Natural course of hepatic focal nodular hyperplasia from childhood to adulthood and review of the literature.

Focal nodular hyperplasia (FNH) is the second most common benign tumor of the liver and constitutes 4% of all primary hepatic tumors in pediatric population. Imaging characteristics of FNH in adults are well known, but those in children have rarely been reported. Here we describe the natural course of a giant hepatic FNH, which was followed up from childhood to adulthood for 12 years using computed tomography (CT) imaging and liver enzyme tests (LET). Differences in CT imaging characteristics were demonstrated. Changes were found in the FNH size in CT images and they were correlated with LET findings. The regression of FNH in our case was compared with the findings in the literature. Hepatic capsular retraction was observed in a benign focal liver lesion in the medical literature for the first time.

Multiple ß-catenin mutations in hepatocellular lesions arising in Abernethy malformation.

An 18-year-old man underwent liver transplantation due to an Abernethy malformation associated with multiple hepatocellular nodules including one which was rapidly enlarging and was suspicious for malignant transformation. Analysis of the explanted liver showed a spectrum of multiple hepatocellular nodules ranging in appearance from focal nodular hyperplasia, hepatocellular adenoma and to a well-differentiated hepatocellular neoplasm borderline for hepatocellular carcinoma. Mutational analysis revealed wild-type ß-catenin expression in the background liver and some nodules, whilst different variants were present in other lesions irrespective of their morphological appearance. No telomerase reverse transcriptase (TERT) promoter mutation was identified. Abernethy malformations can lead to independent genetic events which can result in ß-catenin mutations associated with malignant transformation of hepatocellular nodules. When following up such patients, one must therefore have a high index of suspicion, particularly if radiological surveillance reveals a change in the nature of hepatic lesions.

Diagnostic utility and limitations of glutamine synthetase and serum amyloid-associated protein immunohistochemistry in the distinction of focal nodular hyperplasia and inflammatory hepatocellular adenoma.

Inflammatory hepatocellular adenoma can show overlapping histological features with focal nodular hyperplasia, including inflammation, fibrous stroma, and ductular reaction. Expression of serum amyloid-associated protein in inflammatory hepatocellular adenoma and map-like pattern of glutamine synthetase in focal nodular hyperplasia can be helpful in this distinction, but the pitfalls and limitations of these markers have not been established. Morphology and immunohistochemistry were analyzed in 54 inflammatory hepatocellular adenomas, 40 focal nodular hyperplasia, and 3 indeterminate lesions. Morphological analysis demonstrated that nodularity, fibrous stroma, dystrophic blood vessels, and ductular reaction were more common in focal nodular hyperplasia, while telangiectasia, hemorrhage, and steatosis were more common in inflammatory hepatocellular adenoma, but there was frequent overlap of morphological features. The majority of inflammatory hepatocellular adenomas demonstrated perivascular and/or patchy glutamine synthetase staining (73.6%), while the remaining cases had diffuse (7.5%), negative (3.8%), or patchy pattern of staining (15%) that showed subtle differences from the classic map-like staining pattern and was designated as pseudo map-like staining. Positive staining for serum amyloid-associated protein was seen in the majority of inflammatory hepatocellular adenomas (92.6%) and in the minority of focal nodular hyperplasia (17.5%). The glutamine synthetase staining pattern was map-like in 90% of focal nodular hyperplasia cases, with the remaining 10% of cases showing pseudo map-like staining. Three cases were labeled as indeterminate and showed focal nodular hyperplasia-like morphology but lacked map-like glutamine synthetase staining pattern; these cases demonstrated a patchy pseudo map-like glutamine synthetase pattern along with the expression of serum amyloid-associated protein. Our results highlight the diagnostic errors that can be caused by variant patterns of staining with glutamine synthetase and serum amyloid-associated protein in inflammatory hepatocellular adenoma and focal nodular hyperplasia.

Immunostaining of glutamine synthetase is a sensitive and specific marker for diagnosing focal nodular hyperplasia in needle biopsy.

AIMS: Focal nodular hyperplasia (FNH) has characteristic histological features which may not be seen in needle biopsy specimens. We investigate the diagnostic role of glutamine synthetase (GS) in needle biopsy specimens. METHODS: Sixty-one hepatic tumours were categorised into 20 'definite' FNHs, 13 'probable' FNHs, and 28 cases without specific diagnosis. Needle biopsy specimens of 92 non-tumourous lesions, 25 well-differentiated hepatocellular carcinomas (WDHCCs), and 4 high-grade dysplastic nodules (HGDNs) and resection specimens of 10 macroregenerative nodules were also selected for immunohistochemical stain of GS for comparison. RESULTS: All 20 'definite' FNHs, nine 'probable' FNHs, and five cases without specific diagnosis expressed typical map-like staining pattern of GS. The demographic data of these five cases were similar to those of FNH. All cases of chronic hepatitis B and C, cirrhosis, macroregenerative nodule and peritumourous liver tissue showed normal pericentral/periseptal pattern. Fifteen of 25 WDHCCs and one HGDN showed diffuse pattern. Ten WDHCCs and two HGDNs showed negative staining. One HGDN showed mosaic pattern. CONCLUSIONS: Immunohistochemical staining of GS increases the diagnostic sensitivity of FNH in needle biopsy, especially in those without typical morphology. It also helps in differentiating FNH from other tumourous and non-tumourous lesions.

Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology.

BACKGROUND AND AIMS: Glutamine synthetase (GS) is a useful marker in tumour liver pathology, including hepatocellular adenomas and nodules in cirrhosis. We investigated the use of GS as a marker in various clinical situations, in which FNH diagnosis had been firmly established to determine its contribution to diagnosis. METHODS: Seventy-nine cases of resected FNH, all on normal (or occasionally steatotic) livers, were retrieved from our collection. The control group was composed of hepatocellular adenomas and well-differentiated hepatocellular carcinoma. The following stains: H&E, Masson's trichrome, Gordon-Sweet, PAS, perls and immunostains: CK7 and 19, and GS were carried out. FNH was diagnosed based on traditional pathological techniques. In case of uncertainty, particularly with hepatocellular adenoma, additional immunostainings including liver fatty acid-binding protein, serum amyloid A and beta-catenin were performed. RESULTS: Glutamine synthetase immunostaining was similar in all FNH cases. Positive GS staining of hepatocytic cytoplasms formed large areas, anastomosed in a 'map-like' pattern, often surrounding hepatic veins, whereas GS was not expressed in hepatocytes close to fibrotic bands containing arteries and ductules. In comparison, hepatocellular adenoma staining was completely different, even in cases of fibrotic bands due to tumour remodelling related to necrosis or haemorrhage. In hepatocellular adenomas or well-differentiated hepatocellular carcinoma presenting beta-catenin mutation, GS was positive but with a completely different pattern that appeared diffuse and not 'map-like'. CONCLUSION: Regardless of the FNH size or steatotic content, GS produced a similar and characteristic pattern and consequently represents a good marker for easily identifying resected FNH from other hepatocellular nodules.

Angiotensin I-converting enzyme (CD143) is down-regulated in focal nodular hyperplasia of the liver.

In surgical pathology, focal nodular hyperplasia (FNH) is sometimes difficult to diagnose, and liver cirrhosis (LC) and hepatocellular adenoma (HA) are often among the differential diagnoses. Recently, we found a reduced expression of angiotensin I-converting enzyme (CD143) in FNH compared with cirrhotic and noncirrhotic liver. Intrigued by this observation, we investigated the expression pattern of CD143 in FNH, LC, and HA and its possible diagnostic value. The expression of CD143 was studied by immunohistochemistry in 20 FNHs, 13 corresponding extralesional noncirrhotic liver parenchyma, 20 patients with LC, and four HAs. Endothelial cells were identified with antibodies directed against CD31 and CD34. CD31+, CD34+, and CD143+ sinusoidal endothelial cells were found in extralesional liver, LC, HA, and FNH. However, the number of CD143+ sinusoidal endothelial cells and the intensity of immunostaining were significantly reduced in FNH compared with extralesional liver, LC, and HA. The expression of CD143 was further assessed using a numerical scoring system ranging from 0 to 6. The mean immunoreactivity score for CD143 was 2.4 +/- 1.7 for sinusoidal endothelial cells in FNH, 5.7 +/- 0.6 in extralesional liver, 4.8 +/- 1.1 in LC, and 5.8 +/- 0.5 in HA. The differences between the mean immunoreactivity scores for CD143 were highly significant. The difference between FNH and extralesional liver was confirmed on transcriptional level by fluorescence-mediated real-time RT-PCR, which also showed a significantly decreased level of CD143 mRNA in FNH. Our study provides evidence that CD143 is down-regulated in FNHs and that the phenotype of endothelial cells lining the sinusoids in FNH differs from those in non-neoplastic liver, LC, and HA. The observed variations in expression patterns for CD143 might be of diagnostic use in surgical pathology.

Stochastic simulation of hepatic preneoplastic foci development for four chlorobenzene congeners in a medium-term bioassay.

A combination of experimental and simulation approaches was used to analyze clonal growth of glutathione-S-transferase pi (GST-P) enzyme-altered foci during liver carcinogenesis in an initiation-promotion regimen for 1,4-dichlorobenzene (DCB), 1,2,4,5-tetrachlorobenzene (TECB), pentachlorobenzene (PECB), and hexachlorobenzene (HCB). Male Fisher 344 rats, eight weeks of age, were initiated with a single dose (200 mg/kg, ip) of diethylnitrosamine (DEN). Two weeks later, daily dosing of 0.1 mol/kg chlorobenzene was maintained for six weeks. Partial hepatectomy was performed three weeks after initiation. Liver weight, normal hepatocyte division rates, and the number and volume of GST-P positive foci were obtained at 23, 26, 28, 47, and 56 days after initiation. A clonal growth stochastic model separating the initiated cell population into two distinct subtypes (referred to as A and B cells) was successfully used to describe the foci development data for the four chlorobenzenes. The B cells are initiated cells that display a selective growth advantage under conditions that inhibit the growth of initiated A cells or normal hepatocytes. The simulation exercise for the four chlorobenzenes indicates a positive correlation between the estimated net growth rate of B cells during the 2-week regeneration period following partial hepatectomy and final foci volume at the end of the bioassay. This observation is consistent with the sensitivity analysis of model parameters. While TECB, PECB, and HCB all significantly increased foci volume, only HCB increased normal hepatocyte proliferation. Together, these results indicate that examining effects of chemicals on regenerative responses following partial hepatectomy may be a means for understanding the carcinogenicity potential of chlorobenzene compounds.

Expression of human telomerase reverse transcriptase in regenerative and precancerous lesions of cirrhotic livers.

BACKGROUND/AIMS: The catalytic subunit of human telomerase (hTERT) is known to be expressed in a variety of malignant tumours, including hepatocellular carcinoma (HCC). We studied hTERT expression in regenerative and precancerous lesions arising in cirrhosis. METHODS/RESULTS: As shown by in situ hybridisation, hTERT mRNA was absent in normal liver, but present in varying numbers of hepatocytes and HCC cells of diseased livers, as well as in biliary epithelial cells, lymphocytes, sinusoidal-lining cells and tumour endothelial cells. RT-PCR for two hTERT transcript regions demonstrated hTERT expression in 11 out of 15 cirrhotic liver samples, in 20 out of 21 large regenerative nodules/low-grade dysplastic nodules, in 5 out of 5 high-grade dysplastic nodules, and in 4 out of 4 HCCs. The beta-splice variant was identified in all hTERT-positive cases, while the corresponding full-length transcript was found only in 13 out of 29 positive large nodular lesions and in 4 out of 11 positive cirrhotic samples. The full-length transcript was always found in the presence of the beta-splice variant, usually in low relative levels, and tended to correlate with telomerase activity in the samples, while the beta-splice variant did not. CONCLUSIONS: This study shows that hTERT re-expression takes place both in hepatic regeneration occurring in cirrhosis and in the early steps of hepatocarcinogenesis, and involves mainly the beta-splice variant of this molecule. Additional regulatory mechanisms may be required for the expression of the full-length hTERT transcript.