Case 4 -
Benign Hepatocellular Lesion ?Liver Cell Adenoma
?Focal Nodular Hyperplasia
Stefan G. Hübscher
University of Birmingham
Birmingham, United Kingdom
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This 28 year old woman presented with upper abdominal pain. There was a history of oral contraceptive
pill use. Imaging studies (CT scan) demonstrated a well circumscribed lesion in the left lobe of liver
13cm in maximum dimension, with an area of suspected intra-tumoral haemorrhage. The clinical and
radiological diagnosis was liver cell adenoma. A liver resection was carried out 6 weeks after the
initial clinical presentation.
Left lobe of liver measuring 15 x !0 x 8cm, weight 760g, containing a well circumscribed mass 13 x 8 x
6 cm. Slicing revealed brown, haemorrhagic and necrotic areas. A slide has been submitted from an
apparently viable area at the periphery of the lesion.
Case 4 - Figure 4 - Numerous bile ductules were present throughout the lesion
Case 4 - Figure 5 - Immunostaining for the biliary epithelial marker CK7 confirmed the extensive ductular reaction.
The lesion noted macroscopically was composed of cells closely resembling normal hepatocytes. These
were forming plates slightly thicker than normal. There was focal moderate fatty change and mild spotty
inflammation. There were scattered fibrous septa with a resemblance to portal tracts, but lacking
appropriately sized bile ducts. Several isolated arterial branches were also noted. Reticulin staining
showed a normal sinusoidal framework. Sinusoids were also diffusely immunoreactive for CD31 and CD34.
A striking feature was the presence of numerous bile ductules, which were present throughout the
lesion. Ductules were present both at the periphery of fibrovascular septa and elsewhere.
Immunostaining for biliary epithelial markers (CK7 and AE1) confirmed the presence of extensive ductular
reaction. There were also foci of ductular metaplasia, in places associated with cholestatic rosettes.
Abundant deposits of copper associated protein were noted.
Tumour was well circumscribed, but not encapsulated. Large areas of necrosis were present, as noted
macroscopically. Focal necrosis and fibrosis were also seen in these areas. Occasional foci of
fibrosis, not obviously related to necrosis, were also noted.
Uninvolved liver showed minor abnormalities in keeping with reaction to a nearby space occupying
lesion. There was no evidence of any underlying chronic liver disease.
Benign hepatocellular lesion ?liver cell adenoma ?focal nodular
Liver cell adenoma (LCA) and focal nodular hyperplasia (FNH) are the two commonest examples of
solitary benign hepatocellular lesions occurring in the liver. Both are seen predominantly in young
women and there is frequently a history of oral contraceptive pill usage. The distinction between liver
cell adenoma and focal nodular hyperplasia (FNH) is important clinically, as the management of the two
conditions is different. LCA is associated with a significant risk of serious complications such as
haemorrhage and intra-abdominal rupture. There is also a small but well documented risk of malignant
transformation. Surgical resection is therefore recommended for LCA. By contrast FNH is usually
asymptomatic and conservative management is adequate in most cases.
The distinction between classical examples of liver cell adenoma and FNH is usually fairly
straightforward on clinical and radiological grounds. Pathological findings are also distinctive in most
cases (see Tables 1 and 2) :
Table 1. Comparison of macroscopic findings in liver cell adenoma and focal nodular hyperplasia
| ||Liver cell adenoma ||Focal nodular hyperplasia|
|Size ||5-15cm(rarely up to 30cm) ||Most < 5cm(rare cases >10cm)|
|Well-circumscribed ||Yes ||Yes|
|Fibrous capsule ||Rare, incomplete ||No|
|Haemorrhage/necrosis ||Common ||Very rare|
|Central scar ||Rare(secondary to degeneration) ||Typical|
|Nodularity ||Rare ||Typical|
Table 2. Comparison of microscopic findings in liver cell adenoma and focal nodular hyperplasia
| ||Liver cell adenoma ||Focal nodular hyperplasia|
|Composition ||Purely hepatocellular ||Mixed(hepatocytes and bile ductules)|
|Arrangement of hepatocytes ||Uniformly thickened trabeculae|
Pseudoglandular transformation/ cholestatic rosettes
|Variably thickened trabeculae|
|Other hepatocellular changes|
Large cell change
|Sinusoidal dilatation/peliosis ||Common ||Rare|
|Stellate fibrosis ||No ||Yes|
- abnormal blood vessels centrally
- ductular reaction at the periphery
- variable inflammatory infiltration
|Haemorrhage/necrosis ||Common ||Very rare|
|Kupffer cells ||Yes(often inconspicuous) ||Yes|
|Features of chronic cholestasis ||No ||Yes|
Copper associated protein
|Sinusoidal capillarisation ||Yes ||Yes|
|Other findings ||Unaccompanied arteries ||Progenitor cells|
However there are rare cases, such as the one presented here, where there appear to be overlapping
features between liver cell adenoma and FNH. Features favouring a diagnosis of LCA in the case described
here include the clinical presentation (haemorrhage very uncommon with FNH) and the
radiological findings. The
macroscopic appearances of haemorrhage/necrosis, lack of a central scar and the absence of any
obvious nodularity are also typical of LCA. Many of the microscopic findings would also be compatible
with a diagnosis of LCA. However, the presence of extensive ductular reaction (together with abundant
deposits of copper associated protein) would be most unusual in LCA, which is considered to be a purely
hepatocellular lesion, whereas these are typical findings in FNH.
A number of mechanisms for the development of cases with mixed features of LCA/FNH have been
(1) Liver cell adenoma with secondary FNH changes:
It is generally accepted that FNH represents a localized hyperplastic response to a focus of abnormal
vascularisation, usually increased arterialisation . In most cases this occur as a consequence of a
pre-existing arterial malformation, possibly congenital, which is typically present in the central area
of stellate fibrosis, ("primary" FNH). More rarely FNH may be present in association with other
recognized vascular abnormalities, including vasoformative neoplasms such as liver haemangiomas or
adenomas ("secondary" FNH). In a series of 168 patients undergoing surgical resection for FNH 31 had
nodular lesions elsewhere in the resection specimens - these included 11 haemangiomas and 6 liver cell
adenomas . Associated neoplasms usually occurred in close proximity to areas of FNH but were still
clearly distinct. However in cases where mixed features of FNH and LCA are present within the same
lesion, it is possible that the initial lesion was an adenoma which has resulted in secondary changes of
FNH within the tumour itself.
(2) Atypical variant of FNH:
Up to 20% of cases of FNH may lack one or more of the classical features listed above. In the study
of Nguyen et al 60 non-classical forms of FNH could be subdivided into 3 main subtypes, based on the
dominant morphological features – telangiectatic FNH (n=47), mixed hyperplastic and adenomatous FNH (n=5)
and FNH with cytologic atypia of large cell type (n=8) . The telangiectatic variant is also of
interest as such cases lacked macroscopic scars and grossly resembled adenomas in most instances.
Although fibrous septa were present histologically, they were less well developed than in classical FNH.
Ductular reaction was present to some degree in all cases. One lesion showed extensive central
haemorrhage and necrosis.
(3) Co-incidental lesions with common pathogenetic mechanisms:
Vascular abnormalities, which are the key factor for the formation of FNH could also favour the
development of adenomas. Oestrogenic factors, including oral contraceptive pill may be important in the
pathogenesis of abnormal angiogenesis and a history of oral contraceptive pill use is usually present in
cases with simultaneous occurrence of adenoma and FNH 
The case presented here showed mixed features of liver cell adenoma and focal nodular hyperplasia. It
is not clear if the primary lesion is a liver cell adenoma (with secondary changes of FNH), focal nodular
hyperplasia (with atypical "adenoma-like" features) or a genuine mixed lesion. In cases where
histopathological interpretation is difficult, clonality assessment and gene analysis might help in the
distinction between FNH and LCA
. As far as clinical management is concerned, because of the
abnormal vasculature and the consequent risk of haemorrhage, cases such as this are probably best
regarded as adenomas and treated by surgical resection.
- Ishak KG, Goodman ZD, Stocker Benign hepatocellular tumours. In: Atlas of Tumor Pathology. Tumors of the liver and intrahepatic bile ducts.Washington, Armed Forces Institute of Pathology 2001, 9-48
- Wanless IR Vascular disorders. In: Pathology of the liver 4 Edition (Edited by: MacSween RNM BA, Portmann BC, Ishak PJ, Scheur PJ, Anthony PP). London, Churchill Livingstone 2002, 539-573.
- Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C 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.
- Laurent C, Trillaud H, Lepreux S, Balabaud C, Bioulac-Sage P. Association of adenoma and focal nodular hyperplasia: experience of a single French academic center. Comp Hepatol. 2003 23;2(1):6.
- Paradis V, Laurent A, Flejou JF, Vidaud M, Bedossa P Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology 1997, 26:891-895.
- Bluteau O, Jeannot E, Bioulac-Sage P, Marques JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 2002, 32:312-315.