November 2016 Case

Brent K. Larson, D.O. and Maha Guindi, M.D.

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.

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