RESUMO
Focal liver lesions (FLLs) have become an increasingly common finding on abdominal imaging, especially asymptomatic and incidental liver lesions. Gastroenterologists and hepatologists often see these patients in consultation and make recommendations for management of multiple types of liver lesions, including hepatocellular adenoma, focal nodular hyperplasia, hemangioma, and hepatic cystic lesions including polycystic liver disease. Malignancy is important to consider in the differential diagnosis of FLLs, and healthcare providers must be familiar with the diagnosis and management of FLLs. This American College of Gastroenterology practice guideline uses the best evidence available to make diagnosis and management recommendations for the most common FLLs.
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Adenoma de Células Hepáticas , Cistos , Hiperplasia Nodular Focal do Fígado , Hemangioma , Hepatopatias , Neoplasias Hepáticas , Humanos , Hiperplasia Nodular Focal do Fígado/diagnóstico , Hiperplasia Nodular Focal do Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/diagnóstico por imagem , Hepatopatias/diagnóstico , Hepatopatias/terapia , Hepatopatias/diagnóstico por imagem , Hepatopatias/patologia , Hemangioma/diagnóstico , Hemangioma/terapia , Hemangioma/patologia , Hemangioma/diagnóstico por imagem , Cistos/diagnóstico , Cistos/diagnóstico por imagem , Cistos/patologia , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/terapia , Adenoma de Células Hepáticas/diagnóstico por imagem , Diagnóstico Diferencial , Gastroenterologia/normas , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/diagnóstico por imagemRESUMO
BACKGROUND AND AIMS: The natural history of hepatocellular adenomas (HCAs) remains to be better described, especially in nonresected patients. We aim to identify the predictive factors of HCA evolution after estrogen-based contraception discontinuation. APPROACH AND RESULTS: We retrospectively included patients with a histological diagnosis of HCA from three centers. Clinical, radiological, and pathological data were collected to identify predictive factors of radiological evolution per Response Evaluation Criteria in Solid Tumors, version 1.1, and occurrence of complications (bleeding, malignant transformation). We built a score using variables that modulate estrogen levels: body mass index and duration of estrogen-based contraception. An external cohort was used to validate this score. 183 patients were included in the cohort, including 161 women (89%) using estrogen-based contraception for a median of 12 years. Thirty percent of patients had at least one HNF1A -inactivated HCA, 45.5% at least one inflammatory HCA, and 11% at least one HCA with activation of ß-catenin (bHCA). Twenty-one symptomatic bleedings (11%) and eleven malignant transformations (6%) occurred. Ages < 37 years old ( p = 0.004) and HCA > 5 cm at imaging were independently associated with symptomatic bleeding ( p = 0.003), whereas a bHCA was associated with malignant transformation ( p < 0.001). After a median follow-up of 5 years, radiological regression was observed in 31%, stabilization in 47%, and progression in 22% of patients. Weight loss was associated with regression ( p < 0.0001) and weight gain with progression ( p = 0.02). The estrogen exposure score predicted radiological regression (odds ratio, 2.33; confidence interval 95%, 1.29-4.19; p = 0.005) with a linear relationship between the rate of estrogen exposure and the probability of regression. This result was confirmed in an external cohort of 72 female patients ( p = 0.003). CONCLUSION: Weight variation is strongly associated with radiological evolution after oral contraception discontinuation. A score of estrogen exposure, easily assessable in clinical practice at diagnosis, predicts regression of HCA.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Feminino , Adulto , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Estudos Retrospectivos , Anticoncepcionais Orais Hormonais/efeitos adversos , Anticoncepção/efeitos adversos , Estrogênios , Hemorragia , Peso CorporalRESUMO
BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign neoplasm, seldom ascribed as the cause of endocrine and metabolic derangement. We herein report a case of primary amenorrhea, growth arrest and metabolic syndrome. En bloc resection of the tumor normalized all the disturbances. CASE PRESENTATION: A 16-year-old girl complained of primary amenorrhea and growth arrest for the past 2 years. Her height and weight were at the 3rd percentile, whereas waist circumference was at the 90th percentile for chronological age. She was hypertensive on admission. Plasma cholesterol, triglyceride and uric acid were elevated. Evaluation of GH/IGF-1 axis showed extremely low IGF-1 concentration, which was unresponsive to hGH stimulation. Computer tomography identified a huge liver mass (18.2 cm×13.7 cm×21 cm). The patient underwent an uneventful open right hepatic lobectomy. The tumor was en bloc resected. Immunohistochemistry indicated an unclassified HCA, which was confirmed by genetic screening. IGF-1 concentration, blood pressure, lipid profile and ovarian function were all normalized after surgery, and the girl had reduction in waist circumference and gain in height during the follow up. CONCLUSION: We provide evidence that liver-derived IGF-1 has a direct effect on skeletal and pubertal development, blood pressure, visceral adiposity and dyslipidemia independent of insulin resistance and obesity in the circumstance of undernutrition. Though rare, we propose the need to look into HCA cases for the existence of IGF-1 deficiency and its impact on metabolic derangement.
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Adenoma de Células Hepáticas , Amenorreia , Fator de Crescimento Insulin-Like I , Neoplasias Hepáticas , Síndrome Metabólica , Humanos , Feminino , Síndrome Metabólica/complicações , Adolescente , Fator de Crescimento Insulin-Like I/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/complicações , Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/cirurgia , Adenoma de Células Hepáticas/complicações , Adenoma de Células Hepáticas/etiologia , Amenorreia/etiologia , Seguimentos , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/complicações , Transtornos do Crescimento/patologia , Prognóstico , Peptídeos Semelhantes à InsulinaRESUMO
Hepatocellular adenoma (HCA) represents a rare benign hepatic neoplasm with potential for malignant transformation into hepatocellular carcinoma (HCC), yet the underlying mechanism remains elusive. In this study, we investigated the genomic landscape of this process to identify therapeutic strategies for blocking malignant transformation. Using micro-detection techniques, we obtained specimens of adenoma, cancerous neoplasm and adjacent normal liver from three patients undergoing hepatic resection surgery. Whole-exome sequencing (WES) was performed, and genomic interactions between HCA and HCC components within the same tumour were evaluated using somatic variant calling, copy number variation (CNV) analysis, clonality evaluation and mutational signature analysis. Our results revealed genomic heterogeneity among patient cases, yet within each sample, HCA and HCC tissues exhibited a similar mutational landscape, suggesting a high degree of homology. Using nonnegative matrix factorization and phylogenetic trees, we identified shared and distinct mutational characteristics and uncovering necessary pathways associated with HCA-HCC malignant transformation. Remarkably, we found that HCA and HCC shared a common monoclonal origin while displaying significant genetic diversity within HCA-HCC tumours, indicating fundamental genetic connections or evolutionary pathways between the two. Moreover, elevated immune therapy-related markers in these patients suggested heightened sensitivity to immune therapy, providing novel avenues for the treatment of hepatic malignancies. This study sheds light on the genetic mechanisms underlying HCA-HCC progression, offering potential targets for therapeutic intervention and highlighting the promise of immune-based therapies in managing hepatic malignancies.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Transformação Celular Neoplásica , Sequenciamento do Exoma , Neoplasias Hepáticas , Mutação , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/genética , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Masculino , Feminino , Variações do Número de Cópias de DNA , Pessoa de Meia-Idade , Análise Mutacional de DNARESUMO
Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims to better define what mechanisms lie under the development of this condition. Six HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A, which has a dominant negative effect. All HAs were molecularly characterized. Four of them were shown to harbor a second somatic HNF1A variant and one had a mutation in the ARID1A gene, while no additional somatic changes were found in the remaining HA and normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including the tricarboxylic acid cycle, the metabolism of fatty acids, and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated, while the immune response was down-modulated. This work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA while identifying potential new therapeutic targets for non-surgical treatment.
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Fator 1-alfa Nuclear de Hepatócito , Neoplasias Hepáticas , Transcriptoma , Humanos , Fator 1-alfa Nuclear de Hepatócito/genética , Fator 1-alfa Nuclear de Hepatócito/metabolismo , Masculino , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Adolescente , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/metabolismo , Mutação , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Genômica/métodos , Proteínas de Ligação a DNARESUMO
Borderline hepatocellular adenomas (BL-HCA) are characterized by focal architectural/cytologic atypia and reticulin loss, features that are insufficient for a definitive diagnosis of hepatocellular carcinoma (HCC). The diagnosis and management of BL-HCA are challenging as their biological behavior, especially in terms of malignant potential, is still debated. We aimed to compare the clinicopathologic and molecular features of BL-HCA with those of typical HCA (T-HCA), HCA with malignant transformation (HCC on HCA), and HCC to assess the risk of malignancy. One hundred six liver resection specimens were retrospectively selected from 2 reference centers, including 39 BL-HCA, 42 T-HCA, 12 HCC on HCA, and 13 HCC specimens. Somatic mutations, including TERT promoter mutations associated with HCA malignant transformation and the gene expression levels of 96 genes, were investigated in 93 frozen samples. Additionally, TERT promoter mutations were investigated in 44 formalin-fixed, paraffin-embedded samples. The clinical features of patients with BL-HCA were similar to those of patients with T-HCA, patients being mainly women (69%) with a median age of 37 years. The median tumor size was 7.5 cm, 64% of patients had a single nodule, and no recurrence was observed. Compared with T-HCA, BL-HCA was significantly enriched in ß-catenin-mutated HCA in exon 3 (41% vs 6%; P < .001). Unsupervised statistical analysis based on gene expression showed that BL-HCA overlapped with T-HCA and HCC on HCA, favoring a molecular continuum of the tumors. TERT promoter mutations were observed only in HCC on HCA (42%) and in HCC (38%). In conclusion, these results suggest that despite their worrisome morphologic features, the clinicopathologic and molecular features of BL-HCA are much closer to those of T-HCA than those of HCC on HCA or HCC. This strongly supports the usefulness of combining morphologic and molecular analyses in a practical diagnostic approach for guiding the management of BL-HCA.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Feminino , Adulto , Masculino , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Hepatectomia , Transformação Celular NeoplásicaRESUMO
BACKGROUND: Hepatocellular adenoma (HCA) is a rare liver tumour, which can have atypical morphological features such as cytological atypia, pseudoglandular architecture, and altered reticulin framework. Little is known about the genetic and epigenetic alterations of such HCAs and whether they show the alterations classically found in hepatocellular carcinoma (HCC) or in HCA without atypical morphology. METHODS: We analysed five HCAs with atypical morphological features and one HCA with transition to HCC. Every tumour was subtyped by immunohistochemistry, sequenced by a targeted NGS panel, and analysed on a DNA methylation microarray. RESULTS: Subtyping of the five HCAs with atypical features revealed two ß-catenin mutated HCA (b-HCA), two ß-catenin mutated inflammatory HCA (b-IHCA), and one sonic hedgehog activated HCA (shHCA). None of them showed mutations typically found in HCC, such as, e.g. TERT or TP53 mutations. The epigenomic pattern of HCAs with atypical morphological features clustered with reference data for HCAs without atypical morphological features but not with HCC. Similarly, phyloepigenetic trees using the DNA methylation data reproducibly showed that HCAs with morphological atypia are much more similar to nonmalignant samples than to malignant samples. Finally, atypical HCAs showed no relevant copy number variations (CNV). CONCLUSION: In our series, mutational, DNA methylation, as well as CNV analyses, supported a relationship of atypical HCAs with nonatypical HCAs rather than with HCC. Therefore, in cases with difficult differential diagnosis between HCC and HCA, it might be advisable to perform targeted sequencing and/or combined methylation/copy number profiling.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , beta Catenina/genética , Variações do Número de Cópias de DNA , Proteínas Hedgehog , Epigênese GenéticaRESUMO
Hepatocellular adenomas (HCAs) are a family of liver tumors that are associated with variable prognoses. Since the initial description of these tumors, the classification of HCAs has expanded and now includes eight distinct genotypic subtypes based on molecular analysis findings. These genotypic subtypes have unique derangements in their cellular biologic makeup that determine their clinical course and may allow noninvasive identification of certain subtypes. Multiphasic MRI performed with hepatobiliary contrast agents remains the best method to noninvasively detect, characterize, and monitor HCAs. HCAs are generally hypointense during the hepatobiliary phase; the ß-catenin-mutated exon 3 subtype and up to a third of inflammatory HCAs are the exception to this characterization. It is important to understand the appearances of HCAs beyond their depictions at MRI, as these tumors are typically identified with other imaging modalities first. The two most feared related complications are bleeding and malignant transformation to hepatocellular carcinoma, although the risk of these complications depends on tumor size, subtype, and clinical factors. Elective surgical resection is recommended for HCAs that are persistently larger than 5 cm, adenomas of any size in men, and all ß-catenin-mutated exon 3 HCAs. Thermal ablation and transarterial embolization are potential alternatives to surgical resection. In the acute setting of a ruptured HCA, patients typically undergo transarterial embolization with or without delayed surgical resection. This update on HCAs includes a review of radiologic-pathologic correlations by subtype and imaging modality, related complications, and management recommendations. © RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.
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Adenoma de Células Hepáticas , Adenoma , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/patologia , beta Catenina , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
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), ß-catenin-activated HCA (b-HCA), and ß-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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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Masculino , Humanos , Criança , Adolescente , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , beta Catenina/genética , Proteínas Hedgehog , Fenótipo , GenótipoRESUMO
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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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/diagnóstico por imagem , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , AlgoritmosRESUMO
In the last two decades there has been significant progress in research on 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 discuss novel methods to identify HCA subtypes, in particular the sonic hedgehog HCAs and the interpretation of glutamine synthetase patterns for the recognition of ß-catenin-mutated HCAs. The major complications of HCAs, i.e. bleeding and malignant transformation, are considered, including the dilemmas of atypical and borderline lesions. HCAs in different clinical and geographical settings, e.g. pregnancy, cirrhosis and non-western countries, are also discussed. The natural history of the different HCA subtypes in relation to age, sex and risk factors is a feature that is 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 tumour, a multicentre and multidisciplinary approach across geographical boundaries will be the appropriate method to establish prospective programmes with which to identify, classify and manage HCAs, focusing on several aspects, e.g. aetiology, underlying liver disease, complications, regression, and growth. Updating what we know and identifying and addressing what we do not know matters for optimal patient management.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica , Proteínas Hedgehog , Hemorragia , Humanos , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Estudos ProspectivosRESUMO
Hepatocellular adenomas (HCAs), hepatocellular carcinomas (HCCs), and intrahepatic cholangiocarcinomas (iCCAs) are a highly heterogeneous group of liver tumors with diverse pathomolecular features and prognoses. High-throughput gene sequencing techniques have allowed discovery of distinct genetic and molecular underpinnings of these tumors and identified distinct subtypes that demonstrate varied clinicobiologic behaviors, imaging findings, and complications. The combination of histopathologic findings and molecular profiling form the basis for the morphomolecular classification of liver tumors. Distinct HCA subtypes with characteristic imaging findings and complications include HNF1A-inactivated, inflammatory, ß-catenin-activated, ß-catenin-activated inflammatory, and sonic hedgehog HCAs. HCCs can be grouped into proliferative and nonproliferative subtypes. Proliferative HCCs include macrotrabecular-massive, TP53-mutated, scirrhous, clear cell, fibrolamellar, and sarcomatoid HCCs and combined HCC-cholangiocarcinoma. Steatohepatitic and ß-catenin-mutated HCCs constitute the nonproliferative subtypes. iCCAs are classified as small-duct and large-duct types on the basis of the level of bile duct involvement, with significant differences in pathogenesis, molecular signatures, imaging findings, and biologic behaviors. Cross-sectional imaging modalities, including multiphase CT and multiparametric MRI, play an essential role in diagnosis, staging, treatment response assessment, and surveillance. Select imaging phenotypes can be correlated with genetic abnormalities, and identification of surrogate imaging markers may help avoid genetic testing. Improved understanding of morphomolecular features of liver tumors has opened new areas of research in the targeted therapeutics and management guidelines. The purpose of this article is to review imaging findings of select morphomolecular subtypes of HCAs, HCCs, and iCCAs and discuss therapeutic and prognostic implications. Online supplemental material is available for this article. ©RSNA, 2022.
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Adenoma de Células Hepáticas , Neoplasias dos Ductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , Neoplasias dos Ductos Biliares/diagnóstico por imagem , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/metabolismo , Ductos Biliares Intra-Hepáticos/patologia , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/diagnóstico por imagem , Colangiocarcinoma/patologia , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , beta Catenina/genéticaRESUMO
Hepatocellular adenomas (HCA) in infants are exceedingly rare with only 5 cases reported to the best of our knowledge, all of them preceding the classification of HCA. Here we present an autopsy case of a 9-month-old girl with Burn-McKeown syndrome with an incidental liver nodule in the right lobe measuring 1.5 cm in greatest dimension. The lesion was composed of an unencapsulated proliferation of hepatocytes with multiple unaccompanied arteries without well-formed portal tracts, and an intact reticulin framework without thickened hepatic plates, findings consistent with an HCA. Glutamine synthetase (GS), lipid fatty acid-binding protein (LFABP), c-reactive protein (CRP), serum amyloid-a (SAA), beta-catenin and CD34 immunostains were performed. GS was diffusely and strongly positive in the lesion, CD34 showed heterogenous staining of sinusoids within the lesion without a well-formed rim from the background liver and beta-catenin was negative for nuclear staining. CRP and SAA were considered negative, and LFABP was retained. Molecular testing showed no CTNNB1 variants and found two tier 3 variants involving CHEK2 and PTEN genes. These findings are consistent with an unclassified HCA (U-HCA) per the 2019 WHO Classification of Tumors, representing the youngest patient reported. This raises the possibility that some HCAs are congenital or develop very early in life, remaining undiagnosed until later in life.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Feminino , Lactente , Humanos , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patologia , beta Catenina/genética , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/genética , Imuno-Histoquímica , Biomarcadores Tumorais/genética , Glutamato-Amônia Ligase/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismoRESUMO
AIMS: Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. METHODS AND RESULTS: The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, ß-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) ß-catenin-activated HCAs, three (6%) ß-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumour diameter of 60 mm. In the ß-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the ß-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. CONCLUSION: In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that ß-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.
Assuntos
Adenoma de Células Hepáticas/classificação , Adenoma de Células Hepáticas/patologia , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/análise , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Turquia , Organização Mundial da Saúde , Adulto JovemRESUMO
AIMS: The diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. We aimed to evaluate the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH. METHODS AND RESULTS: The study included virtual needle biopsies generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non-lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). The presence of two or more of the classic histological features had 89.6% sensitivity and 86.2% specificity for a diagnosis of FNH. Diagnostic accuracy was significantly higher with the addition of a GS stain. A map-like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non-map-like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42). CONCLUSIONS: Pathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo-map-like GS staining pattern were associated with increased difficulty. Therefore, although a map-like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map-like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH.
Assuntos
Hiperplasia Nodular Focal do Fígado , Glutamato-Amônia Ligase/análise , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/patologia , Biomarcadores Tumorais/análise , Biópsia por Agulha , Confiabilidade dos Dados , Diagnóstico Diferencial , Feminino , Hiperplasia Nodular Focal do Fígado/diagnóstico , Hiperplasia Nodular Focal do Fígado/patologia , Humanos , Imuno-Histoquímica , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , MasculinoRESUMO
OBJECTIVES: Hepatocellular adenoma (HCA) is a benign well-differentiated hepatocellular neoplasm that can be difficult to distinguish from well-differentiated hepatocellular carcinoma (HCC). The term "well-differentiated hepatocellular neoplasm of uncertain malignant potential" (HUMP) has been proposed for neoplasms resembling HCAs, but arising in atypical clinical situations (in females over 50 years old or under 15, in males, with anabolic steroid use, or in some congenital conditions), and/or with atypical pathological features (focal cytological/architectural atypia, ß-catenin activation, or focal reticulin loss) insufficient for an unequivocal diagnosis of HCC. METHODS: This study evaluated HUMP criteria on 42 previously diagnosed HCAs from 33 patients. RESULTS: Twenty-six (62%) masses from 21 patients were classified as HUMPs. Eleven (42%) had focal cytological atypia, and two (8%) had focal architectural atypia. Four (15%) showed focal reticulin loss. Five (19%) showed evidence of ß-catenin activation. Four (12%) HUMP patients were male. CONCLUSIONS: In this series, HUMP did not correlate with an increased rate of synchronous or metachronous HCC compared to HCA. Clinical colleagues may not accept such a high rate of tumors placed in a category of "uncertain malignant potential". Additional study is warranted to refine criteria for designating well-differentiated hepatocellular neoplasms as of uncertain malignant potential.
Assuntos
Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/patologia , Adolescente , Adulto , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/patologia , Diagnóstico Diferencial , Feminino , Humanos , Fígado/patologia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem , beta Catenina/análise , beta Catenina/metabolismoRESUMO
BACKGROUND: Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype. METHODS: 657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing. RESULTS: We identified 296 IHCA (45%), 81% of them were mutated in either IL6ST (61%), FRK (8%), STAT3 (5%), GNAS (3%) or JAK1 (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving ROS1, FRK or IL6 genes. ROS1 fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver (PLG, RBP4, APOB) fused with exon 33-35 to 43 of ROS1 including the tyrosine kinase domain. In two cases a truncated ROS1 transcript from exon 36 to 43 was identified. ROS1 rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to ROS1 overexpression. Among the 5 IHCA with FRK rearrangements, 5 different partners were identified (MIA3, MIA2, LMO7, PLEKHA5, SEC16B) fused to a common region in FRK that included exon 3-8. No overexpression of FRK transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2-SH3 domains. In two IHCA, we identified truncated 3'UTR of IL6 associated with overexpression of the transcript. CONCLUSION: Recurrent chromosomal alterations involving ROS1, FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.
Assuntos
Adenoma de Células Hepáticas , Receptor gp130 de Citocina/genética , Neoplasias Hepáticas , Proteínas de Neoplasias/genética , Proteínas Tirosina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/imunologia , Adenoma de Células Hepáticas/patologia , Adulto , Feminino , Perfilação da Expressão Gênica/estatística & dados numéricos , Rearranjo Gênico/imunologia , Humanos , Inflamação/genética , Janus Quinases/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Mutação , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
BACKGROUND & AIMS: The presence of hepatocellular adenoma (HCA) in pregnant women requires special consideration, as it has been reported to carry the risk of growth and clinically significant haemorrhage. In this prospective study we assessed aspects of growth of HCA <5â¯cm during pregnancy. METHODS: This was a multicentre prospective cohort study in pregnant women with suspected HCA <5â¯cm on imaging. Definitive HCA diagnosis was established by MRI with hepatobiliary contrast agents (LCE-MRI), preferably before pregnancy. If at study inclusion a definitive diagnosis was lacking, LCE-MRI was performed after giving birth. Growth of the adenoma (defined as an increase of >20%) was closely monitored with ultrasound examinations throughout pregnancy. RESULTS: Of the 66 women included, 18 were excluded from analysis because postpartum LCE-MRI did not confirm the diagnosis of HCA and showed the lesion to be focal nodular hyperplasia. The remaining 48 women, with an HCA confirmed by LCE-MRI, were followed during 51 pregnancies. Median age was 30â¯years (IQR 27-33) and median body mass index 31.9â¯kg/m2 (IQR 26.3-36.6). Growth of HCA was seen in 13 of the pregnancies (25.5%); the median increase was 14â¯mm (IQR 8-19). One woman whose HCA grew to >70â¯mm successfully underwent transarterial embolization at week 26 of pregnancy to prevent further growth. The other 50 pregnancies proceeded without complications. CONCLUSION: This study suggests that an HCA <5â¯cm confers minimal risk to a pregnant woman and none to her child. HCA increased in size during a quarter of pregnancies, so we recommend close monitoring with ultrasound examinations, enabling intervention if needed. In light of the large proportion of misdiagnosed HCA, LCE-MRI should be performed to prevent unnecessary anxiety in women with a benign liver lesion. LAY SUMMARY: The presence of hepatocellular adenoma in pregnant women requires special consideration, as it carries the risk of growth and haemorrhage. In this study we followed 48 patients with hepatocellular adenoma <5â¯cm during 51 pregnancies and found that a hepatocellular adenoma during pregnancy confers minimal risk to the pregnant woman and none to her child.
Assuntos
Adenoma de Células Hepáticas/diagnóstico por imagem , Carcinogênese , Hiperplasia Nodular Focal do Fígado/diagnóstico por imagem , Neoplasias Hepáticas/diagnóstico por imagem , Adenoma de Células Hepáticas/epidemiologia , Adenoma de Células Hepáticas/patologia , Adulto , Biópsia , Meios de Contraste , Diagnóstico Diferencial , Feminino , Hiperplasia Nodular Focal do Fígado/epidemiologia , Seguimentos , Humanos , Fígado/patologia , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/patologia , Imageamento por Ressonância Magnética/métodos , Países Baixos/epidemiologia , Gravidez , Estudos Prospectivos , Ultrassonografia/métodosRESUMO
BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell-cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onward. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and nontransgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. RESULTS: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of nonperpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. CONCLUSIONS: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress; all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.
Assuntos
Adenoma de Células Hepáticas/genética , Carcinoma Hepatocelular/genética , Instabilidade Cromossômica/genética , Ciclina E/genética , Neoplasias Hepáticas/genética , Fígado/metabolismo , Proteínas Oncogênicas/genética , Adenoma de Células Hepáticas/patologia , Adenoma de Células Hepáticas/virologia , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/virologia , Estruturas Cromossômicas , Dano ao DNA/genética , Replicação do DNA , Dependovirus , Fibroblastos , Hepatite B Crônica , Hepatócitos , Fígado/patologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/virologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Camundongos , Estresse Oxidativo/genética , Infecções por Parvoviridae , Parvovirinae , Poliploidia , Pontos de Checagem da Fase S do Ciclo CelularRESUMO
Background Hepatocellular adenomas (HCAs) are rare benign liver tumors. Guidelines recommend continued surveillance of patients diagnosed with HCAs, but these guidelines are mainly based on small studies or expert opinion. Purpose To analyze the long-term evolution of HCAs, including solitary and multiple lesions, and to identify predictive features of progression with MRI. Materials and Methods In a retrospective study, patients diagnosed with pathologically proven solitary or multiple HCAs between January 2004 and December 2015 were included; ß-catenin-mutated HCAs and HCAs with foci of malignancy were considered to be at risk for progression. MRI examinations were analyzed, and tumor evolution was evaluated by using Response Evaluation Criteria in Solid Tumors, version 1.1. Student t, Mann-Whitney, χ2, Fisher exact, and McNemar tests were used, as appropriate. Results In total, 118 patients (mean age, 40 years ± 10 [standard deviation]; 108 women) were evaluated, including 41 with a solitary HCA (mean age, 40 years ± 14; 36 women) and 77 with multiple HCAs (mean age, 40 years ± 10; 72 women). At a median follow-up of 5 years, 37 of 41 (90%) patients with a solitary HCA and 55 of 77 (71%) patients with multiple HCAs showed stable or regressive disease. After resection of solitary HCAs, new lesions appeared in only two of 29 (7%) patients, both of whom had HCAs at risk of progression. In patients with multiple HCAs, hepatocyte nuclear factor 1α-inactivated HCAs showed a higher rate of progression compared with inflammatory HCAs (11 of 26 [42%] vs seven of 37 [19%], P = .04) despite lower use (28 of 32 patients [88%] vs 45 of 45 patients [100%]; P = .03) and shorter duration (mean, 12.0 years ± 7.5 vs 19.2 years ± 9.2; P = .001) of oral contraceptive intake. Conclusion Long-term MRI follow-up showed that 78% of hepatocellular adenomas had long-term stability or regression. After resection of solitary hepatocellular adenomas, new lesions occurred only in hepatocellular adenomas at risk of progression. Patients with multiple hepatocellular adenomas were more likely to show progressive disease, with hepatic nuclear factor 1α-inactivated hepatocellular adenomas being the most common subtype showing progression. © RSNA, 2020 Online supplemental material is available for this article.