Screening and surveillance of hepatocellular carcinoma by serum des-gamma-carboxy prothrombin in patients with glycogen storage disease type Ia.

No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha-fetoprotein and carcino-embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des-gamma-carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.

Surgical Management of a Giant Inflammatory Hepatocellular Adenoma in a Young Female.

Hepatocellular adenomas are rare and benign primary neoplasms of phenotypically mature hepatocytes. Our understanding of this pathology has greatly improved due to advances in molecular and anatomic knowledge. This article provides an in-depth review of hepatic adenomas (HCA) while presenting the case of a 20-year-old patient with a giant inflammatory hepatocellular adenoma with an atypical presentation, in whom surgical intervention was performed via right hepatectomy. In the post-surgical course, the patient had an in-hospital stay of three days with no complications. During outpatient monitoring via laboratory tests and imaging at eight months, the patient did not present any trace of recurrence.

Whole-exome sequencing-based mutational profiling of hepatocellular adenoma malignant transformation to hepatocellular carcinoma.

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.

Liver Transplantation as a Treatment for Unresectable Hepatic Adenoma in a Patient With Abernethy Syndrome.

Abernethy syndrome is a rare congenital anomaly characterized by an intrahepatic or extrahepatic portosystemic shunt. Most patients are asymptomatic; however, due to the alteration in, or lack of, a portovenous flow, patients with Abernethy syndrome are at high risk of developing sequelae of liver failure. Once these complications develop, the only definitive treatment is transplantation. Patients with Abernethy syndrome are also at a higher risk of developing benign and malignant liver lesions, including hepatic adenomas. Here, we describe the first case of deceased donor liver transplantation as a treatment for a patient with type 1 Abernethy syndrome complicated by large, unresectable hepatic adenoma, found to have focal hepatocellular carcinoma on pathologic examination. Our male patient was found to have elevated liver enzymes at age 33, during a routine outpatient medical appointment. Despite being asymptomatic, his history of prior liver resection prompted CT imaging, which revealed two large liver lesions concerning for hepatic adenomas. When surveillance imaging showed a significant growth of the liver lesions, biopsy was pursued, which confirmed a diagnosis of hepatic adenomas. However, given the size of these lesions, resection was not a viable option for the patient. Instead, the patient underwent liver transplantation at age 41, which he tolerated well. Our case demonstrates the utility of deceased donor liver transplantation as a treatment for patients with Abernethy syndrome complicated by unresectable adenomas.

Indocyanine green (ICG)-guided robotic resection for liver adenoma: combined technologies for precision surgery.

HCA resection is crucial to prevent bleeding and malignant transformation. The aim of this study was to enhance the precision of tumor resection in hepatocellular adenoma (HCA) through the combination of intraoperative ultrasound (IOUS) and indocyanine green (ICG) fluorescence imaging. ICG was intravenously injected 24 h before surgery, enabling positive staining of HCA nodules. IOUS guided the parenchymal transection performed using the RoboLap approach. IOUS combined with ICG effectively demarcated lesions, allowing precision surgery while sparing healthy liver tissue. Intraoperative frozen examination further validated the potential of ICG to identify previously undetected lesions. The study showed promising advantages of ICG in HCA resections, potentially reducing the risk of recurrence and malignant transformation. The combined robotic and laparoscopic approach improved the feasibility of parenchymal-sparing surgery, offering a cautious assessment of HCA lesions.

Benign to Malignant Hepatic Lesion Transformation in Abernethy Malformation.

Abernethy malformation or congenital extrahepatic portosystemic shunt is an extremely rare condition whereby the portomesenteric blood drains into a systemic vein and bypasses the liver through a complete or partial shunt. Severe complications include hyperammonemia and encephalopathy, benign and malignant liver tumors, and hepatopulmonary syndrome. We describe a case where a female adult diagnosed with congenital extrahepatic portosystemic shunt subsequently developed focal nodular hyperplasia and then hepatocellular carcinoma.

Laparoscopic hepatectomy for hepatocellular adenoma using the hepatic vein as anatomic markers,How I do it.(with video).

TECHNIQUE: Hepatocellular adenoma (HCA) is a benign monoclonal tumour that originates from mature hepatocytes.Liver resection is recommended in case of overt malignant transformation to hepatocellular carcinoma.However, hepatobiliary surgeries are technically challenging in patients with giant HCA (GHCA) owing to the risk of catastrophic intraoperative bleeding and difficulty with its control during laparoscopic treatment. We present a technical note on the utilization of the hepatic vein as anatomical landmarks for laparoscopic removal of giant hepatic glands, without intraoperative ultrasonography and with the aid of an augmented reality navigation system during surgery. RESULTS: This video shows aA 37-year-old man was recommended treatment for a progressively increasing HCA (from 3 to 10 cm in a year) involving the right hepatic vein (RHV), inferior vena cava (IVC) and middle hepatic vein (MHV), resulting in the invisibility of the above intrahepatic anatomic markers in CT. Laparoscopic hepatectomy was performed using the hepatic vein as anatomic markers in a treatment centre specialising in minimally invasive surgeries. The procedure involved fully mobilising the right liver, transecting the parenchyma along the demarcation line in the caudal-to-cranial direction, exposing the involved caudal MHV, isolating and transecting the involved RHV and preserving the integrity of the involved IVC. CONCLUSIONS: Laparoscopic hepatectomy for intractable GHCA using the involved intrahepatic anatomic markers is feasible and effective. It reduces pre-operative haemorrhage and open conversion rates while maximising postoperative hepatic function.

Hepatic adenoma: evolution of a more individualized treatment approach.

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.

Dynamic Contrast Enhanced-MRI and Apparent Diffusion Coefficient Quantitation for Differentiate Hepatocellular Carcinoma from Hepatocellular Adenoma.

BACKGROUND: Due to their overlapping radiological characteristics, hepatic lesions, such as hepatocellular carcinoma (HCC) and hepatocellular adenoma (HCA), present a substantial diagnostic challenge. Accurate differentiation between HCC and HCA is essential for the best clinical treatment and therapeutic decision-making. This study aims to assess the potential role of DCE-MRI and Apparent Diffusion Coefficient (ADC) quantitation in the diagnosis of hepatocellular carcinoma (HCC) from hepatocellular adenoma (HCA). METHODS: 103 patients (56 HCC, 47 HCA) with histopathologically proven hepatocellular lesions were the subjects of a cross-sectional investigation. A standardized imaging technique was used for DCE-MRI on all patients. Diffusion-weighted imaging (DWI) provided the ADC values. The diagnostic efficacy of DCE-MRI and ADC in differentiation was evaluated using statistical analyses, such as t-tests and receiver operating characteristic (ROC) curve analysis. SPSS VER 16 was used for the analysis of the collected data. RESULTS: A total of 103 patients (female: male= 52:51, 57.14±3.09 years) were included in the study. The study revealed significant differences in DCE-MRI parameters and ADC values between HCC and HCA lesions. ADC value was significantly lower in HCC than in HCA (p < 0.001). The area under the curve (AUC) was 0.78 (95% CI: 0.69-0.87) for ADC, 0.84 (95% CI: 0.76-0.91) for Ktrans, and 0.72 (95% CI: 0.62-0.82) for Ve. Sensitivity and specificity for ADC were 76.59% and 71.42%, respectively. Also, PPV and NPV of ADC were 69.23% and 78.43%, respectively. Sensitivity and specificity for Ktrans were 82.14% and 76.59%, respectively. Also, PPV and NPV of Ktrans were 80.7% and 78.26%, respectively. CONCLUSION: In conclusion, DCE-MRI-derived parameters, along with ADC values, exhibit promise as non-invasive tools for differentiating HCC from HCA.

The contribution of ultrasound in the diagnostic pathway of a symptomatic hepatocellular adenoma arising from ectopic liver.

Ectopic liver (EL) is a rare congenital anomaly characterized by the presence of a mass composed of hepatic tissue localized in a different anatomical location with no connection to the native liver. Usually an incidental finding, EL can rarely cause symptoms such as abdominal pain due to torsion, intraperitoneal bleeding, compression, obstruction, or neoplastic transformation, both benign and malignant. EL is often suspected after instrumental investigations such as ultrasound, CT and MRI, however a definitive diagnosis is necessarily bioptic. Here we report a case of a 22-year-old Italian female patient with acute abdominal pain, who underwent abdominal ultrasound, CEUS with Sonovue®, CT scan and ultrasound-guided biopsy which raised the suspicion of hepatocellular adenoma (H-HCA). After a laparoscopic excision of the lesion a diagnosis of H-HCA was formulated.

Comparing Texture Analysis of Apparent Diffusion Coefficient MRI in Hepatocellular Adenoma and Hepatocellular Carcinoma.

AIM: This study aimed to assess the effectiveness of using MRI-apparent diffusion coefficient (ADC) map-driven radiomics to differentiate between hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC) features. MATERIALS AND METHODS: The study involved 55 patients with liver tumors (20 with HCA and 35 with HCC), featuring 106 lesions equally distributed between hepatic carcinoma and hepatic adenoma who underwent texture analysis on ADC map MR images. The analysis identified several imaging features that significantly differed between the HCA and HCC groups. Four classification models were compared for distinguishing HCA from HCC including linear support vector machine (linear-SVM), radial basis function SVM (RBF-SVM), random forest (RF), and k-nearest neighbor (KNN). RESULTS: The k-nearest neighbor (KNN) classifier displayed the top accuracy (0.89) and specificity (0.90). Linear-SVM and KNN classifiers showcased the leading sensitivity (0.88) for both, with the KNN classifier achieving the highest precision (0.9). In comparison, the conventional interpretation had lower sensitivity (70.1%) and specificity (77.9%). CONCLUSION: The study found that utilizing ADC maps for texture analysis in MR images is a viable method to differentiate HCA from HCC, yielding promising results in identified texture features.

Spatial characterisation of ß-catenin-mutated hepatocellular adenoma subtypes by proteomic profiling of the tumour rim.

Background & Aims: Hepatocellular adenomas (HCAs) are rare, benign, liver tumours classified at the clinicopathological, genetic, and proteomic levels. The ß-catenin-activated (b-HCA) subtypes harbour several mutation types in the ß-catenin gene (CTNNB1) associated with different risks of malignant transformation or bleeding. Glutamine synthetase is a surrogate marker of ß-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 ß-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.

Hepatic Precancerous Lesions and Early Hepatocellular Carcinoma.

This review discusses the diagnostic challenges of diagnosing and treating precursor lesions of hepatocellular carcinoma (HCC) in both cirrhotic and non-cirrhotic livers. The distinction of high-grade dysplastic nodule (the primary precursor lesion in cirrhotic liver) from early HCC is emphasized based on morphologic, immunohistochemical, and genomic features. The risk factors associated with HCC in hepatocellular adenomas (precursor lesion in non-cirrhotic liver) are delineated, and the risk in different subtypes is discussed with emphasis on terminology, diagnosis, and genomic features.

Patient with a novel syndrome with multiple benign hepatic lesions and extrahepatic neoplasms.

Simultaneous occurrence of benign hepatic lesions of different types is a sporadic phenomenon. To the best of our knowledge, we report the first clinical case of a syndrome with simultaneous manifestations of three different entities of benign liver tumors (hepatocellular adenoma, focal nodular hyperplasia and hemangioma) with a novel mutation detected in the liver adenoma and in the presence of a number of further extrahepatic organ neoplasms. Furthermore, we describe for the first time the presence of liver epithelial cells of hepatocytic phenotype expressing cytokeratin 7 (CK7) at the border of the adenoma. These findings may be important for explaining pathogenesis of benign as well as malignant tumors based on genetic and histopathological features.

Estrobolome and Hepatocellular Adenomas-Connecting the Dots of the Gut Microbial ß-Glucuronidase Pathway as a Metabolic Link.

Hepatocellular adenomas are benign endothelial tumors of the liver, mostly associated with female individual users of estrogen-containing medications. However, the precise factors underlying the selective development of hepatic adenomas in certain females remain elusive. Additionally, the conventional profile of individuals prone to hepatic adenoma is changing. Notably, male patients exhibit a higher risk of malignant progression of hepatocellular adenomas, and there are instances where hepatic adenomas have no identifiable cause. In this paper, we theorize the role of the human gastrointestinal microbiota, specifically, of bacterial species producing ß-glucuronidase enzymes, in the development of hepatic adenomas through the estrogen recycling pathway. Furthermore, we aim to address some of the existing gaps in our knowledge of pathophysiological pathways which are not yet subject to research or need to be studied further. As microbial ß-glucuronidases proteins recycle estrogen and facilitate the conversion of inactive estrogen into its active form, this process results in elevated levels of unbound plasmatic estrogen, leading to extended exposure to estrogen. We suggest that an imbalance in the estrobolome could contribute to sex hormone disease evolution and, consequently, to the advancement of hepatocellular adenomas, which are estrogen related.

Sonic hedgehog hepatocellular adenoma: magnetic resonance imaging features and correlation with histology.

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.

Pathology and Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease-Associated Hepatic Tumors.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive fat accumulation in the livers of patients without a history of alcohol abuse. It is classified as either simple steatosis (nonalcoholic fatty liver) or nonalcoholic steatohepatitis (NASH), which can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Recently, it was suggested that the terms "metabolic dysfunction-associated steatotic liver disease (MASLD)" and "metabolic dysfunction-associated steatohepatitis (MASH)" should replace the terms "nonalcoholic fatty liver disease (NAFLD)" and "nonalcoholic steatohepatitis (NASH)", respectively, with small changes in the definitions. MASLD, a hepatic manifestation of metabolic syndrome, is rapidly increasing in incidence globally, and is becoming an increasingly important cause of HCC. Steatohepatitic HCC, a histological variant of HCC, is characterized by its morphological features resembling non-neoplastic steatohepatitis and is closely associated with underlying steatohepatitis and metabolic syndrome. Variations in genes including patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), and membrane-bound O-acyltransferase domain-containing protein 7 (MBOAT7) are associated with the natural history of MASLD, including HCC development. The mechanisms of HCC development in MASLD have not been fully elucidated; however, various factors, including lipotoxicity, inflammation, reactive oxygen species, insulin resistance, and alterations in the gut bacterial flora, are important in the pathogenesis of MASLD-associated HCC. Obesity and MASLD are also recognized as risk factors for hepatocellular adenomas, and recent meta-analyses have shown an association between MASLD and intrahepatic cholangiocarcinoma. In this review, we outline the pathology and pathogenesis of MASLD-associated liver tumors.

Novel Y RNA-Derived Fragments Can Differentiate Canine Hepatocellular Carcinoma from Hepatocellular Adenoma.

Hepatocellular carcinomas (HCC) are common tumors, whereas hepatocellular adenomas (HCA) are rare, benign tumors in dogs. The aberrant expression of noncoding RNAs (ncRNAs) plays a pivotal role in HCC tumorigenesis and progression. Among ncRNAs, micro RNAs have been widely researched in human HCC, but much less widely in canine HCC. However, Y RNA-derived fragments have yet to be investigated in canine HCC and HCA. This study targeted canine HCC and HCA patients. We used qRT-PCR to determine Y RNA expression in clinical tissues, plasma, and plasma extracellular vesicles, and two HCC cell lines (95-1044 and AZACH). Y RNA was significantly decreased in tissue, plasma, and plasma extracellular vesicles for canine HCC versus canine HCA and healthy controls. Y RNA was decreased in 95-1044 and AZACH cells versus normal liver tissue and in AZACH versus 95-1044 cells. In plasma samples, Y RNA levels were decreased in HCC versus HCA and Healthy controls and increased in HCA versus Healthy controls. Receiver operating characteristic analysis showed that Y RNA could be a promising biomarker for distinguishing HCC from HCA and healthy controls. Overall, the dysregulated expression of Y RNA can distinguish canine HCC from HCA. However, further research is necessary to elucidate the underlying Y RNA-related molecular mechanisms in hepatocellular neoplastic diseases. To the best of our knowledge, this is the first report on the relative expression of Y RNA in canine HCC and HCA.

Focal nodular hyperplasia-like nodules arising in the setting of hepatic vascular disorders with portosystemic shunting show ß-catenin activation.

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.