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Updates in SurgeryOfficial Journal of the Italian Society ofSurgery ISSN 2038-131XVolume 66Number 1 Updates Surg (2014) 66:9-21DOI 10.1007/s13304-013-0222-3

Focal nodular hyperplasia and hepaticadenoma: current diagnosis andmanagement

Agustin Cristiano, Agustin Dietrich,Juan Carlos Spina, Victoria Ardiles &Eduardo de Santibañes

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REVIEW ARTICLE

Focal nodular hyperplasia and hepatic adenoma: currentdiagnosis and management

Agustin Cristiano • Agustin Dietrich •

Juan Carlos Spina • Victoria Ardiles •

Eduardo de Santibanes

Received: 25 March 2013 / Accepted: 16 June 2013 / Published online: 27 June 2013

� Springer-Verlag Italia 2013

Abstract Benign liver tumors are common lesions that

can be classified into cystic and solid lesions. Cystic lesions

are the most frequent; however, they rarely represent a

diagnostic or therapeutic challenge. In contrast, solid

lesions are more difficult to characterize and management

remains controversial. The wide availability and use of

advanced imaging modalities, including ultrasonography,

computed tomography, and magnetic resonance imaging

have led to increased identification of incidental liver

masses. Although some of these incidentally discovered

masses are malignant, most are benign and must be

included in the differential diagnosis. In this article we

review FNH and HA. Its etiology, biological behavior,

diagnosis, and treatment will be highlighted.

Keywords Benign liver tumors � Focal nodular

hyperplasia � Hepatocellular adenoma � Diagnosis �Management � Treatment

Introduction

Benign liver tumors are common lesions that can be found

in 20–52 % of the population according to different

autopsy-based series [1, 2]. Cystic lesions are the most

frequent; however, they rarely represent a diagnostic or

therapeutic challenge. In contrast, solid lesions are more

difficult to characterize and their management remains

controversial.

Solid liver lesions may originate from blood vessels, the

epithelium of the bile ducts, or liver parenchymal cells.

After simple cysts, hepatic hemangiomas are the most

common tumors, followed by focal nodular hyperplasia

and hepatocellular adenomas [3, 4].

Over the past few decades the diagnosis of solid liver

lesions has risen. Although there is an increase in the risk

factors for developing these lesions, such as the use of

hormonal treatments, the advent of better diagnostic

imaging methods has led to an improvement in the inci-

dental diagnosis of these diseases. Now there are more and

better studies that allow us to detect smaller lesions, earlier

and with superior anatomic and spatial resolution. With the

advent of positron emission tomography (PET–CT) and

new magnetic resonance imaging (MRI) techniques,

information on the metabolic activity of the lesions can be

obtained. These advances have improved the diagnosis of

benign and malignant liver lesions.

It is sometimes difficult to elucidate the malignant or

benign condition of liver tumors only by their character-

istics with just one imaging method. In these situations, it is

necessary to use multiple studies that complement one

another to make the best therapeutic decision. The risk of

conservative treatment in malignant tumors is much higher

than the risk of benign liver tumor resection.

To arrive at a correct diagnosis we should not only rely

on imaging studies: the past medical history, physical

examination and laboratory tests are also of vital impor-

tance. Personal history of previous cancer disease, alcohol

consumption, viral infections, cirrhosis, and use of oral

A. Cristiano � A. Dietrich � V. Ardiles (&) � E. de Santibanes

Liver Transplant Unit and General Surgery Department,

Hospital Italiano de Buenos Aires, Gascon 450,

1181 Buenos Aires, Argentina

e-mail: victoria.ardiles@hiba.org.ar

E. de Santibanes

e-mail: Eduardo.desantibanes@hospitalitaliano.org.ar

J. C. Spina

Radiology Department, Hospital Italiano de Buenos Aires,

Buenos Aires, Argentina

123

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DOI 10.1007/s13304-013-0222-3

Author's personal copy

contraceptives or other steroids can help guide the diag-

nosis as well.

In this article we review focal nodular hyperplasia and

hepatocellular adenoma. Its etiology, biological behavior,

diagnosis, and treatment will be highlighted.

Focal nodular hyperplasia

Focal nodular hyperplasia (FNH) is the second solid liver

tumor in order of frequency, representing approximately

8 % of all primary hepatic neoplasms and is present in

0.3–3 % of the general population [5–7]. These tumors are

more frequent in women (10:1) aged between 20 and

50 years [8]. Despite the increased prevalence of FNH in

women there is no evidence linking these tumors with the

use of oral contraceptives (OC) [9]. However, in our

clinical experience we have observed growth of these

tumors in patients consuming OC; therefore, we suggest

discontinuing the medication.

Pathogenesis

The genesis of FNH is probably secondary to a vascular

malformation that produces blood hyper-perfusion in an

area of liver parenchyma, which determines a hyperplastic

response to this phenomenon without risk of malignant

transformation, [5, 10] or bleeding, justifying no aggressive

treatment [11]. Furthermore, FNH is associated with other

vascular malformations and hemangiomas in the liver and

brain, reinforcing the theory of the vascular etiology [10].

At present, the pathophysiology of FNH remains

unclear. However, in the past few years, the biomolecular

study of B-catenin, glutamine synthetasa (GS), and TGF-

beta, which are involved in liver proliferation, has led to a

better understanding of the genetic pathways of these

tumors.

Due to the major role of B-catenin in the regulation of

hepatocyte proliferation [12], its activation could conse-

quently contribute to tumor formation. Moreover, there are

several genes that are up-regulated in FNH, almost all of

them regulated by the B-catenin. The biomolecular study

of its over-expression in FNH showed heterogeneous dis-

tribution due to the polyclonal nature of the disease [13]. In

contrast, a subtype of HCA (activated b-catenin), which

presents a monoclonal origin, has a completely different

pattern of staining [13, 14].

Nowadays, the histopathological study of the GS has

also become a very useful tool for rapid identification of

FNH. For Bioulac-Sage et al. [15] GS immunostaining was

similar in all FNH cases. GS was present in large hepato-

cytic areas, anastomosed in a ‘map-like’ pattern, often

surrounding hepatic veins; whereas GS was not expressed

in hepatocytes close to fibrotic bands containing arteries

and ductules. In HCA or well-differentiated hepatocellular

carcinoma (HCC) presenting b-catenin mutation, GS was

positive but with a completely different pattern that

appeared diffuse and not ‘map-like’.

Histopathology

Histopathologically, FNH are well-differentiated tumors

without capsule, consisting of hepatocellular nodules

accompanied by stromal tissue [16]. FNH can be divided

into classical (80 %) and atypical (20 %), and within the

latter three subtypes can be distinguished: telangiectatic,

with cell atypia, and mixed (hyperplastic and adenomatous)

[17]. The abnormal hystoarchitecture or vascular malfor-

mations may be absent in non-classical forms, but bile duct

proliferation is always present [18]. The clinical relevance

of these three subtypes of FNH is not yet defined. Nowa-

days, the telangiectatic form as a variant of HNF is dis-

cussed. They often present clinical and morphologic signs

of hemorrhage like patients with adenomas [19]. Due to

this behavior, this variant may be treated as a HCA.

Diagnosis

Patients are generally asymptomatic and FNH manifests as

an incidental finding on an imaging study. However, 25 %

of the patients may have related symptoms. The most

common symptoms include epigastric pain, early satiety,

and/or a palpable abdominal mass [20].

The differential diagnosis with other hepatic tumors is

not easy, especially with other hypervascular tumors such

as HCA, HCC, and hypervascular metastases. MRI and CT

are able to provide some information for the diagnosis of

FNH, especially when the lesion depicts typical features,

such as uniform hypervascularity after intravenous contrast

administration and a central scar of fibro vascular tissue,

but unfortunately they are not always present [18, 21]. In a

series of 305 FNH, Nguyen et al. [17] describe that a

central scar could only be found in about 50 % of the cases.

At ultrasound FNH appears as a hypo or isoechoic solid

lesion and may rarely present as a hyperechoic lesion [22].

Sometimes there is a pseudocapsule caused by compression

of the underlying liver parenchyma. The central scar can be

seen in approximately 20 % of cases and looks slightly

hyperechoic [18]. Using Doppler, a central artery with

branches with a star pattern can be seen [21, 23]. Often the

information obtained through the abdominal ultrasound is

non-specific; however, when performed with IV contrast

the revenue of the study is better [21, 22, 24]. Most lesions

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demonstrate enhancement during the arterial phase with the

presence of central stellate arteries and a centrifugal con-

trast pattern with a transient peripheral unenhanced zone

that reflects a peripheral part of the lesion that is not ini-

tially enhanced [25, 26]. In portal and delayed phases, FNH

shows isoechogenicity compared with adjacent paren-

chyma [18, 27, 28].

CT should be performed with and without IV contrast in

arterial, portal, and equilibrium phases for a proper char-

acterization of the lesion. Early studies, dating from the

late 1980s, reported the usefulness of CT for the diagnosis

of FNH and showed a sensitivity of 75 % and specificity of

92 % [29, 30]. In unenhanced series FNH appears hypo or

isodense to normal liver parenchyma. In the context of

steatosis, FNH could appear as a hyperdense lesion because

of the parenchymal attenuation caused by hepatic steatosis

[31]. After an injection of IV contrast, FHN enhances

homogeneously during the arterial phase due to the pre-

dominant arterial vascularization. The arterial enhance-

ment allows the identification of a hypodense central scar

that becomes evident in up to 60 % of cases [32]. During

the portal venous phase, FNH is less conspicuous and

becomes isoattenuating with the rest of the liver. In the

equilibrium phase, approximately 5 min after the bolus

injection, the lesion remains isoattenuating and the central

scar may enhance slightly due to uptake of contrast mate-

rial by the fibroconective tissue [33, 34]. Generally, it is

easier to observe the central scar and other characteristics

as vascular abnormalities in lesions larger than 3 cm

(Fig. 1). In smaller lesions, these features are less obvious

and may be absent in up to 70 % of cases [34].

Other features of FNH also appear to be related to its

size. Smaller lesions invariably enhance homogeneously,

rarely distort liver architecture, and rarely have displaced

or enlarged peritumoral blood vessels. Larger lesions may

be slightly heterogeneous (mostly attributable to the pres-

ence of fibrous septa) and demonstrate dilated feeding

arteries or draining veins in 34 % of lesions. Enlarged

vessels on the surface of a FNH penetrating to the central

scar are a well-recognized pathologic feature of FNH, and

the demonstration of such vessels on CT scans should not

be regarded as suggestive of malignancy [31].

A pseudocapsule has been reported by Brancatelli et al.

[31] in 8 % of FNH. In patients with fatty liver, a

pseudocapsule may become evident due to compressed

liver and mild fibrosis along the periphery of the lesion

may be denser than the rest the liver [35]. Other sources of

a pseudocapsules are the dilated vessels and sinusoids that

can be present around the FNH [29]. Hence, the presence

of a pseudocapsule should not be regarded as an invariable

sign of malignancy. On the other hand, calcification is a

rare finding in FNH, suggesting the need for further eval-

uation [31].

Currently, MR imaging is considered a highly accurate,

non-ionizing radiation diagnostic procedure for the detec-

tion and characterization of focal liver lesions and is often

used as a problem-solving modality when equivocal find-

ings are obtained with other imaging techniques. It should

Fig. 1 MDCT showing typical

FNH in segment IV. a Hepatic

arterial phase: shows FNH

enhancing brightly except for

the central scar and thin septa.

Note enlarged feeding artery

penetrating to the center of the

lesion. b Portal venous phase:

FNH is less conspicuous and

becomes isoattenuating with the

rest of the liver. Scar begins to

fade toward isoattenuation.

c Equilibrium phase: the lesion

remains isoattenuating and the

central scar shows slight

enhancement. d Coronal

maximum intensity projection

(MIP) during arterial phase

shows enlarged feeding artery

branches along the surface of

the lesion and penetrating to the

center

Updates Surg (2014) 66:9–21 11

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be used instead of CT for the characterization of liver

lesions, in particular, for asymptomatic young women.

At MRI, FNH is typically homogeneously isointense or

slightly hyperintense with respect to the normal surrounding

liver parenchyma on T2-weighted images, and isointense or

slightly hypointense on T1-weighted images before admin-

istration of gadolinium [36]. However, these characteristics

are shared by other benign and malignant liver tumors. The

administration of IV contrast allows a definitive diagnosis if a

typical behavior is present. The enhancement pattern parallels

that of contrast-enhanced CT, with a rapid and homogeneous

enhancement during the arterial phase that becomes isoin-

tense during the portal venous phase and equilibrium images.

A central scar, when present, is hyperintense on T2-weighted

images and hypointense on T1-weighted images. During the

dynamic phase of contrast enhancement, it is hypointense

during the arterial and portal venous phases and slightly

hyperintense during the delayed phase [33, 37] (Fig. 2).

Occasionally, FNH may have atypical features such as

lesion heterogeneity, hypointensity in portal venous or

delayed phases, absence of a central scar, scar hypointen-

sity on T2-weighted images or in the delayed phase fol-

lowing contrast agent injection. Other atypical features can

be represented by the presence of a pseudocapsule (com-

plete hyper intense peri-lesional ring during the delayed

phase) and the presence of hemorrhage or areas of necrosis

[22, 33, 37]. In these situations, it can be difficult to dif-

ferentiate these lesions with atypical behavior from other

hypervascular tumors such as adenomas, fibrolamellar and

conventional HCC, and hypervascular metastases.

Fibrolamellar HCC usually occurs in young adults and is

first detected on images as a large heterogeneous mass with

broad central or eccentric scars, radiating septa, and cal-

cifications. Its main distinguishing feature is the central

scar which is purely fibrous and, therefore, is seen as

hypointense in both T1 and T2-weighted images [38].

Conventional HCC usually occurs in a setting of chronic

liver disease and has different imaging characteristics than

those of FNH. It is hyperintense relative to the liver on T2-

weighted images and hypointense on T1-weighted images

and shows early enhancement in the arterial phase and

contrast medium washout in the portal venous phase with a

thin rim-enhancing tumor capsule in the delayed phase

[38].

Hypervascular metastases usually occur in the setting of

a known malignancy and, as compared with FNH, are often

multiple, heterogeneous, and less likely to be isoattenuat-

ing on portal venous and delayed phases after IV contrast

administration [31]. The addition of diffusion weighted

imaging (DWI) to the MR protocol contributes greatly to

the detection and characterization of liver lesions. Differ-

ences in cellularity between benign and malignant liver

lesions result in different diffusion properties of water

protons within these lesions that are reflected by different

apparent diffusion coefficient (ADC) values measured by

DWI. A visual assessment shows malignant lesions as

hyperintense in DWI with high b-values and hypointense

on ADC maps [39].

In our experience, malignant lesions can be discarded in

most cases taking into account all the findings previously

Fig. 2 MRI showing typical

FNH in segment VIII–V.

a Axial T2 weighted image

depicts homogeneously

isointense lesion with respect to

the normal surrounding liver

parenchyma. Note hyperintense

central scar. b Axial T1

weighted image: the lesion is

isointense or slightly

hypointense. Central scar is

hpoyntense. c Axial arterial

phase T1-weighted images

shows rapid and homogeneous

enhancement. Central scar is

hpoyntense. d Equilibrium

phase: FNH is slightly

hypointense and the central scar

shows enhancement

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described. Therefore, the main differential diagnosis is

with adenomas when the lesions enhance strongly during

the arterial phase and then either retain a hyperintense

appearance or demonstrate isointensity with the normal

liver parenchyma during subsequent portal venous and

delayed phases. Unfortunately, DWI does not contribute to

this differential diagnosis because both quantitative and

qualitative assessment of ADC values for FNH and ade-

nomas are similar.

In these patients, MRI hepato-specific contrast agents

(gadobenatedimeglumine, MultiHance, Bracco, Milan,

Italy, formerly known as Gd-BOPTA and gadoxetate,

Primovist, Bayer-Schering, Berlin, Germany, formerly

known as Gd-EOB-DTPA) can be used as a problem

solving tool [40]. They are gadolinium-based agents with

combined perfusion and hepatocyte-specific properties.

Both gadobenate and gadoxetate are taken up by the

hepatocytes and excreted by the biliary system. These

agents are useful in differentiating FNH from other

hypervascular lesions, particularly adenoma [40]. The key

lies in the histological absence of bile ducts in adenomas

and malignant lesions against the histological structure of

FNH that is similar to that of normal hepatic parenchyma.

Hence, on delayed phase images (acquired at 15–20 min to

3 h depending on the type of contrast used) a substantial

hepatocellular enhancement is noted in FNH that is iden-

tified as iso-hyperintense lesion while adenomas, hepato-

carcinomas, and metastases are identified as hypointense

lesions [41]. This typical pattern makes these agents very

effective in the characterization of FNH. Indeed, the

combination of strong enhancement on arterial phase

images and iso or hyperintensity on hepatobiliary phase

images showed 83.8 % sensitivity and 98.5 % specificity

for the diagnosis of FNH [40].

Treatment

Due to the lack of randomized clinical trials assessing the

benefits of elective surgery versus conservative treatment,

management of patients with diagnosis of FNH remains

controversial.

However, the absence of malignant transformation and

the low rate of tumor complications support the indication

of a conservative treatment, especially in the case of small,

asymptomatic FNH without enlargement during follow-up

[42].

On the other side, the inability to rule out malignancy,

tumor enlargement (3–5 cm/year), and symptomatic

patients should undergo surgical resection [43–46].

Several studies have demonstrated that elective surgery

for the treatment of FNH is a safe procedure in selected

cases, with low morbidity and long-term relief of symp-

toms [42, 47, 48].

Adenoma

HCAs are uncommon benign tumors. In the 1970s, with the

development of oral contraception, there was an increased

incidence of HCA in women consuming OC [49–51].

Further studies specified this relationship by showing that

those patients treated with high estrogenic doses and/or for

prolonged periods of time have a risk of developing HCA

25 times higher (3–4 cases per 100,000 people) than the

general population [50, 51]. More controversial is the

hypothesis that the lesion can have regression after dis-

continuation of treatment, although there are publications

that support it [52, 53]. Another risk factor for development

of HCA is pregnancy, which is related to increased

endogenous steroids, which are related to the formation of

these tumors [54, 55]. There are other less common pre-

disposing factors such as consumption of anabolic steroids,

iron metabolic diseases, endocrine disorders, or glycogen

storage diseases (especially type I) [56, 57]. A recent study

showed that being overweight/obese represents a novel

factor favoring the emergence of HCA [58]. These patients

would also have an increased risk of having a complicated

tumor (bleeding and malignant transformation).

Hepatic adenomas are generally located in the right lobe

of the liver and are mostly single, but several simultaneous

lesions in the liver parenchyma can be seen [59–61]. The

term Hepatic adenomatosis was classically reserved for

those patients with over ten lesions separated by normal

parenchyma that could be present in 10–24 % of patients

with HCA [60, 61]. Nowadays, the adenomatosis is not

considered a specific type of HCA and the number of

nodules would not have therapeutic implications [62].

Pathogenesis

The pathogenesis is controversial although some reports

associate the presence of steatosis with this form of the

disease [63]. In this situation of multiple adenomas, the

relationship with the use of oral contraceptives or steroids

is controversial, but some authors suggested an association

between hepatic adenomatosis and glycogen storage dis-

eases [60, 64].

Histopathology

Macroscopically, most HCAs are solitary, unencapsulated

tumors that vary from \1 cm to up to 20 cm in size that

may have central areas of necrosis or hemorrhage [65, 66].

In the histological study, there are plates of two or three

cells with high intracellular lipid content grouped into

cords, with no portal spaces, separated by dilated

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sinusoidal vessels supplied only by arterial blood [67, 68].

The lack of portal space and bile ducts differentiates HCA

from FNH (86).

HCA had been classified into three histopathological

varieties: steatosic, telangiectatic, and indeterminate,

which have different clinical and biological behaviors.

Telangiectatic and indeterminate varieties have an

increased risk of complications such as bleeding and

malignancy [56, 60, 69, 70]. However, nowadays hepato-

cellular adenomas are classified into three distinct sub-

types: HCAs with hepatocyte nuclear factor 1 (HNF1)

mutated (HNF-HCAs), HCAs characterized by B-catenin

mutations, and inflammatory HCAs (I-HCAs) due to

mutations involving interleukin-6 (IL-6) signal transducer.

Inflammatory HCAs and HNF-HCAs are the two major

subgroups of HCAs [6, 65]. I-HCAs represent the most

common variant (35–50 % of HCAs). They present an

increased risk of bleeding and small risk of malignant

transformation and are associated with obesity. HNF-HCAs

represent 30–45 % of HCAs, with risk of bleeding but no

risk of malignant transformation. These two subtypes are

more frequent in women in treatment with OCs. The third

group is HCAs with activation of B-catenin and represents

10–17 % of HCAs. In this form of HCA there is no sex

distinction, and it presents a relationship with glycogene

storage disease and treatment with androgens [65].

B-catenin-activated lesions seem to have a higher risk of

malignant transformation in patients with HCA. Therefore,

identifying a b-catenin mutation is of major interest.

Additional markers may help to discriminate these lesions.

As mentioned above, glutamine synthetase (GS) is another

useful marker in tumor liver pathology. A strong and

homogeneous GS staining is shown in b-catenin-mutated

HCA [11]. This pattern can be also seen in hepatocelullar

carcinoma (HCC), in which even 50 % of the HCC,

including early forms, present diffuse and strong GS

immunostaining [71]. During the past decade, new tissue

markers have become available, especially to identify

malignant lesions like Glypican-3 and Heat Shock Protein-

70 (HSP-70) (see Table 1). Although these markers have a

low sensibility (35–50 %), they are highly specific when

combined (95–100 %) [72–75].

However, despite the importance of histopathological

analyses to confirm the subtypes of HCAs, GS and

b-catenin immunohistochemical staining are not sensitive

enough to detect all b-catenin mutations in HCA, and the

interpretation of b-catenin staining may also be difficult

because of the heterogeneous staining pattern [76].

However, regarding these specific histopathologic

characteristics, there are potential problems regarding

biopsy, like sampling errors, risk of hemorrhage or tumor

seeding along the needle-track [77]. Limited core biopsies

may present difficulties in differentiating HCA from

normal hepatocytes, FNH, and well-differentiated hepato-

cellular carcinoma, making the indication of biopsy con-

troversial [78, 79].

Clinical presentation

In the past, most of the HCA were diagnosed in symp-

tomatic patients [71]; however, with the improvement of

radiological techniques, the number of incidentalomas

increased and, therefore, the number of sympomatic

patients decrease [80].

Chronic upper-right quadrant and epigastric pain asso-

ciated with nausea or early satiety are common symptoms

and are produced by the tumor size and mass effect [59,

81]. Less frequently, patients may present sudden pain

followed by hypotension which translates into subcapsular

or intraperitoneal bleeding as a complication of the tumor

[59].

Diagnosis

Ultrasound is certainly one of the first methods in the study

of a liver mass. In the case of HCA its value is debated.

Although some authors report up to 50 % in diagnostic

sensitivity, specificity is low [60, 82]. The lesions may be

hypo-iso or hyperechoic, and this depends on the tumor

characteristics (amount of lipids, calcification, intratumoral

hemorrhage, necrosis, etc.) and underlying liver paren-

chyma [68, 82]. Doppler demonstrated intratumoral arterial

flow and peritumoral arterial and venous flow, showing a

continuous plane wave [68, 83]. The combination of ultra-

sound associated with IV contrast infusion enhances the

ability to differentiate HCA from other liver lesions.

According to tumor histology, HCAs show homogeneous

enhancement during the hepatic arterial phase preceding

enhancement of normal liver parenchyma, sometimes with

centripetal filling, with no radial vascular structures. Rapid

wash out and no portal venous enhancement during the

hepatic portal venous phase is seen, with isoechoic or, more

often, slight hypoechoic appearance in the later parenchy-

mal phases. This pattern allows its differentiation from FNH

that enhances both in arterial and portal phase [26, 28].

CT findings of adenomas depend on the characteristics

of the lesion and surrounding liver parenchyma. Therefore,

they can show hyperattenuation on unenhanced images in

patients with steatosis or hypoattenuation in high lipid

content lesions surrounded by normal parenchyma [68, 84].

If necrosis or hemorrhage is present, as described in 25 %

of lesions, a more heterogeneous pattern can be seen

showing hyperattenuation in regions with recent bleeding,

and hypoattenuation in region with previous bleeding. The

incidence of calcification varies from 5 to 10 % and a

tumor capsule was described in 25 % of lesions [68].

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Therefore, at CT, HCAs are usually isodense prior to the

injection of IV contrast, but may often be heterogeneous

with hyperdense areas through the presence of bleeding or

hypodense areas through the presence of lipid or fat [85].

After IV contrast administration, the lesions enhance rap-

idly and relatively homogeneously during the arterial phase

in the case of small tumors (\3 cm) and heterogeneously in

the larger lesions that usually present bleeding complica-

tion or fat deposition. In the portal venous and delayed

phases adenomas became more homogeneous and similar

in attenuation to normal liver. Nevertheless, in 19 % of

cases they can be hypoattenuated in delayed phase images

[68, 84].

At MRI the imaging features of hepatocellular adeno-

mas vary on the basis of the histopathologic findings and

associated complications, so there are also various

appearances either due to the presence of fat, old or recent

hemorrhage, necrosis, or calcification foci [68]. On T1-

weighted images, HCA tend to appear as hyperintense

lesions although there are publications in which these

findings were present in only a minority of cases [86–88].

Such hyper intensity is due to the presence of fat, glycogen,

or bleeding. Since fat is present in the intracellular space,

adenomas show significant signal intensity drop due to fat

content on opposed-phase images [86–88]. On T2-weigh-

ted images, most of these lesions are slightly hyperintense

and heterogeneous because of a combination of hyper and

hypointense areas that correspond to hemorrhage and

necrosis [86–88]. After IV contrast, they enhance quickly

and heterogeneously during arterial phase and tend to

homogenize with the surrounding parenchyma during the

portal venous and delayed phases, sometimes showing

wash out [88]. These features preclude making a differ-

ential diagnosis with other malignant lesions featuring

similar behavior (HCC or hypervascular metastases).

Unlike what happens with FNH, the use of gadolinium-

based hepato-specific contrast agents does not provide

additional information to differentiate between adenomas

and malignant lesions since both are hypointense on

delayed phase images (acquired at 15–20 min to 3 h

depending on the type of contrast used) [40].

As previously mentioned for FNH, diffusion weighted

images can help to differentiate HCAs from metastases but

are not useful in differentiating HCA from FNH.

MRI is the imaging modality of choice for subtype char-

acterization of hepatocellular adenomas. Laumonier et al.

[89] described that HNF-HCA and I-HCA are associated

with specific MR imaging patterns that are related to diffuse

fat distribution and to sinusoidal dilatation, respectively [89].

Inflammatory hepatocellular adenomas are diffusely

hyperintense on T2-weighted images, with higher signal

intensity in the periphery of the lesion, correlating with

dilated sinusoids. On T1-weighted images, they are isoin-

tense or mildly hyperintense, with minimal or no signal

drop on opposed-phase images. After the administration of

gadolinium, they usually show intense enhancement during

the arterial phase, which persists in the portal venous and

delayed phases [90] (Fig. 3).

Marked T2 hyper intensity associated with delayed,

persistent enhancement showed 85 % sensitivity and 87 %

specificity for the diagnosis of inflammatory hepatocellular

adenomas [89].

HNF-HCAs are isointense to slightly hyperintense on

T2-weighted images and predominantly hyper or isointense

on T1-weighted images, with diffuse signal drop on

opposed-phase because of intracellular steatosis. They

show moderate enhancement in the arterial phase with no

persistent enhancement in the portal venous or delayed

phases [90] (Fig. 4).

The presence of signal drop on opposed-phase images

showed 86 % sensitivity and 100 % specificity for the

diagnosis of this subtype of HCA [89].

No specific MR imaging patterns have yet been pro-

posed to identify either b-catenin-mutated hepato-cellular

adenomas or unclassified hepatocellular adenomas.

Figure 5 shows a flow-chart for the imaging diagnosis of

focal hepatic lesion.

Treatment

Liver resection for treatment of HCA has a morbidity of

10–25 % and mortality lower than 2 % [44, 60, 91], and

Table 1 Pathological features/

immunohistochemistry

HCA hepatocellular adenoma,

FNH focal nodular hyperplasia,

HCC hepatocellular carcinoma

HCA FNH HCC

Glypican-3 Negative staining Negative staining Diffuse cytoplasmatic staining.

HSP-70 Negative staining Negative staining Focal nucleocytoplasmatic

staining

GS Diffuse cytoplasmatic

staining

Cytoplasmatic

staining. ‘Map-

like’ pattern

Diffuse staining

B-catenine Homogeneous nuclear

staining, especially in

B-catenine-activated

subtype

Heterogeneous distribution Homogenous nuclear staining.

Updates Surg (2014) 66:9–21 15

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Author's personal copy

should be performed on all patients with risk of bleeding

(20–30 and up to 50 %) or malignant transformation.

In non-surgical cases, the suspension of OC and imaging

follow-up is mandatory [56, 92]. Patients with HCA\5 cm

in size are rarely associated with risk of hemorrhage or

malignant transformation and hence can safely be managed

conservatively with imaging follow-up. Many authors

recommend early surveillance with multiphase CT or MRI

[93]. Some authors suggest adding to the follow-up peri-

odic dosage of alpha-feto protein [94].

To the present, there is no evidence in the literature, of

well-established protocols of surveillance in patients with

HCA. We recommend a close follow-up. Surveillance with

periodical US (every 3 month) can be a useful tool to detect

Fig. 3 MRI showing

inflammatory hepatocellular

adenoma in segment III. a Axial

T2 weighted image depicts a

diffusely hyperintense lesion.

b Axial T1 weighted image in-

phase and oppose phase shows

the lesion with heterogeneous

hypointensity but with no signal

drop on opposed-phase images.

c Axial arterial phase T1-

weighted image shows intense

enhancement. d Axial portal

venous phase T1-weighted

image showing persistent

enhancement of the lesion

during portal venous and

delayed phases (not shown)

Fig. 4 MRI showing HNF-1a–

mutated hepatocellular adenoma

in segment VI. a Axial T2

weighted image depicts a

slightly hyperintense focal

lesion. b Axial T1 weighted in-

phase and opposed phase

images: The lesion is isointense

on T1-weighted images (in-

phase), with diffuse signal drop

on oppose-phase. c Axial

arterial phase T1-weighted

image shows mild enhancement,

particularly in the anterior

region of the lesion. d Axial

portal venous phase T1-

weighted image shows no

persistent enhancement in the

portal venous and delayed

phases (not shown)

16 Updates Surg (2014) 66:9–21

123

Author's personal copy

change in size or tumor’s characteristics in those patients

with small and asymptomatic HCA.

Most small HCAs remain stable during surveillance and

a small number of them may disappear [62].

Currently, liver resection is recommended in patients

with adenomas greater than 5 cm, inflammatory forms, and

patients unable to discontinue hormone therapy [70, 95–

97]. Also, due to the high risk of malignancy, HCAs in men

or evidence of B-catenin activation demonstrated on biopsy

are also indications of surgery [76, 98].

Patients presenting abdominal symptoms related to the

adenoma should be evaluated as candidates for surgery,

depending on their comorbidities. Most of previously

published series demonstrated low postoperative morbidity

and mortality [79, 80, 99].

The rupture of the HCA is a serious situation that

compromises the patient’s life. Resection in these cases has

a mortality rate of around 10 % [100–102]. Therefore,

resuscitation should be performed with hemodynamic sta-

bilization and angiographic embolization leaving hepatic

resection only for experienced surgeons [102, 103]. In case

of not having a specialized surgeon, damage control sur-

gery (liver packing) should be performed [101].

Although pregnancy is not contraindicated in patients

with HCAs, in women with HCAs greater than 5 cm

surgical resection is mandatory before conception [54, 55,

104]. Resection in the second trimester of pregnancy has a

low morbidity and mortality for both the mother and fetus

[105]. When the diagnosis is made in the third trimester,

we recommend a watchful waiting with strict clinical and

ultrasound follow-up, because in this period estrogen levels

are higher and the concomitant risk of bleeding is greater

[104]. Spontaneous rupture of the HCA during pregnancy

is a rare but extremely serious complication [106].

With regard to liver adenomatosis, a recent study

showed that the rates of intrahepatic bleeding and intra

tumoral bleeding in asymptomatic, incidentally discovered

HCA are 2 and 13 %, respectively, rates that are similar to

solitary HCAs [63].

Moreover, the potential risk of complications would be

related to the underlying histologic subtype and tumor size

rather than the number of HCAs [62, 76]. Resection of

large or complicated lesions is generally indicated with a

strict observance of those lesions left behind, as the risk of

complications in these is low [56, 60, 64, 93]. The indi-

cation for liver transplantation is reserved for those patients

who are symptomatic, who presented several episodes of

complications, and/or whose condition cannot be resolved

with surgical resection [60, 64, 93, 107, 108]. It is also

controversial whether the glycogen storage disease in these

Fig. 5 Flow-chart for the imaging diagnosis of focal hepatic lesion

Updates Surg (2014) 66:9–21 17

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patients represents an indication for liver transplantation.

Some authors recommend it, but others only suggest this

procedure when the disease is accompanied by suspicion of

malignancy [109, 110].

Conflict of interest None.

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