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Jain E, Anderson SA, Ollila E, Johnson DB, Chandrashekar DS, Osme A, Goksel B, Lee G, Al Diffalha S, Kakar S, Harada S, Dhall D. Hepatic adenomas in males: Is molecular characterization helpful in guiding its management? Hum Pathol 2025; 159:105795. [PMID: 40379140 DOI: 10.1016/j.humpath.2025.105795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 05/13/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND AND AIMS Hepatocellular adenomas (HCAs) in males are very rare. We performed detailed clinicopathologic, immunohistochemical and molecular characterization of HCAs in males, to understand their pathogenesis and malignant potential. METHODS Seven cases of HCA in males formed our study cohort. The histologic slides, clinical and follow-up information were reviewed and immunohistochemical stains were performed. DNA was extracted and targeted sequencing was performed using Ion Torrent chemistry. Filtered variants were annotated to identify pathogenic mutations. RESULTS Six (86 %) patients were morbidly obese. All showed at least focal cytologic atypia. Three lesions were markedly steatotic and 2 were hemorrhagic. One lesion showed focal reticulin loss, diffuse glutamine synthetase (GS) positivity and beta-catenin (β-catenin) nuclear staining, suggestive of atypical hepatocellular neoplasm. Three (42.8 %) cases were inflammatory-type, showing diffuse serum amyloid-associated protein/C-reactive protein. One other inflammatory-type HCA showed peripheral accentuation with GS and another non-inflammatory HCA showed patchy staining with GS; both revealed CTNBB1 mutations but no β-catenin nuclear staining. None showed TP53, TERT promotor mutations, or significant copy number alterations. CONCLUSION A significant proportion of HCAs in males occurred in obese patients and were inflammatory-type. While some are beta-catenin mutated and need to be resected, a subset of HCAs in males appears to be low-risk by molecular features and may be treated conservatively.
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Affiliation(s)
- Ekta Jain
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Sarah A Anderson
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Eric Ollila
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | | | | | - Abdullah Osme
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Behiye Goksel
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Goo Lee
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Sameer Al Diffalha
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, USA
| | - Shuko Harada
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA.
| | - Deepti Dhall
- Department of Pathology, The University of Alabama at Birmingham, Alabama, USA.
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2
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Saeed U, Piracha ZZ, Khan M, Tariq MN, Gilani SS, Raza M, Munusamy R, Bose N, Ozsahin DU, Özşahin İ, Nauli SM. Cracking the code of HBV persistence: cutting-edge approaches to targeting cccDNA in chronic hepatitis B with or without pyogenic liver Abscesses. Front Med (Lausanne) 2025; 12:1504736. [PMID: 40166066 PMCID: PMC11955850 DOI: 10.3389/fmed.2025.1504736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 02/20/2025] [Indexed: 04/02/2025] Open
Abstract
Chronic Hepatitis B Virus (HBV) infection remains a formidable global health challenge, driving severe liver complications such as hepatocellular carcinoma (HCC) and pyogenic liver abscesses (PLA). At the core of HBV persistence lies covalently closed circular DNA (cccDNA), a viral reservoir that fuels ongoing infection despite antiviral treatments. This review highlights molecular mechanisms governing cccDNA formation, maintenance, and clearance, spotlighting innovative therapeutic strategies to disrupt this key viral element. We explore cutting-edge approaches, including epigenetic modulation to silence cccDNA, RNA interference (RNAi) for viral RNA degradation, and CRISPR/Cas genome editing to excise cccDNA directly. Additionally, emerging antiviral therapies and immunotherapies, such as therapeutic vaccines and immune checkpoint inhibitors, offer new avenues for enhanced treatment efficacy. Special attention is given to the clinical complexities of managing HBV in patients with co-morbid conditions like HCC and PLA, emphasizing the necessity of a multidisciplinary approach. The interplay between antibacterial and antiviral therapies in PLA-associated HBV cases is critically examined to prevent treatment antagonism, ensuring optimal patient outcomes. Advanced therapeutic strategies, including nucleos(t)ide analogs, interferon therapy, and novel genomic interventions, are explored in both isolated HBV infection and PLA co-infections. Personalized regimens remain pivotal in enhancing therapeutic efficacy and long-term disease control. Current review advocates for a shift toward precision medicine, highlighting the critical need for interdisciplinary collaboration to bridge molecular discoveries with clinical innovations. Ultimately, these advancements promise to revolutionize the management of chronic HBV, paving the way for potential cures and improved patient outcomes.
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Affiliation(s)
- Umar Saeed
- Operational Research Center in Healthcare, Near East University, Nicosia, Türkiye
- Department of Clinical and Biomedical Research Center (CBRC), Foundation University School of Health Sciences (FUSH), Foundation University Islamabad (FUI), Islamabad, Pakistan
| | - Zahra Zahid Piracha
- Department of Medical Lab Technology, Al-Mizan Islamic International Medical College Trust (IIMCT) Complex, Riphah International University, Rawalpindi, Pakistan
- International Center of Medical Sciences Research (ICMSR), Austin, TX, United States
- International Center of Medical Sciences Research (ICMSR), Essex, United Kingdom
- International Center of Medical Sciences Research (ICMSR), Islamabad, Pakistan
| | - Mahmood Khan
- School of Rehabilitation, Kunming Medical University, Kunming, Yunnan, China
| | | | | | - Muhammad Raza
- Akhtar Saeed Medical and Dental College, Lahore, Pakistan
| | - Rakshana Munusamy
- Department of Medical Sciences, The Tamil Nadu Dr. M.G.R University, Chennai, India
| | - Naveen Bose
- Department of Medical Sciences, The Tamil Nadu Dr. M.G.R University, Chennai, India
| | - Dilber Uzun Ozsahin
- Operational Research Center in Healthcare, Near East University, Nicosia, Türkiye
- Department of Medical Diagnostic Imaging, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
- Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - İlker Özşahin
- Operational Research Center in Healthcare, Near East University, Nicosia, Türkiye
| | - Surya M. Nauli
- Department of Pharmacy, Chapman University, Irvine, CA, United States
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Nocita MA, Brady CW, Kuller JA, Gatta LA. Perinatal Management of Hepatic Adenomas. Obstet Gynecol Surv 2024; 79:735-740. [PMID: 39792602 DOI: 10.1097/ogx.0000000000001331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Importance With a strong association between hepatic adenomas and estrogen established, understanding the risks, evaluation, and perinatal management of hepatic adenomas is necessary for obstetric clinicians. Objective The aim of this study is to review the preconception counseling, perinatal management, and postpartum care of hepatic adenomas. Evidence Acquisition A literature review identified relevant research, review articles, textbook chapters, databases, and societal guidelines. Results Hepatic adenomas require individualized recommendations based on their prepregnancy size and evolution over pregnancy. Hepatic adenomas measuring greater than 5 cm are associated with a significantly increased risk during pregnancy including rupture. Ideally, optimal management of hepatic adenoma includes accurate diagnosis, discontinuation of estrogen-containing contraception, and surgical resection of large masses prior to conception. Patients should undergo serial surveillance of the adenoma during the antenatal and postpartum periods, with surgical intervention as indicated with multidisciplinary planning. Conclusions and Relevance An individualized approach is necessary when managing hepatic adenomas in the patient who is pregnant or intends pregnancy. More contemporary data are required to guide management and patient counseling.
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Affiliation(s)
- Megan A Nocita
- Resident, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, R-1200 Medical Center North, Nashville, TN
| | | | - Jeffrey A Kuller
- Professor, Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC
| | - Luke A Gatta
- Assistant Professor, Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, TN
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Bonatti M, Valletta R, Corato V, Gorgatti T, Posteraro A, Vingiani V, Lombardo F, Avesani G, Mega A, Zamboni GA. I thought it was a hemangioma! A pictorial essay about common and uncommon liver hemangiomas' mimickers. Insights Imaging 2024; 15:228. [PMID: 39298015 DOI: 10.1186/s13244-024-01745-1] [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: 03/11/2024] [Accepted: 06/16/2024] [Indexed: 09/21/2024] Open
Abstract
Focal liver lesions are frequently encountered during imaging studies, and hemangiomas represent the most common solid liver lesion. Liver hemangiomas usually show characteristic imaging features that enable characterization without the need for biopsy or follow-up. On the other hand, there are many benign and malignant liver lesions that may show one or more imaging features resembling hemangiomas that radiologists must be aware of. In this article we will review the typical imaging features of liver hemangiomas and will show a series of potential liver hemangiomas' mimickers, giving radiologists some hints for improving differential diagnoses. CRITICAL RELEVANCE STATEMENT: The knowledge of imaging features of potential liver hemangiomas mimickers is fundamental to avoid misinterpretation. KEY POINTS: Liver hemangiomas typically show imaging features that enable avoiding a biopsy. Many benign and malignant liver lesions show imaging features resembling hemangiomas. Radiologists must know the potentially misleading imaging features of hemangiomas' mimickers.
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Affiliation(s)
- Matteo Bonatti
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy.
| | - Riccardo Valletta
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Valentina Corato
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Tommaso Gorgatti
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Andrea Posteraro
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Vincenzo Vingiani
- Department of Radiology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Fabio Lombardo
- Department of Radiology, IRCCS Ospedale Sacro Cuore - Don Calabria, Negrar (VR), Italy
| | - Giacomo Avesani
- Department of Radiology, Radiation Oncology and Hematology, Fondazione Policlinico Universitario, A. Gemelli IRCCS, Rome, Italy
| | - Andrea Mega
- Department of Gastroenterology, Hospital of Bolzano (SABES-ASDAA), Teaching Hospital of Paracelsus Medical University (PMU), Bolzano, Italy
| | - Giulia A Zamboni
- Department of Diagnostics and Public Health, Institute of Radiology, University of Verona, Policlinico GB Rossi, P.Le LA Scuro 10, 37134, Verona, Italy
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Linge H, Nevermann N, Schmelzle M, Quante M. [Sex differences in hepatobiliary and transplantation surgery]. CHIRURGIE (HEIDELBERG, GERMANY) 2024; 95:715-720. [PMID: 39090449 DOI: 10.1007/s00104-024-02139-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 07/08/2024] [Indexed: 08/04/2024]
Abstract
Gender-specific differences in hepatobiliary and transplantation surgery are decisive for the diagnosis, treatment and long-term outcomes. Men exhibit a higher risk of late recurrences and cancer-specific death after liver cancer resection. The emphasis on screening recommendations and ensuring equal access to treatment options are vital to minimize disparities. In kidney and liver transplantations, women are less frequently listed and endure longer waiting times, while men dominate the waiting list. Gender-specific disparities in drug compatibility necessitate differentiated dosing. Further studies are needed to ensure equity in transplantation treatment. Individualized treatment considering these differences can enhance treatment outcomes and the quality of life of patients.
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Affiliation(s)
- H Linge
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland.
| | - N Nevermann
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - M Schmelzle
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - M Quante
- Klinik für Allgemein‑, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover, Hannover, Deutschland
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Ducatel A, Trillaud H, Reizine E, Vilgrain V, Sempoux C, Schmidt-Kobbe S, Gouw ASH, de Haas RJ, Julien C, Paradis V, Blanc JF, Chiche L, Balabaud C, Bioulac-Sage P, Frulio N. Sonic hedgehog hepatocellular adenoma: magnetic resonance imaging features and correlation with histology. Eur Radiol 2024; 34:4649-4662. [PMID: 38012454 DOI: 10.1007/s00330-023-10344-5] [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: 05/08/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 11/29/2023]
Abstract
OBJECTIVES Sonic hedgehog hepatocellular adenoma (shHCA) is a new hepatocellular adenoma (HCA) subgroup characterized by high risk of hemorrhage. ShHCA account for below 10% of all HCA cases and are often associated with female gender, obesity, and non-alcoholic steatohepatitis. No specific MRI characteristics have been described to date. The objective of this study was to assess the value of using MRI to identify shHCA, and correlate MRI findings with histology. METHODS We retrospectively collected MRI scans of 29 patients with shHCA from our center and from different liver referral centers to include 35 lesions. Diagnosis of shHCA was assessed by immunohistochemical overexpression of argininosuccinate synthase 1 or prostaglandin D2 synthase, then confirmed by molecular analysis of sonic hedgehog pathway activation and/or by proteomic analysis. RESULTS In 46% (n = 16/35) of shHCA cases, we detected intralesional fluid-filled cavities defined on MR images as fluid-like foci markedly hyperintense on T2-weighted sequences, and hypointense on T1-weighted sequences, with or without delayed enhancement. Pathologically, these cavities were observed in 54% of cases as vacuoles filled with blood at different stages of degradation. Hemorrhage and/or necrosis were detected among 71% of cases by MRI analysis (n = 25/35) versus 82% pathologically. Seventeen percent of shHCA cases (n = 6/35) were completely homogeneous via MRI and pathological analysis. No MRI criteria was found in favor of focal nodular hyperplasia, HNF1A-mutated HCA, or typical inflammatory HCA. CONCLUSION We reveal the presence of intralesional fluid-filled cavities among 46% of our shHCA cases that represent a new MRI finding possibly helpful for shHCA diagnosis. CLINICAL RELEVANCE STATEMENT This multicenter study is the first clinical study about the radiological aspect of this new hepatocellular adenoma subgroup. This highlights a strong correlation between MRI and histological analysis, with a specific pattern emerging for diagnosis. KEY POINTS • Sonic hedgehog hepatocellular adenoma is a new hepatocellular adenoma subgroup associated with high risk of hemorrhage, but imaging features of this subgroup remain unknown. • Analysis of MR images and correlation with pathology revealed intralesional fluid-filled cavities and necrotic-hemorrhagic changes. • Intralesional fluid-filled cavities have not yet been described in other adenoma subtypes and represent a new MRI finding for sonic hedgehog hepatocellular adenoma.
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Affiliation(s)
- Arnaud Ducatel
- Department of Radiology, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France.
| | - Hervé Trillaud
- Department of Radiology, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France
| | - Edouard Reizine
- Department of Radiology, APHP Nord, Hôpital Beaujon, Université Paris Cité, Clichy, France
| | - Valérie Vilgrain
- Department of Radiology, APHP Nord, Hôpital Beaujon, Université Paris Cité, Clichy, France
| | - Christine Sempoux
- Department of Clinical Pathology, Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Sabine Schmidt-Kobbe
- Department of Diagnostic and Interventional Radiology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Annette S H Gouw
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Robbert J de Haas
- Department of Radiology, University Medical Center Groningen, Groningen, The Netherlands
| | - Céline Julien
- Department of Digestive Surgery, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France
| | - Valérie Paradis
- Department of Pathology, APHP, Université de Paris, Hôpital Beaujon, Clichy, France
| | - Jean-Frédéric Blanc
- Department of Hepatogastroenterology and Digestive Oncology, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France
| | - Laurence Chiche
- Department of Digestive Surgery, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France
| | - Charles Balabaud
- UMR 1053, University Bordeaux, INSERM, F-33076, Bordeaux, France
| | | | - Nora Frulio
- Department of Radiology, University Bordeaux Hospital, Hôpital Haut-Lévêque, F-33604, Pessac, France
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7
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Declaux G, Denis de Senneville B, Trillaud H, Bioulac-Sage P, Balabaud C, Blanc JF, Facq L, Frulio N. Assessment of a multivariable model using MRI-radiomics, age and sex for the classification of hepatocellular adenoma subtypes. RESEARCH IN DIAGNOSTIC AND INTERVENTIONAL IMAGING 2024; 10:100046. [PMID: 39077731 PMCID: PMC11265376 DOI: 10.1016/j.redii.2024.100046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/01/2024] [Indexed: 07/31/2024]
Abstract
Objectives Non-invasive subtyping of hepatocellular adenomas (HCA) remains challenging for several subtypes, thus carrying different levels of risks and management. The goal of this study is to devise a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics and to evaluate its diagnostic performance. Methods This single-center retrospective case-control study included all consecutive patients with HCA identified within the pathological database from our institution from January 2003 to April 2018 with MRI examination (T2, T1-no injection/injection-arterial-portal); volumes of interest were manually delineated in adenomas and 38 textural features were extracted (LIFEx, v5.10). Qualitative (i.e., visual on MRI) and automatic (computer-assisted) analysis were compared. The prognostic scores of a multivariable diagnostic model based on basic clinical features (age and sex) combined with MRI-radiomics (tumor volume and texture features) were assessed using a cross-validated Random Forest algorithm. Results Via visual MR-analysis, HCA subgroups could be classified with balanced accuracies of 80.8 % (I-HCA or ß-I-HCA, the two being indistinguishable), 81.8 % (H-HCA) and 74.4 % (sh-HCA or ß-HCA also indistinguishable). Using a model including age, sex, volume and texture variables, HCA subgroups were predicted (multivariate classification) with an averaged balanced accuracy of 58.6 %, best=73.8 % (sh-HCA) and 71.9 % (ß-HCA). I-HCA and ß-I-HCA could be also distinguished (binary classification) with a balanced accuracy of 73 %. Conclusion Multiple HCA subtyping could be improved using machine-learning algorithms including two clinical features, i.e., age and sex, combined with MRI-radiomics. Future HCA studies enrolling more patients will further test the validity of the model.
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Affiliation(s)
- Guillaume Declaux
- Service d'imagerie diagnostique et Interventionnelle, centre médicochirurgical Magellan, hôpital Saint-André, centre hospitalier universitaire de Bordeaux, 33000, Bordeaux, France
| | | | - Hervé Trillaud
- Service d'imagerie diagnostique et Interventionnelle, centre médicochirurgical Magellan, hôpital Saint-André, centre hospitalier universitaire de Bordeaux, 33000, Bordeaux, France
- Université de Bordeaux, CNRS, Inria, Bordeaux INP, IMB, UMR 5251, 33400, Talence, France
| | - Paulette Bioulac-Sage
- Service de pathologie, hôpital Pellegrin, centre hospitalier universitaire de Bordeaux, Bordeaux, France
- Université de Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France
| | - Charles Balabaud
- Université de Bordeaux, Bordeaux Research in Translational Oncology, Bordeaux, France
- Service d'hépato-gastroentérologie et oncologie digestive, centre médicochirurgical Magellan, hôpital Haut-Lévêque, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - Jean-Frédéric Blanc
- Service d'hépato-gastroentérologie et oncologie digestive, centre médicochirurgical Magellan, hôpital Haut-Lévêque, centre hospitalier universitaire de Bordeaux, Bordeaux, France
| | - Laurent Facq
- Université de Bordeaux, CNRS, Inria, Bordeaux INP, IMB, UMR 5251, 33400, Talence, France
| | - Nora Frulio
- Service d'imagerie diagnostique et Interventionnelle, centre médicochirurgical Magellan, hôpital Saint-André, centre hospitalier universitaire de Bordeaux, 33000, Bordeaux, France
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8
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Toniutto P, Shalaby S, Mameli L, Morisco F, Gambato M, Cossiga V, Guarino M, Marra F, Brunetto MR, Burra P, Villa E. Role of sex in liver tumor occurrence and clinical outcomes: A comprehensive review. Hepatology 2024; 79:1141-1157. [PMID: 37013373 DOI: 10.1097/hep.0000000000000277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 12/06/2022] [Indexed: 04/05/2023]
Abstract
Clinical research on sex-based differences in the manifestations, pathophysiology, and prevalence of several diseases, including those affecting the liver, has expanded considerably in recent years. Increasing evidence suggests that liver diseases develop, progress, and respond to treatment differently depending on the sex. These observations support the concept that the liver is a sexually dimorphic organ in which estrogen and androgen receptors are present, which results in disparities between men and women in liver gene expression patterns, immune responses, and the progression of liver damage, including the propensity to develop liver malignancies. Sex hormones play protective or deleterious roles depending on the patient's sex, the severity of the underlying disease, and the nature of precipitating factors. Moreover, obesity, alcohol consumption, and active smoking, as well as social determinants of liver diseases leading to sex-related inequalities, may interact strongly with hormone-related mechanisms of liver damage. Drug-induced liver injury, viral hepatitis, and metabolic liver diseases are influenced by the status of sex hormones. Available data on the roles of sex hormones and gender differences in liver tumor occurrence and clinical outcomes are conflicting. Here, we critically review the main gender-based differences in the molecular mechanisms associated with liver carcinogenesis and the prevalence, prognosis, and treatment of primary and metastatic liver tumors.
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Affiliation(s)
- Pierluigi Toniutto
- Hepatology and Liver Transplantation Unit, Azienda Sanitaria Universitaria Integrata, Department of Medical Area, University of Udine, Udine, Italy
| | - Sarah Shalaby
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Laura Mameli
- Liver and Pancreas Transplant Center, Azienda Ospedaliera Brotzu Piazzale Ricchi 1, Cagliari, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Martina Gambato
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Valentina Cossiga
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Maria Guarino
- Department of Clinical Medicine and Surgery, Departmental Program "Diseases of the Liver and Biliary System," University of Naples "Federico II," Napoli, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology, and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Erica Villa
- Gastroenterology Department, University of Modena and Reggio Emilia, Modena, Italy
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9
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Vélez C, Newman KL, Paul S, Berli JU, Tangpricha V, Targownik LE. Approaching Digestive Health Care in Transgender and Gender-Diverse Communities. Gastroenterology 2024; 166:369-375.e2. [PMID: 38395524 DOI: 10.1053/j.gastro.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Affiliation(s)
- Christopher Vélez
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kira L Newman
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Sonali Paul
- Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago, Chicago, Illinois
| | - Jens U Berli
- Division of Plastic and Reconstructive Surgery, Oregon Health and Science University, Portland, Oregon
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism, and Lipids, Emory University, Atlanta, Georgia
| | - Laura E Targownik
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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10
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Vélez C, Newman KL, Paul S, Berli JU, Tangpricha V, Targownik LE. Approaching Digestive Health Care in Transgender and Gender-Diverse Communities. Clin Gastroenterol Hepatol 2024; 22:441-447.e2. [PMID: 38395527 DOI: 10.1016/j.cgh.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Indexed: 02/25/2024]
Affiliation(s)
- Christopher Vélez
- Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts
| | - Kira L Newman
- Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan
| | - Sonali Paul
- Section of Gastroenterology Hepatology, and Nutrition, University of Chicago, Chicago, Illinois
| | - Jens U Berli
- Division of Plastic and Reconstructive Surgery, Oregon Health and Science University, Portland, Oregon
| | - Vin Tangpricha
- Division of Endocrinology Metabolism, and Lipids, Emory University, Atlanta, Georgia
| | - Laura E Targownik
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
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Di Tommaso S, Dourthe C, Dupuy JW, Dugot-Senant N, Cappellen D, Cazier H, Paradis V, Blanc JF, Le Bail B, Balabaud C, Bioulac-Sage P, Saltel F, Raymond AA. Spatial characterisation of β-catenin-mutated hepatocellular adenoma subtypes by proteomic profiling of the tumour rim. JHEP Rep 2024; 6:100913. [PMID: 38304236 PMCID: PMC10831953 DOI: 10.1016/j.jhepr.2023.100913] [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: 02/20/2023] [Revised: 09/06/2023] [Accepted: 09/09/2023] [Indexed: 02/03/2024] Open
Abstract
Background & Aims Hepatocellular adenomas (HCAs) are rare, benign, liver tumours classified at the clinicopathological, genetic, and proteomic levels. The β-catenin-activated (b-HCA) subtypes harbour several mutation types in the β-catenin gene (CTNNB1) associated with different risks of malignant transformation or bleeding. Glutamine synthetase is a surrogate marker of β-catenin pathway activation associated with the risk of malignant transformation. Recently, we revealed an overexpression of glutamine synthetase in the rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA compared with the rest of the tumour. A difference in vascularisation was found in this rim shown by diffuse CD34 staining only at the tumour centre. Here, we aimed to characterise this tumour heterogeneity to better understand its physiopathological involvement. Methods Using mass spectrometry imaging, genetic, and proteomic analyses combined with laser capture microdissection, we compared the tumour centre with the tumour rim and with adjacent non-tumoural tissue. Results The tumour rim harboured the same mutation as the tumour centre, meaning both parts belong to the same tumour. Mass spectrometry imaging showed different spectral profiles between the rim and the tumour centre. Proteomic profiling revealed the significant differential expression of 40 proteins at the rim compared with the tumour centre. The majority of these proteins were associated with metabolism, with an expression profile comparable with a normal perivenous hepatocyte expression profile. Conclusions The difference in phenotype between the tumour centres and tumour rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA does not depend on CTNNB1 mutational status. In a context of sinusoidal arterial pathology, tumour heterogeneity at the rim harbours perivenous characteristics and could be caused by a functional peripheral venous drainage. Impact and implications Tumour heterogeneity was revealed in β-catenin-mutated hepatocellular adenomas (b-HCAs) via the differential expression of glutamine synthase at tumour rims. The combination of several spatial approaches (mass spectrometry imaging, genetic, and proteomic analyses) after laser capture microdissection allowed identification of a potential role for peripheral venous drainage underlying this difference. Through this study, we were able to illustrate that beyond a mutational context, many factors can downstream regulate gene expression and contribute to different clinicopathological phenotypes. We believe that the combinations of spatial analyses that we used could be inspiring for all researchers wanting to access heterogeneity information of liver tumours.
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Affiliation(s)
- Sylvaine Di Tommaso
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | - Cyril Dourthe
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | | | | | - David Cappellen
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Bordeaux University Hospital Center, Tumor Bank and Tumor Biology Laboratory, Pessac, France
| | - Hélène Cazier
- Pathology Department, Henri Mondor AP-HP Hospital, Créteil, France
| | - Valérie Paradis
- Pathology Department, Henri Mondor AP-HP Hospital, Créteil, France
| | - Jean-Frédéric Blanc
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Department of Hepatology and Oncology, Bordeaux University Hospital, INSERM CIC 1401, Bordeaux, France
| | - Brigitte Le Bail
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Pathology Department, Bordeaux University Hospital, Bordeaux, France
| | - Charles Balabaud
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
| | - Paulette Bioulac-Sage
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
| | - Frédéric Saltel
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | - Anne-Aurélie Raymond
- Université Bordeaux, Inserm UMR1312 BoRdeaux Institute of onCology (BRIC), Bordeaux, France
- Oncoprot Platform, TBM-Core US 005, Bordeaux, France
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Chattaraj B, Nandi A, Lin WY. Role of the gallbladder in our metabolism and immune system. GALLSTONE FORMATION, DIAGNOSIS, TREATMENT AND PREVENTION 2024:23-38. [DOI: 10.1016/b978-0-443-16098-1.00008-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Annamaraju SS, Mullaguri SC, Putta S, Vishnubhotla R, Kancha RK. Liver Cancer. BIOMEDICAL ASPECTS OF SOLID CANCERS 2024:61-71. [DOI: 10.1007/978-981-97-1802-3_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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14
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Chen YH, van Zon S, Adams A, Schmidt-Arras D, Laurence ADJ, Uhlig HH. The Human GP130 Cytokine Receptor and Its Expression-an Atlas and Functional Taxonomy of Genetic Variants. J Clin Immunol 2023; 44:30. [PMID: 38133879 PMCID: PMC10746620 DOI: 10.1007/s10875-023-01603-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Accepted: 10/30/2023] [Indexed: 12/23/2023]
Abstract
Genetic variants in IL6ST encoding the shared cytokine receptor for the IL-6 cytokine family GP130 have been associated with a diverse number of clinical phenotypes and disorders. We provide a molecular classification for 59 reported rare IL6ST pathogenic or likely pathogenic variants and additional polymorphisms. Based on loss- or gain-of-function, cytokine selectivity, mono- and biallelic associations, and variable cellular mosaicism, we grade six classes of IL6ST variants and explore the potential for additional variants. We classify variants according to the American College of Medical Genetics and Genomics criteria. Loss-of-function variants with (i) biallelic complete loss of GP130 function that presents with extended Stüve-Wiedemann Syndrome; (ii) autosomal recessive hyper-IgE syndrome (HIES) caused by biallelic; and (iii) autosomal dominant HIES caused by monoallelic IL6ST variants both causing selective IL-6 and IL-11 cytokine loss-of-function defects; (iv) a biallelic cytokine-specific variant that exclusively impairs IL-11 signaling, associated with craniosynostosis and tooth abnormalities; (v) somatic monoallelic mosaic constitutively active gain-of-function variants in hepatocytes that present with inflammatory hepatocellular adenoma; and (vi) mosaic constitutively active gain-of-function variants in hematopoietic and non-hematopoietic cells that are associated with an immune dysregulation syndrome. In addition to Mendelian IL6ST coding variants, there are common non-coding cis-acting variants that modify gene expression, which are associated with an increased risk of complex immune-mediated disorders and trans-acting variants that affect GP130 protein function. Our taxonomy highlights IL6ST as a gene with particularly strong functional and phenotypic diversity due to the combinatorial biology of the IL-6 cytokine family and predicts additional genotype-phenotype associations.
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Affiliation(s)
- Yin-Huai Chen
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Sarah van Zon
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Alex Adams
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK
| | - Dirk Schmidt-Arras
- Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria
| | | | - Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK.
- Biomedical Research Centre, University of Oxford, Oxford, UK.
- Department of Paediatrics, University of Oxford, Oxford, UK.
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Gao Y, Zhou J, Xie YC, Qiu LJ, Duan L, A ZX, Wu HF, Lv MX. Hepatic adenoma in a 7-year-old girl: a case report and literature review. BMC Pediatr 2023; 23:420. [PMID: 37620840 PMCID: PMC10464010 DOI: 10.1186/s12887-023-04209-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 07/21/2023] [Indexed: 08/26/2023] Open
Abstract
BACKGROUND Hepatocellular adenomas (HCAs) are rare benign tumors of the liver that occur predominantly in women taking oral contraceptives. In children, HCAs comprise < 5% of hepatic tumors. We report a case of HCAs in a 7-year-old girl with estrogen and glucose imbalance. CASE PRESENTATION A 7-year-old girl was presented to our hospital with bilateral breast enlargement for 2 months, polydipsia, polyuria, polyphagia, hyperglycemia, and significant weight gain. Computed tomography (CT) showed a 7.2 cm×6.9 cm×5.3 cm round-shaped mass in the left inner lobe of the liver, ovarian ultrasound showed multiple follicles in the ovaries bilaterally, and cranial magnetic resonance imaging (MRI) showed an enlarged superior pituitary. Hematological and biochemical results were as follows: fasting glucose was 19.7 mmol/L, estradiol was 122.9 pmol/L, follicle-stimulating hormone 10.81 IU/L, luteinizing hormone 10.99 IU/L, insulin-like growth factor 1,513 ng/mL, glutamine aminotransferase 86 U/L, and alkaline phosphatase 362 U/L. Thyroid functions, methemoglobin, fetal protein, carcinoembryonic antigen, and chorionic gonadotropin were normal. The patient had a complete surgical resection of the liver tumor, and the postoperative histopathological diagnosis was HCAs. After the surgery, insulin was injected and the glucose levels were stable. During the 36-month follow-up period, neither tumor recurrence nor significant abnormalities were detected using color Doppler ultrasound of the liver. The child's precocious puberty is currently under control. CONCLUSIONS HCAs are particularly rare in children with liver tumors, and risk factors for the development of HCAs in children include sex hormone imbalance, obesity, Fanconi anemia (FA), glycogen storage diseases (GSDs) type I, III, and IV, galactosemia, immunodeficiency, congenital portosystemic shunts (CPSS), cardiac hepatopathy status-post Fontan procedure, Hurler syndrome, familial adenomatous polyposis, germline HNF1A mutations, and maturity-onset diabetes of the young type 3. Most HCAs are detected during a physical examination without clinical symptoms, and some patients may present with symptoms such as abdominal pain, abdominal distension, and abdominal masse. Serum liver function tests can show increased alkaline phosphatase (ALP) and γ- glutamyl transferase (GT), whereas α-Fetoprofein (AFP) levels are normal. The definitive diagnosis relies mainly on histopathological examination. Because HCAs can rupture and bleed and become malignant. Early surgical treatment is recommended after detection.
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Affiliation(s)
- Yan Gao
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Jun Zhou
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Yu-Cheng Xie
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Li-Juan Qiu
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Ling Duan
- Second People's Hospital of Yunnan Province, 176 Qingnian Road, Kunming, 650034, Yunnan, China
| | - Zhi-Xiang A
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Hong-Fang Wu
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China
| | - Meng-Xing Lv
- Department of pathology, Kunming Children's Hospital, 288 Qianxing Road, Kunming, 650028, Yunnan, China.
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Safaei S, Sajed R, Shariftabrizi A, Dorafshan S, Saeednejad Zanjani L, Dehghan Manshadi M, Madjd Z, Ghods R. Tumor matrix stiffness provides fertile soil for cancer stem cells. Cancer Cell Int 2023; 23:143. [PMID: 37468874 PMCID: PMC10357884 DOI: 10.1186/s12935-023-02992-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Accepted: 07/12/2023] [Indexed: 07/21/2023] Open
Abstract
Matrix stiffness is a mechanical characteristic of the extracellular matrix (ECM) that increases from the tumor core to the tumor periphery in a gradient pattern in a variety of solid tumors and can promote proliferation, invasion, metastasis, drug resistance, and recurrence. Cancer stem cells (CSCs) are a rare subpopulation of tumor cells with self-renewal, asymmetric cell division, and differentiation capabilities. CSCs are thought to be responsible for metastasis, tumor recurrence, chemotherapy resistance, and consequently poor clinical outcomes. Evidence suggests that matrix stiffness can activate receptors and mechanosensor/mechanoregulator proteins such as integrin, FAK, and YAP, modulating the characteristics of tumor cells as well as CSCs through different molecular signaling pathways. A deeper understanding of the effect of matrix stiffness on CSCs characteristics could lead to development of innovative cancer therapies. In this review, we discuss how the stiffness of the ECM is sensed by the cells and how the cells respond to this environmental change as well as the effect of matrix stiffness on CSCs characteristics and also the key malignant processes such as proliferation and EMT. Then, we specifically focus on how increased matrix stiffness affects CSCs in breast, lung, liver, pancreatic, and colorectal cancers. We also discuss how the molecules responsible for increased matrix stiffness and the signaling pathways activated by the enhanced stiffness can be manipulated as a therapeutic strategy for cancer.
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Affiliation(s)
- Sadegh Safaei
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Roya Sajed
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Ahmad Shariftabrizi
- Division of Nuclear Medicine, Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
- Division of Nuclear Medicine, Department of Radiology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
| | - Shima Dorafshan
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Leili Saeednejad Zanjani
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Department of Pathology and Genomic Medicine, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA
| | - Masoumeh Dehghan Manshadi
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran
| | - Zahra Madjd
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
| | - Roya Ghods
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Hemmat Street (Highway), Next to Milad Tower, Tehran, 14496-14530, Iran.
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Jiao J, Finberg KE, Jain D, Morotti R. Hepatocellular Adenoma: Report of 2 Cases That Highlight the Relevance of Phenotype-Genotype Correlation in the Pediatric Population. Pediatr Dev Pathol 2023; 26:394-403. [PMID: 37334553 DOI: 10.1177/10935266231175426] [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] [Indexed: 06/20/2023]
Abstract
BACKGROUND Hepatocellular adenoma (HCA) in the pediatric population is very rare and there are only limited studies, especially with molecular characterization of the tumors. Main HCA subtypes recognized in the current WHO classification include HNF1A-inactivated HCA (H-HCA), inflammatory HCA (IHCA), β-catenin-activated HCA (b-HCA), and β-catenin-activated IHCA (b-IHCA) and sonic hedgehog HCA (shHCA) is reported as an emerging subtype. METHODS Clinical history, pathological information, and molecular studies for a series of 2 cases of pediatric HCA were reviewed. RESULTS Case 1 was a b-HCA characterized by somatic CTNNB1 S45 mutation in a 11-year-old male with Abernethy malformation. Case 2 was a H-HCA characterized by germline HNF1A variant (c.526+1G>A) in a 15-year-old male associated with maturity-onset diabetes of the young type 3 (MODY3). CONCLUSION Our findings highlight the rarity of these 2 cases associated with adenomatosis, and the contribution of molecular/genetic analysis for proper sub-typing, prognosis and family surveillance.
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Affiliation(s)
- Jingjing Jiao
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Karin E Finberg
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Dhanpat Jain
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
| | - Raffaella Morotti
- Department of Pathology, Yale School of Medicine, New Haven, CT, USA
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18
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Liu X, Espin-Garcia O, Khalvati F, Namdar K, Fischer S, Haider MA, Jhaveri KS. Hepatocellular adenoma subtyping by qualitative MRI features and machine learning algorithm of integrated qualitative and quantitative features: a proof-of-concept study. Clin Radiol 2023:S0009-9260(23)00231-3. [PMID: 37365116 DOI: 10.1016/j.crad.2023.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 03/23/2023] [Accepted: 05/24/2023] [Indexed: 06/28/2023]
Abstract
AIM To evaluate hepatocellular adenoma (HCA) subtyping using qualitative magnetic resonance imaging (MRI) features and feasibility of differentiating HCA subtypes using machine learning (ML) of qualitative and quantitative MRI features with histopathology as the reference standard. MATERIALS AND METHODS This retrospective study included 39 histopathologically subtyped HCAs (13 hepatocyte nuclear factor (HNF)-1-alpha mutated [HHCA], 11 inflammatory [IHCA], one beta-catenin-mutated [BHCA], and 14 unclassified [UHCA]) in 36 patients. HCA subtyping by two blinded radiologists using the proposed schema of qualitative MRI features and using the random forest algorithm was compared against histopathology. For quantitative features, 1,409 radiomic features were extracted after segmentation and reduced to 10 principle components. Support vector machine and logistic regression was applied to assess HCA subtyping. RESULTS Qualitative MRI features with proposed flow chart yielded diagnostic accuracies of 87%, 82%, and 74% for HHCA, IHCA, and UHCA respectively. The ML algorithm based on qualitative MRI features showed AUCs (area under the receiver operating characteristic curve [ROC] curve) of 0.846, 0.642, and 0.766 for diagnosing HHCA, IHCA, and UHCA, respectively. Quantitative radiomic features from portal venous and hepatic venous phase MRI demonstrated AUCs of 0.83 and 0.82, with a sensitivity of 72% and a specificity of 85% in predicting HHCA subtype. CONCLUSIONS The proposed schema of integrated qualitative MRI features with ML algorithm provided high accuracy for HCA subtyping while quantitative radiomic features provide value for diagnosis of HHCA. The key qualitative MRI features for differentiating HCA subtypes were concordant between the radiologists and the ML algorithm. These approaches appear promising to better inform clinical management for patients with HCA.
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Affiliation(s)
- X Liu
- Joint Department of Medical Imaging, University Health Network, Sinai Health System, University of Toronto, 585 University Ave., Toronto, ON, M5G 2N2, Canada
| | - O Espin-Garcia
- Department of Biostatistics, Princess Margaret Centre, University Health Network and Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, 610 University Ave, Toronto, ON, M5G 2M9, Canada
| | - F Khalvati
- Diagnostic Imaging, Neurosciences and Mental Health, Research Institute, The Hospital for Sick Children, 555 University Ave., Toronto, ON, M5G 1X8, Canada; Department of Medical Imaging, Institute of Medical Science (IMS), University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada
| | - K Namdar
- The Hospital for Sick Children, Institute of Medical Science, University of Toronto, 555 University Ave., Toronto, ON, M5G 1X8, Canada
| | - S Fischer
- Laboratory Medicine Program, University Health Network, University of Toronto, Laboratory Medicine and Pathobiology, 200 Elizabeth Street, Toronto, ON, M5G 2C4, Canada
| | - M A Haider
- Joint Department of Medical Imaging, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 585 University Ave., Toronto, ON, M5G 2N2, Canada
| | - K S Jhaveri
- Joint Department of Medical Imaging, University Health Network, Sinai Health System, University of Toronto, 585 University Ave., Toronto, ON, M5G 2N2, Canada.
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Qureshy Z, Lokken RP, Kakar S, Grab J, Mehta N, Sarkar M. Influence of progestin-only hormonal use on hepatocellular adenomas: A retrospective cohort study. Contraception 2023; 119:109915. [PMID: 36476331 PMCID: PMC10266542 DOI: 10.1016/j.contraception.2022.11.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 11/09/2022] [Accepted: 11/28/2022] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Exogenous estrogen is associated with growth of hepatocellular adenomas (HCAs), although the influence of progestin-only agents is unknown. We therefore evaluated the association of progestin-only agents on HCA progression compared to no hormone exposure and compared to estrogen exposure in female patients. STUDY DESIGN In this single-center, retrospective cohort study of reproductive-aged female patients (ages 16-45) with diagnosed HCAs between 2003 and 2021, we evaluated radiographic HCA growth during discrete periods of well-defined exogenous hormone exposures. RESULTS A total of 34 patients were included. Nineteen (55.9%) had follow-up scans during periods without hormone exposure, 7 (20.6%) during estrogen exposure, and 8 (23.5%) during progestin-only exposure. Over a median follow-up of 11 months, percent change in sum of adenoma diameters from baseline to last available scan was -15.0% with progestin-only agents versus 29.4% with estrogen exposure (p = 0.04), and -7.4% with no hormonal exposure (p = 0.52 compared to progestin-only). Greater than 10% growth was observed in two individuals (25.0%) with progestin-only agent use (one patient on high-dose progestin for menorrhagia) versus five individuals (71.4%) with estrogen use (p = 0.13), and 7 (36.8%) with no exogenous hormone use (p = 0.68 vs progestin-only). CONCLUSIONS During discrete periods of progestin-only use, HCA growth overall declined, similar to declining growth during periods without exogenous hormonal exposure. This differed from discrete periods of exogenous estrogen exposure, during which time HCAs demonstrated overall increased growth. Though larger studies are needed, these findings support recent guidance supporting progestin-only agents for female patients with HCAs seeking non-estrogen alternatives for contraception. IMPLICATIONS In this small retrospective study, we observed overall decrease in HCA size during discrete periods of progestin-only contraception use, similar to that observed during periods without exogenous hormone exposure, supporting their use as a safe alternative to estrogen-containing contraceptives in this patient population.
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Affiliation(s)
- Zoya Qureshy
- Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - R Peter Lokken
- Department of Radiology, Division of Interventional Radiology, University of California San Francisco, San Francisco, CA, United States
| | - Sanjay Kakar
- Department of Pathology, University of California San Francisco, San Francisco, CA, United States
| | - Joshua Grab
- Department of Medicine, UCSF Liver Center, University of California San Francisco, San Francisco, CA, United States
| | - Neil Mehta
- Department of Medicine, UCSF Liver Center, University of California San Francisco, San Francisco, CA, United States; Department of Medicine, Division of Gastroenterology/Hepatology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States
| | - Monika Sarkar
- Department of Medicine, UCSF Liver Center, University of California San Francisco, San Francisco, CA, United States; Department of Medicine, Division of Gastroenterology/Hepatology, Department of Medicine, University of California San Francisco, San Francisco, CA, United States.
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Maruyama H, Tobari M, Nagamatsu H, Yamaguchi T, Shiina S. Ablation for Benign Liver Tumors: Current Concepts and Limitations. J Clin Transl Hepatol 2023; 11:244-252. [PMID: 36406314 PMCID: PMC9647100 DOI: 10.14218/jcth.2022.00205] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 12/04/2022] Open
Abstract
Percutaneous ablation under imaging guidance is a curative treatment that can induce complete tumor necrosis with advantages of minimal invasiveness and a low risk of complications. Thermal ablation, which includes radiofrequency ablation and microwave ablation, is a representative technique that has sufficient antitumor effects in cases of hepatocellular carcinoma with ≤3 lesions measuring ≤3 cm and preserved liver function. The short- and long-term outcomes of patients are comparable with those achieved with surgical resection. Despite their nonmalignant nature, some benign liver tumors require treatment for symptoms caused by the presence of the tumor and/or continuous enlargement. Ablation may be the treatment of choice because it has lower burden on patients than surgical treatment. This review describes the recent concepts, progress, and limitations of ablation-based treatment for benign liver tumors.
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Affiliation(s)
- Hitoshi Maruyama
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
- Correspondence to: Hitoshi Maruyama, Department of Gastroenterology, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. ORCID: https://orcid.org/0000-0003-3371-3157. Tel: +81-3-38133111, Fax: +81-3-56845960, E-mail:
| | - Maki Tobari
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
| | | | - Tadashi Yamaguchi
- Center for Frontier Medical Engineering, Chiba University, Chiba, Japan
| | - Shuichiro Shiina
- Department of Gastroenterology, Juntendo University, Tokyo, Japan
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Wang M, Sarkar M, Mehta N. Now you see it, now you don't: Estrogen exposure and obesity effects on HCA development and regression. Hepatology 2023; 77:341-343. [PMID: 36176041 DOI: 10.1002/hep.32814] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Accepted: 09/23/2022] [Indexed: 01/31/2023]
Affiliation(s)
- Melinda Wang
- Department of Medicine , University of California , San Francisco , California , USA
| | - Monika Sarkar
- Division of Gastroenterology, Department of Medicine , University of California , San Francisco , California , USA
| | - Neil Mehta
- Division of Gastroenterology, Department of Medicine , University of California , San Francisco , California , USA
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22
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Wakasa Y, Toyoki Y, Kusumi T, Kameyama Y, Odagiri T, Jin H, Nakai M, Aoki K, Kawashima H, Endo M. β-Catenin-activated inflammatory hepatocellular adenoma with pigmentation and atypical features: a case report. Clin J Gastroenterol 2023; 16:237-243. [PMID: 36640247 DOI: 10.1007/s12328-023-01757-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 01/06/2023] [Indexed: 01/15/2023]
Abstract
Hepatocellular adenomas are rare diseases, defined as benign liver neoplasms composed of cells with hepatocellular differentiation. Differential diagnosis of hepatocellular adenoma from other lesions, including focal nodular hyperplasia and hepatocellular carcinoma, is crucial to determine treatment strategy. We describe a case of β-catenin-activated inflammatory hepatocellular adenoma with malignant transformation. A 50-year-old man with a suspected liver tumor, based on abdominal ultrasonography findings, was referred to our hospital. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a liver tumor in S2 which was enhanced in the arterial phase to the delayed phase. Based on diagnostic imaging findings, hepatocellular adenoma or focal nodular hyperplasia was suspected. We considered the possibility of malignant potential because of the enlargement of the lesion. Thus, we performed a laparoscopic hepatectomy. Histological examination showed pigment deposition in the hepatocytes, which was determined to be lipofuscin. Mild nuclear swelling and atypia in the tumor area indicated nodular growth. Based on the histological and immunohistochemical findings, the diagnosis was ꞵ-catenin-activated inflammatory hepatocellular adenoma with atypical features. The imaging features of hepatocellular adenoma and focal nodular hyperplasia are similar, but if the tumor tends to grow, surgical treatment should be performed because of the possibility of malignant hepatocellular adenoma.
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Affiliation(s)
- Yusuke Wakasa
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan.
| | - Yoshikazu Toyoki
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Tomomi Kusumi
- Department of Pathology, Aomori City Hospital, Aomori, Japan
| | - Yuma Kameyama
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Tadashi Odagiri
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Hiroyuki Jin
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Makoto Nakai
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Kazunori Aoki
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Hiroaki Kawashima
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
| | - Masaaki Endo
- Department of General Surgery, Aomori City Hospital, 1-14-20, Katta, Aomori, 030-0821, Japan
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23
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Nault JC, Paradis V, Ronot M, Zucman-Rossi J. Benign liver tumours: understanding molecular physiology to adapt clinical management. Nat Rev Gastroenterol Hepatol 2022; 19:703-716. [PMID: 35835851 DOI: 10.1038/s41575-022-00643-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/01/2022] [Indexed: 12/08/2022]
Abstract
Improvements in understanding the pathophysiology of the different benign liver nodules have refined their nosological classification. New criteria have been identified using imaging, histology and molecular analyses for a precise diagnosis of these tumours. Improvement in the classification of liver tumours provides a more accurate prediction of disease progression and has modified patient management. Haemangioma and focal nodular hyperplasia, the most common benign liver tumours that develop in the absence of chronic liver disease, are usually easy to diagnose on imaging and do not require specific treatment. However, hepatocellular adenomas and cirrhotic macronodules can be difficult to discriminate from hepatocellular carcinoma. The molecular subtyping of hepatocellular adenomas in five major subgroups defined by HNF1A inactivation, β-catenin mutation in exon 3 or exon 7/8, and activation of inflammatory or Hedgehog pathways helps to identify the tumours at risk of malignant transformation or bleeding. New clinical, biological and molecular tools have gradually been included in diagnostic and treatment algorithms to classify benign liver tumours and improve patient management. This Review aims to explain the main pathogenic mechanisms of benign liver tumours and how this knowledge could influence clinical practice.
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Affiliation(s)
- Jean-Charles Nault
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France. .,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France. .,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team «Functional Genomics of Solid Tumors», Paris, France. .,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.
| | - Valérie Paradis
- Service de Pathologie, Hôpital Beaujon, AP-HP Nord, Clichy, France.,Université de Paris, INSERM U1149 "Centre de Recherche sur l'inflammation", CRI, Paris, France
| | - Maxime Ronot
- Université de Paris, INSERM U1149 "Centre de Recherche sur l'inflammation", CRI, Paris, France.,Department of Radiology, Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, AP-HP Nord, Clichy, France
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team «Functional Genomics of Solid Tumors», Paris, France. .,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France. .,Hôpital Européen Georges Pompidou, APHP, Paris, France.
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24
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Luo L, Wang T, Cheng M, Ge X, Song S, Zhu G, Xiao Y, Deng W, Xie J, Shan R. Rare benign liver tumors that require differentiation from hepatocellular carcinoma: focus on diagnosis and treatment. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04169-w. [PMID: 35789428 DOI: 10.1007/s00432-022-04169-w] [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: 05/14/2022] [Accepted: 06/21/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND/AIM Recently, an increase in the number of asymptomatic rare benign liver tumors (BLTs) has been reported during health check-ups. It is difficult to determine the nature of partial rare BLTs and not easy to distinguish from malignant liver tumors. This study aimed to analysis clinical features, diagnosis and treatment of rare BLTs to reduce misdiagnosis and provide reference for clinical practice. METHODS From January 2012 to January 2021, we treated 112 rare BLTs by hepatectomy, including 54 focal nodular hyperplasias, 14 hepatocellular adenomas, 28 hepatic angiomyolipomas, 3 hepatic granulomas, 2 inflammatory pseudotumors of the liver, 2 nodular regenerative hyperplasia, 2 hepatic lipomas, 1 solitary fibrous tumor of the liver, 1 hepatic schwannoma and 1 hepatic myelolipoma. RESULTS The majority of patients were middle-aged female and asymptomatic. Single tumors were dominant. The diagnostic accuracies of computed tomography (CT) and magnetic resonance imaging (MRI) were 32.5% and 44.2%, respectively. The majority of tumors were likely to be misdiagnosed as hepatocellular carcinoma (HCC) or difficult to distinguish from HCC. All patients underwent surgical treatment. Postoperative pathological and immunohistochemical examination can confirm the diagnosis. No patients without tumor recurrence or metastasis during follow-up period. CONCLUSION Altogether, the clinical symptoms of rare BLTs lack specificity, and their preoperative diagnosis largely depends on imaging examination, with a low diagnostic accuracy rate and high chances of misdiagnosis as HCC. Diagnosis is confirmed by pathological and immunohistochemical examination. Surgical resection for rare BLT is safe and effective, regular postoperative follow-up is necessary.
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Affiliation(s)
- Laihui Luo
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Tao Wang
- Department of Day Surgery Ward, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Mengting Cheng
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Xian Ge
- Department of Pathology, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Shengjiang Song
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Guoqing Zhu
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Yongqiang Xiao
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Wei Deng
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Jin Xie
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China
| | - Renfeng Shan
- Department of General Surgery, First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, 330006, Jiangxi, China.
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25
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Focal Benign Liver Lesions and Their Diagnostic Pitfalls. Radiol Clin North Am 2022; 60:755-773. [DOI: 10.1016/j.rcl.2022.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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26
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Aziz H, Brown ZJ, Eskander MF, Aquina CT, Baghdadi A, Kamel IR, Pawlik TM. A Scoping Review of the Classification, Diagnosis, and Management of Hepatic Adenomas. J Gastrointest Surg 2022; 26:965-978. [PMID: 35083725 DOI: 10.1007/s11605-022-05246-8] [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: 08/09/2021] [Accepted: 01/05/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND Hepatic adenomas (HA), or hepatocellular adenomas, are benign, solid liver lesions that develop in otherwise normal livers, often in the setting of increased estrogen levels. While considered a benign tumor, there is a risk for substantial complications such as hemorrhage and malignant transformation. We review the diagnosis, classification, and potential therapeutic management options for patients with HA. METHODS A scoping narrative review was conducted based on recent literature regarding classification, diagnosis, and management of HA. RESULTS While HAs are typically considered benign, complications such as hemorrhage and malignant transformation may occur in approximately 25% and 5% of patients, respectively. Recent advances in imaging and molecular profiling have allowed for the classification of HAs into subtypes allowing for patient risk stratification that helps guide management. Surgical resection should be considered in asymptomatic patients who are male, have an adenoma ≥5 cm in diameter, or have the β-catenin-activated subtype due to an increased risk of hemorrhage and/or malignant transformation. CONCLUSION Molecular profiling has aided in the stratification of patients relative to the risk of complications to predict better the potential behavior of HAs.
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Affiliation(s)
- Hassan Aziz
- Department of Surgery, Tufts University School of Medicine, Boston, MA, USA
| | - Zachary J Brown
- Department of Surgery, The Ohio State University Wexner Medical Center, 395 W. 12th Ave., Suite, Columbus, OH, 670, USA
| | - Mariam F Eskander
- Department of Surgery, The Ohio State University Wexner Medical Center, 395 W. 12th Ave., Suite, Columbus, OH, 670, USA
| | - Christopher T Aquina
- Department of Surgery, The Ohio State University Wexner Medical Center, 395 W. 12th Ave., Suite, Columbus, OH, 670, USA
| | | | - Ihab R Kamel
- Department of Radiology, Johns Hopkins University, Baltimore, MD, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, 395 W. 12th Ave., Suite, Columbus, OH, 670, USA.
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27
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Desjonqueres E, Campani C, Marra F, Zucman-Rossi J, Nault JC. Preneoplastic lesions in the liver: Molecular insights and relevance for clinical practice. Liver Int 2022; 42:492-506. [PMID: 34982503 DOI: 10.1111/liv.15152] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the most frequent primary liver cancers, accounting for approximately 80% and 15%, respectively. HCC carcinogenesis occurs mostly in cirrhosis and is a complex multi-step process, from precancerous lesions (low-grade and high-grade dysplastic nodules) to progressed HCC. During the different stages of liver carcinogenesis, there is an accumulation of pathological, genetic and epigenetic changes leading to initiation, malignant transformation and finally tumour progression. In contrast, a small subset of HCC occurs in normal liver from the transformation of hepatocellular adenoma (HCA), a benign hepatocellular tumour. The recent molecular classification enables to stratify HCAs according to their risk of complication, in particular malignant transformation, associated with mutations in exon 3 of the catenin beta 1 (CTNNB1) gene. Cholangiocarcinoma (CCA) derives from the multistep malignant transformation of preneoplastic lesions, like biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB), for which a pre-operative diagnosis remains difficult. Different genetic alterations are involved in BilIN and IPNB progression, leading to the development of tubular or intestinal adenocarcinoma. The aims of this review are to describe the main clinical and molecular features of preneoplastic lesions leading to the development of HCC and CCA, their implications in clinical practice and the perspectives for future research.
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Affiliation(s)
- Elvire Desjonqueres
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
| | - Claudia Campani
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France.,Hôpital Européen Georges Pompidou, APHP, Paris, France
| | - Jean-Charles Nault
- Service d'hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France.,Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris 13, Communauté d'Universités et Etablissements Sorbonne Paris Cité, Paris, France.,Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris, team « Functional Genomics of Solid Tumors », Paris, France.,Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France
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28
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Gomes CC. Recurrent driver mutations in benign tumors. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2022; 789:108412. [PMID: 35690415 DOI: 10.1016/j.mrrev.2022.108412] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 02/02/2022] [Accepted: 02/09/2022] [Indexed: 06/15/2023]
Abstract
The understanding of the molecular pathogenesis of benign tumors may bring essential information to clarify the process of tumorigenesis, and ultimately improve the understanding of events such as malignant transformation. The definition of benign neoplasia is not always straightforward and herein the issues surrounding this concept are discussed. Benign neoplasms share all cancer hallmarks with malignancies, except for metastatic potential. Recently, next-generation sequencing has provided unprecedented opportunities to unravel the genetic basis of benign neoplasms and, so far, we have learned that benign neoplasms are indeed characterized by the presence of genetic mutations, including genes rearrangements. Driver mutations in advanced cancer are those that confer growth advantage, and which have been positively selected during cancer evolution. Herein, some discussion will be brought about this concept in the context of cancer prevention, involving precursor lesions and benign neoplasms. When considering early detection and cancer prevention, a driver mutation should not only be advantageous (i.e., confer survival advantage), but predisposing (i.e., promoting a cancer phenotype). By including the benign counterparts of malignant neoplasms in tumor biology studies, it is possible to evaluate the risk posed by a given mutation and to differentiate advantageous from predisposing mutations, further refining the concept of driver mutations. Therefore, the study of benign neoplasms should be encouraged because it provides valuable information on tumorigenesis central for understanding the progression from initiation to malignant transformation.
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Affiliation(s)
- Carolina Cavalieri Gomes
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.
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29
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Paradis V, Beaufrère A. Regenerative Nodules and Liver Tumors in Vascular Liver Diseases. VASCULAR DISORDERS OF THE LIVER 2022:215-236. [DOI: 10.1007/978-3-030-82988-9_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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30
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Bioulac-Sage P, Gouw ASH, Balabaud C, Sempoux C. Hepatocellular Adenoma: What We Know, What We Do Not Know, and Why It Matters. Histopathology 2021; 80:878-897. [PMID: 34856012 DOI: 10.1111/his.14605] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 11/27/2022]
Abstract
In the last 2 decades there has been significant progress in research and diagnosis of hepatocellular adenoma (HCA), resulting in the establishment of a molecular and immunohistological HCA classification. This review aims to fine-tune the current expertise in order to enhance the histopathological diagnostic possibilities, by refining issues that are already known, addressing diagnostic difficulties and identifying still unknown aspects of HCA. We will discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of beta-catenin mutated HCAs. The major complications of HCAs, bleeding and malignant transformation, will be considered, including the dilemmas of atypical and borderline lesions. Paragraphs on HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries are included. The natural history of the different HCA subtypes in relation with age, sex and risk factors is a feature still insufficiently investigated. This is also true for the risks of clinical bleeding and malignant transformation in association with HCA subtypes. As HCA is a relatively rare tumor, a multicenter and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programs to identify, classify and manage HCAs, focusing on several aspects, e.g. etiology, underlying liver disease, complications, regression and growth. Updating what we know, identifying and addressing features that we do not know matters to warrant optimal patient management.
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Affiliation(s)
| | - Annette S H Gouw
- Departement of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
| | | | - Christine Sempoux
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
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31
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Ren H, Gao YJ, Ma XM, Zhou ST. Large focal nodular hyperplasia is unresponsive to arterial embolization: A case report. World J Clin Cases 2021; 9:9977-9981. [PMID: 34877339 PMCID: PMC8610892 DOI: 10.12998/wjcc.v9.i32.9977] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 07/11/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Focal nodular hyperplasia (FNH) commonly occurs in women; it is usually asymptomatic and sometimes difficult to differentiate from hepatocellular carcinoma (HCC).
CASE SUMMARY A large space-occupying lesion in the right lobe of the liver was incidentally detected in an adult man and diagnosed as HCC. Transcatheter arterial chemoembolization was applied once monthly for 2 years, but the lesion did not decrease in size. It was revealed by biopsy to be FNH. Eleven years later, the patient underwent liver resection due to hemorrhage and the pathological examination confirmed FNH.
CONCLUSION For a space-occupying lesion, it is prerequisite to pathologically confirm the diagnosis and the corresponding intervention can be effective.
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Affiliation(s)
- Hui Ren
- Department of Hepatobiliary and Liver Transplant Center, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100039, China
| | - Yin-Jie Gao
- Department of Hepatobiliary and Liver Transplant Center, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100039, China
| | - Xue-Mei Ma
- Department of Hepatobiliary and Liver Transplant Center, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100039, China
| | - Shao-Tang Zhou
- Department of Hepatobiliary and Liver Transplant Center, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing 100039, China
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32
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Teeli AS, Łuczyńska K, Haque E, Gayas MA, Winiarczyk D, Taniguchi H. Disruption of Tumor Suppressors HNF4α/HNF1α Causes Tumorigenesis in Liver. Cancers (Basel) 2021; 13:cancers13215357. [PMID: 34771521 PMCID: PMC8582545 DOI: 10.3390/cancers13215357] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/14/2021] [Accepted: 10/18/2021] [Indexed: 12/18/2022] Open
Abstract
The hepatocyte nuclear factor-4α (HNF4α) and hepatocyte nuclear factor-1α (HNF1α) are transcription factors that influence the development and maintenance of homeostasis in a variety of tissues, including the liver. As such, disruptions in their transcriptional networks can herald a number of pathologies, such as tumorigenesis. Largely considered tumor suppressants in liver cancer, these transcription factors regulate key events of inflammation, epithelial-mesenchymal transition, metabolic reprogramming, and the differentiation status of the cell. High-throughput analysis of cancer cell genomes has identified a number of hotspot mutations in HNF1α and HNF4α in liver cancer. Such results also showcase HNF1α and HNF4α as important therapeutic targets helping us step into the era of personalized medicine. In this review, we update current findings on the roles of HNF1α and HNF4α in liver cancer development and progression. It covers the molecular mechanisms of HNF1α and HNF4α dysregulation and also highlights the potential of HNF4α as a therapeutic target in liver cancer.
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Affiliation(s)
- Aamir Salam Teeli
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; (A.S.T.); (K.Ł.); (E.H.); (D.W.)
| | - Kamila Łuczyńska
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; (A.S.T.); (K.Ł.); (E.H.); (D.W.)
| | - Effi Haque
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; (A.S.T.); (K.Ł.); (E.H.); (D.W.)
| | - Mohmmad Abrar Gayas
- Department of Surgery and Radiology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST-K, Jammu 19000, India;
| | - Dawid Winiarczyk
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; (A.S.T.); (K.Ł.); (E.H.); (D.W.)
| | - Hiroaki Taniguchi
- Institute of Genetics and Animal Biotechnology of the Polish Academy of Sciences, 05-552 Jastrzebiec, Poland; (A.S.T.); (K.Ł.); (E.H.); (D.W.)
- Correspondence:
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33
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Dourthe C, Julien C, Di Tommaso S, Dupuy JW, Dugot-Senant N, Brochard A, Le Bail B, Blanc JF, Chiche L, Balabaud C, Bioulac-Sage P, Saltel F, Raymond AA. Proteomic Profiling of Hepatocellular Adenomas Paves the Way to Diagnostic and Prognostic Approaches. Hepatology 2021; 74:1595-1610. [PMID: 33754354 DOI: 10.1002/hep.31826] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 02/26/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Through an exploratory proteomic approach based on typical hepatocellular adenomas (HCAs), we previously identified a diagnostic biomarker for a distinctive subtype of HCA with high risk of bleeding, already validated on a multicenter cohort. We hypothesized that the whole protein expression deregulation profile could deliver much more informative data for tumor characterization. Therefore, we pursued our analysis with the characterization of HCA proteomic profiles, evaluating their correspondence with the established genotype/phenotype classification and assessing whether they could provide added diagnosis and prognosis values. APPROACH AND RESULTS From a collection of 260 cases, we selected 52 typical cases of all different subgroups on which we built a reference HCA proteomics database. Combining laser microdissection and mass-spectrometry-based proteomic analysis, we compared the relative protein abundances between tumoral (T) and nontumoral (NT) liver tissues from each patient and we defined a specific proteomic profile of each of the HCA subgroups. Next, we built a matching algorithm comparing the proteomic profile extracted from a patient with our reference HCA database. Proteomic profiles allowed HCA classification and made diagnosis possible, even for complex cases with immunohistological or genomic analysis that did not lead to a formal conclusion. Despite a well-established pathomolecular classification, clinical practices have not substantially changed and the HCA management link to the assessment of the malignant transformation risk remains delicate for many surgeons. That is why we also identified and validated a proteomic profile that would directly evaluate malignant transformation risk regardless of HCA subtype. CONCLUSIONS This work proposes a proteomic-based machine learning tool, operational on fixed biopsies, that can improve diagnosis and prognosis and therefore patient management for HCAs.
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Affiliation(s)
- Cyril Dourthe
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | - Céline Julien
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
| | - Sylvaine Di Tommaso
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | | | | | | | - Brigitte Le Bail
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Department of Pathology, Bordeaux University Hospital, Bordeaux, France
| | - Jean-Frédéric Blanc
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Department of Hepatology and Oncology, Bordeaux University Hospital, Bordeaux, France
| | - Laurence Chiche
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Department of Digestive Surgery, Bordeaux University Hospital, Bordeaux, France
| | | | | | - Frédéric Saltel
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Oncoprot Platform, TBM-Core US 005, Bordeaux, France
| | - Anne-Aurélie Raymond
- Univ. Bordeaux, INSERM, BaRITOn, U1053, Bordeaux, France.,Oncoprot Platform, TBM-Core US 005, Bordeaux, France
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Kotiyal S, Evason KJ. Exploring the Interplay of Telomerase Reverse Transcriptase and β-Catenin in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164202. [PMID: 34439356 PMCID: PMC8393605 DOI: 10.3390/cancers13164202] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 08/12/2021] [Accepted: 08/15/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Liver cancer is one of the deadliest human cancers. Two of the most common molecular aberrations in liver cancer are: (1) activating mutations in the gene encoding β-catenin (CTNNB1); and (2) promoter mutations in telomerase reverse transcriptase (TERT). Here, we review recent findings regarding the interplay between TERT and β-catenin in order to better understand their role in liver cancer. Abstract Hepatocellular carcinoma (HCC) is one of the deadliest human cancers. Activating mutations in the telomerase reverse transcriptase (TERT) promoter (TERTp) and CTNNB1 gene encoding β-catenin are widespread in HCC (~50% and ~30%, respectively). TERTp mutations are predicted to increase TERT transcription and telomerase activity. This review focuses on exploring the role of TERT and β-catenin in HCC and the current findings regarding their interplay. TERT can have contradictory effects on tumorigenesis via both its canonical and non-canonical functions. As a critical regulator of proliferation and differentiation in progenitor and stem cells, activated β-catenin drives HCC; however, inhibiting endogenous β-catenin can also have pro-tumor effects. Clinical studies revealed a significant concordance between TERTp and CTNNB1 mutations in HCC. In stem cells, TERT acts as a co-factor in β-catenin transcriptional complexes driving the expression of WNT/β-catenin target genes, and β-catenin can bind to the TERTp to drive its transcription. A few studies have examined potential interactions between TERT and β-catenin in HCC in vivo, and their results suggest that the coexpression of these two genes promotes hepatocarcinogenesis. Further studies are required with vertebrate models to better understand how TERT and β-catenin influence hepatocarcinogenesis.
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Chopinet S, Cauchy F, Hobeika C, Beaufrère A, Poté N, Farges O, Dokmak S, Bouattour M, Ronot M, Vilgrain V, Paradis V, Soubrane O. Long-term outcomes following resection of hepatocellular adenomas with small foci of malignant transformation or malignant adenomas. JHEP Rep 2021; 3:100326. [PMID: 34368664 PMCID: PMC8326806 DOI: 10.1016/j.jhepr.2021.100326] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 05/12/2021] [Accepted: 06/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND & AIMS Malignant transformation of hepatocellular adenoma (MT-HCA) may occur in up to 5% of tumours. However, the prognostic value of this event remains poorly described. In this study, we aimed to analyse the long-term outcomes of patients undergoing liver resection (LR) for MT-HCA compared to those of patients resected for hepatocellular carcinoma (HCC) occurring on normal liver parenchyma (NP-HCC). METHODS This single-centre retrospective study included all patients who underwent LR for MT-HCA at Beaujon Hospital between 2001 and 2019. MT-HCAs were classified as small foci of malignant transformation HCA (SF-HCA) and as malignant HCA (M-HCA) in cases of predominant HCC foci. Recurrence-free survival (RFS) of MT-HCA was compared with that of NP-HCC after propensity score matching. RESULTS Forty patients (24 men, 16 women) underwent LR for MT-HCA, including 23 with SF-HCA and 17 with M-HCA. Of these cases, 16/40 (40%) had β-catenin mutations, 19/40 (47.5%) were inflammatory, 1 was HNF1α-mutated HCA and 4 (10%) were unclassified HCA. Microvascular invasion (12% vs. 0%, p = 0.091) and satellite nodules (25% vs. 4%, p = 0.028) were more frequently observed in M-HCA than in SF-HCA. After a median follow-up of 67 months, 10 (25%) patients with MT-HCA had tumour recurrence, including 9 with M-HCA and 1 with SF-HCA (p = 0.007). M-HCA was linked to significantly poorer 1-, 3-, 5- and 10-year RFS rates than SF-HCA (76%, 63%, 39%, 37% vs. 100%, 100%, 100%, 91%, p = 0.003). Multivariate analysis showed that SF-HCA was independently associated with improved RFS (hazard ratio 0.064; 95% CI 0.008-0.519; p = 0.01). After propensity score matching, NP-HCC was associated with significantly poorer 1-, 3-, 5- and 10-year RFS rates than MT-HCA (p = 0.01). CONCLUSIONS HCA with malignant transformation yields a better long-term prognosis than NP-HCC. Among MT-HCA, SF-HCA is associated with a better prognosis than M-HCA. LAY SUMMARY The prognostic relevance of malignant transformation of hepatocellular adenoma (HCA) remains unknown. Thus, the aim of our study was to compare the outcomes of patients undergoing liver resection for malignant transformation to those of patients undergoing liver resection for hepatocellular carcinoma (HCC). The main long-term risk after resection for carcinoma is recurrence. In this study, 10/40 patients with malignant transformation of HCA relapsed after resection and we identified age >55 years, presence of satellite nodes, and microvascular invasion as risk factors for long-term recurrence. Compared to patients with HCC, patients who underwent liver resection for HCA with malignant transformation had better long-term survival.
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Key Words
- H-HCA, HNF1α-mutated HCAs
- HCA, hepatocellular adenoma
- HCC, hepatocellular carcinoma
- Hepatocellular adenoma
- IHCA, inflammatory HCA
- LFABP, liver fatty acid binding protein
- LR, liver resection
- MT-HCA, malignant transformation HCA
- NP-HCC, HCC occurring on normal parenchyma
- RFS, recurrence-free survival
- SF-HCA, small foci of malignant transformation HCA
- U-HCA, unclassified HCA
- liver resection
- malignant transformation
- recurrence
- β-HCA, β-catenin-mutated HCA
- β-IHCA, β-catenin-mutated inflammatory HCA
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Affiliation(s)
- Sophie Chopinet
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - François Cauchy
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Christian Hobeika
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Aurélie Beaufrère
- Department of Pathology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Nicolas Poté
- Department of Pathology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Olivier Farges
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Safi Dokmak
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Mohamed Bouattour
- Department of Oncology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Maxime Ronot
- Department of Radiology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Valérie Vilgrain
- Department of Radiology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Valérie Paradis
- Department of Pathology, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
| | - Olivier Soubrane
- Department of HPB and Liver Transplantation, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris and Université de Paris, Clichy, France
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Haring MPD, Cuperus FJC, Duiker EW, de Haas RJ, de Meijer VE. Scoping review of clinical practice guidelines on the management of benign liver tumours. BMJ Open Gastroenterol 2021; 8:e000592. [PMID: 34362758 PMCID: PMC8351490 DOI: 10.1136/bmjgast-2020-000592] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Accepted: 07/18/2021] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Benign liver tumours (BLT) are increasingly diagnosed as incidentalomas. Clinical implications and management vary across and within the different types of BLT. High-quality clinical practice guidelines are needed, because of the many nuances in tumour types, diagnostic modalities, and conservative and invasive management strategies. Yet, available observational evidence is subject to interpretation which may lead to practice variation. Therefore, we aimed to systematically search for available clinical practice guidelines on BLT, to critically appraise them, and to compare management recommendations. DESIGN A scoping review was performed within MEDLINE, EMBASE, and Web of Science. All BLT guidelines published in peer-reviewed, and English language journals were eligible for inclusion. Clinical practice guidelines on BLT were analysed, compared, and critically appraised using the Appraisal of Guidelines, Research and Evaluation (AGREE II) checklist regarding hepatic haemangioma, focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA). Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations (PRISMA) for scoping reviews were adhered to. RESULTS The literature search yielded unique 367 papers, 348 were excluded after screening of title/abstract, and 16 after full-text screening. Three guidelines were included: the American College of Gastroenterology (ACG; 2014), Brazilian Society of Hepatology (SBH; 2015), and European Association for the Study of the Liver (EASL; 2016). There was no uniformity in the assessment methods for grading and gravity of recommendations between guidelines. Among observed differences were: (1) indications for biopsy in all three tumours; (2) advices on contraceptive pills and follow-up in FNH and HCA; (3) use of an individualised approach to HCA; (4) absence of recommendations for treatment of HCA in men; and (5) approaches to HCA subtype identification on magnetic resonance imaging. CONCLUSION Recognising differences in recommendations can assist in harmonisation of practice standards and identify unmet needs in research. This may ultimately contribute to improved global patient care.
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Affiliation(s)
- Martijn P D Haring
- Department of Surgery, University Medical Centre Groningen, Groningen, The Netherlands
| | - Frans J C Cuperus
- Department of Hepatology and Gastroenterology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Evelien W Duiker
- Department of Medical Biology and Pathology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Robbert J de Haas
- Department of Radiology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Department of Surgery, University Medical Centre Groningen, Groningen, The Netherlands
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Miles DA, Holmes S, Minuk GY. Hepatic adenomatosis in a young woman with non-familial maturity-onset diabetes of the young type 3. CANADIAN LIVER JOURNAL 2021; 4:328-331. [DOI: 10.3138/canlivj-2020-0010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/09/2020] [Indexed: 11/20/2022]
Abstract
Hepatic adenomatosis (HA) is a rare condition in which multiple adenomas exist in an otherwise healthy liver. The most common subtype (H-HA) is associated with bi-allelic, somatic hepatic nuclear factor 1-alpha (HNF1A) mutations. Maturity-onset diabetes of the young type 3 (MODY3) is most often seen in young individuals with heterozygous, germline mutations in HNF1A. In this report, we describe a 17-year-old woman with H-HA and non-familial MODY3.
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Affiliation(s)
- David A Miles
- Section of Hepatology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Signy Holmes
- Department of Radiology and Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Gerald Y Minuk
- Section of Hepatology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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Haring MPD, Spijkerboer CS, Cuperus FJC, Duiker EW, de Jong KP, de Haas RJ, de Meijer VE. Behavior and complications of hepatocellular adenoma during pregnancy and puerperium: a retrospective study and systematic review. HPB (Oxford) 2021; 23:1152-1163. [PMID: 33985906 DOI: 10.1016/j.hpb.2021.04.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/30/2021] [Accepted: 04/09/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Hepatocellular adenomas (HCA) are benign liver tumors at risk of hemorrhage. The influence of pregnancy on HCA growth and potential bleeding remains unclear. This study investigates HCA-associated behavior and bleeding complications during or shortly after pregnancy. METHODS (I) Single center retrospective cohort study of HCA during and after pregnancy (II) Systematic literature review. RESULTS The retrospective study included 11 patients, of which 4 with HCA ≥5 cm. In only two patients HCA showed growth during pregnancy. In this local cohort, no HCA-related hemorrhages occurred during median follow-up of 34 months (interquartile range 19-58 months). The systematic review yielded 33 studies, totaling 90 patients with 99 pregnancies. Of 73 pregnancies without prior HCA-related intervention, 39 HCA remained stable (53.4%), 11 regressed (15.1%), and 23 (31.5%) progressed. Fifteen HCA-related hemorrhages occurred in HCA measuring 6.5-17.0 cm. Eight patients experienced bleeding during pregnancy, two during labor and five postpartum. CONCLUSION Although hemorrhage of HCA during or shortly after pregnancy is rare and only reported in HCA ≥6.5 cm, it can be fatal. Pregnancy in women with HCA, regardless of size, warrant a close surveillance strategy. Observational studies on behavior and management of HCA ≥5 cm during and immediately after pregnancy are needed.
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Affiliation(s)
- Martijn P D Haring
- University of Groningen, University Medical Center Groningen, Department of Surgery, the Netherlands
| | - Christiaan S Spijkerboer
- University of Groningen, University Medical Center Groningen, Department of Hepatology and Gastroenterology, the Netherlands
| | - Frans J C Cuperus
- University of Groningen, University Medical Center Groningen, Department of Hepatology and Gastroenterology, the Netherlands
| | - Evelien W Duiker
- University of Groningen, University Medical Center Groningen, Department of Medical Biology and Pathology, the Netherlands
| | - Koert P de Jong
- University of Groningen, University Medical Center Groningen, Department of Surgery, the Netherlands
| | - Robbert J de Haas
- University of Groningen, University Medical Center Groningen, Department of Radiology, the Netherlands
| | - Vincent E de Meijer
- University of Groningen, University Medical Center Groningen, Department of Surgery, the Netherlands.
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Incidental Liver Findings on Cross-sectional Imaging. Radiol Clin North Am 2021; 59:569-590. [PMID: 34053606 DOI: 10.1016/j.rcl.2021.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Hepatic incidental findings often are seen on cross-sectional imaging examinations of the chest, spine, pelvis, or other nondedicated hepatic imaging. Radiologists are tasked with appropriately triaging, which requires further evaluation, even in the setting of an otherwise limited evaluation. This article reviews common benign entities encountered on ultrasound, computed tomography, or magnetic resonance imaging, along with their characteristic imaging features. Imaging features that are suspicious for malignancy or suggest the need for further evaluation also are discussed. Two algorithms are proposed to guide radiologists in their recommendations based on patient risk factors, focal hepatic abnormality size, and available imaging features.
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Herman P, Fonseca GM, Kruger JAP, Jeismann VB, Coelho FF. Guidelines for the Treatment of Hepatocellular Adenoma in the Era of Molecular Biology: An Experience-Based Surgeons' Perspective. J Gastrointest Surg 2021; 25:1494-1502. [PMID: 32666496 DOI: 10.1007/s11605-020-04724-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 06/28/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Hepatocellular adenoma (HA) is a rare benign liver tumor with increasing incidence affecting young women. In the last years, much has changed in diagnosis, classification, and treatment, due to the identification of different molecular subtypes. With the evolving knowledge, especially on molecular characteristics of the disease, we are far from a consensus of how to deal with such a multifaceted benign disease METHODS: In the last 20 years, we have treated 134 patients with HA with a mean age of 28 years, being 126 women. Fifty patients had a history of abdominal pain and 13 patients had an acute episode of pain due to rupture and bleeding. Until 2009, adenomas larger than 4 cm in diameter were resected, regardless of gender. From 2010 to 2016, only adenomas larger than 5 cm were referred for surgical treatment. Since 2016, resection was indicated in all female patients with non-steatotic adenomas larger than 5 cm and all adenomas in men. RESULTS AND DISCUSSION One hundred twenty-four patients were submitted to resection, being in 21 major resections. Since 2010, 74% of resections were done laparoscopically. Patients with ruptured adenomas were treated with transarterial embolization. Morbidity rate was 8.1% with no mortality. Authors discuss point-by-point all the aspects and presentations of the disease and the best approach. We proposed a therapeutic guideline based on the best available evidence and in our experience. CONCLUSIONS Due to the complexity of the disease, the treatment of HA is one the best examples of an individualized approach.
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Affiliation(s)
- Paulo Herman
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil.
| | - Gilton Marques Fonseca
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Jaime Arthur Pirola Kruger
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Vagner Birk Jeismann
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Fabricio Ferreira Coelho
- Digestive Surgery Division, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel) 2021; 13:2621. [PMID: 34073538 PMCID: PMC8198457 DOI: 10.3390/cancers13112621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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Predictive Patterns of Glutamine Synthetase Immunohistochemical Staining in CTNNB1-mutated Hepatocellular Adenomas. Am J Surg Pathol 2021; 45:477-487. [PMID: 33560657 DOI: 10.1097/pas.0000000000001675] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Some hepatocellular adenoma (HCA) subtypes are characterized by different CTNNB1 mutations, leading to different beta-catenin activation levels, hence variable immunostaining patterns of glutamine synthetase (GS) expression, and different risks of malignant transformation. In a retrospective multicentric study of 63 resected inflammatory (n=33) and noninflammatory (n=30) molecularly confirmed CTNNB1-mutated b-(I)HCA, we investigated the predictive potential of 3 known GS patterns as markers for CTNNB1 exon 3, 7/8 mutations. Pattern 1 (diffuse homogenous) allowed recognition of 17/21 exon 3 non-S45 mutated b-(I)HCA. Pattern 2 (diffuse heterogenous) identified all b-(I)HCA harboring exon 3 S45 mutation (20/20). Pattern 3 (focal patchy) distinguished 12/22 b-(I)HCA with exon 7/8 mutations. In exon 3 S45 and 7/8 mutations, both b-HCA and b-IHCA showed a GS+/CD34- rim with diffuse CD34 positivity in the center of the lesion. Interobserver reproducibility was excellent for exon 3 mutations. Comparative analysis of GS patterns with molecular data showed 83% and 80% sensitivity (b-HCA/b-IHCA) and 100% specificity for exon 3 non-S45. For exon 3 S45, sensitivity was 100% for b-(I)HCA, and specificity 93% and 92% (b-HCA/b-IHCA). For exon 7/8, sensitivity was 55% for both subtypes and specificity 100% and 96% (b-HCA/b-IHCA). Preliminary data from 16 preoperative needle biopsies from the same patients suggest that this panel may also be applicable to small samples. In surgically resected HCA, 2 distinct GS patterns can reliably predict CTNNB1 exon 3 mutations, which are relevant because of the higher risk for malignant transformation. The third pattern, although specific, was less sensitive for the identification of exon 7/8 mutation, but the GS+/CD34- rim is a valuable aid to indicate either an exon 3 S45 or exon 7/8 mutation.
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Kim H, Park YN. Hepatocellular adenomas: recent updates. J Pathol Transl Med 2021; 55:171-180. [PMID: 33823565 PMCID: PMC8141970 DOI: 10.4132/jptm.2021.02.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 02/28/2021] [Indexed: 12/30/2022] Open
Abstract
Hepatocellular adenoma (HCA) is a heterogeneous entity, from both the histomorphological and molecular aspects, and the resultant subclassification has brought a strong translational impact for both pathologists and clinicians. In this review, we provide an overview of the recent updates on HCA from the pathologists’ perspective and discuss several practical issues and pitfalls that may be useful for diagnostic practice.
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Affiliation(s)
- Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul, Korea
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Lim M, Kim JM, Kwon JE, Jeong ES, Yang J, Lee O, Kim KD, Kim SJ, Rhu J, Choi GS, Joh JW. Hepatocellular Carcinoma Arising from Hepatocellular Adenoma in an Elderly Male Patient. JOURNAL OF LIVER CANCER 2021; 21:87-91. [PMID: 37384277 PMCID: PMC10035722 DOI: 10.17998/jlc.21.1.87] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 03/02/2021] [Accepted: 03/02/2021] [Indexed: 06/30/2023]
Abstract
Hepatocellular adenoma is a benign tumor of the liver occurring predominantly in young women taking oral contraceptives. The malignant transformation of hepatocellular adenoma into hepatocellular carcinoma has rarely been reported. Herein, we report the case of an elderly male patient with hepatocellular carcinoma that developed from hepatocellular adenoma. The patient's high risk for surgery and conflicting biopsy and imaging results made it difficult to determine the treatment direction. Eventually, the mass was completely removed by laparoscopic left hemi-hepatectomy without complications.
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Affiliation(s)
- Manuel Lim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Eun Kwon
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Sung Jeong
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jaehun Yang
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Okjoo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyeong Deok Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sang Jin Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Alunni-Fabbroni M, Weber S, Öcal O, Seidensticker M, Mayerle J, Malfertheiner P, Ricke J. Circulating Cell-Free DNA Combined to Magnetic Resonance Imaging for Early Detection of HCC in Patients with Liver Cirrhosis. Cancers (Basel) 2021; 13:cancers13030521. [PMID: 33572923 PMCID: PMC7866376 DOI: 10.3390/cancers13030521] [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] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 01/13/2021] [Accepted: 01/21/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Liver cirrhosis can develop into malignant disease over time. Frequent monitoring would be advisable to detect the earliest signs of HCC progress resulting in a possible earlier treatment of the patient. Our study showed that the combination of genetic analysis of DNA freely circulating in the blood of the cirrhotic patients with MRI can represent a powerful strategy to timely identify suspect lesions, which can then be followed up more closely and thus potentially be treated earlier. In this way, personalized medicine can be applied to liver diseases such as cirrhosis. Abstract Liquid biopsy based on circulating cell-free DNA (cfDNA) is a promising non-invasive tool for the prognosis of hepatocellular cancer (HCC). In this exploratory study we investigated whether cfDNA and gene variants associated with HCC may be found in patients with liver cirrhosis (LC) and thus identify those at an increased risk for HCC. A cohort of 40 LC patients with no suspect neoplastic lesions was included in this study. Next generation sequencing (NGS) of cfDNA isolated from plasma was performed on a panel of 597 selected genes. Images of the patients who underwent MRI with hepatospecific contrast media during the study period were retrospectively re-evaluated (imaging was not part of the prospective study). cfDNA was detected in the plasma of 36 patients with LC. NGS-based analyses identified 20 variants in different combinations. Re-evaluation of the MRI images that were available for a proportion of the patients (n = 27) confirmed the absence of lesions in 8 cases carrying cfDNA without variants. In 6 of 19 patients with identified variants and MRI images available, MRI revealed a precursor lesion compatible with HCC and new lesions were discovered at follow-up in two patients. These precursor lesions were amenable for curative treatments. Mutation analysis revealed selective HCC related gene mutations in a subset of patients with LC, raising the suspect that these patients were at an increased risk for HCC development. MRI findings confirmed suspect nodular lesions of early stage HCC not detected with current standard screening procedures, which were only seen in patients carrying cfDNA variants. This opens a perspective for an HCC screening strategy combining both liquid biopsy and MRI in patients with LC.
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Affiliation(s)
- Marianna Alunni-Fabbroni
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (O.Ö.); (M.S.); (P.M.); (J.R.)
- Correspondence: ; Tel.: +49-89-4400-77605
| | - Sabine Weber
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany; (S.W.); (J.M.)
| | - Osman Öcal
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (O.Ö.); (M.S.); (P.M.); (J.R.)
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (O.Ö.); (M.S.); (P.M.); (J.R.)
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany; (S.W.); (J.M.)
| | - Peter Malfertheiner
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (O.Ö.); (M.S.); (P.M.); (J.R.)
- Department of Medicine II, University Hospital, LMU Munich, 81377 Munich, Germany; (S.W.); (J.M.)
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, 81377 Munich, Germany; (O.Ö.); (M.S.); (P.M.); (J.R.)
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Cao JY, Dong Y, Wang WP, Xia HS, Fan PL. Benign Liver Tumors. CONTRAST-ENHANCED ULTRASOUND IMAGING OF HEPATIC NEOPLASMS 2021:101-139. [DOI: 10.1007/978-981-16-1761-4_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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HERMAN P, FONSECA GM, KRUGER JAP, JEISMANN VB, COELHO FF. RESSECÇÃO LAPAROSCÓPICA DE TUMORES BENIGNOS DO FÍGADO: POSIÇÃO ATUAL. ABCD-ARQUIVOS BRASILEIROS DE CIRURGIA DIGESTIVA 2021; 34:e1641. [PMID: 35107503 PMCID: PMC8846456 DOI: 10.1590/0102-672020210002e1641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 11/25/2021] [Indexed: 11/22/2022]
Abstract
The main indications of the use of laparoscopic liver surgery (LLS), in the early
days, were benign liver lesions. As LLS became more popular, indications for
malignant diseases outnumbered those for benign ones. This study aims to rule
out the indications and results of LLS for the treatment of benign liver
tumors.
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Roles of Lysyl Oxidase Family Members in the Tumor Microenvironment and Progression of Liver Cancer. Int J Mol Sci 2020; 21:ijms21249751. [PMID: 33371259 PMCID: PMC7766343 DOI: 10.3390/ijms21249751] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/08/2020] [Accepted: 12/17/2020] [Indexed: 12/13/2022] Open
Abstract
The lysyl oxidase (LOX) family members are secreted copper-dependent amine oxidases, comprised of five paralogues: LOX and LOX-like l-4 (LOXL1-4), which are characterized by catalytic activity contributing to the remodeling of the cross-linking of the structural extracellular matrix (ECM). ECM remodeling plays a key role in the angiogenesis surrounding tumors, whereby a corrupt tumor microenvironment (TME) takes shape. Primary liver cancer includes hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), ranked as the seventh most common cancer globally, with limited therapeutic options for advanced stages. In recent years, a growing body of evidence has revealed the key roles of LOX family members in the pathogenesis of liver cancer and the shaping of TME, indicating their notable potential as therapeutic targets. We herein review the clinical value and novel biological roles of LOX family members in tumor progression and the TME of liver cancers. In addition, we highlight recent insights into their mechanisms and their potential involvement in the development of target therapy for liver cancer.
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Hepatocellular adenomas: review of pathological and molecular features. Hum Pathol 2020; 112:128-137. [PMID: 33307077 DOI: 10.1016/j.humpath.2020.11.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 11/16/2020] [Accepted: 11/30/2020] [Indexed: 12/18/2022]
Abstract
Hepatocellular adenoma (HCA) is a rare benign liver neoplasm which predominantly occurs in women in the reproductive age group taking oral contraception. Since 2002, the terminology HCA has defined an heterogeneous group of neoplastic benign hepatocellular proliferations composed of different subtypes. The genotype-phenotype classification led to the description of 5 well-recognized subtypes based on morphological and immunophenotypical features, that are currently used in practice: HNF1A inactivated HCA, inflammatory HCA, β-catenin mutated HCA, sonic hedgehog HCA, and unclassified HCA. The main complications observed in HCAs are bleeding and malignant transformation. Risk of malignant transformation into hepatocellular carcinoma (HCC), more frequent in men, is also dependent to tumor size and HCA subtype, reaching 40% in β-catenin mutated HCA. The distinction of HCA from well-differentiated HCC remains difficult in some cases, leading to the diagnosis of so-called "atypical/borderline HCA". The management of HCA is now based on multidisciplinary approach including clinicians, radiologists, and pathologists integrating gender, tumor size, and HCA subtyping.
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Abdel-Latif M, Fouda N, Shiha OAG, Rizk AA. Role of shear wave sono-elastography (SWE) in characterization of hepatic focal lesions. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2020. [DOI: 10.1186/s43055-020-00186-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Focal liver lesions are considered a major problem during abdominal examinations. Shear wave sono-elastography (SWE) has been demonstrated to be helpful in assessment of liver fibrosis degree.
The purpose of this study was to evaluate the role of SWE in characterization of benign and malignant hepatic focal lesions.
Results
Seventy-five (75) patients with variable focal liver lesions (52 malignant and 23 benign) were analyzed by SWE. The stiffness values of surrounding hepatic parenchyma were also measured as a reference for readings of the focal lesion stiffness values. Final diagnosis was achieved by core needle biopsy (in 1 benign and 38 malignant cases) and contrast enhanced CT and MRI (in all cases).
Cholangiocarcinoma (CCC) was the stiffest malignant lesion with median stiffness value (35.9 kPa). Focal nodular hyperplasia (FNH) was the stiffest benign lesion (26.7 kPa).
The median stiffness value of malignant focal lesions (20.22 kPa) was significantly higher than that of benign focal lesions (10.68 kPa) (P value < 0.001).
ROC curve of SWE median stiffness values for differentiation of benign from malignant hepatic focal lesions had AUC = 0.834, and using cut of value 14.165 kPa, yielding 98.1% sensitivity, 78.3% specificity, and 92% accuracy.
Conclusion
SWE has high accuracy in differentiating benign form malignant liver focal lesions with promising results in individual characterization of some malignant (HCC and CCC) and benign hepatic focal lesion (FNH from other benign lesions).
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