Background: Hepatocellular adenoma (HCA) is a rare benign tumor of the liver. A subtype classification of HCA (hepatocyte nuclear factor 1? [HNF1?]-mutated, β-catenin-mutated HCA, inflammatory HCA, and unclassified HCA) has recently been established based on a single institutional review of a HCA series by the Bordeaux group. Methods: We used histologic and immunohisto-chemical parameters to classify and evaluate eight cases from our institution. We evaluated the new classification method and analyzed correlations between our results and those of other reports. Results: Seven of our eight cases showed histologic and immunohistochemical results consistent with previous reports. However, one case showed overlapping histologic features, as previously described by the Bordeaux group. Four cases showed glutamine synthetase immuno- histochemical staining inconsistent with their classification, indicating that glutamine synthetase staining may not be diagnostic for β-catenin-mutated HCA. HNF1?-mutated HCA may be indicated by the absence of liver fatty acid binding protein expression. Detection of amyloid A may indicate inflammatory HCA. HCA with no mutation in the HNF1? or β-catenin genes and no inflammatory protein expression is categorized as unclassified HCA. Conclusions: Although the new classification is now generally accepted, validation through follow-up studies is necessary.
Key Words: Adenoma, liver cell; Subtype; Hepatocyte nuclear factor 1-alpha; Beta catenin; Serum amyloid A protein
Hepatocellular adenoma (HCA) is a benign hepatic tumor with a low risk of malignant transformation and a known associ- ation with oral contraceptives.1 The incidence of HCA in wom- en with long-term use of oral contraceptives is less than 4 per 100,000/yr.2 Use of oral contraceptives or anabolic steroids has been proposed as a major risk factor for HCAs1,2 although diabe- tes, glycogen storage disease, and other metabolic disorders are also risk factors.3
There are few reported cases of HCA in Korea. This might re- flect the limited use of oral contraceptives in Korea4 due to fear of side effects and the prevalence of tubal ligation and vasectomy during the 1960s and 1970s as part of government-funded fam- ily planning.5
Recent studies have shown that HCAs are a group of geneti- cally heterogeneous tumors6,7 that are classified into four sub- types according to their genetic and phenotypic characteristics as follows: hepatocyte nuclear factor 1? (HNF1?)-mutated HCA (H-HCA), ?-catenin-mutated HCA (?-HCA), inflammatory HCA (I-HCA), and unclassified HCA.8
Approximately 35-40% of HCAs are H-HCAs, which show marked steatosis but lack cytological atypia and inflammatory infiltrate. This subtype can be identified by the absence of liver fatty acid binding protein (L-FABP) expression on immunohis- tochemistry because the FABP1 gene is positively regulated by HNF1?. This type of adenoma is associated with a biallelic in- activating mutation of the HNF1? gene.9 Although most of these mutations are somatic, rare germline mutations associated with adenomatosis have been reported.10
With the exception of unclassified HCA, ?-HCA is the least common subgroup and accounts for approximately 10-15% of HCAs.11,12 ?-HCA has the highest percentage of male pa- tients6,13 and shows cytological atypia, an acinar pattern, and a lack of steatosis. Overexpression of ?-catenin and glutamine synthetase can be demonstrated on immunohistochemistry. ?-HCAs transform more often than other subtypes but rarely transform malignantly.14 Immunostaining for glutamine syn- thetase, which is a target of ?-catenin,15 is believed to reflect ?-catenin mutation.16 Hepatocellular carcinomas (HCCs) tend to be associated with this subtype, particularly in male patients who have received the administration of male hormones, or have glycogenosis or familial polyposis.6,8,11
I-HCA was previously known as telangiectatic focal nodular hyperplasia, but has recently been classified as an HCA sub- type.17,18 More than 50% of HCAs are inflammatory HCAs, which reveal an inflammatory infiltrate, sinusoidal dilatation or congestion, and thick-walled arteries. I-HCAs are associated with alcohol consumption and a high body mass index (BMI).13 Two inflammation-related markers, serum amyloid A (SAA) and C-reactive protein, are used to detect this subtype.
Unclassified HCA is the least common subtype, accounting for 5-10% of HCAs, and does not show mutations in the HNF1? or ?-catenin genes or inflammatory protein expression.13
We evaluated eight HCA cases from our archives using the histochemical and immunohistochemical methods of the new classification system and compared our results with those of previous reports.
MATERIALS AND METHODS
Hematoxylin and eosin-stained slides and formalin fixed par- affin embedded blocks of eight cases of HCA were retrieved from the archives of the Department of Pathology, Korea Uni- versity Medical Center and Seoul National University Hospital. The hematoxylin and eosin slides were reviewed, and immuno- histochemical stains were performed on the formalin fixed par- affin embedded blocks as followed.
Interpretation of histologic findings
Hematoxylin and eosin-stained slides of each case were re- viewed independently by two authors (H.K. and N.H.W.) and a consensus was reached after discussion. The histological char- acteristics of the tumors were evaluated with emphasis on ste- atosis, sinusoidal dilatation, inflammatory infiltrate, cytological atypia, acinar growth pattern, telangiectasia, and peliosis. The percentage of steatotic area was recorded. Histological parame- ters were recorded as negative if less than 10% of the tumor showed the corresponding morphology.
Immunohistochemistry
Immunohistochemical stainings was performed using the fol- lowing antibodies: L-FABP (1:50, rabbit polyclonal) from Ab- cam (Cambridge, MA, USA); ?-catenin (1:50, mouse monoclo- nal), SAA (1:50, mouse monoclonal), and glutamine synthetase (GS; 1:200, mouse monoclonal) from BD Biosciences (San Di- ego, CA, USA); CD3 (1:100, mouse monoclonal), CD20 (1:100, mouse monoclonal), p53 (1:50, mouse monoclonal) and Ki-67 (1:50, mouse monoclonal) from Dako (Carpentaria, CA, USA); and glypican3 (1:50, mouse monoclonal) from Cell Marque (Rocklin, CA, USA).
Cytoplasmic staining of normal hepatic parenchyma served as a positive control for L-FABP immunostaining. Membranous staining of normal hepatic parenchyma served as a positive con- trol for ?-catenin immunostaining. Focal cytoplasmic staining in the perivenular area of normal hepatic parenchyma served as a positive control for GS immunostaining.
Diffuse cytoplasmic granular staining with or without mem- branous staining was recorded as a positive SAA immunostain- ing result. Focal or faint SAA immunostaining was regarded as negative result. Cytoplasmic staining of normal hepatic paren- chyma served as a positive control for SAA immunostaining.
Immunohistochemical staining and histology were indepen- dently interpreted by two authors (H.K. and N.H.W.) and a consensus was reached after discussion.
Hepatocellular adenoma subtype classification
The recent HCA classification system proposed by the Bor- deaux group was used.8 The histologic and immunohistochemi- cal characteristics for each subtype are described below. Each case was categorized based on combined clinical, histologic, and immunohistochemical parameters.
HNF1?-mutated hepatocellular adenoma
The histologic characteristics of H-HCA are marked steatosis and an absence of cytological abnormalities and inflammatory infiltrate.6,7,13 This subtype shows negative staining for L-FABP because HNF1? positively regulates FABP1 in normal liver tis- sue. Diffuse or focal cytoplasmic staining was interpreted as a positive result for L-FABP immunostaining. The presence of steatosis and negative L-FABP immunostaining were indicators of H-HCA.
?-Catenin mutated hepatocellular adenoma
The histological characteristics of ?-HCAs are nuclear atypia, an acinar (pseudoglandular) growth pattern, and lack of steato- sis.6 ?-Catenin and GS immunostaining was used to detect ?-HCAs.12,13 Diffuse or focal cytoplasmic GS staining was in- terpreted as a positive result. Diffuse or focal nuclear ?-catenin immunostaining was interpreted as a positive result, whereas cytoplasmic ?-catenin immunostaining was recorded as aber- rant expression. Characteristic ?-HCA histologic characteristics and positive GS and/or ?-catenin immunostaining results were indicators of ?-HCA.
Inflammatory hepatocellular adenoma
The histologic characteristics of I-HCA are presence of inflam- matory infiltrate, marked sinusoidal dilatation, and thick-walled arteries.8 Steatosis may be present in patients with I-HCA but is not as extensive as that in patients with H-HCA.8 Diffuse or fo- cal cytoplasmic immunostaining for SAA was interpreted as a positive result. Typical histologic characteristics and positive SAA immunostaining were indicators of I-HCA.
Unclassified hepatocellular adenoma
HCAs without genetic changes in HNF1? or ?-catenin and without protein expression of the previously mentioned mark- ers are categorized into this group.8 HCAs with complete or near-complete necrosis can also be classified in this group.13
RESULTS
Clinical information for the eight cases is summarized in Ta- ble 1. The male:female ratio was 1:1 and the average age was 28 years. There were three cases of H-HCA, four cases of I- HCA, and one cases of ?-HCA. Six cases presented as a single mass. The remaining two cases of multiple masses had underly- ing glycogen storage disease. One patient with ?-HCA had a history of steroid administration for systemic lupus treatment. None of the patients had history of oral contraceptive adminis- tration or occurrence of HCC. Morphologic findings (Table 2) and results of immunohistochemical staining (Table 3) were an- alyzed for each case. None of the cases were interpreted as HCC. This was confirmed by negativity for glypican 3 and p53 im- munostaining and a Ki-67 index < 1% in all eight cases.
HNF1?-mutated hepatocellular adenoma
Three cases (A, B, and C) were classified as H-HCA. Two were female and one was male, and one patient had multiple masses. Morphologically, cases A and B revealed marked steato- sis of 30-40% and 20%, respectively, and did not show most of the characteristic histologic features of the other subtypes, such as sinusoidal dilatation, inflammatory infiltrate, cytological atypia, acinar pattern, thick-walled arteries, or peliosis (Table 2). Case C did not show steatosis but presented with thick-walled arteries and cytological atypia. All three cases lacked L-FABP expression on immunohistochemical analysis (Table 3). There was faint L-FABP staining in the tumoral area, but it was inter- preted as negative because the staining intensity was very weak and identical to the non-specific staining of blood vessels. Based on these findings, these three cases were classified as H-HCA. Cases A (Fig. 1) and B were in accordance with the known characters of H-HCA, but case C was not fully concordant and shared some characteristics with I-HCA.
Inflammatory hepatocellular adenoma
Four cases (D, E, F, and G) were categorized as I-HCA. Three were male and one was female. Cases D, E, and G had an avail- able alcohol history and BMI. Although these three cases had a negative history of alcohol consumption, cases D and G had high BMIs (27.8 kg/m2 and 25.9 kg/m2, respectively). All three cases had morphological characteristics typical of I-HCA, including marked sinusoidal dilation, presence of inflammatory infiltrates, and thick-walled arteries (Table 2). The inflammatory cells were a mixed population of CD3-positive and CD20-positive lym- phocytes. In all four cases L-FABP immunostaining was negative and SAA immunostaining was positive (Table 3). Glutamine synthetase immunostaining, should be negative in I-HCA, was positive in cases E and F. Cases D (Fig. 2) and G showed cyto- logical atypia.
?-Catenin-mutated hepatocellular adenoma
Case H was categorized as ?-HCA. This patient had glyco- gen storage disease. Morphologic analysis showed lack of steato- sis and inflammatory infiltrate, but the presence of an acinar pattern with cytological atypia (Table 2, Fig. 3A). By immuno- histochemical satining the tumor cells were positive for L-FABP and glutamine synthetase (Fig. 3B). However, ?-catenin immu- nostaining showed an aberrant pattern of diffuse cytoplasmic staining and was interpreted as negative because there was no nuclear staining (Fig. 3C). This case was classified as ?-HCA because all morphologic and immunohistochemical findings were in agreement with known characteristics of ?-HCA except for the ?-catenin immunostaining result. A detailed explana- tion is given in the Discussion.
Unclassified HCA
All eight cases were determined to belong to the above sub- types therefore none were categorized as an unclassified HCA.
DISCUSSION
This is the largest Korean HCA series review of the past sev- eral decades and the first to apply the new subtype classification. The incidence of HCA in Korea is very low and only a few cases of HCA have been reported in Korea during the past 25 years.19 The recent HCA classification was established based on previ- ous studies of genetic and phenotypic characteristics of HCA and hepatic nodular hyperplasia.9,10,15,17,18,20
Pathologically, the subtype classification enables an accurate diagnosis of this rare entity even with a small biopsy speci- men.8,21 L-FABP immunohistochemistry is especially helpful in the identification of H-HCA because HNF1? positively regu- lates FABP1 in normal liver tissue. Mutation in the HNF1? gene causes steatosis,22 therefore most cases of H-HCA also show marked steatosis.7,11 A correlation study between geno- type and phenotype of each subtype revealed a strong associa- tion between H-HCA and the presence of steatosis, the absence of cytological atypia, and absence of inflammatory infiltrate.6 However, one of our L-FABP-negative cases was not consistent with the description in the new classificat ion system because it did not have steatosis but did have cytological atypia. Although a lack of steatosis in an L-FABP-negative case is unusual, simi- lar L-FABP-negative cases without steatosis can be found in other reports.6,23 According to Zucman-Rossi et al.,6 fewer than 7% of HNF1?-mutated adenomas show no or < 10% steatosis and fewer than 2% present with cytological atypia.
Four cases were categorized as I-HCA, and cases showed con- sistent I-HCA findings including positive SAA and L-FABP immunostaining in addition to an inflammatory infiltrate. Cases D and G showed cytological atypia. Atypia in I-HCA does not seem to be uncommon, and occurred at a rate of approximately 50% in one previous report.6 The Bordeaux group pointed out the presence of cases with overlapping features of I-HCA and ?-HCA.13 I-HCAs are have been reported to present with a lower than moderate level of steatosis in 94% of cases.6 In our study, two of the four I-HCAs presented with 5% steatosis while the remaining three showed none.
Case H was categorized as ?-HCA because of cytological atypia, an acinar growth pattern, and positive L-FABP stain- inng. However, this case did not have positive staining for ?- catenin. Interpretation of ?-catenin immunostaining in HCA seems to be a common problem; thus, the Bordeaux group re- ported that they rely more on glutamine synthetase immunos- taining as a surrogate marker for detecting ?-HCA than on ?- catenin immunostaining because of the focal distribution or ab- sence of ?-catenin positive cells.11 In one Japanese report, the authors also recognized a certain case as ?-HCA even if the tu- mors expressed only GS.24 The discordance between ?-catenin mutation status and protein expression in HCAs is not as strik- ing as that reported in studies of other tumors.25,26 Glutamine synthetase, a surrogate marker for ?-catenin, showed inconsis- tent results in our series. Although positive glutamine synthe- tase staining is supposed to be characteristics of ?-HCAs, four of our seven cases with non-?-HCA subtypes showed a positive result. We suggest that the glutamine synthetase staining method does not necessarily indicate ?-catenin mutation. Simi- lar findings of inconsistent GS staining results are discussed in a review of HCA cases from Scotland.27 In addition to these diffi- culties with immunohistochemistry, ?-HCA can be difficult or impossible to be distinguished from well differentiated HCC because of the cytological atypia and acinar growth pattern.8
If used alone, none of the histological or immunohistochemi- cal parameters included in the subtype classification seem to be able to properly categorize a particular tumor subtype. As sum- marized in a table created by the Bordeaux group, a small num- ber of cases from each subtype share histological features with other subtypes.6 Furthermore, immunohistochemistry can give inconsistent results in certain cases. However, L-FABP or SAA staining alone seemed to be sufficient for discriminating be- tween H-HCA and inflammatory HCA, respectively. The opin- ion that there is no single histologic or immunohistochemical parameter sufficient for classification of any subtype has been ex- pressed in a previous report.27 In our cases presenting with HNF1?-mutated and inflammatory HCA, most, but not all, had intratumoral hemorrhage. Moreover, female predominance is typically observed in HCA cases, but 50% of the patients in our series, were male. A similar relatively high proportion of males was observed in a Japanese study of HCA.24 The authors assumed that this was a characteristic of Japanese HCA cases. When combined with our result, it seems likely that the rela- tively high proportion of males might be the result of genetic and environmental actors associated with an Asian population. Overall, our results both support and contradict other reports on HCA.
In conclusion, the HCA subtype classification based on ge- netic and phenotypic characteristics provides new insight into the pathological and radiological diagnosis and clinical man- agement of these tumors. The classification is now generally ac- cepted, but remains controversial. The diagnostic and clinical implications of the new classification scheme may need to be validated by other studies.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
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Hyunchul Kim · Ja-June Jang1
Dong-Sik Kim2 · Beom Woo Yeom3
Nam Hee Won3
Department of Pathology, Gachon University Gil Medical Center, Incheon; 1Department of Pathology, Seoul National University College of Medicine; 2Division of and Hepato-bilio-pancreas Surgery and Liver Transplantation, Department of Surgery, 3Department of Pathology, Korea University College of Medicine, Seoul, Korea
Received: March 7, 2013
Revised: July 15, 2013
Accepted: August 1, 2013
Corresponding Author
Nam Hee Won, M.D.
Department of Pathology, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 136-705, Korea
Tel: +82-2-920-6142
Fax: +82-2-953-3130
E-mail: [email protected]
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Copyright Korean Society of Pathologists, Korean Society for Cytopathology Oct 2013
Abstract
Hepatocellular adenoma (HCA) is a rare benign tumor of the liver. A subtype classification of HCA (hepatocyte nuclear factor 1? [HNF1?]-mutated, β-catenin-mutated HCA, inflammatory HCA, and unclassified HCA) has recently been established based on a single institutional review of a HCA series by the Bordeaux group. We used histologic and immunohisto-chemical parameters to classify and evaluate eight cases from our institution. We evaluated the new classification method and analyzed correlations between our results and those of other reports. Seven of our eight cases showed histologic and immunohistochemical results consistent with previous reports. However, one case showed overlapping histologic features, as previously described by the Bordeaux group. Four cases showed glutamine synthetase immuno- histochemical staining inconsistent with their classification, indicating that glutamine synthetase staining may not be diagnostic for β-catenin-mutated HCA. HNF1?-mutated HCA may be indicated by the absence of liver fatty acid binding protein expression. Detection of amyloid A may indicate inflammatory HCA. HCA with no mutation in the HNF1? or β-catenin genes and no inflammatory protein expression is categorized as unclassified HCA. Although the new classification is now generally accepted, validation through follow-up studies is necessary. [PUBLICATION ABSTRACT]
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Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer