, Vera Sempere FJ, Brisa Estelles C, Huart Peris MC, Hernandez Giron S. [Immunophenotypic classification of 3 cases of hepatocellular adenoma. Differential diagnosis with focal nodular hyperplasia]. GASTROENTEROLOGIA Y HEPATOLOGIA 2013; 36:388-95. [PMID: 23664829 DOI: 10.1016/j.gastrohep.2013.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2012] [Revised: 01/14/2013] [Accepted: 02/05/2013] [Indexed: 10/26/2022]
Abstract
Interest in adenomas has been renewed by the discovery of the molecular changes in these tumors. The latest World Health Organization publication on gastrointestinal tract tumors (2010) includes four types of hepatic adenomas, which are well characterized immunohistochemically, genotypically and phenotypically. In these tumors, medical history and morphological behavior play an important role in determining the risk of malignancy, mainly in adenomas with a b-catenin mutation. The presence of steatosis, inflammation, vascular changes linked to response to L-FABP, serum amyloid A, and glutamyl synthetase help to classify these tumors into four groups: hepatocellular adenomas with the HNF1A mutation (H-HCA), those with the b-catenin mutation (b-HCA), inflammatory HCA (IHCA), and HCA without markers. The absence of glypican 3 expression, HSP 70 and perivenular mapping of glutamyl synthetase helps to distinguish these tumors from well differentiated hepatocellular carcinoma. We describe the clinical, morphological and immunophenotypic features of three patients diagnosed with hepatic adenomas in a 2-year period.
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Affiliation(s)
- Judith Pérez Rojas
- Servicio de Anatomía Patológica, Hospital Universitario La Fe, Valencia, España.
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Goodman ZD, Terracciano LM, Wee A. Tumours and tumour-like lesions of the liver. MACSWEEN'S PATHOLOGY OF THE LIVER 2012:761-851. [DOI: 10.1016/b978-0-7020-3398-8.00014-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Shanbhogue AK, Prasad SR, Takahashi N, Vikram R, Sahani DV. Recent advances in cytogenetics and molecular biology of adult hepatocellular tumors: implications for imaging and management. Radiology 2011; 258:673-93. [PMID: 21339346 DOI: 10.1148/radiol.10100376] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Focal nodular hyperplasia (FNH), hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC) compose hepatocellular neoplasms that occur in adults. These tumors demonstrate characteristic epidemiologic and histopathologic features and clinical and imaging manifestations. HCAs are monoclonal neoplasms characterized by increased predilection to hemorrhage or rupture and occasional transformation to HCC. On the other hand, FNH is a polyclonal tumorlike lesion that occurs in response to increased perfusion and has an indolent clinical course. Up to 90% of HCCs occur in the setting of cirrhosis. Chronic viral hepatitis (hepatitis B and hepatitis C) infection and metabolic syndrome are major risk factors that can induce HCCs in nonfibrotic liver. Recent advances in pathology and genetics have led to better understanding of the histogenesis, natural history, and molecular events that determine specific oncologic pathways used by these neoplasms. HCAs are now believed to result from specific genetic mutations involving TCF1 (transcription factor 1 gene), IL6ST (interleukin 6 signal transducer gene), and CTNNB1 (β catenin-1 gene); FNHs are characterized by an "imbalance" of angiopoietin. While the β catenin signaling pathway is associated with well- and moderately differentiated HCCs, mutations involving p53 (tumor protein 53 gene), MMP14 (matrix metalloproteinase 14 gene), and RhoC (Ras homolog gene family, member C) are associated with larger tumor size, higher tumor grade with resultant shortened tumor-free survival, and poor prognosis. Fibrolamellar carcinoma (FLC), a unique HCC subtype, exhibits genomic homogeneity that partly explains its better overall prognosis. On the basis of recent study results involving cytogenetics and oncologic pathways of HCCs, novel drugs that act against molecular targets are being developed. Indeed, sorafenib (a multikinase inhibitor) is currently being used in the successful treatment of patients with advanced HCC. Characterization of genetic abnormalities and genotype-phenotype correlations in adult hepatocellular tumors provides better understanding of tumor pathology and biology, imaging findings, prognosis, and response to molecular therapeutics.
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Affiliation(s)
- Alampady K Shanbhogue
- Department of Radiology, University of Texas Health Science Center-San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78229, USA
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Di Bisceglie AM, Befeler AS. Tumors and Cysts of the Liver. SLEISENGER AND FORDTRAN'S GASTROINTESTINAL AND LIVER DISEASE 2010:1569-1592.e6. [DOI: 10.1016/b978-1-4160-6189-2.00094-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Yan BC, Hart JA. Recent developments in liver pathology. Arch Pathol Lab Med 2009; 133:1078-86. [PMID: 19642734 DOI: 10.5858/133.7.1078] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/05/2009] [Indexed: 11/06/2022]
Abstract
CONTEXT Hepatocellular carcinoma is the sixth most common malignancy and the third leading cause of cancer deaths worldwide, making pathologic identification of precursor lesions essential. Recent molecular genetic, pathologic, and clinical data have led to the stratification of hepatic adenomas into subgroups with unique molecular profiles and varying potential for malignant transformation, as well as to the reclassification of telangiectatic focal nodular hyperplasia as telangiectatic adenoma. Clinical, morphologic, and molecular genetic studies have also established juvenile hemochromatosis and pediatric nonalcoholic steatohepatitis as entities distinct from their adult counterparts. OBJECTIVE To review the recent molecular genetic characterization of telangiectatic hepatic adenomas and juvenile hemochromatosis, as well as the recent clinicopathologic characterization of pediatric nonalcoholic steatohepatitis. DATA SOURCES Literature review, personal experience, and material from the University of Chicago. CONCLUSIONS Basic science and translational research have led to the classification of many pathologic entities of the liver according to molecular genetic and protein expression profiles that correspond to traditional morphologic categories. Insights into signal transduction pathways that are activated in, and protein expression patterns unique to, an individual disease may lead to the development of new therapeutic agents and novel diagnostic biomarkers.
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Affiliation(s)
- Benjamin C Yan
- Department of Pathology, University of Chicago Hospitals, Chicago, Illinois 60637, USA
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Tward AD, Jones KD, Yant S, Cheung ST, Fan ST, Chen X, Kay MA, Wang R, Bishop JM. Distinct pathways of genomic progression to benign and malignant tumors of the liver. Proc Natl Acad Sci U S A 2007; 104:14771-6. [PMID: 17785413 PMCID: PMC1964540 DOI: 10.1073/pnas.0706578104] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We used several of the genetic lesions commonly associated with human liver tumors to reconstruct genetic progression to hepatocellular carcinoma and adenoma in mouse models. We initiated tumorigenesis with a transgene of the protooncogene MET or by hydrodynamic transfection of MET in combination with other genes into the livers of adult animals. Hepatocellular carcinoma in both instances arose from cooperation between MET and constitutively active versions of beta-catenin. In contrast, adenomas were produced by cooperation between MET and defective signaling through the transcription factor HNF1alpha. Prompted by these findings, we uncovered a coincidence between activation of the protein-tyrosine kinase encoded by MET and activating mutations of beta-catenin in a subset of human hepatocellular carcinomas. Inactivation of MET transgenes led to regression of hepatocellular carcinomas despite the persistence of activated beta-catenin. The tumors eventually recurred in the absence of MET expression, however, presumably after the occurrence of one or more events that cooperated with activated beta-catenin in lieu of MET. These results offer insight into hepatic tumorigenesis, provide mouse models that should be useful in the further study of hepatic tumorigenesis and for preclinical testing, and identify a subset of human hepatocellular carcinomas that may be susceptible to combination therapy directed against Met and the Wnt signaling pathway.
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MESH Headings
- Adenoma, Liver Cell/etiology
- Adenoma, Liver Cell/genetics
- Adenoma, Liver Cell/metabolism
- Adenoma, Liver Cell/pathology
- Animals
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Disease Models, Animal
- Gene Expression Regulation, Neoplastic
- Hepatocyte Nuclear Factor 1-alpha/genetics
- Hepatocyte Nuclear Factor 1-alpha/metabolism
- Humans
- Liver Neoplasms, Experimental/etiology
- Liver Neoplasms, Experimental/genetics
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Mice
- Mice, Transgenic
- Mutation
- Precipitin Tests
- Proto-Oncogene Proteins c-met/genetics
- Sequence Analysis, DNA
- Transfection
- Transgenes
- beta Catenin/genetics
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Affiliation(s)
- Aaron D. Tward
- *G. W. Hooper Foundation and Department of Microbiology and Immunology
- To whom correspondence may be addressed. E-mail: or
| | | | - Stephen Yant
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305; and
| | - Siu Tim Cheung
- Department of Surgery and Centre for the Study of Liver Disease, University of Hong Kong, Pok Fu Lam Road, Hong Kong, China
| | - Sheung Tat Fan
- Department of Surgery and Centre for the Study of Liver Disease, University of Hong Kong, Pok Fu Lam Road, Hong Kong, China
| | - Xin Chen
- Department of Biopharmaceutical Sciences, and
| | - Mark A. Kay
- Departments of Pediatrics and Genetics, Stanford University, Stanford, CA 94305; and
| | - Rong Wang
- **Departments of Anatomy and Surgery and the Pacific Vascular Research Laboratory, University of California, San Francisco, CA 94143
| | - J. Michael Bishop
- *G. W. Hooper Foundation and Department of Microbiology and Immunology
- To whom correspondence may be addressed. E-mail: or
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15
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Bioulac-Sage P, Blanc JF, Rebouissou S, Balabaud C, Zucman-Rossi J. Genotype phenotype classification of hepatocellular adenoma. World J Gastroenterol 2007; 13:2649-54. [PMID: 17569132 PMCID: PMC4147112 DOI: 10.3748/wjg.v13.i19.2649] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria (presence of a TCF1/HNF1α or β-catenin mutation), and an additional histological criterion (presence or absence of an inflammatory infiltrate), subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups: the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 (HNF1α); the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia (FNH), and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.
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16
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Flemming P, Lehmann U, Steinemann D, Kreipe H, Wilkens L. [Hepatocellular adenoma. Malignancy potential and differentiation from hepatocellular carcinoma]. DER PATHOLOGE 2006; 27:238-43. [PMID: 16736176 DOI: 10.1007/s00292-006-0835-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In contrast to hepatocellular carcinoma (HCC), very few molecular pathological studies have been carried out on hepatocellular adenoma (HCA). Particularly from the surgical point of view, based on views passed on verbally and in the literature of the 1970s and 1980s, a possible degeneration of the HCA provides grounds for operating. Published cases of transitions from HCA into HCC were evaluated on the basis of today's morphological standards. A comparison was made between the patterns of new molecular pathological studies of HCA, above all the work of our own groups, and those of HCC. The results speak against the suggestion that a typical solitary HCA in pre-menopausal women is a precursor lesion of HCC. After a critical review of the literature, only one casuistic case of a transition of HCA to HCC under a hormone therapy, which is no longer practiced today, remained. A limitation of particular HCA in genetic and metabolic diseases, children, adult males, adenomatosis, and HCA-like tumors with known risk factors of HCC would seem pragmatically meaningful. With classic HCA, however, the oncological indication for surgery does not apply. A prerequisite is a histological clarification, if necessary with the support of molecular pathological methods.
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Affiliation(s)
- P Flemming
- Pathologisches Institut, Siemensplatz 4, 29223, Celle.
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17
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Vander Borght S, Libbrecht L, Blokzijl H, Faber KN, Moshage H, Aerts R, Van Steenbergen W, Jansen PL, Desmet VJ, Roskams TA. Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver. J Pathol 2005; 207:471-82. [PMID: 16161006 DOI: 10.1002/path.1852] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Hepatocellular adenoma and focal nodular hyperplasia (FNH) are benign liver tumours. The differential diagnosis of these lesions and of well- to moderately differentiated hepatocellular carcinomas is often difficult but is very important in view of their different treatment. Although neither type of lesion is connected to the biliary tree, FNHs are cholestatic, whereas this is rarely the case for hepatocellular adenomas. This suggests that hepatocellular uptake and secretion of bile constituents is different in FNHs compared to adenomas. We therefore evaluated the expression and localization of hepatic transporters in hepatocellular adenomas, different types of FNH and well- to moderately differentiated hepatocellular carcinomas in non-cirrhotic liver and compared them with normal liver, using real-time RT-PCR and (semi-)quantitative immunohistochemistry. The parenchymal expression of the uptake transporter OATP2/8 (OATP1B1/3) was minimal or absent in adenoma, while there was strong and diffuse expression in FNH. We observed diffuse parenchymal expression of the basolateral export pump MRP3 in adenomas, while only reactive bile ductules and adjacent cholestatic hepatocytes were MRP3-positive in FNH. The MRP3/OATP2/8 expression pattern of atypical FNHs resembled that of adenomas, suggesting that both types of lesion are related. Most hepatocellular carcinomas showed decreased expression of one or more of the canalicular transporters (MDR1, MDR3, BSEP). The differences in transporter expression profile between FNHs and adenomas are most likely pathogenetically important and may explain why only FNHs are cholestatic. The finding that each type of focal lesion in non-cirrhotic liver has a specific transporter expression pattern may be useful in the establishment of a correct diagnosis by imaging or on needle biopsy.
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Affiliation(s)
- Sara Vander Borght
- Laboratory of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium.
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18
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Abstract
PURPOSE OF REVIEW This review highlights recent publications on hepatobiliary pathology concerning several unusual types of hepatitis, fatty liver disease, disorders of the biliary tree and other topics that have a substantial impact on liver biopsy interpretation. RECENT FINDINGS In the outbreak of severe acute respiratory syndrome (SARS), many patients had abnormalities in liver function tests. Liver biopsy findings in three cases were reported that showed a generic picture of hepatitis, with exceptionally increased mitotic activity. The role of portal myofibroblasts in cirrhosis was examined in several studies. A newly described lesion, isolated ductular hyperplasia (IDH) was found in patients with prolonged abnormalities of liver function tests of uncertain origin. Hyperplastic, well-differentiated bile ductules were seen on liver biopsy in the absence of any identifiable biliary disease. Hereditary hemochromatosis is now a complex entity with various clinicopathological forms based on mutations in the HFE gene and other iron-homeostatic genes such as transferrin receptor 2 and ferroportin 1. In some of these heritable forms of primary iron overload, stainable iron is present in both hepatocytes and Kupffer cells. After liver transplantation, differentiating recurrent HCV infection from acute rejection on liver biopsy is problematic, with exceptionally low inter- and intra-observer reliability shown in one study. SUMMARY The hepatitis associated with the SARS coronavirus, Isolated Ductular Hyperplasia in patients with liver function test abnormalities and other topics with pathologic relevance are reviewed.
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Affiliation(s)
- Jay H Lefkowitch
- Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
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19
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Bioulac-Sage P, Rebouissou S, Sa Cunha A, Jeannot E, Lepreux S, Blanc JF, Blanché H, Le Bail B, Saric J, Laurent-Puig P, Balabaud C, Zucman-Rossi J. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology 2005; 128:1211-8. [PMID: 15887105 DOI: 10.1053/j.gastro.2005.02.004] [Citation(s) in RCA: 157] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND & AIMS Telangiectatic focal nodular hyperplasia (TFNH) of the liver is generally believed to belong to the focal nodular hyperplasia (FNH) family. The aim of this study was to use molecular markers, in addition to morphologic features, to better characterize TFNH. METHODS Thirteen patients with TFNH were compared with 28 patients with FNH and 17 patients with hepatocellular adenoma. Full clinical and morphologic data were analyzed. Molecular markers included determination of clonality by examining the active X chromosome, genome-wide allelotyping, a search for hepatocyte nuclear factor 1alpha (HNF1alpha) mutations, and determination of ANGPT1/ANGPT2 transcript levels. RESULTS No clinical differences were evident between patients with TFNH and adenoma; in particular, bleeding was observed in 77% and 53% of the cases, respectively. Patients with TFNH were more likely to experience nodule recurrence and the presence of multiple nodules than those with either FNH or adenoma. All TFNH and adenoma samples that were available for analysis were monoclonal, in contrast to 40% of the FNH samples. Chromosome losses confirmed monoclonality and were significantly less frequent in TFNH and FNH (22% and 26%) than in adenoma (53%). HNF1alpha mutations were found exclusively in half of the adenomas. ANGPT2 was overexpressed in TFNH and down-regulated in adenoma (P < .01) and FNH (P < .0005). CONCLUSIONS TFNHs are monoclonal lesions frequently subject to bleeding that are similar to adenomas not carrying HNF1alpha mutations and require a similar type of treatment. However, morphologic and molecular data support the hypothesis that TFNH is a separate entity.
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