RESUMEN
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.
Asunto(s)
Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Transformación Celular Neoplásica , Secuenciación del Exoma , Neoplasias Hepáticas , Mutación , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Transformación Celular Neoplásica/genética , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Masculino , Femenino , Variaciones en el Número de Copia de ADN , Persona de Mediana Edad , Análisis Mutacional de ADNRESUMEN
Glycogen storage disease type 1A (GSD1A), also known as Von Gierke's disease, is a rare autosomal recessive disorder affecting glycogen metabolism in the liver. It most commonly presents in infancy with hypoglycaemia and failure to thrive, but cases have been reported as undiagnosed until adulthood. A woman in her early 20s with diabetes mellitus presented with right upper quadrant pain and was found to have several haemorrhagic hepatic adenomas. This patient had insulin-dependent diabetes since a pancreatectomy at age 9 months due to continued episodes of hypoglycaemia and suspected insulinoma. During the hospital stay, the hepatic adenomas were embolised, but significant lactic acidosis and hypoglycaemia continued. Further workup revealed a chronic lactic acid level, during several hospital stays, of above 5 mmol/L. After cytology of hepatic tissue ruled out hepatocellular carcinoma, the patient was discharged and recommended to follow-up for genetic testing, which confirmed the diagnosis of GSD1A.
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Hiperinsulinismo Congénito , Enfermedad del Almacenamiento de Glucógeno Tipo I , Neoplasias Hepáticas , Humanos , Femenino , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/diagnóstico , Hiperinsulinismo Congénito/genética , Hiperinsulinismo Congénito/diagnóstico , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/diagnóstico , Adulto , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/diagnóstico , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Adulto Joven , Adenoma/genética , Adenoma/diagnóstico , Adenoma/complicaciones , Adenoma/cirugía , Diagnóstico DiferencialRESUMEN
BACKGROUND: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay. CASE PRESENTATION: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient's father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of ß-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred. CONCLUSION: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.
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Enfermedad del Almacenamiento de Glucógeno Tipo I , Neoplasias Hepáticas , Trasplante de Hígado , Humanos , Enfermedad del Almacenamiento de Glucógeno Tipo I/genética , Enfermedad del Almacenamiento de Glucógeno Tipo I/complicaciones , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Femenino , Adolescente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/complicaciones , Adenoma/genética , Adenoma/complicaciones , Adenoma/patología , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/complicaciones , Adenoma de Células Hepáticas/patología , Inflamación/genética , Inflamación/patología , Inflamación/complicacionesRESUMEN
BACKGROUND: Hepatic adenomas (HAs) are benign, solid liver lesions, which carry a risk of hemorrhage and malignant transformation. This review article highlights the advances in the diagnosis and management of HAs. METHODS: A comprehensive review was performed using MEDLINE/PubMed and Web of Science databases with a search period ending on September 30, 2023. Using PubMed, the terms "hepatocellular," "hepatic," and "adenoma" were searched. RESULTS: HA has been classified into at least 8 subtypes based on molecular pathology, each exhibiting unique histopathologic features, clinical considerations, and risk of malignant transformation. The most common subtype is inflammatory HA, followed by hepatocyte nuclear factor 1α-inactivated HA, ß-catenin exon 3-mutated HA (ßex3-HA), ß-catenin exon 7- or 8-mutated HA, sonic hedgehog HA, and unclassified HA. Magnetic resonance imaging is the best imaging method for diagnosis and can distinguish among HA subtypes based on fat and telangiectasia pathologic characteristics. The risk of malignant transformation varies among molecular subtypes, ranging from <1% to approximately 50%. Up to 42% of HAs present with spontaneous intratumoral hemorrhage and peritoneal hemorrhage. In general, only 15% to 20% of patients require surgery. HA larger than 5 cm are more likely to be complicated by bleeding and malignant transformation, regardless of subtype, and should generally be resected. In particular, ßex3-HA carries a high risk of malignant transformation and can be considered a true precancerous lesion. CONCLUSION: The management of HAs is based on a multidisciplinary approach. Clinical decision-making should integrate information on gender, tumor size, and HA subtyping. In the future, patients with HA will benefit from novel medical therapies tailored to the individual molecular subtypes.
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Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Medicina de Precisión/métodos , Adenoma/genética , Adenoma/terapia , Adenoma/patología , Adenoma de Células Hepáticas/terapia , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/patología , Adenoma de Células Hepáticas/clasificación , Transformación Celular Neoplásica/patología , Imagen por Resonancia MagnéticaRESUMEN
Hepatocellular nodules can develop in the setting of chronic hepatic vascular disorders including those characterized by portosystemic shunts such as Abernethy malformation and post-Fontan procedure. The nodules can range from benign lesions such as regenerative nodules, focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA) to malignant neoplasms such as hepatocellular carcinoma (HCC). In many instances, these nodules are difficult to place into well-defined categories based on radiologic or histologic features. Nodular lesions that resemble FNH are common in this context and have been described as FNH-like nodules, the nature of which is not well-established. This study examines 6 liver resections from patients with vascular disease characterized by portosystemic shunts. A wide range of nodules were present in these cases, including regenerative nodules (n = 2), FNH and FNH-like (n = 30), HCA (n = 10), HCA-like (n = 13), and HCC (n = 2). Six nodules from 3 patients were categorized as FNH-like due to one or more features such as nodular architecture, fibrous septa, and ductular reaction, but lack of typical map-like glutamine synthetase (GS) staining. Further characterization of these 6 FNH-like nodules showed diffuse GS staining in all nodules (3 diffuse homogeneous, 3 diffuse heterogeneous). Targeted next-generation sequencing identified CTNNB1 alterations in all tested FNH-like nodules (n = 4). These results indicate that FNH-like nodules in the setting of chronic hepatic vascular disorders can be neoplastic. Since the presence of ß-catenin activation portends a potential risk for malignant progression, GS and ß-catenin immunohistochemistry should be obtained in all cases showing FNH-like morphology, with molecular analysis performed in cases with indeterminate staining pattern.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Hiperplasia Nodular Focal , Neoplasias Hepáticas , Enfermedades Vasculares , Humanos , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/diagnóstico , beta Catenina/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/cirugía , Carcinoma Hepatocelular/diagnóstico , Diagnóstico Diferencial , Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/patología , Hiperplasia Nodular Focal/cirugía , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/cirugía , Neoplasias Hepáticas/diagnósticoRESUMEN
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 , Niño , Adolescente , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , beta Catenina/genética , Proteínas Hedgehog , Fenotipo , GenotipoRESUMEN
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 , Femenino , Adulto , Masculino , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Estudios Retrospectivos , Hepatectomía , Transformación Celular NeoplásicaRESUMEN
The methylated SEPT9 DNA ( mSEPT9 ) in plasma is a US Food and Drug Administration (FDA)-approved screening biomarker in colorectal cancer and is emerging as a promising diagnostic and prognostic biomarker in hepatocellular carcinoma (HCC). We evaluated the SEPT9 protein expression by immunohistochemistry (IHC) in various hepatic tumors from 164 hepatectomies and explants. Cases diagnosed as HCC (n=68), hepatocellular adenoma (n=31), dysplastic nodule (n=24), and metastasis (n=41) were retrieved. SEPT9 stain was performed on representative tissue blocks showing tumor/liver interface. For HCC, archived IHC (SATB2, CK19, CDX2, CK20, and CDH17) slides were also reviewed. The findings were correlated with demographics, risk factors, tumor size, alpha fetoprotein levels at diagnosis, T stage and oncologic outcomes, with significance defined as P <0.05. Percentage of SEPT9 positivity differed significantly among hepatocellular adenoma (3%), dysplastic nodule (0%), HCC (32%), and metastasis (83%, P <0.001). Compared with patients with SEPT9- HCC, those with SEPT9+ HCC were older (70 vs. 63 y, P =0.01). The extent of SEPT9 staining correlated with age ( rs =0.31, P =0.01), tumor grade ( rs =0.30, P =0.01), and extent of SATB2 staining ( rs =0.28, P =0.02). No associations were found between SEPT9 staining and tumor size, T stage, risk factors, CK19, CDX2, CK20, or CDH17 expression, alpha fetoprotein levels at diagnosis, METAVIR fibrosis stage, and oncologic outcome in the HCC cohort. SEPT9 is likely implicated in liver carcinogenesis in a HCC subset. Similar to mSEPT9 DNA measurement in liquid biopsies, SEPT9 staining by IHC may prove helpful as an adjunct diagnostic biomarker with potential prognostic ramifications.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/sangre , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/metabolismo , alfa-Fetoproteínas , Biomarcadores de Tumor/metabolismo , Carcinoma Hepatocelular/sangre , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , ADN , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismoRESUMEN
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 , Femenino , Lactante , Humanos , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , beta Catenina/genética , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/genética , Inmunohistoquímica , Biomarcadores de Tumor/genética , Glutamato-Amoníaco Ligasa/metabolismo , Proteínas de Unión a Ácidos Grasos/metabolismoRESUMEN
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, ß-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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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Hiperplasia Nodular Focal , Neoplasias Hepáticas , Humanos , Adenoma de Células Hepáticas/diagnóstico , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/terapia , Proteínas Hedgehog/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Hiperplasia Nodular Focal/diagnóstico , Hiperplasia Nodular Focal/patología , Hiperplasia Nodular Focal/terapia , Carcinoma Hepatocelular/patología , Hígado/patologíaRESUMEN
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 de los Conductos Biliares , Carcinoma Hepatocelular , Colangiocarcinoma , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Neoplasias de los Conductos Biliares/diagnóstico por imagen , Neoplasias de los Conductos Biliares/patología , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/metabolismo , Colangiocarcinoma/diagnóstico por imagen , Colangiocarcinoma/patología , Proteínas Hedgehog/metabolismo , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , beta Catenina/genéticaRESUMEN
Hepatocellular adenoma (HCA) is a benign hepatocellular neoplasm, commonly occurs in young women with a history of oral contraceptive use. Complications including hemorrhage and malignant transformation necessitate the need for a thorough understanding of the underlying molecular signatures in this entity. Recent molecular studies have significantly expanded our knowledge of HCAs. The well-developed phenotype-genotype classification system improves clinical management through identifying "high risk" subtype of HCAs. In this article, we attempt to provide updated information on clinical, pathologic and molecular features of each subtype of HCAs.
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Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/terapia , Carcinoma Hepatocelular/complicaciones , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Transformación Celular Neoplásica , Femenino , Hemorragia , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapiaRESUMEN
Hepatic adenomas occur most commonly in women between the ages of 20 and 40 years, but rarely they occur in older aged persons, including those 60 years of age or older. This group of adenomas, however, has not been systemically examined. Twenty-six hepatic adenomas in persons 60 years of age or older were studied, along with a control group of 50 hepatic adenomas in persons aged 30 to 39. Hepatic adenomas in persons 60 or more years of age were found in 21 women and 5 men, while the control group had 44 women and 6 men. Subtyping the adenomas in persons 60 years or older showed the following results: 18 HNF1A-inactivated adenomas (69%), 4 inflammatory adenomas (15%), and 4 unclassified adenomas (15%). In contrast, the control group showed a significantly different pattern (P=0.003), with a greater percentage of inflammatory adenomas (28, 56%), fewer HNF1A-inactivated adenomas (8, 16%), and more unclassified adenomas (14, 28%). Atypia and malignant transformation within the hepatic adenomas was studied next. Of the hepatic adenomas in persons age 60 or greater, 3 (12%) showed atypical histologic features, and 6 (23%) had a malignant transformation. In contrast, for hepatic adenomas in the control group, only 4 (8%) adenomas showed atypical histologic features, and 3 (6%) had undergone malignant transformation. In addition, the hepatic adenomas that were atypical or showed early malignant transformation were less likely to have beta-catenin activation in patients over 60 (2/9 cases) compared with those between 30 and 39 years (5/7 cases). Myxoid change and heavy lipofuscin deposition were also more common in adenomas in older aged persons. In conclusion, hepatic adenomas in persons 60 years of age or older are enriched for HNF1A-inactivated adenomas and have a higher frequency of malignant transformation. Malignant transformation, however, is less likely to develop through activation of the beta-catenin pathway.
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Adenoma de Células Hepáticas , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Adulto , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Femenino , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Lipofuscina , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , beta Catenina/genéticaRESUMEN
Hypertriglyceridaemia in infancy is usually secondary to underlying metabolic disorder which usually has a genetic basis unlike the adult population. One such recently described entity is transient infantile hypertriglyceridaemia (HTGTI). In this disorder, mutation in glycerol-3-phosphate (G3P) dehydrogenase gene leads to deficiency of G3P dehydrogenase resulting in hypertriglyceridaemia and hepatomegaly. Clinical features tend to improve with age but may develop fibrosis. Our patient presented in infancy with hypoglycaemia, hepatomegaly, high transaminases and hypertriglyceridaemia. Limited genetic test for glycogen storage disorder was negative and was kept under follow-up. On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted. There are only a few cases reported worldwide and none has reported development of adenoma so far. This could be the first report of development of adenoma in transient HTGTI.
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Adenoma de Células Hepáticas , Hipertrigliceridemia , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Adulto , Homocigoto , Humanos , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/genética , Neoplasias Hepáticas/genética , Masculino , MutaciónAsunto(s)
Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Encondromatosis , Neoplasias Hepáticas , Adenoma de Células Hepáticas/genética , Carcinoma Hepatocelular/genética , Encondromatosis/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Humanos , Isocitrato Deshidrogenasa/genética , Neoplasias Hepáticas/genética , MutaciónRESUMEN
Myxoid hepatic adenomas are a rare subtype of hepatic adenomas with distinctive deposition of extracellular myxoid material between the hepatic plates. A total of 9 cases were identified in 6 women and 3 men with an average of 59±12 years. The myxoid adenomas were single tumors in 5 cases and multiple in 4 cases. In 1 case with multiple adenomas, the myxoid adenoma arose in the background of GNAS-mutated hepatic adenomatosis. Myxoid hepatic adenomas had a high frequency of malignant transformation (N=5 cases). They were characterized at the molecular level by HNF1A inactivating mutations, leading to loss of LFABP protein expression. In addition, myxoid adenomas had recurrent mutations in genes within the protein kinase A (PKA) pathway or in genes that regulate the PKA pathway: GNAS, CDKN1B (encodes p27), and RNF123. In sum, myxoid adenomas are rare, occur in older-aged persons, have a high risk of malignant transformation, and are characterized by the combined inactivation of HNF1A and additional mutations that appear to cluster in the PKA pathway.
Asunto(s)
Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Adulto , Anciano , Biomarcadores de Tumor/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
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.
Asunto(s)
Adenoma de Células Hepáticas/metabolismo , Neoplasias Hepáticas/metabolismo , Adenoma de Células Hepáticas/clasificación , Adenoma de Células Hepáticas/complicaciones , Adenoma de Células Hepáticas/genética , Adolescente , Adulto , Carcinogénesis , Bases de Datos Factuales , Femenino , Hemorragia/etiología , Humanos , Neoplasias Hepáticas/clasificación , Neoplasias Hepáticas/complicaciones , Neoplasias Hepáticas/genética , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Proteómica , Medición de Riesgo , Adulto JovenRESUMEN
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.
Asunto(s)
Adenoma de Células Hepáticas , Biomarcadores de Tumor , Glutamato-Amoníaco Ligasa/análisis , Inmunohistoquímica , Neoplasias Hepáticas , Mutación , beta Catenina/genética , Adenoma de Células Hepáticas/enzimología , Adenoma de Células Hepáticas/genética , Adenoma de Células Hepáticas/patología , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia con Aguja , Análisis Mutacional de ADN , Europa (Continente) , Exones , Femenino , Humanos , Neoplasias Hepáticas/enzimología , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Adulto JovenRESUMEN
Preoperative imaging and histopathology, immunohistochemistry and molecular analysis after resection of 2 hepatocellular adenomas (HCAs) (20 and 2cm) in a 53-year-old female patient were performed. On imaging, the large lesion resembled a myxoid HCA, while the small lesion resembled a more conventional HCA with a small myxoid/fluid area. On microscopy, the large lesion showed cords and nests of hepatocytes embedded in abundant myxoid matrix, while the small lesion resembled a conventional HCA with small foci of myxoid change and serosities; both consistent with a myxoid HCA. Immunophenotyping and molecular subtyping excluded inflammatory HCA, CTNNB1 mutated HCA and sonic hedgehog HCA, and was consistent with HNF1A mutated HCA. The myxoid change as well as the serosities may allow imaging diagnosis of myxoid HCA. As fluid vacuoles can also be present in ASS1+HCA, sonic hedgehog HCA has to be considered in the differential diagnosis.
Asunto(s)
Adenoma de Células Hepáticas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Adenoma de Células Hepáticas/diagnóstico por imagen , Adenoma de Células Hepáticas/genética , Femenino , Proteínas Hedgehog , Humanos , Inmunohistoquímica , Neoplasias Hepáticas/diagnóstico por imagen , Persona de Mediana EdadRESUMEN
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, ß-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 ß-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.