The British Journal of Radiology, 78 (2005), 704707

DOI: 10.1259/bjr/88181612

2005 The British Institute of Radiology

Differentiation of focal nodular hyperplasia and hepatocellular

adenoma by contrast-enhanced ultrasound
1

C F DIETRICH, MD, 1G SCHUESSLER, MD, 2J TROJAN, MD, 3C FELLBAUM, MD and 1A IGNEE, MD

1st Department of Internal Medicine, Caritas Hospital Bad Mergentheim, Uhlandstr. 7, 97980 Bad Mergentheim, 22nd
Department of Internal Medicine and 3Senckenberg Center of Pathology, Johann Wolfgang Goethe University, Theodor
Stern Kai 7, D-60590 Frankfurt am Main, Germany

Abstract. Non-invasive differentiation of focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA)
is difficult. The aim of this study was to assess the accuracy of contrast-enhanced phase inversion ultrasound to
differentiate between histologically proven FNH and HCA, analysing the arterial and (early) portal venous
phase. 32 patients with histological proven FNH (n524) or HCA (n58) have been included in this prospective
study. Examination technique: Siemens Elegra, phase inversion harmonic imaging (PIHI) with low mechanical
index (MI),0.20.3 using SonoVueH (BR 1). The contrast enhancing tumour characteristics were evaluated
during the hepatic arterial (starting 822 s) and early portal venous phase (starting 1230 s). The image analysis
was performed by three examiners. In 23 of 24 patients with FNH the contrast pattern revealed pronounced
arterial and (early) portal venous enhancement. Homogeneous enhancement was detected during the hepatic
arterial phase in all eight patients with HCA. In contrast to patients with FNH, no enhancement was seen
during the portal venous phase. In conclusion, contrast-enhanced phase inversion ultrasound demonstrated
pronounced arterial and portal venous enhancement in patients with focal nodular hyperplasia. In contrast,
after homogeneous enhancement during hepatic arterial phase, no enhancement during hepatic portal venous
phase was detected in patients with hepatocellular adenoma. Therefore, this technique might improve the
functional characterization of benign hypervascular focal liver lesions.

Focal nodular hyperplasia (FNH) and hepatocellular

adenoma (HCA) are two benign, mostly incidentally
discovered, hepatic neoplasms which occur predominantly
in young and middle-aged women. Differentiation is
essential because of different therapeutic approaches:
HCA is an indication for surgery due to the risk of
haemorrhage and a potential for malignant transformation; by contrast, FNH may be managed conservatively.
However, until recently the non-invasive differentiation of
FNH from HCA and other benign or malignant neoplasm
has remained challenging with no satisfactory tests apart
from histological examination of a liver biopsy sample [1].
Ultrasound features of FNH are often non-specific,
whereas helical CT and MRI are able to provide some
information for the diagnosis of FNH, especially when the
lesion depicts typical features, such as a central scar and
uniform hypervascularity. Typical histological features are
controversial in the literature [27] and only reported in
about 5070% of patients. In a series of 305 FNH, a
central scar could be found only in about 50% [8].
To improve the ultrasound detection and characterization of liver tumours micro-bubble echo-enhancers have
been developed, which can be optimally utilized with the
phase-inversion mode [9].
The aim of this study was to assess the accuracy of
contrast-enhanced phase inversion ultrasound to differentiate between FNH and HCA analysing the arterial and
portal venous phase.

Received 1 July 2004 and in final form 13 January 2005, accepted 11

February 2005.

704

Subjects and methods

Between 2000 and 2002, 32 patients with histologically
proven FNH (n524) or HCA (n58) were included in this
prospective study evaluating the tumour characteristics
using SonoVueH (Bracco, Milan, Italy) contrast enhanced
ultrasound before biopsy. Tumours suspected to be FNH
or adenoma before biopsy, but which proved to be of
different origin have been excluded from study analysis.
All patients underwent B-mode ultrasound (Sonoline
Elegra; Siemens, Erlangen, Germany) with a 3.5 MHz
and a 7 MHz multifrequency transducer. The pattern of
tumours was described as hypoechoic, isoechoic, or
hyperechoic compared with the surrounding liver tissue;
tumour vascularity was classified as hypervascular, isovascular, or hypovascular by power Doppler ultrasound.
The internal vascular architecture was also documented.
All examinations were carried out by the same examiner
(CFD), but image analysis was performed by two
additional examiners. Contrast sequences were regarded
sufficiently evaluable, if all three examiners agreed on
the adequate visualization; in three patients a second
injection was necessary to ensure full agreement between
examiners.
In a pre-study phase of 10 consecutive patients we could
observe the onset of hepatic arterial enhancement between
8 s and 22 s, and the early onset of portal venous
enhancement between 12 s and 30 s. Therefore, intravenous application of 4.8 ml SonoVueH was used with phase
inversion ultrasound before biopsy using the following
imaging parameters: mechanical index 0.20.3, power 3%,
gain 5260 dB and frame rate 1014 s21. The liver was
scanned continuously for up to 5 min. Using this
approach, contrast enhancing tumour characteristics
The British Journal of Radiology, August 2005

Differentiation of FNH and hepatocellular adenoma

(a)

(b)

Figure 1. Contrast-enhanced phase inversion ultrasound imaging of a patient with focal nodular hyperplasia. (a) Contrast-enhanced
phase inversion ultrasound scanning 822 s (onset of arterial phase) after administration of SonoVueH revealed an hyperechoic hypervascular liver tumour with radial vascular architecture. (b) During the portal venous phase (onset 1230 s after administration of
SonoVueH) a pronounced enhancement could be detected by contrast-enhanced phase inversion ultrasound scanning. Hepatic artery
(HA) and portal vein (PV) are indicated.

were evaluated during the hepatic arterial (starting

822 s) and early portal venous phase (starting 1230 s),
as described previously, comparing the contrast enhancement in comparison with the enhancing hepatic artery and
portal vein branches (Figure 1) [11].
Reference imaging examinations (e.g. CT, MRI and
scintigraphy) were performed as part of the clinical workup of the patients, in several cases outside our institution,
and not for the purpose of this study. The standard
practice used in our department included two different
image procedures (US/CT/MRI) with inconclusive findings
before liver biopsy. Institutional Board approval and oral
informed consent, from all patients according to the
ethical guidelines from Helsinki, were obtained. Patients
characteristics are summarized in (Table 1).
In a post-study phase we used Acuson Sequoia (contrast
pulse sequencing (CPS); Siemens, Erlangen, Germany)
techniques in an additional 12 patients with FNH and 2
patients with hepatocellular adenoma. Intravenous application of 1.2 ml/2.4 ml SonoVueH was applied using the
following imaging parameters: mechanical index 0.21, gain
80 dB.

Results
In all 32 patients, enhancement of the hepatic artery and
portal vein was observed. In 23 of 24 patients with FNH
the contrast pattern revealed pronounced arterial and
portal venous enhancement after SonoVueH. Only one
patient with FNH lacked early portal venous enhancement, which might be explained by extensive histologically
documented fibrosis. Using SonoVueH homogeneous
tumour enhancement was detected during the hepatic
arterial phase in all eight patients with HCA, preceding
enhancement of normal liver parenchyma (Figure 2a). In
contrast to patients with FNH, no portal venous
enhancement was seen in HCA during the hepatic portal
venous phase (Figure 2b) with isoechoic or, more often,
slight hypoechoic appearance in the parenchymal later
The British Journal of Radiology, August 2005

phases. Ultrasound findings of this study are summarized

in Table 1.
In the post-study phase using Acuson Sequoia CPStechnology, contrast-enhancing tumour characteristics
were visible during the arterial and early portal venous
phase in all 12 examined patients with FNH and only
arterial enhancement in the two patients, with adenoma
with slight hypoechoic appearance in the parenchymal
later phases.

Discussion
The combination of phase inversion ultrasound and
micro-bubble echo-enhancers has been demonstrated to
Table 1. Patient characteristics and ultrasound findings
FNH

HCA

Number
Male/Female
Age (years)
Size of lesion (mm)

24
2/22
3710 (1864)
5521 (26110)

8
0/8
3710 (2347)
3215 (1555)

Conventional B-mode US
Echotexture
Hypoechoic
Isoechoic
Hyperechoic
Central scar

7a
16
1
10

4a
4

23

10

Colour/power Doppler
Imaging
Hypervasular
Radial vascular
architecture

Contrast-enhanced US
Arterial phase enhancement 24
(Early) Portal venous phase
enhancement
23

8
0

All in a sonographically bright liver.

705

C F Dietrich, G Schuessler, J Trojan et al

(a)

(b)

Figure 2. Contrast-enhanced phase inversion ultrasound of a patient with hepatocellular adenoma (arrows). (a) Contrast-enhanced
phase inversion ultrasound scanning revealed only arterial phase enhancement for 10 s (1020 s) after administration of SonoVueH.
(b) At the end of the arterial phase (22 s after administration of SonoVueH) a slightly hypoechoic liver tumour was detected by contrast-enhanced phase inversion ultrasound and no portal venous sinusoidal enhancement was observed.

significantly improve the detection of liver metastases [9].

Moreover, late-phase contrast-enhanced ultrasound can
also differentiate between benign and malignant focal
hepatic lesions [10, 11]. However, no systematic studies
using contrast-enhanced phase inversion ultrasound for
the further characterization of liver lesions with acoustic
properties similar to those of surrounding normal liver
parenchyma, especially FNH and HCA, have been
reported. Here, we demonstrate that examination of the
hepatic arterial and early portal venous phase by contrastenhanced phase inversion ultrasound could consistently
differentiate between FNH and HCA. This important
finding could be explained by the lack of portal veins of
HCA in contrast to FNH which presents (atypical)
portal veins in many but not all patients. It is of
importance that the described typical features can be
observed in tumours ,50 mm without regressive
changes. The contrast behaviour in larger FNH and
adenoma might be different due to regressive changes such
as intratumoural haemorrhage, necrosis, fibrous tissue and
calcifications.
The dose of SonoVueH was 4.8 ml, and the mechanical
index 0.20.3 in the presented study lead to some bubble
destruction and, therefore, improved visualization of
vascularity but less homogeneous enhancement in the
later phases. It has also to be taken into account that the
dosage of 4.8 ml is too large to evaluate the wash-out
kinetics using more recent technology since arterioportal
overlap is too long. Therefore, using newer technology,
2.4 ml and even 1.2 ml may be superior for tumour
perfusion analysis.
The even more important differential diagnosis between
FNH and adenoma and malignant tumours was recently
addressed [10, 11]. Analysis of the late portal venous
(sinusoidal) phase shows that differentiation of benign and
malignant lesions is possible in most patients without
parenchymal (diffuse) liver disease. In our experience,
results in patients with pronounced fatty liver disease and
liver cirrhosis are less impressive, leading to false negative
findings in some patients. In summary, contrast-enhanced
706

phase inversion ultrasound with SonoVueH, can show

more functional and morphological features of focal
nodular hyperplasia and hepatocellular adenoma.

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