Inflammatory Hepatocellular Adenoma Research Articles

A case study of a liver transplant-treated patient with glycogen storage disease type Ia presenting with multiple inflammatory hepatic adenomas: an analysis of clinicopathologic and genetic data

BackgroundGlycogen 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 presentationHere, 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 β-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.ConclusionThe 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.

Hepatocellular Adenoma: A Life-Threatening Presentation of a Rare Liver Tumor – Case Report and Literature Review

Hepatocellular adenoma is a rare benign liver tumor that occurs predominantly in young women who use exogenous estrogens. We describe a case of a 40-year-old woman on birth control pill who presented with acute right hypochondrial pain and signs of hemodynamical instability triggered by a large bleeding tumor in the right liver lobe. Arterial embolization was performed with cessation of bleeding. To determine etiology, magnetic resonance imaging was conducted with findings suggestive of a hepatocellular adenoma. The tumor was surgically resected, and histologic examination made the definite diagnosis of an inflammatory hepatocellular adenoma. This is a noteworthy case of a rare but potentially fatal complication of liver tumors, whose diagnosis requires a high index of suspicion. Clinicians should consider this diagnosis in young women on oral contraceptive pills who present with severe unexplained abdominal pain and hemodynamical instability. This case aimed to raise awareness of this condition, while reviewing important aspects concerning the management of hepatocellular adenomas.

Disappearance of Hepatocellular Adenoma in a Patient with Cornelia de Lange Syndrome after Treatment with Transcatheter Arterial Embolization.

Cornelia de Lange syndrome (CdLS) is a congenital disorder occasionally associated with congenital portosystemic shunt (CPSSs). We herein report a patient with CdLS and CPSS who developed hepatocellular adenomas (HCAs). The patient presented to our hospital for the further investigation of newly diagnosed liver tumors. Imaging findings and pathological examination results indicated that the liver tumors were inflammatory HCAs that subsequently shrank following transcatheter arterial embolization (TAE). Patients with CdLS and CPSS are at risk of developing HCAs, and TAE may be an effective management strategy for HCA in these patients.

Phospholipase A2 Group IIA Is Associated with Inflammatory Hepatocellular Adenoma.

Although benign hepatocellular adenomas (HCA) are very rare, recent observations have shown their occurrence in patients with diabetes mellitus. Consequently, most of these cases are treated by resection due to concerns regarding their potential progression to hepatocarcinoma (HCC). This decision is largely driven by the limited number of studies on HCC subtyping and the lack of molecular and biological insights into the carcinogenic potential of benign tumors. This study aimed to comprehensively investigate the subtype classification of HCA and to compare and analyze gene expression profiling between HCA and HCC tissues. One fresh inflammatory HCA (I-HCA), three non-B non-C HCCs, two hepatitis B virus-HCCs, and one normal liver tissue sample were subjected to single-cell RNA sequencing (scRNA-seq). Comparative analysis of scRNA-seq among different tissues showed that phospholipase A2 group IIA (PLA2G2A) mRNA was specifically expressed in I-HCA, following RNA-seq analysis in formalin-fixed paraffin-embedded tissues from other HCAs. Immunohistochemistry using the PLA2G2A antibody in these tissues indicated that the positive reaction was mainly observed in hepatocytes of I-HCAs and stromal cells surrounding the tumor tissue in HCC were also stained. According to a clinical database, PLA2G2A expression in HCC does not correlate with poor prognosis. This finding may potentially help develop a new definition for I-HCA, resulting in a significant clinical contribution, but it requires validation with other fresh HCA samples.

Hepatocellular Adenoma: Report of 2 Cases That Highlight the Relevance of Phenotype-Genotype Correlation in the Pediatric Population.

Hepatocellular adenoma (HCA) in the pediatric population is very rare and there are only limited studies, especially with molecular characterization of the tumors. Main HCA subtypes recognized in the current WHO classification include HNF1A-inactivated HCA (H-HCA), inflammatory HCA (IHCA), β-catenin-activated HCA (b-HCA), and β-catenin-activated IHCA (b-IHCA) and sonic hedgehog HCA (shHCA) is reported as an emerging subtype. Clinical history, pathological information, and molecular studies for a series of 2 cases of pediatric HCA were reviewed. 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). 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.

Clinicopathologic characterization of hepatocellular adenomas in men: a multicenter experience

Hepatocellular adenomas (HCAs) are benign liver neoplasms which most commonly present in women in their reproductive age. In men they are rare and have a higher risk of malignant transformation to hepatocellular carcinoma (HCC), with current guidelines advocating their complete resection. Here we present our multicenter experience of HCA in men in the United States. A total of 27 HCA cases were included with a mean age of presentation of 37 years (9 - 69 years) and a mean size of 6.8 cm (0.9 - 18.5 cm). Based on the 2019 WHO classification, the most common subtype identified was inflammatory HCA (IHCA) (10 cases, 37.0%) followed by unclassified HCA (U-HCA) (7 cases, 25.9%), HNF1A-inactivated HCA (H-HCA) (6 cases, 22.2%), β-catenin activated IHCA (b-IHCA) (3 cases, 11.1%), and β-catenin activated HCA (b-HCA) (1 case, 3.7%). Six additional cases diagnosed as hepatocellular neoplasm of uncertain malignant potential (HUMP) were also included in the study. These cases presented in a mean age of 46 years (17 - 64 years) and size of 10.8 cm (4.2 - 16.5 cm). We further evaluated the significance of androgen receptor (AR) expression by immunohistochemistry (IHC); of the 16 cases with materials available, 8 were considered positive using the Allred score system (2 I-HCA, 2 H-HCA, 1 U-HCA, and 3 HUMP). Of the total cases, 12 were diagnosed on biopsies, for which follow-up information is available for 7 (47.6 months, 8 - 160 months), and none of them show evidence of malignant transformation. Of the 21 resection cases, a concomitant well differentiated hepatocellular carcinoma (HCC) within the same lesion was identified in 5 cases (23.8%) which were diagnosed as HCA (n=4) or HUMP (n=1). Overall, 15% of cases in our entire cohort of HCA and HUMP showed concomitant HCC, while none of the 7 biopsy cases showed any malignant transformation on follow-up (22 - 160 months; mean 61.8).

Hepatocellular Adenomas: Molecular Basis and Multimodality Imaging Update.

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 β-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 β-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.

Hepatocellular Adenoma Subtypes Based on 2017 Classification System: Exploratory Study of Gadoxetate Disodium-Enhanced MRI Features With Proposal of a Diagnostic Algorithm.

BACKGROUND. The classification of hepatocellular adenomas (HCAs) was updated in 2017 on the basis of genetic and molecular analysis. OBJECTIVE. The purpose of this article was to evaluate features on gadoxetate disodium-enhanced MRI of HCA subtypes on the basis of the 2017 classification and to propose a diagnostic algorithm for determining subtype using these features. METHODS. This retrospective study included 56 patients (49 women, seven men; mean age, 37 ± 13 [SD] years) with histologically confirmed HCA evaluated by gadoxetate disodium-enhanced MRI from January 2010 to January 2021. Subtypes were reclassified using 2017 criteria: hepatocyte nuclear factor-1α mutated HCA (HHCA), inflammatory HCA (IHCA), β-catenin exon 3 activated HCA (β-HCA), mixed inflammatory and β-HCA (β-IHCA), sonic hedgehog HCA (shHCA), and unclassified HCA (UHCA). Qualitative MRI features were assessed. Liver-to-lesion contrast enhancement ratios (LLCERs) were measured. Subtypes were compared, and a diagnostic algorithm was proposed. RESULTS. The analysis included 65 HCAs: 16 HHCAs, 31 IHCAs, six β-HCA, four β-IHCA, five shHCA, and three UHCAs. HHCAs showed homogeneous diffuse intralesional steatosis in 94%, whereas all other HCAs showed this finding in 0% (p < .001). IHCAs showed the "atoll" sign in 58%, whereas all other HCAs showed this finding in 12% (p < .001). IHCAs showed moderate T2 hyperintensity in 52%, whereas all other HCAs showed this finding in 12% (p < .001). The β-HCAs and β-IHCAs occurred in men in 63%, whereas all other HCAs occurred in men in 4% (p < .001). The β-HCAs and β-IHCAs had a mean size of 10.1 ± 6.8 cm, whereas all other HCAs had a mean size of 5.1 ± 2.9 cm (p = .03). The β-HCAs and β-IHCAs showed fluid components in 60%, whereas all other HCAs showed this finding in 5% (p < .001). Hepatobiliary phase iso- or hyperintensity was observed in 80% of β-HCAs and β-IHCAs versus 5% of all other HCAs (p < .001). Hepatobiliary phase LLCER was positive in nine HCAs (eight β-HCAs and β-IHCAs; one IHCA). The shHCA and UHCA did not show distinguishing features. The proposed diagnostic algorithm had accuracy of 98% for HHCAs, 83% for IHCAs, and 95% for β-HCAs or β-IHCAs. CONCLUSION. Findings on gadoxetate disodium-enhanced MRI, including hepatobiliary phase characteristics, were associated with HCA subtypes using the 2017 classification. CLINICAL IMPACT. The algorithm identified common HCA subtypes with high accuracy, including those with β-catenin exon 3 mutations.

Genetic and epigenetic analysis of hepatocellular adenomas with atypical morphological features.

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. 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. Subtyping of the five HCAs with atypical features revealed two β-catenin mutated HCA (b-HCA), two β-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). 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.

Subtyping of hepatocellular adenomas using Gd-EOB-DTPA: a qualitative and quantitative analysis.

The goal of medical imaging is not only to identify the entity "hepatocellular adenoma," but to detect typical magnetic resonance (MR) patterns of the subtypes so that lesions with a higher malignant transformation rate could be differentiated from those that should just be controlled. To evaluate the differentiation between subtypes of hepatocellular adenomas using hepatobiliary specific contrast agent (Gd-EOB-DTPA) in MR imaging. A total of 11 patients with 39 lesions with histologically proven hepatocellular adenomas were evaluated. Of the, 34 were inflammatory hepatocellular adenomas (IHCA) and 5 were HNF1α adenomas. No β-catenin-mutated adenoma was found. In all patients, a standard protocol considering the guidelines of the international consensus conference of Gd-EOB-DTPA was performed in a 1.5-T scanner. Besides a qualitative analysis of all sequences, we measured the quantitative signal intensity (SI) ratio in all examinations. Qualitative analysis showed that best sequences for differentiation of HNF1α adenomas from IHCA were T1-weighted (T1W) precontrast (P = 0.03) and portalvenous phase (P < 0.0001) as well as arterial phase (P = 0.002). All adenomas were hypointense in hepatobiliary phase (15 min). The quantitative analyses of the SI ratio and of lesion-to-liver contrast (LLC) ratio show statistically significant differences in T1W precontrast (SI: P = 0.035; LLC: P = 0.049) and portalvenous phase (SI: P = 0.002; LLC: P = 0.002). Subtyping of hepatocellular adenomas using Gd-EOB-DTPA is possible due to qualitative and quantitative analyses regarding T1W precontrast and portalvenous phase. In addition, the SI ratio and liver-to-lesion contrast ratio in the arterial phase gave additional qualitative information for differentiation.

β-Catenin-activated inflammatory hepatocellular adenoma with pigmentation and atypical features: a case report.

Hepatocellular adenomas are rare diseases, defined as benign liver neoplasms composed of cells with hepatocellular differentiation. Differential diagnosis of hepatocellular adenoma from other lesions, including focal nodular hyperplasia and hepatocellular carcinoma, is crucial to determine treatment strategy. We describe a case of β-catenin-activated inflammatory hepatocellular adenoma with malignant transformation. A 50-year-old man with a suspected liver tumor, based on abdominal ultrasonography findings, was referred to our hospital. Contrast-enhanced computed tomography and magnetic resonance imaging revealed a liver tumor in S2 which was enhanced in the arterial phase to the delayed phase. Based on diagnostic imaging findings, hepatocellular adenoma or focal nodular hyperplasia was suspected. We considered the possibility of malignant potential because of the enlargement of the lesion. Thus, we performed a laparoscopic hepatectomy. Histological examination showed pigment deposition in the hepatocytes, which was determined to be lipofuscin. Mild nuclear swelling and atypia in the tumor area indicated nodular growth. Based on the histological and immunohistochemical findings, the diagnosis was ꞵ-catenin-activated inflammatory hepatocellular adenoma with atypical features. The imaging features of hepatocellular adenoma and focal nodular hyperplasia are similar, but if the tumor tends to grow, surgical treatment should be performed because of the possibility of malignant hepatocellular adenoma.

Hepatocellular Adenoma: A Case Report, Current Updates on Subtyping, and Diagnostic Pitfalls

Abstract Hepatocellular adenoma (HCA) is a benign liver neoplasm that typically arises in the noncirrhotic liver. Based on molecular findings, HCA can be subclassified into the following subtypes: hepatocyte nuclear factor 1α–inactivated HCA, inflammatory HCA, β-catenin–activated HCA, sonic hedgehog-activated HCA, and unclassified HCA. Mixed β-catenin–activated inflammatory HCA may rarely occur. We report a case of HCA that was initially diagnosed as inflammatory HCA on a biopsy but finally was confirmed to be β-catenin–activated inflammatory HCA on the resection specimen. Most recent updates on molecular classification, key histologic features of each subtype, and common diagnostic pitfalls are discussed.

Update in Pathology of Practically Encountered Lesions and Diseases in the Liver

This issue of the American Journal of Surgical Pathology, Reviews and Reports is devoted to recent advances and update in the pathology of the liver. The articles provide insights into the current nomenclature, classification, diagnosis, differential diagnoses, clinical and prognostic aspects of various liver diseases, and lesions that are informative to pathologists in their daily practice. Hepatocellular adenomas (HCAs) is generally a benign liver neoplasm that typically arises in the noncirrhotic liver; however, malignant transformation does occur, and hence, subtyping is critical. Drs Jung and Liu present a case of HCA that was initially diagnosed as inflammatory HCA on a biopsy and subsequently was confirmed to be β-catenin–activated inflammatory HCA on the resection specimen. They then comprehensively review recent updates on molecular classification and the key histologic features of each subtype and discuss common diagnostic pitfalls. Over the past decades, hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have been recognized to be heterogeneous in morphology, molecular features, and biological behavior. Recent World Health Organization classification describes various histomorphological subtypes of HCC and iCCA, some with characteristic molecular profiles, clinical correlates, and prognostic implications. In their review, Drs Hwang and Kim nicely discuss recently described subtypes of HCC and iCCA: macrotrabecular HCC, steatohepatitic HCC, scirrhous HCC, and small duct iCCA. Congestive hepatopathy shows a unique pattern of fibrosis, that is, pericentral fibrosis at early stage, which may progress to bridging fibrosis and cirrhosis. Making a diagnosis of congestive hepatopathy and staging its fibrosis are important tasks for pathologists, as patients may undergo liver biopsies before cardiac transplantation to assess the degree of liver fibrosis, which may impact clinical decision-making. Besides patients' own cardiac dysfunction, congestive hepatopathy can also be seen after a Fontan procedure. Drs Gosse and Bosch describe a case of congestive hepatopathy due to altered circulation with a Fontan procedure. They then discuss the fibrosis scoring systems recently described for Fontan-associated liver disease and congestive heart disease–associated hepatopathy. Combined hepatocellular-cholangiocarcinoma is a rare primary liver tumor with neoplastic components of both hepatocytic and cholangiocytic differentiation within the same tumor. There is recent consensus paper and World Health Organization classification of this unique tumor. Drs Kondo, Akiba, and Yano herein report a case of this tumor and thoughtfully review the terminology, classification, and clinical and pathological characteristics of combined hepatocellular-cholangiocarcinoma and its differential diagnosis. Hemophagocytic lymphohistiocytosis is a rare disease with a high mortality. Liver involvement is common, with most patients demonstrating acute hepatitis. Therefore, liver biopsies are frequently performed when this entity is suspected. Dr Xiong and colleagues summarize the clinical features of hemophagocytic lymphohistiocytosis, emphasizing its hepatic manifestations. They describe the highly variable histologic patterns and address difficulties encountered by pathologists. We are extremely grateful to all the contributors for sharing their expertise and knowledge in forming this issue. We hope that the information provides highlights and elucidates the practically encountered lesions in the liver. Guest Editors

Body weight changes and duration of estrogen exposure modulate the evolution of hepatocellular adenomas after contraception discontinuation.

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. 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 β-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). 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.

Morphomolecular Classification Update on Hepatocellular Adenoma, Hepatocellular Carcinoma, and Intrahepatic Cholangiocarcinoma

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, β-catenin-activated, β-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 β-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.

Fat in mass in primary liver lesions: are usual MRI diagnostic criteria of both malignant and benign liver lesions still applicable?

To evaluate the accuracy of the usual MRI diagnostic patterns of primary liver lesions applied to the diagnosis of pathologically proven fat-containing liver lesions. This monocentric IRB approved retrospective study included all patients with pathologically proven focal liver lesions and documented intra-tumoral fat on pathology and who underwent preoperative liver MRI for characterization. Both liver morphology and usual lesion MRI features were analyzed and their distribution correlated to the final pathological result (Khi-2 or Fisher exact tests, Student t-test or Mann-Whitney U test, as appropriate). The Sensitivity (Se) and Specificity (Sp) of MRI patterns known to be associated to both Hepatocellular Carcinoma (HCC), Focal Nodular Hyperplasia (FNH), and Hepatocellular Adenoma (HCA) subtypes were evaluated. Between March 2014 and November 2021, 66 lesions were included, corresponding to: 26 HCC, 32 HCA, 6 FNH and 2 hepatic angiomyolipoma (HAML). All lesions developed on a dysmorphic liver were HCC. A non-rim arterial phase hyperenhancement with a washout and an enhancing capsule had a 98% specificity for HCC diagnosis; A homogeneous dropout of signal on the opposed phase had a sensitivity of 92% and a specificity of 89% for the diagnosis of HNF1alpha inactivated subtype of HCA (HHCA). The FNH pattern was specific at 100% for the diagnosis of FNH with a 40% Se. Finally, the accuracy of inflammatory hepatocellular adenoma (IHCA) pattern had a low 60% Se but a high 89% Sp for IHCA diagnosis. Known MRI patterns remain reliable for the accurate diagnosis of primary liver tumors on MRI even in fat-containing lesions.

Differentiation of hepatocellular adenoma by subtype and hepatocellular carcinoma in non-cirrhotic liver by fractal analysis of perfusion MRI

BackgroundTo investigate whether fractal analysis of perfusion differentiates hepatocellular adenoma (HCA) subtypes and hepatocellular carcinoma (HCC) in non-cirrhotic liver by quantifying perfusion chaos using four-dimensional dynamic contrast-enhanced magnetic resonance imaging (4D-DCE-MRI).ResultsA retrospective population of 63 patients (47 female) with histopathologically characterized HCA and HCC in non-cirrhotic livers was investigated. Our population consisted of 13 hepatocyte nuclear factor (HNF)-1α-inactivated (H-HCAs), 7 β-catenin-exon-3-mutated (bex3-HCAs), 27 inflammatory HCAs (I-HCAs), and 16 HCCs. Four-dimensional fractal analysis was applied to arterial, portal venous, and delayed phases of 4D-DCE-MRI and was performed in lesions as well as remote liver tissue. Diagnostic accuracy of fractal analysis was compared to qualitative MRI features alone and their combination using multi-class diagnostic accuracy testing including kappa-statistics and area under the receiver operating characteristic curve (AUC). Fractal analysis allowed quantification of perfusion chaos, which was significantly different between lesion subtypes (multi-class AUC = 0.90, p < 0.001), except between I-HCA and HCC. Qualitative MRI features alone did not allow reliable differentiation between HCA subtypes and HCC (κ = 0.35). However, combining qualitative MRI features and fractal analysis reliably predicted the histopathological diagnosis (κ = 0.89) and improved differentiation of high-risk lesions (i.e., HCCs, bex3-HCAs) and low-risk lesions (H-HCAs, I-HCAs) from sensitivity and specificity of 43% (95% confidence interval [CI] 23–66%) and 47% (CI 32–64%) for qualitative MRI features to 96% (CI 78–100%) and 68% (CI 51–81%), respectively, when adding fractal analysis.ConclusionsCombining qualitative MRI features with fractal analysis allows identification of HCA subtypes and HCCs in patients with non-cirrhotic livers and improves differentiation of lesions with high and low risk for malignant transformation.

Subtyping of hepatocellular adenoma: a machine learning-based approach.

Subtyping of hepatocellular adenoma (HCA) is an important task in practice as different subtypes may have different clinical outcomes and management algorithms. Definitive subtyping is currently dependent on immunohistochemical and molecular testing. The association between some morphologic/clinical features and HCA subtypes has been reported; however, the predictive performance of these features has been controversial. In this study, we attempted machine learning based methods to select an efficient and parsimonious set of morphologic/clinical features for differentiating a HCA subtype from the others, and then assessed the performance of the selected features in identifying the correct subtypes. We first examined 50 liver HCA resection specimens collected at the University of Washington and Kobe University/Kings College London, including HNF1α-mutated HCA (H-HCA) (n = 16), inflammatory HCA (I-HCA) (n = 20), beta-catenin activated HCA (β-HCA) (n = 8), and unclassified HCA (U-HCA) (n = 6). Twenty-six morphologic/clinical features were assessed. We used LASSO (least absolute shrinkage and selection operator) to select key features that could differentiate a subtype from the others. We further performed SVM (support vector machine) analysis to assess the performance (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy) of the selected features in HCA subtyping in an independent cohort of liver resection samples (n = 20) collected at the University of Wisconsin-Madison. With some overlap, different combinations of morphologic/clinical features were selected for each subtype. Based on SVM analysis, the selected features classified HCA into correct subtypes with an overall accuracy of at least 80%. Our findings are useful for initial diagnosis and subtyping of HCA, especially in clinical settings without access to immunohistochemical and molecular assays.

抗てんかん薬長期服用中の若年男性に生じた炎症性肝細胞腺腫の1切除例

抗てんかん薬長期服用中の若年男性に生じた炎症性肝細胞腺腫の1切除例

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria

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. 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, β-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%) β-catenin-activated HCAs, three (6%) β-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 34years and a median tumour diameter of 60mm. In the β-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the β-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. 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 β-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.