Hepatocellular Adenoma, Inflammatory (Telangiectatic) Type
Zachary D. Goodman
Inova Fairfax Hospital
Falls Church, VA
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.
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.
- Hepatocellular adenoma, inflammatory (telangiectatic) type
- Hepatocellular adenoma, usual type
- Focal nodular hyperplasia
- Nodular regenerative hyperplasia
- Well differentiated hepatocellular carcinoma
Hepatocellular Adenoma, Inflammatory (Telangiectatic) Type
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
Resection specimens from typical cases are
easily distinguishable, and needle biopsies are usually also diagnostic . 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  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  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
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
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.
This case is an hepatocellular adenoma, inflammatory (telangiectatic) type
- 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.