Resolution of a Contraceptive-Steroid-Induced Hepatic Adenoma with Subsequent Evolution into Hepatocellular Carcinoma

Sc, Gordon; Reddy, K. Rajender; As, Livingstone; Jeffers, L; Er, Schiff

doi:10.7326/0003-4819-105-4-547

Cited by 100 publications

(52 citation statements)

References 7 publications

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“…Here, we found that malignant transformation can occur and be detected at the time of the HCA diagnosis and also during follow-up, which echoes previous cases described. [15][16][17] Our key finding concerns the now possible early and robust detection of these ␤-catenin-activated adenomas, which can be very difficult to differentiate from an already well-differentiated grade 1 HCC, as previously demonstrated. 4 However, we have to stress the well-known difficulty of making the distinction between dysplastic HCA, exhibiting some cytonuclear abnormalities (corresponding mainly in our study to ␤-catenin-activated HCA) and well-differentiated HCC.…”

Section: Discussionmentioning

confidence: 95%

Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry

et al. 2007

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Hepatocellular adenomas (HCA) with activated ␤-catenin present a high risk of malignant transformation. To permit robust routine diagnosis to allow for HCA subtype classification, we searched new useful markers. We analyzed the expression of candidate genes by quantitative reverse transcription polymerase chain reaction QRT-PCR followed by immunohistochemistry to validate their specificity and sensitivity according to hepatocyte nuclear factor 1 alpha (HNF1␣) and ␤-catenin mutations as well as inflammatory phenotype. Quantitative RT-PCR showed that FABP1 (liver fatty acid binding protein) and UGT2B7 were downregulated in HNF1␣-inactivated HCA (P < 0.0002); GLUL (glutamine synthetase) and GPR49 overexpression were associated with ␤-catenin-activating mutations (P < 0.0005), and SAA2 (serum amyloid A2) and CRP (C-reactive protein) were upregulated in inflammatory HCA (P ‫؍‬ 0.0001). Immunohistochemistry validation confirmed that the absence of liver-fatty acid binding protein (L-FABP) expression rightly indicated HNF1␣ mutation (100% sensitivity and specificity), the combination of glutamine synthetase overexpression and nuclear ␤-catenin staining were excellent predictors of ␤-catenin-activating mutation (85% sensitivity, 100% specificity), and SAA hepatocytic staining was ideal to classify inflammatory HCA (91% sensitivity and specificity). Finally, a series of 93 HCA was unambiguously classified using our 4 validated immunohistochemical markers. Importantly, new associations were revealed for inflammatory HCA defined by SAA staining with frequent hemorrhages (P ‫؍‬ 0.003), telangiectatic phenotype (P < 0.001), high body mass index, and alcohol intake (P < 0.04). Previously described associations were confirmed and in particular the significant association between ␤-catenin-activated HCA and hepatocellular carcinomas (HCC) at diagnosis or during follow-up (P < 10 -5 ). Conclusion: We refined HCA classification and its phenotypic correlations, providing a routine test to classify hepatocellular adenomas using simple and robust immunohistochemistry. (HEPATOLOGY 2007;46:740-748.) H epatocellular adenomas (HCA) are rare benign liver tumors, most frequently occurring in women who are using oral contraception. Although HCA are mostly found as a single nodule, the presence of more than 10 in the liver indicates a specific nosological entity termed liver adenomatosis. 1 Two genetic alterations, the biallelic inactivation of hepatocyte nuclear factor 1 alpha (HNF1␣) and the activating mutation of ␤-catenin, have been described in HCA. 2,3 Recently, a comprehensive analysis of genetic, pathological, and clinical features in a series of 96 HCA enabled the identification of 4 HCA subtypes. 4 Biallelic HNF1␣ mutations defined the first group of HCA, phenotypically characterized by marked steatosis, lack of cytological abnormalities, and inflammatory infiltrates. Presence of a ␤-catenin-activating mutation defined the second group of HCA representing 15% of the cases generally characterized by a higher risk of malignant tr...

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Section: Discussionmentioning

confidence: 95%

Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry

et al. 2007

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“…To our knowledge, only one case of malignant transformation among patients with adenomatosis 4 and nine cases among patients with hepatic adenoma have been reported. 8,[30][31][32][33][34][35][36][37] Among 17 patients in the literature with LA in whom follow-up was available (mean follow-up, 30.8 months), 3 developed new benign lesions [27][28][29] and 1 developed HCC 4 ; however, in those reports, the follow-up was very short and imaging studies were not performed routinely during the follow-up period. Therefore, the true rate of appearance of new lesions is unknown.…”

Section: Discussionmentioning

confidence: 99%

Management of liver adenomatosis: Results with a conservative surgical approach

et al. 1998

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Liver adenomatosis is defined by the presence of multiple hepatic adenomas (more than three lesions). The natural history and treatment of liver adenomatosis are not yet well defined. The Mayo Clinic (Rochester, MN) experience with liver adenomatosis in the past 11 years was reviewed and a rational treatment approach is presented. Records from patients with liver adenomatosis and hepatic adenoma seen at the Mayo Clinic from January 1986 to June 1997 were reviewed. Estrogen-and progesterone-receptor status was assessed by immunohistochemistry. Eight women with liver adenomatosis were identified. All patients had undergone surgical treatment. Abdominal pain was the presenting symptom in 87.5% of the patients with adenomatosis and in 42.1% of the patients with hepatic adenoma. Tumor bleeding was present in 62.5% of the patients with adenomatosis and in 26.3% of the patients with hepatic adenomas. Bleeding occurred predominantly in lesions greater than 4 cm. All patients with liver adenomatosis reported improvement of symptoms after surgery, and the mean bleedingfree period after resection in 5 patients was 52.6 ؎ 23.6 months. In 6 patients, estrogen receptorpositive and estrogen receptor-negative tumors were identified in the same liver. Based on the good outcome after resection in symptomatic patients with liver adenomatosis, we recommend resection of large (H5 cm) or symptomatic lesions with observation of smaller lesions (I3 cm). Lack of estrogen receptors in many lesions suggests that estrogen does not play a dominant role in the pathogenesis of liver adenomatosis.

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“…GSD-I has been reported to be a cause of HA (3). An adenoma-carcinoma progression sequence may be expected in HCC, similar to colon cancer (11).…”

Section: Discussionmentioning

confidence: 99%

Malignant transformation of hepatocellular adenoma with bone marrow metaplasia arising in glycogen storage disease type I: A case report

Iguchi

Yamagata²,

Sonoda³

et al. 2016

Molecular and Clinical Oncology

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Abstract. Malignant transformation of hepatocellular adenoma (HA) is relatively rare and has been reported to be associated with dysregulation of the β-catenin pathway. The presence of bone marrow metaplasia in HA is an uncommon histological characteristic. The current report presents the case of a 46-year-old woman with glycogen storage disease type I (von Gierke's disease) who underwent resection of hepatocellular carcinoma (HCC) arising in a HA with associated bone marrow metaplasia producing three series of hematopoietic cells. The serum level of proteins induced by des-gamma-carboxy prothrombin (DCP) gradually increased as the tumors grew; following hepatic resection, DCP levels returned to normal. Nuclear accumulation of β-catenin was shown in HCC by immunohistochemistry; however, no mutation was detected in exon 3 of β-catenin. To the best of our knowledge, this is the first report of HA with absolute bone marrow metaplasia producing three series of hematopoietic cells. This occurrence suggests that elevated DCP may be an indicator of malignant transformation of HA. IntroductionHepatocellular adenoma (HA) is a benign tumor usually associated with oral contraceptive intake, glycogen storage disease (GSD) type I and III, and a history of excess androgen exposure (1-4). Malignant transformation of HA is relatively rare and has been reported to be associated with dysregulation of the β-catenin pathway (2,5,6). Nuclear translocation and accumulation of β-catenin is induced by a dysregulation, such as a mutation of exon 3 (7), and may be detected by immunohistochemistry. The presence of bone marrow metaplasia in HA is an uncommon histological characteristic, with only 2 cases of HA with bone marrow metaplasia reported to date (8,9).We herein report a case with increased levels of proteins induced by des-gamma-carboxy prothrombin (DCP), resected hepatocellular carcinoma (HCC) and HA with bone marrow metaplasia arising in a patient with GSD-I. Case reportHistory. A 46-year-old woman was diagnosed with GSD-I during childhood. From that time onwards, she was followed up in a local hospital and received treatment with atorvastatin and allopurinol. At the age of 42 years, the patient consulted a physician at the Saiseikai Karatsu Hospital (Karatsu, Japan), as she continued to experience developmental disorders, such as short stature (135 cm) and low weight (36 kg), but was asymptomatic, apart from abdominal enlargement. The liver edge was palpable 6-7 cm below the right costal margin. The patient had no other risk factors for liver tumors, such as hepatitis B or C viral infection, alcohol use, or autoimmune disease.Liver function and tumor markers. Laboratory data at the first consult revealed elevated values of aspartate aminotransferase (96 IU/l), alanine aminotransferase (69 IU/l), alkaline phosphatase (700 U/l), gamma-glutamyl transpeptidase (2610 IU/l) and DCP (421 mAU/ml). Serum total bilirubin,

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Resolution of a Contraceptive-Steroid-Induced Hepatic Adenoma with Subsequent Evolution into Hepatocellular Carcinoma

Cited by 100 publications

References 7 publications

Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry

Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry

Management of liver adenomatosis: Results with a conservative surgical approach

Malignant transformation of hepatocellular adenoma with bone marrow metaplasia arising in glycogen storage disease type I: A case report

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