November 2016 Case
Brent K. Larson, D.O. and Maha Guindi, M.D.
Subject: Liver Pathology
A 47-year-old female with no significant past medical history is discovered to have a mass in the liver while undergoing pre-operative clearance for another procedure. She has mildly elevated serum C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and gamma-glutamyl transpeptidase (GGT) values. All other laboratory tests are within normal limits. A laparotomy is performed with a liver wedge biopsy, which reveals a 1.3 cm ill-defined, soft, tan-brown nodule.
Clinical Background: Hepatocellular adenomas are benign proliferations of clonal hepatocytes occurring in non-cirrhotic liver. They can be divided into four subtypes based on molecular alterations: the hepatocyte nuclear factor one alpha-mutated subtype, the beta catenin-activated subtype, the inflammatory subtype, and the unclassified subtype.1
The inflammatory subtype was initially thought to be a morphologic subtype of focal nodular hyperplasia ("telangiectatic focal nodular hyperplasia") until molecular studies proved it to be clonal like hepatocellular adenomas.2 Hepatocellular adenomas are associated with female sex, oral contraceptive use, a risk of hemorrhage, and an overall 4.2% risk of malignant transformation.3 The inflammatory subtype has several unique features that make it important to identify and accurately subtype. It is particularly associated with obesity, elevated serum C-reactive protein, and elevated gamma-glutamyl transpeptidase.5-8 Some cases have even shown a resolution of these serum abnormalities after resection of the adenoma.4, 7 The inflammatory subtype also has a low, but not insignificant, probability of malignant transformation. In addition, this subtype has a tendency to hemorrhage, which can cause life-threatening hemoperitoneum.8
Microscopic Findings: Inflammatory hepatocellular adenomas are characterized by telangiectatic sinusoids, inflammatory infiltrates, ductular reaction, and "pseudo-portal tracts" composed of small islands of collagen with inset arterioles.1,8 Though these are the classical features, individual cases may display a variable mixture of these features. Occasionally, there may be prominent steatosis, which may prompt confusion with the factor one alpha-mutated subtype that is characteristically steatotic.9 Nuclear atypia are absent to minimal, and the nucleus-to-cytoplasm ratio is not appreciably increased. Plates are no more than minimally expanded (2-3 hepatocytes thick), and the sinusoidal reticulin framework is intact, differentiating hepatocellular adenoma from hepatocellular carcinoma. The presence of ductular reaction and arterioles also raises focal nodular hyperplasia as a differential diagnostic consideration, though sinusoidal dilatation and inflammatory infiltrates are not prominent features of focal nodular hyperplasia.
Immunohistochemistry: Inflammatory hepatocellular adenomas show characteristic diffuse immunoreactivity for serum amyloid A and C-reactive protein. Notably, there is a sharp demarcation between the tumor positivity and the negative adjacent liver.8 Liver fatty acid-binding protein is positive (intact) in the inflammatory subtype, differentiating it from the hepatocyte nuclear factor one alpha-mutated subtype.8 Glypican-3 and heat-shock protein 70 are negative. Positivity for either indicate well-differentiated hepatocellular carcinoma or hepatocellular carcinoma ex adenoma. Beta catenin staining is typically membranous, though nuclear staining may be seen. Glutamine synthetase can show a variety of patterns ranging from negative, patchy, perivascular, peripheral, or diffuse strong staining.8, 11 The pattern should not be the "map-like" or "geographic" pattern of anastomosing positive staining of hepatocyte trabecula characteristic of focal nodular hyperplasia.11
Molecular Pathology: 82% of inflammatory adenomas have a mutation in IL6ST, FRK, JAK1, STAT3, or GNAS, which lead to activation of the inflammatory JAK/STAT pathway.12 Secondary mutations in the CTNNB1 gene, coding for the beta catenin protein, are also found in a minority of inflammatory adenomas (beta catenin-activated inflammatory hepatocellular adenomas), which may serve as a first step toward malignant transformation.12 These beta catenin-activated inflammatory adenomas may show nuclear beta catenin staining and diffusely positive glutamine synthetase immunohistochemical staining. Mutations in TERT, the telomerase reverse transcriptase gene, serve as a "second hit" in hepatocellular adenomas with atypical features and lesions with overlapping features between hepatocellular adenoma and hepatocellular carcinoma.12 HNF1A, coding for liver fatty acid-binding protein, is not mutated in inflammatory hepatocellular adenomas.
1. Zucman-Rossi J, Jeannot E, Nhieu JT, et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship to HCC. Hepatology. 2006;43(3):515-524.
2. Paradis V, Benzekri A, Dargère D, et al. Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma. Gastroenterology. 2004;126(5):1323-1329.
3. Stoot JH, Coelen RJ, De Jong MC, Dejong CH. Malignant transformation of hepatocellular adenomas into hepatocellular carcinomas: a systematic review including more than 1600 adenoma cases. HPB (Oxford). 2010;12(8):509-522.
4. Bioulac-Sage P, Taouji S, Possenti L, Balabaud C. Hepatocellular adenoma subtypes: the impact of overweight and obesity. Liver Int. 2012;32(8):1217-1221.
5. Van Aalten SM, Verheij J, Terkivatan T, Dwarkasing RS, de Man RA, Ijzermans JN. Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J Hepatol. 2011;55(1):120-125.
6. Bioulac-Sage P, Cubel G, Balabaud C, Zucman-Rossi J. Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers. Semin Liver Dis. 2011;31(1):91-103.
7. Sa Cunha A, Blanc JF, Lazaro E, et al. Inflammatory syndrome with liver adenomatosis: the beneficial effects of surgical management. Gut. 2007;56(2):307-309.
8. Bioulac-Sage P, Rebouissou S, Thomas C, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology. 2007;46(3):740-748.
9. Albert N, Castain C, Crombe A, Frulio N. Steatotic hepatocellular adenomas with different phenotypic subtypes: a case report. Clin Res Hepatol Gastroenterol. 2015;39(2):e17-22.
10. Bioulac-Sage P, Cubel G, Taouji S, et al. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes. Am J Surg Pathol. 2012;36(11):1691-1699.
11. Joseph NM, Ferrell LD, Jain D, et al. Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma. Mod Pathol. 2014;27(1):62-72.
12. Pilati C, Letouzé E, Nault JC, et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell. 2014;25(4):428-441.
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