Case 1 -

Hepatocellular Adenoma, Inflammatory (Telangiectatic) Type Zachary D. Goodman Inova Fairfax Hospital Falls Church, VA

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Clinical History This 24 year old man presented because of the sudden onset of right periumbilical pain. This persisted, despite treatment with antacids, and further evaluation with upper and lower endoscopy were unrevealing. He was found to have serum alkaline phosphatase five times the upper limit of normal, leading to a CT scan that revealed a large mass in the right lobe of the liver, followed by angiography showing the mass to be well vascularized. A right hepatic lobectomy was performed. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: The section from the resection specimen shows a benign hepatocellular lesion that lacks acinar architecture and has no normal portal areas. There are, however, portal area-like structures that contain arteries but no normal bile ducts or portal vein branches. Some of these contain inflammatory cells and ductules. Many of the sinusoids of the lesion are quite dilated. There is no central scar or radiating septa, and the arteries, although numerous, are not abnormally thickened. Differential Diagnoses: Hepatocellular adenoma, inflammatory (telangiectatic) type Hepatocellular adenoma, usual type Focal nodular hyperplasia Nodular regenerative hyperplasia Well differentiated hepatocellular carcinoma Final Diagnosis: Hepatocellular Adenoma, Inflammatory (Telangiectatic) Type Case Discussion: Tumors such as this have caused diagnostic dilemmas over the years, as they do not fit well into the usual classification of benign hepatocellular tumors and tumor- like lesions (see Table). The principal differential diagnosis is between focal nodular hyperplasia (FNH), which is a tumor-like malformation and hepatocellular adenoma (HCA), which is a neoplasm [1, 2]. Resection specimens from typical cases are easily distinguishable, and needle biopsies are usually also diagnostic [3]. FNH has a central stellate scar that is usually grossly evident and is nodular on cut section while HCA lacks the scar and is smooth. The central scar of FNH contains large, thickened arteries that often have intimal proliferation and disruption of elastic lamina while HCA typically has small blood vessels and sometimes solitary arteries within the tumor. FNH lacks portal areas and true bile ducts, but there are usually ductules and often inflammatory cells in the septa. HCA usually as no ductules, but occasionally longstanding tumors have areas that have undergone necrosis and scarring and may have a few ductules. Clinically, it is quite important to make the distinction, since HCA will grow and may rupture causing fatal abdominal hemorrhage, or it may undergo malignant transformation, while FNH has an entirely benign course and if the diagnosis is made on imaging studies and needle biopsy, the patient can be followed without surgical intervention. The present case lacks the central scar of FNH, but it does have portal area-like structures that contain arteries, inflammatory cells and occasionally a few ductules as well as dilated sinusoids surrounding the vascular structures. Wanless et al [4] 1n 1989 published what is apparently the first description of this lesion. Because of the presence of ductules and dilated, this type of tumor was classified as a telangiectatic variant of FNH. Nguyen et al [5] in 1999 in a review of 305 lesions that they classified as FNH noted that 47 of these were so- called "telangiectatic FNH". Subsequently a few other papers also used this term. Two publications in 2004-5 used molecular techniques to study a number of lesions classified as telangiectatic FNH and to compare them to typical FNH and HCA [6, 7]. The HCA's and so-called telangiectatic FNH were monoclonal and had low expression of angiopoietin and frequently developed necrosis and hemorrhage whereas typical lesions of FNH were polyclonal and had high expression levels of angiopoietin. Thus, it is now accepted that the so-called telangiectatic FNH is really a telangiectatic hepatocellular adenoma. Many cases, such as Case 1, also have considerable inflammation and so the term "inflammatory adenoma" has also been used. A typical HCA is composed of benign hepatocytes arranged in sheets and cords without acinar architecture. The tumor cells are usually, but not always, larger and paler than non tumor hepatocytes in the surrounding tissue, due to increased cytoplasmic glycogen and/or fat. The fat may be quite abundant, simulating fatty liver. Other features that are variably present include bile production, occasionally with pseudogland formation around dilated canaliculi, cytoplasmic lipofuscin granules, Dubin-Johnson pigment, and rarely Mallory bodies. The nuclei of the tumor cells are typically uniform and regular, the nuclear cytoplasmic ratio is low, and mitoses are almost never seen. Nucleoli are seldom prominent. Occasional tumors, especially in patients with long exposure to contraceptive steroids may have a few pleomorphic nuclei, resembling large cell change in non-neoplastic chronic liver disease. A well developed reticulin framework is usually present in the tumor. The sinusoids, with flattened endothelial lining cells, are usually compressed, thus contributing to the sheet like appearance. Sometimes the sinusoids are dilated, especially in the telangiectatic variant, a finding which can be mistaken for peliosis hepatis. Bile ducts are not found in HCA, but ductules and progenitor cells may be present. Thin walled vascular channels and small arteries are scattered throughout the tumors, but large arteries are only seen around the periphery. Kupffer cells are present though usually inconspicuous, and stellate cells are occasionally seen. Hematopoietic elements are noted in the sinusoidal lumen of some tumors, and rare cases have had non-caseating granulomas in the tumor. Areas hemorrhage may be present as well as recent or old infarcts, and areas of scarring containing hemosiderin laden macrophages from old hemorrhages. Molecular studies in the past few years have better defined the subtypes of HCA [7, 8, 9, 10, 11]. Mutations of the TCF1 gene which codes for hepatocyte nuclear factor 1 α (HNF1α) transcription factor have been found to be very important in the pathogenesis of HCA. Approximately 50% of patients with sporadic HCA have biallelic mutations of this gene, and patients with multiple adenomas (liver adenomatosis) may have germline mutations of one allele with superimposed sporadic mutations of the other allele accounting for the multiple tumors. Tumors with this mutation often have cytoplasmic fat in tumor cells and have been reported to lack expression of liver fatty acid binding protein (FABP1). β-catenin mutations have been detected in a minority (approximately 10%) and are associated with cytologic atypia and development of hepatocellular carcinoma (HCC). Most of these shows positive nuclear staining for β-catenin and cytoplasmic glutamine synthetase. Of the remaining 40% of HCA without HNF1α or β-catenin mutations, about one-half have features of the telangiectatic type with abundant inflammation and are reported to show positive staining serum amyloid A2 (SAA2). Histologic distinction of HCA from well differentiated HCC can be difficult and sometimes impossible, but can usually be made on histologic grounds. Recognition of a trabecular growth pattern and cytologic features of malignancy, including high nuclear/cytoplasmic ratios and nuclear irregularities, are most helpful. When a lesion with all the features of HCA has a moderate degree of nuclear irregularity and hyperchromatism, one may wish to take the history into account. If the patient had been taking oral contraceptives or other sex steroids, which are strongly associated with HCA, then the tumor is best regarded as an atypical HCA; but if it is certain that there is no such history, it is probably a well differentiated HCC. Histochemical and immunohistochemical stains add little to the differential diagnosis of HCA from HCC in the difficult cases. Reticulin fibers are generally decreased in the trabeculae of HCC compared to benign lesions, but well differentiated carcinomas may have abundant reticulin. Markers of proliferation, such as Ki67, are much more frequent in malignant than benign hepatocellular tumors, but some clearly malignant tumors are negative for these. Markers of endothelial differentiation such as CD34 are expressed only in periportal or periseptal sinusoids in non-neoplastic liver. Although they are usually strongly expressed in HCC, HCA can sometimes have an identical staining pattern. It remains to be proven whether β-catenin staining will improve our ability to distinguish these tumors. Conclusion(s): This case is an hepatocellular adenoma, inflammatory (telangiectatic) type References: Ishak KG, Goodman ZD, Stocker JT. Tumors of the Liver and Intrahepatic Bile Ducts. Atlas of Tumor Pathology, Third Series, Fascicle 31. Washington D.C., Armed Forces Institute of Pathology, 2001; 9-48. Goodman ZD, Terraccciano L: Tumours and tumour- like lesions of the liver. In: Burt AD, Portmann BC, Ferrell LD, eds. MacSween's Pathology of the Liver, 5th edition. Churchill Livingstone Elsevier, Philadelphia, 2007; 761-814. Makhlouf HR, Abdul-Al HM, Goodman ZD: Diagnosis of focal nodular hyperplasia of the liver by needle biopsy. Hum Pathol 2005; 36:1210-1216. Wanless IR, et al: Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: A new syndrome. Modern Pathol 1989; 2:456-462. Nguyen BN, et al: Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol 1999; 23:1441-1454. Paradis V, et al: Telangiectatic focal nodular hyperplasia: A variant of hepatocellular adenoma. Gastroenterol 2004; 126:1323-1329. Bioulac-Sage P et al: Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastrolenerol 2005; 128:1211-1218. Zucman-Rossi J, et al: Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 2006; 43:515-524. Bioulac-Sage P, et al; Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 2007; 46:740-748. Bioulac-Sage P, et al: Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update. J Hepatol 2007; 46:521-527. 11. Rebouissou S, et al: Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008; 48:163-170.