A nationwide assessment of hepatocellular adenoma resection: Indications and pathological discordance.

Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs < 50 mm compared to HCAs ≥ 50 mm. Changes in final postoperative diagnosis were assessed. We performed a retrospective study that included patients who underwent resection for (suspected) HCAs in the Netherlands from 2014 to 2019. Indication for resection was analyzed and stratified for small (<50 mm) and large (≥50 mm) tumors. Logistic regression analysis was performed on factors influencing change in tumor diagnosis. Out of 222 patients who underwent surgery, 44 (20%) patients had a tumor <50 mm. Median age was 46 (interquartile range [IQR], 33-56) years in patients with small tumors and 37 (IQR, 31-46) years in patients with large tumors ( p  = 0.016). Patients with small tumors were more frequently men (21% vs. 5%, p  = 0.002). Main indications for resection in patients with small tumors were suspicion of (pre)malignancy (55%), (previous) bleeding (14%), and male sex (11%). Patients with large tumors received operations because of tumor size >50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p  < 0.01), male sex (aOR, 3.7; p  = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p  = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis.

Hepatocellular adenoma in men: A nationwide assessment of pathology and correlation with clinical course.

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course. METHODS: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death. RESULTS: A total of 66 patients from 26 centres fulfilling the inclusion criteria with a mean (±SD) age of 45.0 ± 21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow-up of 9.6 years, tumour-related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (P = .031). Four B-catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision. CONCLUSIONS: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well-differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

A cost-effectiveness analysis of the diagnostic strategies for differentiating focal nodular hyperplasia from hepatocellular adenoma.

OBJECTIVES: We evaluated the cost-effectiveness of a gadoxetic acid-enhanced MRI (EOB-MRI) strategy compared with conventional MRI strategy and biopsy to differentiate focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA). METHODS: A decision tree model was constructed to compare the cost-effectiveness of EOB-MRI, conventional MRI with extracellular contrast agents, and biopsy as the initial diagnostic modality in patients with incidentally detected focal liver lesions suspected of being FNH or HCA. We analysed the cost and effectiveness, i.e. probability of successful diagnosis of each strategy. Costs were based on utilisation rates and Medicare reimbursements in the USA and South Korea. RESULTS: In the base case analysis of our decision tree model, the effectiveness of the three strategies was similar. The cost of the EOB-MRI strategy ($1283 in USA, $813 in South Korea) was lowest compared with the biopsy strategy ($1725 in USA, $847 in South Korea) and the conventional MRI strategy ($1750 in USA, $962 in South Korea). One-way, two-way and probabilistic sensitivity analysis showed unchanged results over an acceptable range. CONCLUSIONS: EOB-MRI strategy is the most cost-effective strategy for differentiating FNH from HCA in patients with incidentally detected focal liver lesions in a non-cirrhotic liver. KEY POINTS: • The effectiveness of the three strategies was similar. • The cost of the EOB-MRI strategy was lowest. • EOB-MRI strategy is the most cost-effective for differentiating FNH from HCA.

Histopathological assessment of liver and gonad pathology in continental slope fish from the northeast Atlantic Ocean.

The deep-sea environment is a sink for a wide variety of contaminants including heavy metals and organic compounds of anthropogenic origin. Life history traits of many deep-water fish species including longevity and high trophic position may predispose them to contaminant exposure and subsequent induction of pathological changes, including tumour formation. The lack of evidence for this hypothesis prompted this investigation in order to provide data on the presence of pathological changes in the liver and gonads of several deep-water fish species. Fish were obtained from the north east region of the Bay of Biscay (north east Atlantic Ocean) by trawling at depths between 700 and 1400 m. Liver and gonad samples were collected on board ship and fixed for histological processing and subsequent examination by light microscopy. Hepatocellular and nuclear pleomorphism and individual cases of ovotestis and foci of cellular alteration (FCA) were detected in black scabbardfish (Aphanopus carbo). Six cases of FCA were observed in orange roughy (Hoplostethus atlanticus) (n = 50) together with a single case of hepatocellular adenoma. A wide variety of inflammatory and degenerative lesions were found in all species examined. Deep-water fish display a range of pathologies similar to those seen in shelf-sea species used for international monitoring programmes including biological effects of contaminants. This study has confirmed the utility of health screening in deep-water fish for detecting evidence of prior exposure to contaminants and has also gained evidence of pathology potentially associated with exposure to algal toxins.

Nonclinical assessment of carcinogenic risk and tumor growth enhancement potential of prasugrel, a platelet-inhibiting therapeutic agent.

Prasugrel, a thienopyridine ADP receptor antagonist, is an orally administered prodrug requiring in vivo metabolism to form the active metabolite that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12[sub 12] receptor. A comprehensive nonclinical safety assessment including genotoxicity and carcinogenicity studies supported the chronic use of prasugrel in patients with atherothrombotic disease. In addition, a special assessment of the potential for prasugrel to enhance tumor growth was undertaken to address regulatory concerns relating to increases in human cancers. Prasugrel demonstrated no evidence of genotoxicity and was not oncogenic in a 2-year rat carcinogenicity study. In the 2-year mouse study, an increase in hepatocellular adenomas was considered secondary to enzyme induction and not relevant to human safety. Further, the absence of any increase in common background tumors at any other organ site in either rodent study indicated a lack of tumor promoting activity (apart from the CYP450 induction-related increase in mouse liver tumors). Cell culture studies with 3 human tumor cell lines (lung, colon, prostate) demonstrated that exposure of serum-starved cells to prasugrel's active and major circulating human metabolites does not increase cell proliferation relative to starved cells stimulated to proliferate by addition of 10% FBS. Prasugrel also did not increase tumor growth relative to vehicle controls in nude mice implanted with 3 human tumor cell lines. Thus, traditional genotoxicity and 2-year bioassays as well as specially designed tumor growth enhancement studies in human tumor cell lines and mouse xenograft models clearly demonstrated prasugrel's lack of tumorigenic potential.

Furan in heat-treated foods: formation, exposure, toxicity, and aspects of risk assessment.

Furan is formed in a variety of heat-treated foods through thermal degradation of natural food constituents. Relatively high levels of furan contamination are found in ground roasted coffee, instant coffee, and processed baby foods. European exposure estimates suggest that mean dietary exposure to furan may be as high as 1.23 and 1.01 µg/kg bw/day for adults and 3- to 12-month-old infants, respectively. Furan is a potent hepatotoxin and hepatocarcinogen in rodents, causing hepatocellular adenomas and carcinomas in rats and mice, and high incidences of cholangiocarcinomas in rats at doses ≥ 2 mg/kg bw. There is therefore a relatively low margin of exposure between estimated human exposure and doses that cause a high tumor incidence in rodents. Since a genotoxic mode of action cannot be excluded for furan-induced tumor formation, the present exposures may indicate a risk to human health and need for mitigation. This review summarizes the current knowledge on mechanisms of furan formation in food, human dietary exposure to furan, and furan toxicity, and highlights the need to establish the risk resulting from the genotoxic and carcinogenic properties of furan at doses lower than 2 mg/kg bw.

Can a decision-making model be justified in the management of hepatocellular adenoma?

During recent years, there was a great development in the area of hepatocellular adenomas (HCA), especially regarding the pathological subtype classification, radiological imaging and management during pregnancy. This review discusses the current knowledge about diagnosis and treatment modalities of HCA and proposes a decision-making model for HCA. A Medline search of studies relevant to epidemiology, histopathology, complications, imaging and management of HCA lesions was undertaken. References from identified articles were hand-searched for further relevant articles.

A pictorial review of benign hepatocellular nodular lesions: comprehensive radiological assessment incorporating the concept of anomalous portal tract syndrome.

BACKGROUND/PURPOSE: Although the pathological categorization system advocated by the International Working Party (IWP) on Terminology has been helpful in categorizing benign hepatocellular lesions, the diverse clinicopathological features of the lesions still cause confusion of diagnosis in clinical settings. Recently, an integrated disease concept termed "anomalous portal tract syndrome" (APTS) has been proposed as a congenital anomaly of the portal tract, being a single unifying etiological factor underlying the disorder. In this article, we discuss the radiological features of benign nodular hepatocellular lesions incorporated in the concept of APTS. METHODS: We systematically reviewed the literature on benign hepatocellular lesions based on the concept of APTS, as well as standard IWP terminology. For this pictorial review, we selected six representative cases and assessed the radiological features of the cases based on the concept of APTS. RESULTS: The comprehensive assessment based on APTS enabled the systematic categorization of benign hepatocellular lesions, including nodular regenerative hyperplasia, large regenerative nodules, partial nodular transformation, focal nodular hyperplasia, and hepatocellular adenoma, and was helpful in understanding the overlapping features of these lesions. CONCLUSIONS: Although the disease concept of APTS is still evolving, it is nonetheless helpful in comprehensively understanding the clinicopathological and radiological features of various benign hepatocellular lesions.

Real-time contrast-enhanced and real-time virtual sonography in the assessment of benign liver lesions.

Imaging techniques, in particular ultrasonography, have led to great advances in clinical hepatology in the past few decades. The introduction of second-generation contrast agents and the development of contrast specific techniques have opened new prospects in the detection and characterization of liver lesions. New hybrid imaging techniques that combine in real-time transabdominal ultrasound with other cross-sectional imaging techniques (CT or MR) might add even more valuable information in the cases with focal lesions. The aim of this review is to describe the role of real-time contrast-enhanced and real-time virtual sonography in the assessment of benign liver lesions.

Use of second generation contrast-enhanced ultrasound in the assessment of focal liver lesions.

Ultrasound (US) is often the first imaging modality employed in patients with suspected focal liver lesions. The role of US in the characterisation of focal liver lesions has been transformed with the introduction of specific contrast media and the development of specialized imaging techniques. Ultrasound now can fully characterise the enhancement pattern of hepatic lesions, similar to that achieved with contrast enhanced multiphasic computed tomography (CT) and magnetic resonance imaging (MRI). US contrast agents are safe, well-tolerated and have very few contraindications. Furthermore, real-time evaluation of the vascularity of focal liver lesions has become possible with the use of the newer microbubble contrast agents. This article reviews the enhancement pattern of the most frequent liver lesions seen, using the second generation US contrast media. The common pitfalls for each type of lesion are discussed. The recent developments in US contrast media and specific imaging techniques have been a major advance and this technique, in view of the intrinsic advantages of US, will undoubtedly gain popularity in the years to come.

Assessment of differentiation and progression of hepatic tumors using array-based comparative genomic hybridization.

BACKGROUND & AIMS: To gain more information about the molecular mechanisms leading to dedifferentiation of hepatocellular adenoma (HCA) and hepatocellular carcinoma (HCC), high-resolution array-based comparative genomic hybridization (array-CGH) was performed on 24 cases of HCC and 10 cases of HCA. METHODS: DNA chips containing 6251 individual bacterial artificial chromosome/plasmid artificial chromosome clones were used. They allowed for a genome-wide resolution of 1 Mb and an even higher resolution of up to 100 kb for chromosome regions recurrently involved in human tumors and for regions containing known tumor-suppressor genes and oncogenes. RESULTS: Copy number changes on the genomic scale were found by array-based comparative genomic hybridization in all cases. In HCC, gains of chromosomal regions 1q (91.6%), and 8q (58.3%), and losses of 8p (54%) were found most frequently. Hierarchic cluster analysis branched all HCA from HCC. However, in 2 adenomas with a known history of glycogenosis type I and adenomatosis hepatis gains of 1q were found, too. The critically gained region was narrowed down to bands 1q22-23. Although no significant differences in the mean number of chromosomal aberrations were seen between adenomas and well-differentiated carcinomas (2.7 vs 4.6), a significant increase accompanied the dedifferentiation of HCC (14.1 in HCC-G2 and 16.3 in HCC-G2/3; P < .02). Dedifferentiation of HCC also was correlated closely to losses of 4q and 13q (P <.001 and <.005, respectively). CONCLUSIONS: The increased chromosomal instability during dedifferentiation of HCC leads to an accumulation of structural chromosomal aberrations and losses and gains of defined chromosome regions.

[Effects of biphasic spiral CT, conventional and iron oxide enhanced MRI on therapy and therapy costs in patients with focal liver lesions]. / Einfluss von biphasischer Spiral-CT, nativer und eisenoxidverstärkter MRT auf Therapie und Therapiekosten bei Patienten mit fokalen Leberläsionen.

PURPOSE: Evaluation of the diagnostic efficacy and cost-benefit of contrast enhanced CT (CT) and MRI pre- and post-SPIO-particles in focal hepatic disease with consideration of therapeutic outcome. METHODS: In 52 patients with the suspicion of primary or secondary hepatic malignancy, biphasic spiral CT and breath-hold gradient-echo T1- and fast spin-echo T2-weighted MRI pre- and post-iron oxide administration (1.5 T, body-phased-array coil) were compared. The number of hepatic lesions and the related diagnoses resulting from each imaging modality were recorded and statistically correlated to the final diagnoses established by biopsy/OP (34/52), long term follow-up of 12 months (18/52), and a consensus reading of all imaging modalities considering all clinical imaging information. The most likely induced therapy resulting from each imaging test was correlated to the final therapy. Based on data from the hospitals accountants, the therapy-related costs were estimated without hospitalization costs. RESULTS: In 34/52 (65.4%) of the cases the correct diagnosis was primarily stated by CT (sensitivity [se.] 85.2%, specificity [sp.] 44.0%). In additional 10/52 of the cases unenhanced MRI (se. 91.4%, sp. 75.0%) enabled correct diagnoses, and in another 6 cases the diagnosis was established only by SPIO-MRI (se. 100%, sp. 86.7%). Considering the possible therapeutic recommendation arising from each modality, CT would have induced needles therapy costs of 191,042 DM, unenhanced MRI of 171,035 DM, and SPIO-MRI of 7,311 DM. In comparison to the real therapy costs of 221,873 DM, this would have corresponded to an unnecessary increase of therapy costs of 86.1%, 77.1%, and 3.3%, respectively. In two cases (1 hemangioma, 1 regenerative nodule) all modalities failed, causing unnecessary surgery in one patient. DISCUSSION: In this problem-oriented scenario unenhanced and SPIO-enhanced MRI proved to be superior to CT regarding diagnostic efficacy. The cost-benefit resulted mainly due to preserving patients from unnecessary surgical procedures.

Environmental complex mixture toxicity assessment.

Trichloroethylene (TCE) was found as a contaminant in the well supplying water to an aquatic testing laboratory. The groundwater was routinely screened by a commercial laboratory for volatile and semivolatile compounds, metals, herbicides, pesticides, and polychlorinated biphenyls using U.S. Environmental Protection Agency methods. Although TCE was the only reportable peak on the gas chromatograph, with average concentrations of 0.200 mg/l, other small peaks were also present, indicating the possibility that the contamination was not limited to TCE alone. A chronic 6-month carcinogenicity assay was conducted on-site in a biomonitoring trailer, using the Japanese medaka fish (Oryzias latipes) in an initiation-promotion protocol, with diethylnitrosamine (DEN) as the initiator and the TCE-contaminated groundwater as a promoter. Study results indicated no evidence of carcinogenic potential of the groundwater without initiation. There was, however, a tumor-promotional effect of the groundwater after DEN initiation. A follow-up laboratory study was conducted using reagent grade TCE added to carbon-filtered groundwater to simulate TCE concentrations comparable to those found in the contaminated groundwater. Study results indicated no promotional effects of TCE. These studies emphasize the necessity for on-site bioassays to assess potential environmental hazards. In this instance, chemical analysis of the groundwater identified TCE as the only reportable contaminant, but other compounds present below reportable limits were noted and may have had a synergistic effect on tumor promotion observed with the groundwater exposure. Laboratory toxicity testing of single compounds can produce toxicity data specific to that compound for that species but cannot take into account the possible toxic effects of mixtures of compounds.

The FEMA GRAS assessment of furfural used as a flavour ingredient. Flavor and Extract Manufacturers' Association.

The Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA) has assessed the safety of furfural for its continued use as a flavour ingredient. The safety assessment takes into account the current scientific information on exposure, metabolism, pharmacokinetics, toxicology, carcinogenicity and genotoxicity. Furfural was reaffirmed as GRAS (GRASr) as a flavour ingredient under conditions of intended use based on: (1) its mode of metabolic detoxication in humans; (2) its low level of flavour use compared with higher intake levels as a naturally occurring component of food; (3) the safety factor calculated from results of subchronic and chronic studies, (4) the lack of reactivity with DNA; and (5) the conclusion that the only statistically significant finding in the 2-year NTP bioassays, an increased incidence of hepatocellular adenomas and carcinomas in the high-dose group of male mice, was secondary to pronounced hepatotoxicity. Taken together, these data do not indicate any risk to human health under conditions of use as a flavour ingredient. This evidence of safety is supported by the occurrence of furfural as a natural component of traditional foods, at concentrations in the diet resulting in a 'natural intake' that is at least 100 times higher than the intake of furfural from use as a flavour ingredient.

Hepatic adenoma in the pediatric age group. Clinicopathological observations and assessment of cell proliferative activity.

The clinicopathological findings of eight children with hepatic adenoma in the absence of cirrhosis are presented. The lesions ranged in diameter from 0.1 to 14.5 cm. Associated disorders were Fanconi's anemia, type I glycogen storage disease. Hurler's disease, and severe combined immunodeficiency with ADA deficiency. The remaining three children had adenoma without known associated disorders. In the children with glycogenosis and Hurler's disease the adenomas were multiple. Significant dysplasia occurred in the two children with Fanconi's anemia; however, the lesions behaved in a benign fashion--one with regression of the tumor after cessation of androgen therapy and the other with nonrecurrence after complete resection. Proliferating cell nuclear antigen (PCNA) labeling index (LI) of the adenoma arising in patients with Fanconi's anemia was significantly greater than the PCNA-LI of adenoma in the other children (mean 4.1% versus 0.9% of nuclei), approaching the lower end of the spectrum for reported hepatocellular carcinoma cases. We emphasize that the worrisome pathology that may occur in hepatic adenoma in children, particularly with Fanconi's anemia, does not necessarily predict malignant behavior. The association of hepatic adenoma with Hurler's disease or severe combined immunodeficiency has not been reported previously.