Spontaneous Occurrence of Various Types of Hepatocellular Adenoma in the Livers of Metabolic Syndrome-Associated Steatohepatitis Model TSOD Mice.

Male Tsumura-Suzuki Obese Diabetes (TSOD) mice, a spontaneous metabolic syndrome model, develop non-alcoholic steatohepatitis and liver tumors by feeding on a standard mouse diet. Nearly 70% of liver tumors express glutamine synthetase (GS), a marker of hepatocellular carcinoma. In contrast, approximately 30% are GS-negative without prominent nuclear or structural atypia. In this study, we examined the characteristics of the GS-negative tumors of TSOD mice. Twenty male TSOD mice were sacrificed at 40 weeks and a total of 21 tumors were analyzed by HE staining and immunostaining of GS, liver fatty acid-binding protein (L-FABP), serum amyloid A (SAA), and beta-catenin. With immunostaining for GS, six (29%) tumors were negative. Based on the histological and immunohistological characteristics, six GS-negative tumors were classified into several subtypes of human hepatocellular adenoma (HCA). One large tumor showed generally similar findings to inflammatory HCA, but contained small atypical foci with GS staining and partial nuclear beta-catenin expression suggesting malignant transformation. GS-negative tumors of TSOD mice contained features similar to various subtypes of HCA. Different HCA subtypes occurring in the same liver have been reported in humans; however, the diversity of patient backgrounds limits the ability to conduct a detailed, multifaceted analysis. TSOD mice may share similar mechanisms of HCA development as in humans. It is timely to review the pathogenesis of HCA from both genetic and environmental perspectives, and it is expected that TSOD mice will make further contributions in this regard.

Long-term complete remission of large hepatocellular adenoma after bariatric surgery.

We report the case of an obese woman with a large hepatocellular adenoma (HCA) of 8.0 cm in diameter, followed for 5 years after Roux-en-Y Gastric Bypass, with a complete radiologic remission of the liver mass. Four other cases have been published with HCA regression after bariatric surgery, but none with long-term follow-up. As the association between obesity and HCA has been increasingly described, bariatric surgery should be considered a therapeutic option for stage 2 obese patients.

Should bariatric surgery be offered for hepatocellular adenomas in obese patients?

BACKGROUND: Obesity and metabolic syndrome are increasingly recognized as risk factors for development of hepatocellular adenoma (HCA). The implications of weight loss on HCA regression has not been previously reviewed. OBJECTIVES: To analyze the effects of surgical and nonsurgical weight loss on HCA. SETTING: University Tertiary Hospital. METHODS: Literature review of full-text articles from PubMed and Scopus on patients with HCA who underwent surgical or nonsurgical weight loss was performed. Only English language articles were included and editorial comments were excluded. Wilcoxon signed rank test was used for paired data analysis. Spearman correlation was used for correlation between percent excess weight loss (%EWL) and number and size of HCA lesions. RESULTS: Out of 4 studies, 7 patients were included in this review, all of whom were female. The median preintervention body mass index was 41 kg/m2 compared with the postintervention body mass index of 28 kg/m2 (P = .002). The %EWL following intervention positively correlated to reduction in number of HCA lesions (%) postintervention, with a Spearman correlation of .78 (P = .04). Similarly, %EWL postintervention was positively correlated, though not statistically significant, to reduction in lesion size (%), with a Spearman correlation of .46 (P = .29). All patients who were candidates for liver resection preintervention based on lesion size > 5 cm avoided liver resection postintervention following surgical and nonsurgical weight loss. CONCLUSIONS: Effective long-term weight loss by surgical and nonsurgical methods result in regression of HCAs. Weight loss could avoid major liver resections or decrease the morbidity associated with liver surgery. Bariatric surgery should be considered as an option for management of surgically challenging HCAs in carefully selected obese patients. Multicenter long-term trials, while adjusting for cofounding factors, are required to determine the effects of surgical compared with nonsurgical weight loss on maintenance of HCA regression.

RETROSPECTIVE EVALUATION OF HEPATOCELLULAR NEOPLASMS IN NILE LECHWE (KOBUS MEGACEROS) FROM TWO FLORIDA ZOOLOGICAL INSTITUTIONS.

This case series describes hepatocellular neoplasms in 10 Nile lechwe (Kobus megaceros) at two separate zoological institutions in Florida. Histologically, the neoplasms were classified as hepatocellular carcinoma (n = 7), hepatocellular adenoma (n = 2), and hepatobiliary carcinoma (n = 1). Common clinical signs were nonspecific and included thin body condition (n =7), lethargy (n =6), lameness (n =3), and acute recumbency (n =5). Four males and six females were affected, and the mean age at death was 12.7 yr with a range of 4-18 yr. All cases were diagnosed postmortem, and metastasis to various sites, including lung, lymph nodes, and omentum, was found in 40% of cases (n = 4). A single case of hepatocellular carcinoma in a Nile lechwe was described in 2007; however, this is the first reported series of neoplasms in Reduncinae. The pathogenesis behind the development of hepatocellular neoplasms in Nile lechwe has not yet been identified.

Hepatocellular adenoma in Taiwan: Distinct ensemble of male predominance, overweight/obesity, and inflammatory subtype.

BACKGROUND AND AIM: The clinicopathologic features of hepatocellular adenoma in Asian populations have been poorly defined. The study aimed to characterize this rare entity in a single institution in Taiwan. METHODS: In total, 45 hepatocellular adenomas from 1995 to 2018 were included and sent for pathologic review and molecular subtyping. RESULTS: The numbers of patients with hepatocellular adenoma has doubled in the recent decade. Surprisingly, men outnumbered women in our cohort (n = 26, 58% vs N = 19, 42%). A collection of clinical information revealed that overweight/obesity accounts for most of the associated conditions of hepatocellular adenoma. Only three women took oral contraceptives. There were 34 inflammatory (75%), three LFABP-negative (7%), four ß-catenin activated (9%), and four unclassified (9%) hepatocellular adenomas. Ten inflammatory hepatocellular adenomas demonstrated strong and homogeneous glutamine synthetase staining and were thus also ß-catenin activated. Notably, overweight and obesity were significantly associated with inflammatory hepatocellular adenoma than other subtypes (P = .029 and .056, respectively) and were strongly correlated with steatosis in background liver (P = .028 and.007, respectively). Malignant transformation (four borderline tumors and two hepatocellular carcinomas) was identified in six adenomas (two women and four men). All six hepatocellular adenomas with malignancy were ß-catenin activated; ß-catenin activation could serve as a biomarker for malignant progression. CONCLUSIONS: The clinicopathologic features of hepatocellular adenoma in Taiwan are distinct from those reported in Western countries. Rare oral contraceptive usage and an emerging epidemic of overweight/obesity in Taiwan provides new insights into the pathogenesis of hepatocellular adenoma.

Glycemic control and complications in glycogen storage disease type I: Results from the Swiss registry.

BACKGROUND: Regular carbohydrate intake to avoid hypoglycemia is the mainstay of dietary treatment in glycogen storage disease type I (GSDI). The aim of this study was to evaluate the quality of dietary treatment and glycemic control in a cohort of GSDI patients, in relation to the presence of typical long-term complications. METHODS: Data of 25 patients (22 GSD subtype Ia and 3 GSDIb, median age 20y) from the Swiss hepatic glycogen storage disease registry was analyzed cross-sectionally. Frequency and type of hypoglycemia symptoms were assessed prospectively using a structured questionnaire. Diagnostic continuous glucose monitoring (CGM) was performed as part of usual clinical care to assess glycemic control in 14 patients, usually once per year with a mean duration of 6.2 ±â€¯1.1 consecutive days per patient per measurement. RESULTS: Although maintenance of euglycemia is the primary goal of dietary treatment, few patients (n = 3, 13%) performed capillary blood glucose measurements regularly. Symptoms possibly associated with hypoglycemia were present in 13 patients (57%), but CGM revealed periods of low glucose (<4 mmol/l) in all patients, irrespective of the presence of symptoms. GSDIa patients with liver adenomas (n = 9, 41%) showed a higher frequency and area under the curve (AUC) of low blood glucose than patients without adenomas (frequency 2.7 ±â€¯0.8 vs. 1.5 ±â€¯0.7 per day, AUC 0.11 ±â€¯0.08 vs. 0.03 ±â€¯0.02 mmol/l/d; p < 0.05). Similarly, the presence of microalbuminuria was also associated with the frequency of low blood glucose. Z-Scores of bone density correlated negatively with lactate levels. CONCLUSION: The quality of glucose control is related to the presence of typical long-term complications in GSDI. Many patients experience episodes of asymptomatic low blood glucose. Regular assessment of glucose control is an essential element to evaluate the quality of treatment, and increasing the frequency of glucose self-monitoring remains an important goal of patient education and motivation. CGM devices may support patients to optimize dietary therapy in everyday life.

Hepatocellular adenoma among adult survivors of childhood and young adult cancer.

Hepatocellular adenoma (HCA) is a rare benign epithelial neoplasm with potential for hemorrhage, rupture, or malignant transformation. Reported annual incidence of HCA is approximately 1/1,000,000. We identified 12 cases of HCA among adults with a history of childhood or young adult cancer. The most common cancer diagnosis was leukemia (N = 4). Five had undergone allogeneic hematopoietic stem cell transplant with total body irradiation. All 11 females had prior estrogen therapy; the male case was hypogonadal. This report suggests childhood and young adult cancer survivors may be at increased risk for HCA, but further investigation is needed.

Reappraisal of the Role of Portacaval Shunting in the Growth of Patients With Glycogen Storage Disease Type I in the Era of Liver Transplantation.

BACKGROUND: Instead of dietary modification, surgical management is considered for correcting growth retardation, poor metabolic control, and hepatocellular adenoma (HCA) in glycogen storage disease (GSD) type I. METHODS: The records of 55 GSD type I patients were retrospectively reviewed. Thirty-two patients underwent only dietary management (group D) and 23 underwent surgical management (group S). In group S, 17 underwent portacaval shunting (PCS), 13 underwent liver transplantation (LT; 7 underwent both PCS and LT). Height-for-age and body mass index-for-age Z-scores based on World Health Organization data were used to compare growth patterns before and after surgery. Changes in metabolic abnormalities and HCA after operation were also investigated. RESULTS: Height-for-age Z-scores for group S were higher by an average of 0.377 compared to that for group D. Metabolic abnormalities often disappeared after LT but improved partially after PCS. De novo HCA was detected in 4 patients (13%) from group D, 12 (100%) who underwent PCS, and none who underwent LT. One case of hepatocellular carcinoma and one of hemorrhage from a HCA were noted in group D. Two cases of hepatocellular carcinoma, 2 of hemorrhage, and 1 of necrosis were noted after PCS. CONCLUSIONS: Surgery yielded greater growth improvement than dietary management. However, after PCS, metabolic abnormalities remained unresolved, and the de novo HCA rate was high. Portacaval shunting can be used to improve growth in GSD type I patients when LT is not possible, but close observation for metabolic abnormalities and HCA is essential.

Hepatocellular Adenomas and Carcinoma in Asymptomatic, Non-Cirrhotic Type III Glycogen Storage Disease.

Glycogen storage diseases (GSDs) are a group of inherited metabolic disorders characterized by accumulation of abnormal glycogen in muscle or liver or both. Specific hepatic complications include liver adenomas and hepatocellular carcinoma (HCC). Hepatocellular carcinomas described in GSD type I are often due to the degeneration of liver adenomas. Hepatocellular carcinoma in GSD type III, however, is rare and is thought to be associated with underlying cirrhosis.We present the case of a 63-year old male who was admitted for assessment of suitability for liver transplantation because of development of recurrent HCC in the presence of multiple liver adenomas. A diagnosis of GSD type III was made in this patient without underlying cirrhosis or metabolic disturbances resembling GSD. This case report is the first documentation of HCC development in an asymptomatic, non-cirrhotic patient with GSD type III. This raises the possibility that in GSD type III, the adenoma - carcinoma sequence can occur as it is also seen in GSD type I. Physicians taking care of GSD patients should be aware of this and some form of surveillance for cirrhosis and HCC should be considered. Also male patients with adenomas should have a thorough workup to reveal any underlying disease such as GSD.

The Evolving Role of Nonalcoholic Fatty Liver Disease in Hepatic Neoplasia: Inflammatory Hepatocellular Adenoma in a Man with Metabolic Syndrome.

Growing awareness of the spectrum of liver diseases related to nonalcoholic fatty liver disease (NAFLD) has drawn attention to the complex pathogenetic pathways that are operative in livers with macrovesicular steatosis and to the potential development of hepatocellular adenoma and hepatocellular carcinoma in unusual clinical settings. This report describes an older man with metabolic syndrome who developed a 3.9 cm. right lobe liver mass that on directed needle biopsy showed the features of an inflammatory hepatocellular adenoma, including immunostain positivity for serum amyloid A. The case highlights the many factors involved in the pathogenesis of liver tumors in the steatotic liver of NAFLD, particularly the interplay of inflammatory mediators, adiponectin and leptin, genomics and metabolomics, lipotoxicity, endotoxin, and hepatic stellate cells.

Serum Amyloid A-Positive Hepatocellular Neoplasm: A New Type of Tumor Arising in Patients with Advanced Alcoholic Disease.

This chapter reviews a new type of hepatocellular neoplasm, serum amyloid A-positive hepatocellular neoplasm (SAA-HN), which arises in patients with advanced alcoholic liver disease such as cirrhosis. SAA-HNs share histological and immunohistochemical features with inflammatory hepatocellular adenoma, for example, a strong immunoreactivity for SAA. Clinicopathological features and issues regarding SAA-HN are reviewed with emphasis regarding its potential to develop into hepatocellular carcinoma.

Essential role of constitutive androstane receptor in Ginkgo biloba extract induced liver hypertrophy and hepatocarcinogenesis.

Ginkgo biloba extract (GBE) is commonly used as a herbal supplement. The National Toxicology Program (NTP) study of GBE reported clear evidence of hepatocarcinogenicity in mice. To clarify the mode of action (MOA) for hepatocarcinogenesis by GBE, we investigated the involvement of the constitutive androstane receptor (CAR) in hepatocarcinogenesis induced by GBE using CAR-knockout (CARKO) and wild type (WT) mice. We used the same lot of GBE that was used for the NTP study. In 1-week GBE dietary treatment, hepatocellular DNA replication was increased in WT mice but not in CARKO mice. In 4- or 13-week treatment, greater hepatic Cyp2b10 induction and hepatocellular hypertrophy were observed in WT mice, whereas these effects of GBE were much smaller in CARKO mice. In a two-stage hepatocarcinogenesis model initiated by diethylnitrosamine, 27-week treatment with GBE resulted in an increase of eosinophilic altered foci and adenomas in WT mice. By contrast, foci and adenomas were clearly less evident in CARKO mice. These results indicate that GBE-induced hepatocarcinogenesis is mainly CAR-mediated. Since CAR-mediated MOA for hepatocarcinogenesis in rodents is considered to be qualitatively implausible for humans, our findings would be helpful to evaluate the carcinogenic characterization of GBE to humans.

Giant hepatocellular adenoma in a previously obese thirteen-year-old boy.

Hepatocellular adenoma is an uncommon neoplasm, especially in the childhood age group. We describe a previously obese 13-year-old male with a giant hepatocellular adenoma requiring an extensive hepatic resection. The related pediatric tumor literature, diagnosis and clinical management is discussed.

YAP activation is an early event and a potential therapeutic target in liver cancer development.

BACKGROUND & AIMS: Although the growth suppressing Hippo pathway has been implicated in hepatocellular carcinoma (HCC) pathogenesis, it is unknown at which stage of hepatocarcinogenesis its dysregulation occurs. We investigated in rat and human preneoplastic lesions whether overexpression of the transcriptional co-activator Yes-associated protein (YAP) is an early event. METHODS: The experimental model used is the resistant-hepatocyte (R-H) rat model. Gene expression was determined by qRT-PCR or immunohistochemistry. Forward genetic experiments were performed in human HCC cells and in murine oval cells. RESULTS: All foci of preneoplastic hepatocytes, generated in rats 4weeks after diethylnitrosamine (DENA) treatment, displayed YAP accumulation. This was associated with down-regulation of the ß-TRCP ligase, known to mediate YAP degradation, and of microRNA-375, targeting YAP. YAP accumulation was paralleled by the up-regulation of its target genes. Increased YAP expression was also observed in human early dysplastic nodules and adenomas. Animal treatment with verteporfin (VP), which disrupts the formation of the YAP-TEAD complex, significantly reduced preneoplastic foci and oval cell proliferation. In vitro experiments confirmed that VP-mediated YAP inhibition impaired cell growth in HCC and oval cells; notably, oval cell transduction with wild type or active YAP conferred tumorigenic properties in vitro and in vivo. CONCLUSIONS: These results suggest that (i) YAP overexpression is an early event in rat and human liver tumourigenesis; (ii) it is critical for the clonal expansion of carcinogen-initiated hepatocytes and oval cells, and (iii) VP-induced disruption of the YAP-TEAD interaction may provide an important approach for the treatment of YAP-overexpressing cancers.

[Multiple large hepatocellular adenomas in a patient with glycogen storage disease type Ia].

A man diagnosed at birth with glycogen storage disease type Ia was found to have multiple hepatocellular adenomas at 15 years of age. At 18 years of age, he underwent transarterial tumor embolization in segments 4 and 5. At 27 years of age, the tumor in segment 4 had increased in size on follow-up computed tomography, and he was referred to our hospital. Because the tumor was large, increasing in size, and we could not exclude malignancy, we performed resection of segments 4 and 8 of the liver and partial resection of segment 5 for excisional biopsy. The pathological diagnosis was multiple inflammatory hepatocellular adenomas.