Multiple Hepatocellular Adenomas Research Articles

Long-term Evolution of Hepatocellular Adenomas at MRI Follow-up

Background Hepatocellular adenomas (HCAs) are rare benign liver tumors. Guidelines recommend continued surveillance of patients diagnosed with HCAs, but these guidelines are mainly based on small studies or expert opinion. Purpose To analyze the long-term evolution of HCAs, including solitary and multiple lesions, and to identify predictive features of progression with MRI. Materials and Methods In a retrospective study, patients diagnosed with pathologically proven solitary or multiple HCAs between January 2004 and December 2015 were included; β-catenin-mutated HCAs and HCAs with foci of malignancy were considered to be at risk for progression. MRI examinations were analyzed, and tumor evolution was evaluated by using Response Evaluation Criteria in Solid Tumors, version 1.1. Student t, Mann-Whitney, χ2, Fisher exact, and McNemar tests were used, as appropriate. Results In total, 118 patients (mean age, 40 years ± 10 [standard deviation]; 108 women) were evaluated, including 41 with a solitary HCA (mean age, 40 years ± 14; 36 women) and 77 with multiple HCAs (mean age, 40 years ± 10; 72 women). At a median follow-up of 5 years, 37 of 41 (90%) patients with a solitary HCA and 55 of 77 (71%) patients with multiple HCAs showed stable or regressive disease. After resection of solitary HCAs, new lesions appeared in only two of 29 (7%) patients, both of whom had HCAs at risk of progression. In patients with multiple HCAs, hepatocyte nuclear factor 1α-inactivated HCAs showed a higher rate of progression compared with inflammatory HCAs (11 of 26 [42%] vs seven of 37 [19%], P = .04) despite lower use (28 of 32 patients [88%] vs 45 of 45 patients [100%]; P = .03) and shorter duration (mean, 12.0 years ± 7.5 vs 19.2 years ± 9.2; P = .001) of oral contraceptive intake. Conclusion Long-term MRI follow-up showed that 78% of hepatocellular adenomas had long-term stability or regression. After resection of solitary hepatocellular adenomas, new lesions occurred only in hepatocellular adenomas at risk of progression. Patients with multiple hepatocellular adenomas were more likely to show progressive disease, with hepatic nuclear factor 1α-inactivated hepatocellular adenomas being the most common subtype showing progression. © RSNA, 2020 Online supplemental material is available for this article.

Case of resected multiple hepatocellular adenomas in a young man with severe obesity

BackgroundHepatocellular adenoma (HCA) is a rare liver tumor that has the potential for rupture and malignant transformation. Here, we report a case of multiple hepatocellular adenomas (HCAs) that were treated by surgical resection.Case presentationAn 18-year-old man was admitted to our hospital with proteinuria. His height was 176.5 cm, weight was 126 kg, and body mass index was 40 kg/m2. A liver tumor was incidentally found on abdominal ultrasonography. Contrast-enhanced computed tomography and gadoxetic acid-enhanced magnetic resonance imaging revealed three hepatic tumors that were 68 mm, 16 mm, and 9 mm in segments 3/4, 8, and 1, respectively. A percutaneous needle biopsy of the largest tumor was performed, the diagnosis of unclassified type HCA was made, and laparoscopic partial liver resection was performed of all three. The postoperative course was uneventful, and the patient was discharged 12 days later. An immunohistochemical examination revealed positivity for serum amyloid A protein, no decrease in fatty acid-binding protein, and negativity for β-catenin, glutamine synthetase, and cytokeratin 7. Therefore, these tumors were diagnosed as inflammatory type HCAs.ConclusionsWe reported an extremely rare case of multiple resected HCAs in a young, obese Japanese man. Our findings suggest that HCA should be considered in the differential diagnosis of liver tumor in obese patients. Further studies that consider clinical and molecular risk factors are required to establish individualized treatment plans for HCA in obese patients.

Regression of hepatocellular adenoma after bariatric surgery in severe obese patients.

Obesity and metabolic syndrome are increasingly recognized as risk factors for hepatocellular adenomas (HCA). There is still sparse evidence whether weight loss or bariatric surgery could induce HCA regression in these patients. In this brief report we describe the effect of weight loss on HCA regression in severe obese patients that had undergone bariatric surgery in our centre. We performed an Electronic Patient Database search and included all patients who underwent bariatric surgery in our bariatric referral centre and had an ICD-10 code of benign neoplasm of liver in our centre from (2006-2017). All imaging studies of eligible patients were re-evaluated by the study radiologist. Primary outcome was change in maximal diameter of HCA. Six of 11 eligible patients were excluded because their lesions were classified as probable focal nodular hyperplasia and two were lost to follow-up. Finally, three women with solitary (n=1) or multiple HCA (n=2) and a body mass index (BMI) ranging between 39 and 50kg/m2 were included. In two patients, HCA completely regressed in 1-2years following bariatric surgery, after BMI reductions of 36%-48%. The third patient showed a reduction of >50% in diameter of the largest HCA in 2.5years after bariatric surgery (31% BMI reduction), with complete resolution of smaller HCA. Bariatric induced weight loss results in significant regression of HCA in severe obese women, which emphasizes the role of overweight in HCA pathophysiology.

Molecular Classification of Hepatocellular Adenoma Associates With Risk Factors, Bleeding, and Malignant Transformation

Hepatocellular adenomas (HCAs) are benign liver tumors that can be assigned to molecular subtypes based on inactivating mutations in hepatocyte nuclear factor 1A, activating mutations in β-catenin, or activation of inflammatory signaling pathways. We aimed to update the classification system for HCA and associate the subtypes with disease risk factors and complications. We analyzed expression levels of 20 genes and sequenced exon regions of 8 genes (HNF1A, IL6ST, CTNNB1, FRK, STAT3, GNAS, JAK1, and TERT) in 607 samples of 533 HCAs from 411 patients, collected from 28 centers mainly in France from 2000 and 2014. We performed gene expression profile, RNA sequence, whole-exome and genome sequence, and immunohistochemical analyses of select samples. Molecular data were associated with risk factors, histopathology, bleeding, and malignant transformation. Symptomatic bleeding occurred in 14% of the patients (85% of cases were female, median age, 38 years); 7% of the nodules were borderline between HCA and hepatocellular carcinoma, and 3% of patients developed hepatocellular carcinoma from HCA. Based on molecular features, we classified HCA into 8 subgroups. One new subgroup, composed of previously unclassified HCA, represented 4% of HCAs overall and was associated with obesity and bleeding. These tumors were characterized by activation of sonic hedgehog signaling, due to focal deletions that fuse the promoter of INHBE with GLI1. Analysis of genetic heterogeneity among multiple HCAs, from different patients, revealed a molecular subtype field effect; multiple tumors had different mutations that deregulated similar pathways. Specific molecular subtypes of HCA associated with various HCA risk factors, including imbalances in estrogen or androgen hormones. Specific molecular subgroup of HCA with β-catenin and sonic hedgehog activation associated with malignant transformation and bleeding, respectively. Using sequencing and gene expression analyses, we identified a subgroup of HCA characterized by fusion of the INHBE and GLI1 genes and activation of sonic hedgehog pathway. Molecular subtypes of HCAs associated with different patients' risk factors for HCA,disease progression, and pathology features of tumors. This classification system might be used to select treatment strategies for patients withHCA.

Development of hepatocellular adenomas and carcinomas in mice with liver-specific G6Pase-α deficiency.

Glycogen storage disease type 1a (GSD-1a) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α), and is characterized by impaired glucose homeostasis and a high risk of developing hepatocellular adenomas (HCAs). A globally G6Pase-α-deficient (G6pc−/−) mouse model that shows pathological features similar to those of humans with GSD-1a has been developed. These mice show a very severe phenotype of disturbed glucose homeostasis and rarely live beyond weaning. We generated liver-specific G6Pase-α-deficient (LS‑G6pc−/−) mice as an alternative animal model for studying the long-term pathophysiology of the liver and the potential treatment strategies, such as cell therapy. LS‑G6pc−/− mice were viable and exhibited normal glucose profiles in the fed state, but showed significantly lower blood glucose levels than their control littermates after 6 hours of fasting. LS‑G6pc−/− mice developed hepatomegaly with glycogen accumulation and hepatic steatosis, and progressive hepatic degeneration. Ninety percent of the mice analyzed developed amyloidosis by 12 months of age. Finally, 25% of the mice sacrificed at age 10–20 months showed the presence of multiple HCAs and in one case late development of hepatocellular carcinoma (HCC). In conclusion, LS‑G6pc−/− mice manifest hepatic symptoms similar to those of human GSD-1a and, therefore, represent a valid model to evaluate long-term liver pathogenesis of GSD-1a.

Successful treatment of multiple hepatocellular adenomas with percutaneous radiofrequency ablation

Hepatocellular adenoma (HCA) is one of the important complications of glycogen storage disease type Ia (GSD-Ia) because it can be transformed into hepatocellular carcinoma. Although surgical resection is a standard treatment of choice for solitary HCA, multiple HCAs in GSD-Ia patients present as therapeutic challenges for curative treatment. Therefore, treatment strategy according to malignant potential is important in management of HCAs in GSD-Ia. The authors present a case of histologically proven multiple HCAs without β-catenin mutations occurred in a GSD-Ia patient treated successfully with percutaneous radiofrequency ablation as a minimally invasive therapy.

Multiple hepatocellular adenomas in a patient with glycogen storage disease type I: various enhancement patterns in MRI with Gd-EOB-DTPA

The patient is a 20-year-old man with glycogen storage disease type I (GSD-type I). In his teens, multiple focal hepatic masses were detected on abdominal ultrasonography (US), which were diagnosed as multiple hepatocellular adenomas from the imaging. During follow-up, these masses had shown intermittent growth in size. In the evaluation of Gd-EOB-DTPA (gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid) MR imaging, these masses showed various signal intensities from hypo- to hyperintense during the hepatocyte-specific phase. Intermittent growth and elevation of serum PIVKA-II levels indicate the potential for malignant transformation, so the patient underwent partial hepatectomy. The resected masses were all consistent with benign hepatocellular adenomas histopathologically.

Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas

Glycogen storage disease type 1a (GSD1a) is an inherited disease caused by a deficiency in the catalytic subunit of the glucose-6 phosphatase enzyme (G6Pase). GSD1a is characterized by hypoglycaemia, hyperlipidemia, and lactic acidosis with associated hepatic (including hepatocellular adenomas), renal, and intestinal disorders. A total G6pc (catalytic subunit of G6Pase) knock-out mouse model has been generated that mimics the human pathology. However, these mice rarely live longer than 3 months and long-term liver pathogenesis cannot be evaluated. Herein, we report the long-term characterization of a liver-specific G6pc knock-out mouse model (L-G6pc(-/-)). We generated L-G6pc(-/-) mice using an inducible CRE-lox strategy and followed up the development of hepatic tumours using magnetic resonance imaging. L-G6pc(-/-) mice are viable and exhibit normoglycemia in the fed state. They develop hyperlipidemia, lactic acidosis, and uricemia during the first month after gene deletion. However, these plasmatic parameters improved after 6 months. L-G6pc(-/-) mice develop hepatomegaly with glycogen accumulation and hepatic steatosis. Using an MRI approach, we could detect hepatic nodules with diameters of less than 1 mm, 9 months after induction of deficiency. Hepatic nodules (1 mm) were detected in 30-40% of L-G6pc(-/-) mice at 12 months. After 18 months, all L-G6pc(-/-) mice developed multiple hepatocellular adenomas of 1-10 mm diameter. This is the first report of a viable animal model of the hepatic pathology of GSD1a, including the late development of hepatocellular adenomas.

Liver transplantation for glycogen storage disease type Ia

Hepatocellular carcinoma (HCC) most often occurs within hepatocellular adenomas (HCAs) in glycogen storage disease Ia (GSD Ia) patients. The objective of this retrospective study is to assess outcomes after liver transplantation (LT) for GSD Ia where the principal indication for transplantation was prevention of HCC. Petitions to the United Network for Organ Sharing region 11 review board for additional model for end-stage liver disease listing points were made on behalf of GSD Ia patients. Demographics, pre-operative comorbidity, and outcomes for GSD Ia patients who underwent LT were reviewed. Between 2004 and 2006, five GSD Ia patients underwent LT. Multiple HCAs with focal hemorrhage and/or necrosis but without histological evidence of malignancy were identified in all explanted specimens. Four of five patients had complications after LT, including cytomegalovirus (CMV) infections and steroid responsive allograft rejection. Hemoglobin levels and serum triglyceride, total cholesterol, blood glucose, and lactic acid concentrations improved in all patients after LT. Corn starch feeding was not required in any patient after LT. Renal function worsened in three patients despite modifications to primary immunosuppressive medications. All patients are alive at last follow-up (range 25-48 months) and all post-transplant complications have resolved. By removing all possible adenomatous tissue and reversing the underlying hepatic enzymatic deficiency, LT provides definitive prevention against HCC and correction of most metabolic derangements in GSD Ia patients. Renal dysfunction secondary to GSD Ia persists--underscoring the need for further studies to better understand the mechanisms of renal dysfunction in these patients.

Hepatocellular Neoplasms Induced by Low-Number Pancreatic Islet Transplants in Autoimmune Diabetic BB/Pfd Rats

It has been shown that combined high local hyperinsulinism and hyperglycemia after low-number islet transplantation into the livers of streptozotocin-diabetic rats lead to the development of hepatocellular neoplasms but a substantial cocarcinogenic effect of genotoxic streptozotocin could not be ruled out completely. Thus, we herein investigated this model in BB/Pfd rats (n = 805; nine experimental groups), which develop spontaneous autoimmune diabetes similar to human type 1 diabetes. After low-number islet transplantation (n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione-S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-alpha. After 12 to 15 and 15 to 18 months, 52% and 100% of the animals showed one or multiple hepatocellular adenomas or hepatocellular carcinomas (HCCs), respectively. Conclusively, this study identifies combined hyperinsulinism and hyperglycemia as a carcinogenic mechanism for the development of HCCs in diabetic rats. Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-alpha.

Hepatocellular neoplasms induced by low-number pancreatic islet transplants in autoimmune diabetic BB/Pfd rats

It has been shown that combined high local hyperinsulinism and hyperglycemia after low-number islet transplantation into the livers of streptozotocin-diabetic rats lead to the development of hepatocellular neoplasms but a substantial cocarcinogenic effect of genotoxic streptozotocin could not be ruled out completely. Thus, we herein investigated this model in BB/Pfd rats ( n = 805; nine experimental groups), which develop spontaneous autoimmune diabetes similar to human type 1 diabetes. After low-number islet transplantation ( n = 450), the liver acini downstream of the islets show insulin-induced alterations: massive glycogen and/or fat accumulation, translocation of the insulin receptor, decrease in glucose-6-phosphatase activity, increase in expression of insulin-like growth factor (IGF)-I, IGF-II/mannose-6-phosphate receptor, insulin receptor substrate-1, Raf-1, and Mek-1, corresponding to clear cell preneoplastic foci of altered hepatocytes known from chemical hepatocarcinogenesis and identical to that in streptozotocin-diabetic Lewis rats. After 6 months, many altered liver acini progressed to other types of preneoplasias often accompanied by an overexpression of the glutathione- S transferase (placental form), IGF-I receptor, and transforming growth factor (TGF)-α. After 12 to 15 and 15 to 18 months, 52% and 100% of the animals showed one or multiple hepatocellular adenomas or hepatocellular carcinomas (HCCs), respectively. Conclusively, this study identifies combined hyperinsulinism and hyperglycemia as a carcinogenic mechanism for the development of HCCs in diabetic rats. Hepatocarcinogenesis is independent from additional genotoxic compounds (i.e., streptozotocin), but is primarily triggered by increased intracellular insulin signaling via pathways associated with cell growth and proliferation, such as the Ras-Raf-mitogen-activated protein kinase pathway and the IGF system, and secondarily involves other growth factors, such as TGF-α. (Cancer Res 2006; 66(3): 1833-43)

Decreased Longevity and Enhancement of Age-Dependent Lesions in Mice Lacking the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα)

The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is activated by peroxisome proliferators (PP), a large class of structurally diverse xenobiotic chemicals, hypolipidemic drugs, and endogenous lipids. PPARalpha alters the transcriptional programs of genes whose functions include lipid metabolism, inflammation, cell fate, and stress responses in liver, heart, kidney, and skin. Many of these genes are also under control of PPARalpha in the absence of exogenous peroxisome proliferator exposure. Mice that lack PPARalpha (PPARalpha-null mice) exhibit a number of defects in lipid metabolism and accumulate lipids in the liver. Here, we compared the age-dependent lesions in the liver, kidney, and heart in PPARalpha-null mice with those observed in wild-type SV129 mice, in the absence of exogenous chemical exposure. Groups of mice were sacrificed, at 6, 12, 18, 21, or 24 months of age, or allowed to age until moribund or found dead. PPARalpha-null mice had decreased longevity, due to a variety of causes. Statistically significant differences in the occurrence of a number of lesions between strains was observed. Hepatocellular carcinomas and multiple hepatocellular adenomas occurred in PPARa-null mice but not wild type mice. Various nonneoplastic spontaneous aging lesions occurred at higher incidence, shorter latency, or increased severity in PPARalpha-null mice compared with wild-type mice. In the liver, these included vacuolated hepatocytes and sinusoidal cells and mixed cell inflammation. The kidneys of PPARalpha-null mice exhibited higher incidences and severities of cortical mineralization. Minimal myocardial mineralization occurred at a higher incidence in PPARalpha-null mice. Our results imply that PPARalpha delays the development of some spontaneous lesions associated with aging in the liver, kidney, and heart of SV129 mice.

Enhancement of N-Nitrosodiethylamine-lnitiated Hepatocarcinogenesis by Phenytoin in Male F344/NCr Rats at a Dose Causing Maximal Induction of CYP2B

The effect of the clinically important anticonvulsant phenytoin (DPH) on hepatocarcinogenesis of male F344/NCr rats initiated with a single i.p. dose of N-nitrosodiethylamine (75 mg/kg b.w.) was studied. Beginning 2 weeks post-initiation, the rats received control diet or diet containing 500 or 1500 ppm DPH or 500 ppm phenobarbital. At 52 weeks age, the incidences (and multiplicities, in units of tumors per tumor-bearing rat) of hepatocellular adenomas were 0%, 17% (1 ± 0), 42% (1.8 ± 0.8), or 67% (2.5 ± 1.9) in rats exposed to N-nitrosodiethylamine alone, or the carcinogen followed by 500 ppm DPH, 1500 ppm DPH, or 500 ppm phenobarbital, respectively. Between 53 and 79 weeks of age, 39% of rats receiving N-nitrosodiethylamine alone developed multiple (1.5 ± 0.8) hepatocellular adenomas. A similar incidence (41%) occurred in the rats administered the carcinogen followed by 500 ppm DPH. The incidence of hepatocellular adenomas (88% and 89%) was significantly greater in rats exposed to N-nitrosodiethylamine followed by 1500 ppm DPH or 500 ppm phenobarbital, respectively. Multiplicities of hepatocellular adenomas were significantly greater than the control value in rats fed 1500 ppm DPH or 500 ppm phenobarbital (5.9 ± 4.8 and 10.1 ± 6.7, respectively), but not in the rats receiving 500 ppm DPH (2.3 ± 1.6). No rats exposed to N-nitrosodiethylamine alone or the carcinogen followed by 500 ppm DPH developed hepatocellular carcinomas, while hepatocellular carcinomas occurred in 29% or 67% of the rats given 1500 ppm DPH or 500 ppm phenobarbital, respectively, following initiation. Increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylation activity in rats exposed to 500 and 1500 ppm DPH for 2 or 23 weeks were ∼50% and ∼100%, respectively, of the maximal induction caused by 500 ppm phenobarbital. Thus, in the rat model, DPH enhanced N-nitrosodiethyl-amine-initiated hepatocarcinogenesis when administered at a dose causing maximal CYP2B induction.

Enhancement of N-nitrosodiethylamine-initiated hepatocarcinogenesis by phentoin in male F344/NCr rats at a dose causing maximal induction of CYP2B.

The effect of the clinically important anticonvulsant phenytoin (DPH) on hepatocarcinogenesis of male F344/NCr rats initiated with a single i.p. dose of N-nitrosodiethylamine (75 mg/kg b.w.) was studied. Beginning 2 weeks post-initiation, the rats received control diet or diet containing 500 or 1,500 ppm DPH or 500 ppm phenobarbital. At 52 weeks age, the incidences (and multiplicities, in units of tumors per tumor-bearing rat) of hepatocellular adenomas were 0%, 17% (1 +/- 0), 42% (1.8 +/- 0.8), or 67% (2.5 +/- 1.9) in rats exposed to N-nitrosodiethylamine alone, or the carcinogen followed by 500 ppm DPH, 1,500 ppm DPH, or 500 ppm phenobarbital, respectively. Between 53 and 79 weeks of age, 39% of rats receiving N-nitrosodiethylamine alone developed multiple (1.5 +/- 0.8) hepatocellular adenomas. A similar incidence (41%) occurred in the rats administered the carcinogen followed by 500 ppm DPH. The incidence of hepatocellular adenomas (88% and 89%) was significantly greater in rats exposed to N-nitrosodiethylamine followed by 1,500 ppm DPH or 500 ppm phenobarbital, respectively. Multiplicities of hepatocellular adenomas were significantly greater than the control value in rats fed 1,500 ppm DPH or 500 ppm phenobarbital (5.9 +/- 4.8 and 10.1 +/- 6.7, respectively), but not in the rats receiving 500 ppm DPH (2.3 +/- 1.6). No rats exposed to N-nitrosodiethylamine alone or the carcinogen followed by 500 ppm DPH developed hepatocellular carcinomas, while hepatocellular carcinomas occurred in 29% or 67% of the rats given 1,500 ppm DPH or 500 ppm phenobarbital, respectively, following initiation. Increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylation activity in rats exposed to 500 and 1,500 ppm DPH for 2 or 23 weeks were approximately 50% and approximately 100%, respectively, of the maximal induction caused by 500 ppm phenobarbital. Thus, in the rat model, DPH enhanced N-nitrosodiethyl-amine-initiated hepatocarcinogenesis when administered at a dose causing maximal CYP2B induction.

Multiple hepatocellular adenomas associated with long‐term carbamazepine

HistopathologyVolume 35, Issue 1 p. 92-94 Multiple hepatocellular adenomas associated with long-term carbamazepine K Tazawa, K Tazawa Departments of Pathology,Search for more papers by this authorM Yasuda, M Yasuda Departments of Pathology,Search for more papers by this authorY Ohtani, Y Ohtani Surgery, School of Medicine, Tokai University, School of Medicine, Kanagawa, JapanSearch for more papers by this authorH Makuuchi, H Makuuchi Surgery, School of Medicine, Tokai University, School of Medicine, Kanagawa, JapanSearch for more papers by this authorR Y Osamura, R Y Osamura Departments of Pathology,Search for more papers by this author K Tazawa, K Tazawa Departments of Pathology,Search for more papers by this authorM Yasuda, M Yasuda Departments of Pathology,Search for more papers by this authorY Ohtani, Y Ohtani Surgery, School of Medicine, Tokai University, School of Medicine, Kanagawa, JapanSearch for more papers by this authorH Makuuchi, H Makuuchi Surgery, School of Medicine, Tokai University, School of Medicine, Kanagawa, JapanSearch for more papers by this authorR Y Osamura, R Y Osamura Departments of Pathology,Search for more papers by this author First published: 10 December 2003 https://doi.org/10.1046/j.1365-2559.1999.0728g.xCitations: 15Read the full textAbout ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume35, Issue1July 1999Pages 92-94 RelatedInformation

Multiple hepatocellular adenomas in a patient with a history of oral contraception

We report a previously undescribed association between multiple hepatocellular adenomas and the use of oral contraceptives in a 29-year-old woman. She underwent trisegmentectomy, with 90% of the liver resected. Based on the rather large size of some of the adenomas at the time of diagnosis, most likely, the lesions were already present years before they were discovered. The liver was fully regenerated 6 months after surgery. Four years later, multiple adenomas recurred. During work-up for a liver transplant, she was found to have cryptococcal meningitis and pneumohydrocephalus which caused her demise.

Enhancement of thyroid and hepatocarcinogenesis by 1,4-bis[2-(3,5- dichloropyridyloxy)]benzene in rats at doses that cause maximal induction of CYP2B.

To investigate the promoting effects of 1,4-bis[2-(3,5- dichloropyridyloxy)]benzene (TCPOBOP) on liver and thyroid carcinogenesis of rats at doses that cause maximal induction of hepatic CYP2B, 5-week-old male F344 rats were given either a single i.p. dose of 75 mg N-nitrosodiethylamine (NDEA)/kg body wt in saline or saline alone. After 2 weeks the rats were fed control diet or a diet containing 330 or 1000 p.p.m. TCPOBOP or 500 p.p.m. phenobarbital (PB; a positive control group). A total of four sequential sacrifices (9, 30, 52 and 79 weeks of age) was performed. At 30 weeks the mean volume (mm3) of hepatocellular foci in NDEA-initiated rats exposed to either dose of TCPOBOP or to PB was significantly increased as compared with rats exposed to NDEA followed by control diet (P < 0.05). In addition, the volume percentage of liver occupied by foci was significantly greater in NDEA-initiated/1000 p.p.m. TCPOBOP-promoted rats as compared with rats exposed to NDEA alone (P < 0.05, n = 6). At 52 weeks of age the incidences (and multiplicities, in units of tumors per tumor-bearing rat) of hepatocellular adenomas were 0, 83 (2.6 +/- 1.3), 100 (3.4 +/- 2.1) or 67% (2.5 +/- 1.9) in rats exposed to NDEA alone or NDEA followed by 330 or 1000 p.p.m. TCPOBOP or 500 p.p.m. PB respectively (n = 12). Hepatocellular carcinomas were found only in rats given 1000 p.p.m. TCPOBOP (17% incidence) or PB (8% incidence) following NDEA initiation. The incidences of thyroid follicular cell adenomas were 0, 17, 33 or 8% in rats exposed to NDEA alone or NDEA followed by 330 or 1000 p.p.m. TCPOBOP or 500 p.p.m. PB respectively. Between 53 and 79 weeks of age 38% of rats treated with NDEA alone developed multiple (1.5 +/- 0.8) hepatocellular adenomas. This incidence was enhanced to 100% in rats exposed to NDEA followed by either 330 or 1000 p.p.m. TCPOBOP. Multiplicities of hepatocellular adenomas were also increased significantly (10.5 +/- 3.9, 10.4 +/- 7.0 and 10.1 +/- 6.7 respectively) in rats promoted with 330 or 1000 p.p.m. TCPOBOP or 500 p.p.m. PB. None of the rats exposed to NDEA alone developed hepatocellular carcinomas, while multiple hepatocellular carcinomas occurred in 38% of the rats exposed to 330 p.p.m. and 78% of the rats given 1000 p.p.m. TCPOBOP following NDEA initiation. Thyroid follicular cell tumors occurred at 79 weeks in more than 40 and 50% incidences in rats exposed to NDEA followed by 330 or 1000 p.p.m. TCPOBOP respectively. Also, a significant decrease in serum levels of triiodothyronine and thyroxine were observed in non-initiated 79-week-old rats fed 1000 p.p.m. TCPOBOP, compared with age-matched untreated controls (n = 6). Increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylase activity detected in rats exposed to 330 and 1000 p.p.m. TCPOBOP for 2 or 23 weeks were similar in magnitude to those caused by 500 p.p.m. PB. Thus TCPOBOP at maximal CYP2B induction doses exhibits a strong promoting activity for both liver and thyroid of rats.

Comparative Carcinogenicity of Polybrominated Biphenyls with or without Perinatal Exposure in Rats and Mice

Comparative Carcinogenicity of Polybrominated Biphenyls with or without Perinatal Exposure in Rats and Mice. Chhabra, R. S., Bucher, J. R., Haseman, J. K., Elwell, M. R., Kurtz, P. J., and Carlton, B. D. (1993). Fundam. Appl. Toxicol. 21, 451-460.Chronic toxicity and carcinogenicity studies of a polybrominated biphenyl mixture (PBB) were conducted in F344/N rats and B6C3F1 mice of each sex. The major objective of the study was to determine if exposure to PBB during the perinatal period, in addition to conventional exposure of animals for 2 years, enhances the sensitivity of the bioassay to identify the carcinogenic potential of this chemical. The studies were designed to determine the toxic and carcinogenic effects of dietary PBB in rats and mice receiving (i) perinatal exposure up to 8 weeks of age followed by control diet for 2 years, (ii) exposure for 2 years beginning at the age of 8 weeks, and (iii) combined perinatal/adult exposure to PBB (perinatal exposure to 8 weeks of age followed by adult exposure for 2 years). During the perinatal period, rats were exposed to PBB at close levels ranging from 1 to 10 ppm and adult exposure concentrations ranged from 3 to 30 ppm in the diet. In the mice, the dose levels ranged from 3 to 30 ppm in both perinatal and adult exposure portions of the chronic studies. A total of eight dose groups (including controls) were used with 60 animals in each group. Liver was the major target organ of PBB toxicity. Perinatal exposure alone (through dietary administration of 10 ppm PBB to the dams) had no effect on the incidences of neoplasms in female F344/N rats, but in male rats, perinatal exposure was associated with a marginally increased incidence of hepatocellular adenomas that may have been related to chemical administration. In male and female B6C3F1 mice, perinatal exposure to 30 ppm PBB resulted in significantly increased incidences of hepatocellular neoplasms. In adult-only dietary exposure studies, PBB was carcinogenic in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Combined perinatal and adult dietary exposure to PBB confirmed the findings of the adult-only exposures for the increased incidences of hepatocellular neoplasms in rats and mice. In male rats, there were no enhancing effects of combined perinatal and adult exposure. However, perinatal exposure enhanced the susceptibility of female rats receiving adult exposure of 10 or 30 ppm to the induction of liver neoplasms. For male and female rats, a combined analysis of the incidences of leukemia in the adult-only, perinatal-only, and combined perinatal and adult exposure groups revealed an apparent association between increasing incidences of mononuclear cell leukemia and exposure to PBB. In male and female mice, it was not possible to adequately assess the enhancing effects of combined perinatal and adult exposure on hepatocellular tumors, because adult-only exposure to 10 or 30 ppm PBB resulted in high incidences (84-98%) of liver neoplasms. However, with increased perinatal exposure, there were increases in the numbers of mice with hepatocellular carcinomas and in the numbers of mice with multiple hepatocellular adenomas, suggesting that combined perinatal and adult exposure increases PBB-related hepatocellular carcinogenicity relative to adult-only exposure.

Tumor promotion by an anticonvulsant agent, phenytoin, in mouse liver: correlation with CYP2B induction.

To investigate the liver tumor promoting effects of phenytoin (5,5-diphenylhydantoin; DPH), 5 week old male D2B6F1 mice were given a single i.p. dose of 90 mg N-nitrosodiethylamine (NDEA)/kg body wt in tricaprylin. Control groups received tricaprylin alone. After 2 weeks, the mice were given a diet containing 500, 250 or 125 p.p.m. DPH. Ten mice from each treatment group were killed at 30 weeks of age, at which time 10/10 mice given 500 p.p.m. DPH after NDEA initiation had developed multiple hepatocellular foci and adenomas. Such lesions were found only in 2/10 mice given NDEA alone. By 60 weeks, when the experiment was concluded, the incidences (and multiplicities, in units of tumors per tumor-bearing mouse) of hepatocellular adenomas were 60% (1.8 +/- 0.8), 100% (11.6 +/- 5.5), 77% (4.4 +/- 3.3) or 71% (2.6 +/- 1.3) in mice exposed to NDEA alone, or NDEA followed by 500, 250 or 125 p.p.m. DPH respectively. Hepatocellular carcinomas (87% incidence) and hepatoblastomas (33% incidence) were found only in mice given 500 p.p.m. DPH following NDEA initiation. Dose-dependent and profound increases in hepatic CYP2B-mediated benzyloxyresorufin O-dealkylase activity were detected in livers of B6C3F1 mice exposed for 14 days to dietary DPH (125, 250, 500 or 1000 p.p.m.). Similar increases in this activity were observed in D2B6F1 mice exposed to 500 and 250 p.p.m. for 30 or 60 weeks. Thus, increased hepatic CYP2B activity in mice exposed to DPH correlates with the tumor promoting effect of this compound.

Susceptibility to phenobarbital promotion of hepatotumorigenesis: correlation with differential expression and induction of hepatic drug metabolizing enzymes in heavy an dlight male (C3H × VY) F1 hybrid mice

Higher body and carcass (body - liver) weights in sodium phenobarbital (PB) treated mice correlate with formation of multiple hepatocellular adenomas in yellow Avy/A and agouti A/a (C3H x VY) F1 hybrid male mice. To assess differences in PB induction of hepatic drug metabolizing enzymes, yellow Avy/A (C3H x VY) F1 hybrid male mice were fed 0.05% sodium PB in NIH-31 diet for 7 months. Livers from the heaviest and lightest mice in the untreated and PB groups were assayed. Total cytochrome P450 content, cytochrome P450IA-selective 7-ethoxyresorufin-O-deethylase and P450IIIA-selective testosterone-6 beta-hydroxylase activities were preferentially induced in the light mice. In contrast, P450IIB-selective 7-pentoxyresorufin-O-dealkylase activity was increased only 3-fold by PB in the light mice but 6-fold in the heavy mice. Testosterone UDP-glucuronyltransferase and gamma-glutamyltranspeptidase activities were induced in the light mice but not in the heavy mice. Glutathione-S-transferase N1:1-dependent activity was induced preferentially in the heavy mice. Significant differences also occurred in constitutive expression of P450IIIA-selective testosterone-6 beta-hydroxylase, P450IA-selective 7-ethoxyresorufin-O-deethylase and testosterone UDP-glucuronyltransferase activities between the untreated weight groups. Thus, expression of constitutive and PB-inducible forms of hepatic drug metabolizing enzymes differs between heavy and light Avy/A (C3H x VY) F1 hybrid subpopulations. This suggests that differential susceptibility to PB promotion of hepatocellular adenomas among genetically identical mice is accompanied by differences in the regulation of gene expression.