Journal of Hepatology
Volume 46, Issue 3 , Pages 521-527, March 2007

Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update

Hôpital St André, Service d’Hépatologie Gastroentérologie, CHU Bordeaux, 1 Rue Jean Burguet, Bordeaux cedex, France

published online 02 January 2007.

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1. Introduction 

The classification and nomenclature of benign hepatocytic nodules is largely based on a document written by the International Working Party in 1995 [1]. Since that publication, several important advances have created a need to update the classification, especially with regard to hepatocellular adenoma (HCA) and focal nodular hyperplasia (FNH). A meeting organized by P. Bioulac-Sage, C. Balabaud, P. Bedossa and J.Y. Scoazec with the purpose of clarifying the pathological diagnosis of HCA and FNH was held in Bordeaux in June 2005. Participants included members of the Laennec Liver Pathology Society and of the International Liver Pathology Study Group (Elves), supplemented by hepatologists, radiologists, surgeons, and molecular biologists with an interest in liver tumours.

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2. Clinical-pathological review of standard features of HCA and FNH 

The examination of a liver biopsy or resection specimen remains the gold standard to establish the diagnosis of HCA and FNH when radiographic investigations have failed to establish a definitive diagnosis [1], [2], [3], [4], [5]. However, the diagnosis of each of these lesions may remain difficult in a liver biopsy and occasionally even when the entire specimen is available, particularly in small lesions [6]. The distinction between the two lesions is important because most cases of FNH do not require resection, whereas HCA, which can have serious clinical consequences, should, in general, be surgically excised.

2.1. Hepatocellular adenoma 

HCA is a rare tumour, presenting in a variety of clinical settings or by chance. It is important to stress that, at present, HCA cannot be identified conclusively by any currently available imaging technique. HCA can only be at best suspected strongly and this suspicion may lead to liver biopsy or even surgical resection when the diagnosis may be confirmed (or refuted).

HCAs can be solitary or multiple. They represent a heterogeneous group of tumours [2] in which histopathological features may vary according to the aetiological background. Classically, HCAs are soft, well-demarcated tumours with little or no fibrous capsule, and are composed of liver cell plates that are only mildly thickened or irregular. The tumour parenchyma is supplied by thin-walled arteries without other portal tract elements such as significant amounts of connective tissue, bile ducts, or ductular reaction. Tumour hepatocytes are of normal size, the cytoplasm may be either normal, clear (glycogen-rich) or fatty, and some lesions may be almost entirely steatotic. Nuclear atypia, mitoses, and acinar (“pseudo-glandular”) growth pattern can be seen but are distinctly unusual; in such cases the differential diagnosis from hepatocellular carcinoma (HCC) may be very difficult or even impossible. In contrast, degenerative changes including sinusoidal dilatation, peliosis, infarcts, and haemorrhage are frequent, and may result in oedematous or fibrotic regions, often with haemosiderin-laden macrophages. There are two types of haemorrhage: internal haemorrhage usually admixed with necrotic changes (this type is mostly observed in adenomas larger than 4cm) and the spontaneous rupture which causes subcapsular haematoma and possible haemoperitoneum [7]. HCC can arise in the setting of HCA, but this is a rare occurrence [8].

The definition of adenomatosis requires the presence of at least 10 adenomas in the liver [9], [10]. Patients with glycogenosis, or taking contraceptives, hormones are theoretically excluded [9].

2.2. Focal nodular hyperplasia 

FNH has been reported in 0.6–3 % of the general population [11] and is 10 times more frequently observed than adenomas in referral centers [12]. Most FNH are diagnosed by chance, but some cases are symptomatic. In contrast to adenomas, imaging techniques are sufficient for diagnosis in 70% of cases. Histopathological examination is required for diagnosis in the minority of cases that have non-diagnostic imaging features.

In approximately two-thirds of cases FNH is solitary. The typical histopathological features of classical FNH include a firm, well-delimited but not encapsulated lesion composed of hepatocellular nodules, a central scar, and radiating fibrous cords. The fibrous regions typically contain large dystrophic arteries and ductular reaction, and frequently there is a lymphocytic infiltrate. The diagnosis of FNH can be evident in a liver biopsy [13], [14]. In some cases of FNH the histopathological diagnosis may remain difficult, even in a resected specimen, because the definitive histopathological features may be absent, inconspicuous, or atypical [4], [15].

FNH is associated with vascular abnormalities [5], including hepatic hemangiomas [11], which supports the concept of a vascular component in the pathogenesis of this lesion [16], [17]. FNH has also been reported in patients with a variety of non-hepatic tumours and tumour-like conditions [6], [18].

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3. Review of new advances, including contribution of molecular biology to classification and diagnosis 

3.1. FNH 

Molecular studies have elucidated new features that distinguish FNH from HCA. FNH are polyclonal [19] and characterized by an increase in the Angiopoietin1/Angiopoietin2 mRNA ratio [20] whereas HCAs are monoclonal [19] without significant change in the Angiopoietin1/Angiopoietin2 mRNA ratio [21].

Some lesions have histologic features of both adenoma and FNH. These variant lesions have often been classified as the telangiectatic type of FNH [1], [18]. These tumours are often multiple. Clinical and molecular evidence indicates that telangiectatic “FNH” should be reclassified as adenomas (vide infra) [21], [22].

3.2. HCA 

Studies which correlate lesional genotype with phenotype form the basis of a new histological/molecular classification of hepatocellular adenomas [22]. Based on 2 molecular criteria (HNF1α mutations and β-catenin mutations), and an additional histological criterion (the presence/absence of inflammation), subgroups of hepatocellular adenoma [22] can be defined and distinguished from FNH [21], [23]. Analysis of 96 HCA performed by a French collaborative network showed that they can be divided into four broad subgroups: the first one is defined by the presence of mutations in gene coding for HNF1α ; the second by the presence of mutations in gene coding for β-catenin ; the category without mutations of HNF1α or β-catenin genes is further divided in two subgroups depending on the presence or absence of inflammation.

3.2.1. Hepatocellular adenomas with mutation of HNF1α gene 

HNF1α mutations are observed in ≈40–50% of adenomas [22], [24]. Biallelic inactivating HNF1α mutations have been identified in tumour tissue: in 85% of cases, both mutations are of somatic origin, whereas in the remaining cases, one mutation is germline and the other is somatic. Correlations with pathological and clinical data have shown that HNF1α mutations are mainly observed in a histologically homogeneous group of tumours, characterized by marked steatosis, no cytological abnormalities and no inflammatory infiltrate. HNF1α mutations have been reported in association with HCC, but are uncommon (less than 5% of the HCC cases) [22]. Patients with germline HNF1α mutations are younger than those with somatic mutations, with or without clinical diabetes (see below) and they frequently had a familial history of liver adenomatosis.

3.2.2. Hepatocellular adenomas with mutation of β-catenin gene 

Less than 10% of adenomas have a β-catenin gene mutation including exon 3 deletion or amino-acid substitution altering a site of phosphorylation. In β-catenin-mutated tumours, two β-catenin target genes, Glutamine synthase (GS) and GPR49, are greatly over-expressed when compared to non-tumour tissues. Correlations with the corresponding pathological and clinical data have shown that β-catenin-mutated tumours occur more frequently in males, are usually characterized by the occurrence of cytological abnormalities and acinar pattern whereas they are less frequently steatotic. They are also more frequently interpreted as borderline lesions between HCA and HCC and are more frequently associated with the development of unequivocal HCC [22].

3.2.3. Hepatocellular adenomas without mutations of HNF1α or β-catenin genes 

The remaining broad group (approximately 40%) of HCAs lack HNF1α or β-catenin mutations and represent a heterogeneous group. One subset defined by the presence of inflammatory infiltrates [22] corresponds, at least partly, to the newly characterized entity (previously called telangiectatic FNH), a variant of hepatocellular adenoma often designated as inflammatory adenoma and/or telangiectatic adenoma [25] depending upon the importance of inflammatory infiltrates and/or sinusoidal dilatation. We believe this subset of tumours is HCA [22] rather than FNH for two reasons. First, the lesions display macroscopic appearances of HCA that include typical gross features of soft large tumours with a significant risk of haemorrhage instead of the nodular and fibrous appearance of typical FNH. Secondly, these lesions also have molecular characteristics of HCA, which include monoclonality and Ang1/Ang2 mRNA ratio in the range found in HCA of the usual type [21], [23].

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4. Problem areas requiring further clarification 


1.The diagnosis of HCA variants remains problematic because the pathological appearance is heterogeneous and overlaps with that of FNH. For instance, until now, the presence of ductules (CK7 positive and usually CK19 negative) in hepatocytic nodules has prevented the diagnosis of adenoma for a lesion otherwise closely similar to classical HCA. One important lesson learned from molecular studies is that the presence of ductules does not preclude the diagnosis of HCA particularly when associated with sinusoidal dilatation (the so-called telangiectasia in telangiectactic FNH). These ductules can be dystrophic and differ from those observed in FNH. The cytokeratin 7 positive cells should not be wrongly interpreted as progenitor cells [26], since these cells may also be present in FNH [27]. Thus, a better correlation of histologic and molecular properties of these lesions is needed.

2.It is not clear if all nodules originally called telangiectatic FNH [4], [18], [28] and progressive FNH [29] are histologically the same lesions as those subsequently included in the studies that demonstrated monoclonality [21], [23] and/or were associated with syndromes like meningioma, astrocytoma, telangiectasia of the brain, berry aneurysm, etc. [18].

3.HCA, FNH and haemangioma can occur in the same patient, and the definitive identification of these lesions can be more or less difficult, with the most significant risk being missing the HCA(s) and to wrongly reassure the patient. The association of FNH and HCA may be fortuitous; however, it seems that the presence of FNH is significantly higher than expected in at least two circumstances: adenomatosis and multiple inflammatory HCA [30].

4.The current definition of adenomatosis is difficult to apply in practice. The underlying aetiology of the tumours may be an important consideration as it might appear unduly restrictive to exclude patients with glycogenosis, or individuals taking oral contraceptives or anabolic steroids [31], from the concept of adenomatosis. Nevertheless, for the present it is recommended that the definition requiring 10 nodules be retained for the definition of adenomatosis [9], [10].

5.Additional studies are needed to determine if there are different clinico-pathologic consequences of the number of HCAs in any given patient. In addition it is important to record the size of each HCA since the risk of malignant transformation increases with lesional size, regardless of the number of lesions.

6.Little is known concerning the growth and involution of liver nodules (either HCA or FNH), and this aspect deserves further study [32], [33], [34], [35]. A small isolated nodule (measuring a few millimeters) without the characteristic features of classical FNH could be a FNH precursor [15] or a microadenoma [36]. On the other hand, HCA may contain fibrotic areas resulting from haemorrhage or necrosis, making difficult the differential diagnosis between HCA and FNH, particularly in the evaluation of core biopsy material.

7.The risk of haemorrhage in a liver cell adenoma is unpredictable and is not clearly related only to large lesional size. Thus, the actual risk factors for this complication are not completely understood, and further data are needed.

8.There are no longitudinal studies of the transformation of hepatocellular adenomas into HCC. It has been shown recently that malignancy was only found in adenomas larger than 4cm and occurred more often in men than in women [37]. Imaging criteria to detect malignant transformation are often disappointing except when signs of invasion such as vascular invasion are present. Changes in size of a lesion have been found to be useful in cirrhotic patients with dysplastic nodules, but this feature has not yet been adequately evaluated in adenomas.

It is therefore very difficult to offer generalised practical, evidence-based management guidelines.The details of each case have to be considered such as patient preference, age, gender, lesional size, location, number; aetiology (glycogenosis, factors associated with HCA such as oral contraceptives, androgens, diabetes), mode of presentation (haemorrhage, mass lesion and associated symptoms), availability of specialist techniques and expertise (hepatology, pathology, radiology, and surgery).

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5. Specific recommendations/practical considerations 

It is important to stress that in a number of cases, we do not have the tools to answer two major questions with a liver biopsy (and in a smaller number of cases to a resected lesion):

1.How can HCA be distinguished from FNH when imaging techniques have failed, knowing that the specimen may not be representative of the entire nodule?

2.How can we differentiate an adenoma with borderline atypical features from an HCC?

Since molecular techniques are not routinely available, histologic criteria remain the standard to characterize HCA and FNH. From a practical point of view, we must then approach the diagnosis and management of these lesions with the tools at hand.

5.1. Radiology 

Imaging and especially MR imaging is accurate in the diagnosis of FNH [38], but not of HCA. There is a role for liver biopsy in FNH when imaging cannot establish firmly the diagnosis (absence of scar, scar remaining hypodense or isodense on delayed scans or are hypointense on T2-weighted images, lesion heterogeneity, rapid washout or delayed contrast enhancement, etc.). It has been shown that in the absence of definitive radiologic diagnosis of FNH, the histologic diagnosis can be made in most cases. Using a scoring system incorporating major and minor diagnostic features and concomitant analysis of non lesional parenchyma, FNH can be recognized reliably in liver biopsies [14]. Interestingly, most radiologically atypical tumours were non-classic forms of FNH histopathologically. It is important in such cases to biopsy a representative sample of lesional tissue as well as specifically to take a separate adequate biopsy sample of background liver remote from the lesion. Imaging findings [39] of HCA and adenomatosis are similar and vary according to the particular characteristics of the lesional tissue: there are fatty patterns, peliotic patterns and heterogeneous patterns with necrotic and haemorrhagic foci. Currently imaging techniques are unable to detect early malignant transformation in HCA.

5.2. Histopathology 

Difficulties persist in the diagnosis of some cases, as in the past, in differentiation of HCA from FNH on a needle biopsy. In addition to the usual haematoxylin–eosin (H&E) and trichrome histochemical methods, use of a histological score [14], immunohistochemical stains with antibodies to CD34 [40], cytokeratin 7 or hepatic transporters [41] may help to differentiate between FNH and HCA. HCAs with cytological abnormalities may be premalignant and may even contain identifiable malignant foci [8]. If molecular techniques are not available to test for β-catenin mutation on frozen or formalin-fixed tissue, it may be helpful to perform the immunolocalization of β-catenin [42], [43], [44] or glutamine synthase (GS) on paraffin sections. GS is a β-catenin target gene, the protein product of which is easier to visualize by immunocytochemistry than β-catenin [45]. Additional studies are needed for, but early results suggest that expression of either β-catenin or GS requires consideration of resection and/or close clinical follow-up.

The differential diagnosis between HCA and well differentiated HCC remains a major problem particularly in men and in specific circumstances (i.e. aetiologies including glycogenosis, and androgens). FISH or CGH might be able to distinguish between HCA (without chromosomal aberrations) from HCC (usually with chromosomal aberrations) [46]. The term “atypical adenoma” is often used to indicate that the distinction between HCA and HCC remains problematic and resection and/or close clinical follow-up may be needed.

The pathology report (for a surgical specimen or biopsy) should comment on key features such as steatosis, haemorrhage, necrosis, and cytologic and vascular abnormalities. The final histopathological diagnosis should state whether the HCA is typical or if it contains some unusual features. In the latter case, if the term variant HCA is applied (indicating that the lesion is an adenoma subtype), then this usage must be described and explained in order to avoid the overuse of this term for any small variation from the usual pattern of HCA.

5.3. Surgery 

The challenge is to determine the nature of the tumour, or more precisely, its risk of progression, in order to determine if resection is necessary [37]. With a preliminary diagnosis of “atypical nodules” or multiple small nodules, laparoscopic exploration is an excellent and minimally invasive tool, allowing visual and ultrasonographic examination as well as multiple biopsies of the tumour(s) and of non-tumoural liver [47]. In case of large solitary adenoma (⩾4–5cm, whatever the subtype), resection remains justified (because of the risk of bleeding and difficulty of excluding HCC especially in male patients). In cases of multiple nodules and particularly adenomatosis, management is more problematic. HCA resection is necessary in cases of large, or symptomatic nodule(s) particularly those with a higher perceived risk of bleeding, or when there are factors that favour malignant transformation such as rapid growth, change in radiological characteristics, or elevated serum AFP. Liver transplantation is hardly ever mandated, except in rare forms of progressive or, symptomatic adenomatosis or malignant transformation.

There are two significant risks potentially associated with HCA and FNH, that should be kept in mind, if it is clinically decided that resection should not be performed. One, of course, is failure to diagnose malignancy. The other is the risk of potentially life-threatening bleeding.

If the diagnosis of FNH is established with radiological certainty, large tumours do not necessarily have to be resected unless they are symptomatic or unless their location compromises liver function.

5.4. Hepatology 

A young patient with HCA and maturity-onset diabetes of the young, type 3 (MODY 3) should be investigated for HNF1α constitutional mutation [48], [49], [50]. If the blood test is positive, a familial investigation for both diabetes and liver nodules is mandatory [51], [52].

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6. Conclusion 

The approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era (Table 1) directed by new molecular information. It is hoped that the development of more readily available immunohistological tools will permit significant improvements in liver biopsy interpretation in our ability to distinguish HCA from FNH, and to delineate clinically meaningful entities within each group. The optimal care of patients with a liver nodule requires the combined expertise of hepatologists, pathologists, radiologists, and surgeons. Progress will also need the expertise of molecular biologists. Finally, in view of the fact that there have been and continue to be considerable difficulties in correctly identifying some cases of HCA and FNH, the literature concerning this group of tumours should be read critically and interpreted with care.

Table 1. Distinguishing features of hepatocellular adenoma and focal nodular hyperplasia
Pathological featuresResearch toolsClinical relevanceAssociated conditions
Hepatocellular adenoma
Archetypal HCA: soft lesion with little or no fibrous capsule, little cytological atypia, regular liver cell plates up to 3 cells thick, thin-walled arteries without other portal tract elements, bile ducts, or ductular reactionMonoclonalityRisk of bleedingFNH
Variant 1- marked steatosis/clear cellsHNF1α mutation (most cases are biallelic somatic mutation)Risk of bleedingaCases with germline HNF1α constitutional mutation associated with (MODY 3) diabetes and familial adenomatosis, and present at a younger age
Variant 2- cytological atypia and acinar pattern. Less steatosis. May be interpreted as “atypical HCA”, or “HCA/HCC borderline lesion”β-Catenin mutation, diffuse glutamine synthetase expressionRisk of bleedinga, risk of malignant transformationbOccurs more frequently in males. HCCc
Variant 3 (Previously “telangiectatic FNH”)- telangiectasia and inflammatory infiltrate. May contain CK7 positive ductulesNo known mutationRisk of bleedingaLesions may be multiple, and possible association with vascular or neurological disorders
Variant 4- no specific traitNo known mutationRisk of bleedinga

Focal nodular hyperplasia
Archetypal FNH: firm, circumscribed but not encapsulated, central scar containing abnormal arteries, with lymphoid and ductular reaction. Interlobular bile ducts usually absent. Fibrous bands and nodularity resulting in a “focal (biliary) cirrhosis” appearancePolyclonality, elevated Angiopoietin1/Angio- poietin2 mRNA ratio Association with haemangioma and adenomas
Lack of, inconspicuous or only some of the key diagnostic features noted above Differential diagnosis with adenomas may be difficult
Unusual features (steatosis) Differential diagnosis with adenomas may be difficult/impossible when nodules are small (<10mm) lacking key diagnostic features

aThe degree of risk of bleeding in each of the different categories is unknown.

bThe risk of malignant transformation seems to be higher in β-catenin mutated cases than in other types of adenoma (which may also have a small risk of HCC). However, the precise degree of risk in each of the different categories is unknown.

cThe association in the same coalescent nodule of HCC and adenoma (β-catenin and glutamine synthetase positive) can be explained by either malignant transformation of adenoma, or an HCC with both very well differentiated and less differentiated areas. At present, this issue remains unresolved.

Participants to the Bordeaux update listed below, the great majority being members of the Laennec Liver Pathology Society and of the International Liver Pathology Study Group (Elves), took part in the manuscript elaboration.

P. Bioulac-Sage, C. Balabaud, P. Bedossa, J.Y. Scoazec, V. Alves, P. Bhathal, L. Chiche, J. Craig, A.P. Dhillon, L. Ferrell, S. Geller, Z. Goodman, A. Gouw, M. Guido, M. Guindi, P. Hytiroglou, M. Kage, M. Kojiro, F. Kondo, M. Kudo, M. Nakano, V. Paradis, N.Y. Park, A. Quaglia, M. Roncalli, T. Roskams, B. Ruebner, M. Sakamoto, R. Saxena, D. Tiniakos, N. Theise, S. Thung, H. Trillaud, V. Vilgrain, I.R. Wanless, J. Zucman-Rossi.

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PII: S0168-8278(06)00678-7

doi:10.1016/j.jhep.2006.12.007

Journal of Hepatology
Volume 46, Issue 3 , Pages 521-527, March 2007

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