Pediatric Hepatocellular Adenomas: The Influence of Age and Syndrome on Subtype.

Hepatocellular adenomas are rare in children. A large study focused on pediatric patients has not been undertaken. A natural language search was performed at 5 institutions for hepatocellular adenomas in patients younger than 21 years old. Clinical characteristics as well as immunohistochemical staining profile was reviewed and adenomas subtyped per standard classification. Patients were divided into prepubescent and postpubescent age group. Thirty-one patients were included. Eleven (35%) were male and 10 (32%) were prepubescent. Fifteen (54%) of 28 patients with known clinical histories had adenomas associated with a syndrome. The percentage of the different adenoma subtypes was: 16% ß-catenin activated, 10% combined inflammatory and ß-catenin activated, 29% HFN1α-inactivated, 35% inflammatory, and 10% unclassified subtype by immunohistochemical staining. Interestingly 53% of patients with syndromes were male, while 85% of patients in the nonsyndromic group were female. The total number of ß-catenin activated tumors was greater in the syndromic group (5/15, 33%) and prepubescent group (5/10, 50%) than in the nonsyndromic group (2/13, 16%) and postpubescent group (3/21, 14%), P=0.4 and 0.07, respectively. Inflammatory type adenoma was more frequent in the postpubescent (10/21, 48%) than in the prepubescent group (1/10, 10%), P=0.06, trending toward significance. Pediatric patients with hepatocellular adenomas frequently have syndromes, especially in the prepubescent group. In patients with syndromes a greater percentage of adenomas were ß-catenin activated. In patients without a known syndrome the distribution of hepatocellular adenoma subtypes appears similar to adults.

Malignant transformation of liver fatty acid binding protein-deficient hepatocellular adenomas: histopathologic spectrum of a rare phenomenon.

The molecular classification of hepatocellular adenomas highlights a distinctive genotype-phenotype correlation. Malignant transformation is an exceptionally rare complication of hepatocyte nuclear factor 1α (HNF1A)-inactivated hepatocellular adenomas. This subtype is characterized by loss of liver fatty acid binding protein immunoexpression. In this study, we characterized the histopathologic spectrum of 13 liver fatty acid binding protein-deficient hepatocellular adenoma cases showing malignant transformation from multiple centers. Clinicopathologic characteristics of these patients were evaluated. Stains for reticulin, liver fatty acid binding protein, beta-catenin and glutamine synthetase were applied to these lesions. Moreover, the findings were compared to patients with ß-catenin mutated hepatocellular adenoma. Liver fatty acid binding protein-deficient hepatocellular adenomas with borderline features/carcinoma were seen predominantly in females (77%) with an average age of 46 ± 18 years and multiple lesions (77%; five patients with adenomatosis). Meanwhile, ß-catenin mutated hepatocellular adenoma patients with malignant transformation were predominantly male (67%, p = 0.018) with single lesion (86%, p = 0.0009). The largest liver fatty acid binding protein-deficient hepatocellular adenoma nodule in each patient ranged from 4 to 15.5 cm. Loss of liver fatty acid binding protein by immunohistochemistry was noted in all adenoma and borderline/carcinoma components. Features of malignant transformation were pseudoglandular architecture (85%), cytologic atypia (85%), architectural atypia (100%) and lack of steatosis (100%). Other findings included myxoid change (39%), peliosis (46%) and sinusoidal dilatation (46%). Molecular studies confirmed somatic inactivation of HNF1A in 3 cases and absence of TERT promotor and exon 3 CTNNB1 mutations in five cases. To summarize, liver fatty acid binding protein-deficient hepatocellular adenoma with malignant transformation is most frequently seen in female patients with multiple lesions. Most of these lesions demonstrate pseudoglandular architecture, cytologic and architectural atypia, with lack of steatosis. The natural history of these lesions is relatively benign with the exception of disease recurrence in 1 patient.

Immunohistochemical approach for the diagnosis of a liver mass on small biopsy specimens.

Well-differentiated hepatocellular carcinoma (HCC) shares overlapping histological features with benign hepatocellular lesions, including hepatocellular adenoma and focal nodular hyperplasia in non-cirrhotic liver, and with high-grade dysplastic nodule in cirrhotic liver. Several metastatic tumors, such as neuroendocrine tumor, renal cell carcinoma, adrenocortical carcinoma, melanoma, and epithelioid angiomyolipoma, can be indistinguishable from HCC on histologic grounds. Since this distinction has important therapeutic implications, judicious use of immunohistochemical markers plays an important role in establishing an accurate diagnosis, especially when limited material of tumor is available on cell block or a small core biopsy. This review describes commonly used immunohistochemical markers used in the diagnosis of HCC, highlighting advantages and disadvantages of each marker, and suggests appropriate immunohistochemical panels for specific clinicopathologic situations.

Distinction between inflammatory hepatocellular adenoma and mass effect on liver sampling.

Inflammatory hepatocellular adenoma (IHA) is characterized by sinusoidal dilation, inflammation, and bile ductular reaction. However, these changes can also be seen in nonneoplastic liver tissue adjacent to a mass lesion. This differential may arise in biopsy tissue attempting to sample a liver mass. Serum amyloid A (SAA) immunostaining is useful for the diagnosis of IHA but is not entirely specific. In addition, the histologic pattern of mass effect (ME) has received little formal scrutiny. We compared the clinical, morphologic, and immunohistochemical findings in 18 IHA and 36 livers with ME. Several histologic findings were evaluated in all cases. SAA and CD34 staining were also performed. Patients with IHA were younger (P<.0001) and more often female (P=.0044) than patients with specimens showing ME, but lesions were multifocal on imaging in two-thirds of patients in each category. Unpaired arteries were only seen in IHA (P<.0001), whereas ductular reaction was more common in ME (P=.012). Strong SAA immunostaining was observed in 100% of IHAs and 56% of ME cases (P=.0004), and CD34 staining was seen in 95% of IHAs and 6% of ME cases (P<.0001). Unpaired arteries and staining for SAA and CD34 best distinguish IHA from ME. However, unpaired arteries may be absent because of sampling, and SAA is not available in all laboratories. Ductular reaction can occur in IHA but is more common in ME.

Hepatocellular adenoma classification: a comparative evaluation of immunohistochemistry and targeted mutational analysis.

BACKGROUND: Four subtypes of hepatocellular adenomas (HCA) are recognized: hepatocyte-nuclear-factor-1α mutated (H-HCA), ß-catenin-mutated type with upregulation of glutamine synthetase (b-HCA), inflammatory type (IHCA) with serum-amyloid-A overexpression, and unclassified type. Subtyping may be useful since b-HCA appear to have higher risk of malignant transformation. We sought to apply subtype analysis and assess histological atypia, correlating these with next-generation sequencing analysis. METHODS: Twenty-six HCA were stained with serum amyloid A (SAA), liver fatty acid-binding protein (LFABP), glutamine synthetase (GS), and ß-catenin IHC, followed by analysis with a targeted multiplex sequencing panel. RESULTS: By IHC, 4 HCA (15.4 %) were classified as b-HCA, 11 (42.3 %) as IHCA, 9 (34.6 %) as H-HCA, and two (7.7 %) unclassifiable. Eight HCA (30.8 %) showed atypia (3 b-HCA, 4 IHCA and 1 H-HCA). Targeted sequencing confirmed HNF1A mutations in all H-HCA, confirming reliability of LFABP IHC in identifying these lesions. CTNNB1 mutations were detected in 1 of 4 (25 %) of GS/ß-catenin-positive cases, suggesting that positive GS stain does not always correlate with CTNNB1 mutations. CONCLUSIONS: Immunohistochemistry does not consistently identify b-HCA. Mutational analysis improves the diagnostic accuracy of ß-catenin-mutated HCA and is an important tool to assess risk of malignancy in HCA.

Expression of liver fatty acid binding protein in hepatocellular carcinoma.

Loss of expression of liver fatty acid binding protein (LFABP) by immunohistochemistry has been shown to be characteristic of a subset of hepatocellular adenomas (HCAs) in which HNF1A is inactivated. Transformation to hepatocellular carcinoma is thought to be a very rare phenomenon in the HNF1A-inactivated variant of HCA. However, we recently observed 2 cases at our institution, 1 definite hepatocellular carcinoma and 1 possible hepatocellular carcinoma, with loss of LFABP staining, raising the possibility that LFABP down-regulation may be associated with hepatocellular carcinogenesis. Our aim was to evaluate hepatocellular carcinomas arising in various backgrounds and with varying degrees of differentiation for loss of LFABP staining. Twenty total cases of hepatocellular carcinoma were examined. Thirteen cases arose in a background of cirrhosis due to hepatitis C (n = 8) or steatohepatitis (n = 5); 7 cases arose in a noncirrhotic background, with 2 cases arising within HNF1A-inactivated variant HCA and 2 cases arising within inflammatory variant HCA. Complete loss of expression of LFABP was seen in 6 of 20 cases, including 2 cases of hepatocellular carcinoma arising within HNF1A-inactivated variant HCA. Thus, loss of staining for LFABP appears to be common in hepatocellular carcinoma and may be seen in well-differentiated hepatocellular carcinoma. Therefore, LFABP loss should not be interpreted as evidence for hepatocellular adenoma over carcinoma, when other features support a diagnosis of hepatocellular carcinoma. The findings raise consideration for a role of HNF1A inactivation in hepatocellular carcinogenesis, particularly in less differentiated tumors.

The Evolving Role of Nonalcoholic Fatty Liver Disease in Hepatic Neoplasia: Inflammatory Hepatocellular Adenoma in a Man with Metabolic Syndrome.

Growing awareness of the spectrum of liver diseases related to nonalcoholic fatty liver disease (NAFLD) has drawn attention to the complex pathogenetic pathways that are operative in livers with macrovesicular steatosis and to the potential development of hepatocellular adenoma and hepatocellular carcinoma in unusual clinical settings. This report describes an older man with metabolic syndrome who developed a 3.9 cm. right lobe liver mass that on directed needle biopsy showed the features of an inflammatory hepatocellular adenoma, including immunostain positivity for serum amyloid A. The case highlights the many factors involved in the pathogenesis of liver tumors in the steatotic liver of NAFLD, particularly the interplay of inflammatory mediators, adiponectin and leptin, genomics and metabolomics, lipotoxicity, endotoxin, and hepatic stellate cells.

Simultaneous occurrence of focal nodular hyperplasia and HNF1A-inactivated hepatocellular adenoma: a collision tumor simulating a composite FNH-HCA.

Mixed focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) within a single tumor mass is rarely reported, and most of these cases are examples of tumors with features intermediate between FNH and HCA. Although a few reported cases are probably examples of true mixed tumors, none was evaluated immunohistochemically or confirmed by molecular analysis. We report a mixed FNH and HCA arising in a woman with several HNF1A-inactivated adenomas. Our case is the first case of mixed FNH and HNF1A-inactivated HCA documented by immunohistochemistry.

Giant hepatocellular adenoma in a previously obese thirteen-year-old boy.

Hepatocellular adenoma is an uncommon neoplasm, especially in the childhood age group. We describe a previously obese 13-year-old male with a giant hepatocellular adenoma requiring an extensive hepatic resection. The related pediatric tumor literature, diagnosis and clinical management is discussed.

Primary hepatic tumors with myxoid change: morphologically unique hepatic adenomas and hepatocellular carcinomas.

Mucin production in primary liver neoplasms is typically interpreted as evidence for biliary differentiation. However, we have observed benign and malignant liver tumors that have abundant extracellular myxoid/mucinous material, yet have only evidence of hepatocellular differentiation. To further characterize these unusual findings, 9 cases were identified and further studied. Four cases were hepatic adenomas, whereas 5 were hepatocellular carcinomas. Extracellular myxoid/mucinous material was diffuse in 7 cases and patchy in 2 cases. The extracellular myxoid/mucinous material was typically weakly mucicarmine positive (N=6) and Alcian blue positive (N=8). All tumors were well differentiated, and none had evidence for biliary differentiation by morphology or immunohistochemistry. The hepatic adenomas arose in nondiabetic and nonobese patients. Both the hepatic adenomas and the hepatocellular carcinomas were strongly and diffusely HepPar1 positive, CK19 negative, and showed loss of LFABP protein expression. These findings indicate that extracellular myxoid/mucinous material in isolation should not be interpreted as cholangiocarcinoma. Furthermore, the unique morphology, the clinical characteristics, and the immunophenotype results suggest that myxoid hepatic adenomas and hepatocellular carcinoma may be unique tumor variants.

Hepatocellular carcinoma arising in adenoma: similar immunohistochemical and cytogenetic features in adenoma and hepatocellular carcinoma portions of the tumor.

Well-differentiated hepatocellular carcinoma in non-cirrhotic liver can show morphological features similar to hepatocellular adenoma. In rare instances, hepatocellular carcinoma can arise in the setting of hepatocellular adenoma. This study compares the immunohistochemical and cytogenetic features of the hepatocellular adenoma-like and hepatocellular carcinoma portions of these tumors. Immunohistochemistry for ß-catenin, glutamine synthetase, serum amyloid A protein, glypican-3, and heat-shock protein 70 was done in 11 cases of hepatocellular carcinoma arising in hepatocellular adenoma in non-cirrhotic liver. Tumors with nuclear ß-catenin and/or diffuse glutamine synthetase were considered ß-catenin activated. Fluorescence in situ hybridization (FISH) was done in nine cases for gains of chromosomes 1, 8 and MYC. There were seven men (33-75 years) and four women (29-65 years). Focal atypical morphological features were seen in hepatocellular adenoma-like areas in 7 (64%) cases. Hepatocellular adenoma-like areas showed features of inflammatory hepatocellular adenoma in 7 (64%) cases; 4 of these were also serum amyloid A-positive in the hepatocellular carcinoma portion. ß-Catenin activation, heat-shock protein 70 positivity, and chromosomal gains on FISH were seen in the hepatocellular adenoma portion in 55%, 40%, and 56% of cases, and 73%, 60%, and 78% of cases in the hepatocellular carcinoma portion, respectively. In conclusion, the hepatocellular adenoma-like portion of most cases of hepatocellular carcinoma arising in hepatocellular adenoma shows features typically seen in hepatocellular carcinoma such as focal morphological abnormalities, ß-catenin activation, heat-shock protein 70 expression, and chromosomal gains. Hepatocellular adenoma-like areas in these tumors, especially in men and older women, may represent an extremely well-differentiated variant of hepatocellular carcinoma, whereas the morphologically recognizable hepatocellular carcinoma portion represents a relatively higher grade component of the tumor.

Immunohistochemical stains of proliferating cell nuclear antigen, insulin-like growth factor 2 and clusterin help distinguish malignant from benign liver nodular lesions.

AIMS: To explore the immunohistochemical utility of proliferating cell nuclear antigen (PCNA), insulin-like growth factor 2 (IGF2) and clusterin in the distinction between malignant and benign liver nodular lesions. METHODS: Immunohistochemical stains for PCNA, IGF2 and clusterin were performed on 284 liver nodular lesions, including 33 hepatocellular adenomas (HCA), 40 focal nodular hyperplasias (FNH), 77 large regenerative nodules (LRN) and 134 hepatocellular carcinomas (HCC). RESULTS: Strong and diffuse nuclear PCNA immunoreactivity was observed in 103 (77%) HCCs but in only 2 (6%) HCAs. None of the FNH and LRN cases showed a strong and diffuse staining pattern. All HCAs, 95% of FNHs and 92% of LRNs showed cytoplasmic IGF2 expression, with a strong staining observed in 70% of HCAs, 20% of FNHs and 30% of LRNs. This was in marked contrast to that observed in HCCs, where 66% of HCCs demonstrated a weak and focal/patchy immunostaining pattern and another 25% showed no detectable IGF2 immunoreactivity. In comparison with their adjacent non-lesional hepatocytes, 75% of HCCs showed decreased IGF2 expression. However, decreased IGF2 expression was not evident in HCAs, FNHs and LRNs. Cytoplasmic staining for clusterin was seen in both benign and malignant nodular lesions. However, an enhanced and exaggerated pericanalicular staining pattern was observed in 75% of HCCs, which was not demonstrated in HCAs, FNHs and LRNs. CONCLUSIONS: PCNA, IGF2 and clusterin show unique immunostaining characteristics in HCCs, which can be useful adjuncts to other currently available markers to aid in the distinction of HCC from benign liver nodular 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.

Beta-catenin-activated hepatocellular adenoma showing hyperintensity on hepatobiliary-phase gadoxetic-enhanced magnetic resonance imaging and overexpression of OATP8.

We report a male case of beta-catenin-activated hepatocellular adenoma (HCA) focusing on findings of gadoxetic-acid-enhanced magnetic resonance imaging (EOB-MRI) and discussing the molecular background and possible clinical significance. The patient was a 31-year-old man in whom computed tomography (CT) showed a large nodule of 14 cm in diameter in the right liver lobe. On dynamic contrast-enhanced CT, heterogeneous and slight to moderate enhancement was observed during the early phase, with washout in the late phase. Focal fat deposits and a scar-like portion in the lesion were also seen. Most of the lesion was slightly hyperintense compared with the background liver on the hepatobiliary phase of EOB-MRI. After operation, this patient was confirmed pathologically as having beta-catenin-activated HCA with a portion suggestive of malignant transformation. In addition, intense organic anion transporter polypeptide 8 expression was observed throughout the tumor by immunohistochemical staining.

Hepatocellular hypertrophy and cell proliferation in Sprague-Dawley rats from dietary exposure to potassium perfluorooctanesulfonate results from increased expression of xenosensor nuclear receptors PPARα and CAR/PXR.

The present study investigated the potential role for activation of PPARα and CAR/PXR by potassium PFOS (K⁺ PFOS) with respect to the etiology of hepatic hypertrophy and hepatocellular adenoma in rats. Male Sprague-Dawley rats were fed K⁺ PFOS (20 or 100 ppm) for either 1, 7, or 28 days. Wyeth 14,643 (Wy 14,643, 50 ppm) and phenobarbital (PB, 500 ppm) were the controls for PPARα and CAR/PXR activation, respectively. Measurements included: plasma ALT, AST, cholesterol, triglycerides, and glucose; liver protein and DNA content; liver activities of palmitoyl CoA oxidase (ACOX), Cyp4A, CYP2B, and CYP3A; induction of liver CYP4A1, CYP2E1, CYP2B1/2, and CYP3A1 proteins (SDS-PAGE and Western blots); liver and thyroid microscopic histopathology, apoptotic index, and cell proliferation index. Terminal body weight was decreased by K⁺ PFOS (100 ppm) and Wy 14,643. All test-compound treatments increased liver weight. Plasma lipids were decreased by both PFOS and Wy 14,643. After treatment for 1 day, K⁺ PFOS (100 ppm), PB, and Wy 14,643 increased mean hepatic DNA concentration and total hepatic DNA, and total DNA remained elevated after treatment for 7 days and 28 days (PB and Wy 14,643 only). Hepatic P450 concentration was elevated after 7 and 28 days by K⁺ PFOS and by PB. K⁺ PFOS and Wy 14,643 increased liver activities of ACOX and CYP4A as well as increased liver CYP4A1 protein. By 28 days of treatment, K⁺ PFOS and PB increased liver activities of CYP2B and CYP3A as well as increased liver CYP2B1/2 and CYP3A1 proteins, and Wy 14,643 increased CYP2B enzyme activity to a slight extent. All test compounds increased the liver cell proliferative index and decreased the liver apoptotic index. No histological changes of the thyroid were noted; however, PB and WY increased thyroid follicular cell proliferation index (seven-day treatment only), while K⁺ PFOS did not. The thyroid follicular cell apoptotic index did not differ between groups. The hepatomegaly and hepatocellular adenoma observed after dietary exposure of Sprague-Dawley rats to K⁺ PFOS likely are due to the increased expression of xenosensor nuclear receptors PPARα and CAR/PXR. Given the markedly lower or absent response of human hepatocytes to the proliferative stimulus from activation of PPARα and CAR/PXR, the hepatocellular proliferative response from activation of these receptors by PFOS observed in rats is not expected to be of human relevance.

Chronic dietary toxicity and carcinogenicity study with potassium perfluorooctanesulfonate in Sprague Dawley rats.

To investigate toxicity and neoplastic potential from chronic exposure to perfluorooctanesulfonate (PFOS), a two-year toxicity and cancer bioassay was conducted with potassium PFOS (K⁺ PFOS) in male and female Sprague Dawley rats via dietary exposure at nominal K⁺ PFOS concentrations of 0, 0.5, 2, 5, and 20 µg/g (ppm) diet for up to 104 weeks. Additional groups were fed 20 ppm for the first 52 weeks, after which they were fed control diet through study termination (20 ppm Recovery groups). Scheduled interim sacrifices occurred on Weeks 4, 14, and 53, with terminal sacrifice between Weeks 103 and 106. K⁺ PFOS appeared to be well-tolerated, with some reductions in body weight occurring in treated rats relative to controls over certain study periods. Male rats experienced a statistically significant decreased trend in mortality with significantly increased survival to term at the two highest treatment levels. Decreased serum total cholesterol, especially in males, and increased serum urea nitrogen were consistent clinical chemistry observations that were clearly related to treatment. The principal non-neoplastic effect associated with K⁺ PFOS exposure was in livers of males and females and included hepatocellular hypertrophy, with proliferation of endoplasmic reticulum, vacuolation, and increased eosinophilic granulation of the cytoplasm. Statistically significant increases in hepatocellular adenoma were observed in males (p=0.046) and females (p=0.039) of the 20 ppm treatment group, and all of these tumors were observed in rats surviving to terminal sacrifice. The only hepatocellular carcinoma observed was in a 20 ppm dose group female. There were no treatment-related findings for thyroid tissue in rats fed K⁺ PFOS through study termination; however, male rats in the 20 ppm Recovery group had statistically significantly increased thyroid follicular cell adenoma, which was considered spurious. There was no evidence of kidney or bladder effects. In rats, the dietary dose estimated as the lower 95% confidence limit of the benchmark dose for a 10% increase in hepatic tumors was 8 ppm for both sexes. Recent mechanistic studies suggest a PPARα/CAR/PXR-mediated mode of action for the liver tumors observed in the present two-year study.

Revisiting the pathology of resected benign hepatocellular nodules using new immunohistochemical markers.

In this review, the authors focus on the use of immunohistochemistry to characterize the different types and subtypes of benign hepatocellular nodules. They describe the classical and currently accepted features leading to the easy and formal diagnosis of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). In addition, they report some atypical features and difficulties in the interpretation of section staining analyses, which represent important parameters for pathologists. A significant contribution of molecular biology to the characterization of FNH has been to reclassify some cases of FNH as inflammatory HCA. Furthermore, the pattern of overexpression of glutamine synthetase (GS), a target gene of ß-catenin has been successfully used to identify FNH by immunohistochemistry. Molecular approaches have demonstrated that HCA is a heterogeneous entity. Genotype classification of HCA has allowed the identification of three subtypes: HNF1A-mutated HCA (H-HCA) in 35% of cases, ß-catenin-mutated HCA (b-HCA) in 10%, and inflammatory HCA (IHCA) in 55%. Following molecular data, the diagnosis of H-HCA relies on the lack of liver fatty acid binding protein (LFABP) immunostaining. The diagnosis of b-HCA is straightforward when GS is strongly and diffusely expressed by lesional hepatocytes, and is accompanied by nuclear ß-catenin immunoreactivity. In IHCA, serum amyloid protein and C- reactive protein are strongly and usually diffusely expressed by tumoral hepatocytes with a sharp limit with the surrounding nontumoral liver. IHCA can also be ß-catenin activated (10%). Due to the strong association of b-HCA with hepatocellular carcinoma transformation, the identification of this HCA subtype is extremely important.

Two case reports of childhood liver cell adenomas harboring beta-catenin abnormalities.

The benign epithelial neoplasm liver cell adenoma is rare, especially in childhood. We report 2 such cases, 1 of which was associated with Prader-Willi syndrome. Differential diagnosis of the liver cell adenomas on the basis of histopathologic findings proved difficult and was based on the absence of cellular and nuclear atypia, mitotic activity, and invasive growth. In both cases, immunohistochemical staining demonstrated the nuclear accumulation of beta-catenin, and in 1 case, the tumor cells carried a mutation of the beta-catenin gene. Recently, disregulation of the Wnt/beta-catenin pathway, attributable to abnormalities of the beta-catenin gene, has been reported to be a major event in the development of hepatocellular carcinomas and hepatoblastomas. Our report may be the first to describe the beta-catenin abnormalities in childhood liver cell adenoma. These findings imply that abnormalities of beta-catenin can be an early initiating event in human liver tumorigenesis.

Hepatic progenitor cells in hepatocellular adenomas.

Hepatocellular adenoma is a benign tumor of the liver that has a small but not negligible risk of malignant transformation into hepatocellular carcinoma. In analogy with the established role of oval cells in hepatocarcinogenesis in rodent models, human hepatic progenitor cells may have a function in the development of liver tumors. To investigate this issue, we performed immunohistochemistry on biopsies of 10 consecutively resected hepatocellular adenomas using markers for hepatic progenitor cells. Sections of paraffin-embedded and frozen biopsies were stained using antibodies against cytokeratins 7, 8, 18, and 19, chromogranin-A, OV-6, and neural cell adhesion molecule. Hepatic progenitor cells were observed in five of 10 hepatocellular adenomas. These five tumors also contained cells with an immunohistochemical phenotype intermediate between hepatic progenitor cells and hepatocytes. Hepatic progenitor cells and intermediate hepatocyte-like cells were scattered throughout the tumors with a density that varied from area to area. Ultrastructural examination confirmed the presence of hepatic progenitor cells. Our study shows that hepatic progenitor cells are present in a considerable proportion of hepatocellular adenomas, supporting the hypothesis that human hepatic progenitor cells can play a role in the development of hepatocellular tumors.

Pigmented liver cell adenoma in two male patients.

We report two cases of hepatocyte neoplasia with extensive deposition of Dubin-Johnson-like pigment in men without Dubin-Johnson syndrome. This pigment has previously been described in hepatocellular carcinoma but not in liver cell adenoma. The tumors of both patients showed some atypical cytologic features, but no frank histologic evidence of malignancy. Long-term follow up for several years showed no evidence of recurrence after limited surgical excision. We conclude that tumors with this structure may be cured by limited surgical excision and should be considered as pigmented liver cell adenomas.