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Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
Available online at
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MINI REVIEW
Imaging of benign hepatocellular lesions: Current concepts and recent updates Maxime Ronot a,∗,b, Valérie Vilgrain a,b a
Department of Radiology, Hôpital Beaujon, Assistance Publique—Hôpitaux de Paris, AP—HP, 100, boulevard du Général-Leclerc, 92110 Clichy, France b INSERM Centre de recherche Biomédicale Bichat-Beaujon, université Paris-Diderot, Sorbonne-Paris-Cité, CRB3 U773, 75018 Paris, France
Summary Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are a variety of solid lesions mostly found in the absence of underlying chronic liver disease in young patients. HCA is no longer to be considered as a unique lesion but as a recollection of different entities sharing common points but most of all separated by different typical morphological aspects. Accurate diagnosis is of clinical importance as the management is most of the time conservative for FNH, whereas HCAs expose patients to hemorrhage and malignant transformation, and may lead to a more invasive treatment, mainly surgical resection. Moreover, the different HCA subtypes expose to different risks of complication. The best imaging techniques for the differentiation between FNH and HCAs and for the subtyping of HCAs are contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI), as specific combinations of imaging features have been associated with the different lesions. They should be considered as complementary examinations. Atypical or multiple lesions, lesions containing fat or presence of an associated steatosis represent diagnostic challenges. Recently, MR hepatospecific contrast agents have been shown to be useful. Emergent elastography techniques might also be helpful in the near future. Biopsy should always be performed in case of uncertain diagnosis to reach a final diagnosis and avoid unnecessary invasive treatment. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction Benign hepatocellular lesions are rare epithelial solid entities encountered mostly in young women. They are
∗ Corresponding author. Tel.: +33 1 40 87 5358; fax: +33 1 40 87 0548. E-mail address: [email protected] (M. Ronot).
classically divided into two groups that do not share the same pathogenesis or course of evolution and do not expose to the same complications. Focal nodular hyperplasias (FNH) are regenerative polyclonal formations that generally remain asymptomatic and follow a very benign course of evolution, while hepatocellular adenomas (HCA) correspond to neoplastic monoclonal lesions [1,2], subject to hemorrhage and rare malignant transformation [3,4]. Differentiating these two entities has been an issue for many years because management is different for each. Most
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Please cite this article in press as: Ronot M, Vilgrain V. Imaging of benign hepatocellular lesions: Current concepts and recent updates. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.01.014
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FNH are managed conservatively and treatments are indicated only for the few symptomatic ones. HCAs, on the other hand, may lead more frequently to an invasive treatment, mainly surgical resection. Final diagnosis relies on pathological analysis performed on biopsy. However, as most of these lesions are discovered fortuitously in young patients and develop on normal liver parenchyma, non-invasive characterization techniques shall be preferred. This is why imaging plays a central role in the diagnosis of these lesions. In the present review, we will detail the imaging features of FNH and HCAs, as recent advances in imaging studies allow an accurate diagnosis in the majority of cases, thus limiting the need for liver biopsies. Pathogenesis and pathological considerations are beyond the scope of the present text.
Focal nodular hyperplasia FNH is the most frequent benign hepatocellular lesion (.9%), with a sex ratio around nine women for one man [5]. They are most of the time asymptomatic, and, when large or pediculated, may result in non-specific abdominal symptoms. In more than half of all cases, hepatic tests are normal. When not, isolated elevation of gammaglutamyl transpeptidase and/or alkalin phosphatases is found.
Ultrasound and computed tomography Most lesions are fortuitously discovered on an ultrasound or CT. At ultrasound, FNH is usually slightly hypoechoic or isoechoic, and may only be detected because they displace the surrounding vessels. Hypoechoic halo or lobulated contours are often observed. The central scar is difficult to visualize at US (20% of the cases) [6]. When visible, it is slightly hyperechoic. Typical findings at color Doppler include the presence of a central feeding artery with a stellate or spokewheel pattern corresponding to the artery running from the central scar to fibrous septa. On CT scans, FNH spontaneously appears as a focal hypoattenuating mass. The central hypoattenuating scar is depicted in only one-third of the cases [6], and calcifications within the central scar, very rare, are observed in only about 1% of the cases [7] At the arterial phase of contrast-enhanced CT, the lesion enhances rapidly in most cases (95—100%) [8]. At the portal venous phase the lesion is either iso- or slightly hyperattenuating relative to normal liver. Furthermore, lesion is homogeneous in 90% of all cases, present with lobulated contour and no capsule. The central feeding artery is visible in the majority of cases [9] and the central element enhances is 89% on the late phase [9].
Contrast-enhanced ultrasound and magnetic resonance imaging A second examination is often required for definite noninvasive diagnosis. It can be achieved with imaging using contrast-enhanced ultrasound (CEUS) or MR imaging, as specific features have been associated with both the techniques [10]. CEUS has been less studied, and imaging features still require prospective validation. This is why MRI
is considered the best imaging tool with a sensitivity of 70% and a specificity of 98% [11]. With ultrasound contrast agents or non-linear continuous imaging, FNH enhances at the very arterial phase, and becomes homogeneously isoechoic after 30 seconds in the vast majority of the cases. They have been associated with two specific features: • a spoke-wheel aspect, encountered in 20—25% of the lesions; • a centrifugal filling, more frequent in lesion smaller than 3 cm [12]. The central scar is detected in around 40% of the lesion, mostly in FNHs larger than 3 cm [9], and appears hypoechoic on both arterial and portal phases. According to Kim et al., by showing centrifugal enhancement with radiated vascularisation, differentiation with adenoma is possible in most cases [13]. Recently, Wang et al. advocated that CEUS should be the first-line imaging technique for the diagnosis of FNH [9]. In our experience, the combination of CEUS and MR imaging is often performed [10]. On MR imaging, one has to remember that the diagnosis of FNH is based on a combination of features, none of them being specific of FNH. There are seven major criteria to assess a proper diagnosis: • lesion not different from the liver before contrast injection, i.e. iso- or hypointense on T1-weighted images (94—100%) and iso- or slightly hyperintense on T2weighted images (94—100%) [14]; • homogeneity apart the central scar; • presence of a central scar, corresponding to a central hypointense area on T1-weighted images and strongly hyperintense on T2-weighted images (78—84%) [15]; • intense enhancement at arterial phase without washout; • no capsule; • lobulated aspect; • absence of underlying chronic liver disease or clinical history of cancer. When all the criteria are present, the diagnostic specificity is close to 100%. One point must be stressed: the prevalence of typical features of FNH in literature ranges from 22—70%, and may be explained by variations in the stringency of the criteria sets used to diagnose FNH, and recruitment bias. Hepatobiliary contrast agents can be used to highlight the hepatocellular origin of the lesions. After injection of Gadolinium-BOPTA (Multihance, Bracco) FNH appears hyperintense in comparison to the surrounding liver [16,17]. After injection of Gadolinium-EOB-DTPA (Primovist/Eovist Schering) most of FNH enhance on the hepatospecific phase, usually homogeneously [18—21]. A rim-like enhancement is also described [22]. Finally, on diffusion-weighted MR sequence, FNHs often show hyperintensity on high-b-values, which could suggest malignancy. Yet, ADC values of FNH are close to the surrounding liver, the vast majority of lesions present with an ADC value 15% inferior to the liver [23].
Please cite this article in press as: Ronot M, Vilgrain V. Imaging of benign hepatocellular lesions: Current concepts and recent updates. Clin Res Hepatol Gastroenterol (2014), http://dx.doi.org/10.1016/j.clinre.2014.01.014
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Imaging of hepatocellular benign lesions
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Hepatocellular adenomas
Ultrasound and CT
HCA are very rare lesions (< 1/1000) that concern mostly young women. They are associated with oral contraception uptake (OC). The risk for developing an HCA increases with the duration and the estrogen content of OC [3]. This tumor can also occur in men receiving anabolic steroids or be associated with diabetes or underlying metabolic diseases: type I and III glycogen storage disease, tyrosinemia, galactosemia. The prevalence of obesity is high in patients with HCA [3] and it was recently described in patients with non-alcoholic steatohepatitis [24]. Although patients with adenoma can present with symptoms, the majority of patients, (80%) are asymptomatic [3]. HCAs can be revealed by an acute abdominal pain in relation with intratumoral bleeding. Lesions also expose to the risk of malignant transformation. Liver function tests are abnormal in two third of cases. When abnormal, they concern cholestatic enzymes (2—10N) and less frequently (one quarter) transaminases (2—8N) [3]. Recent studies, mainly coming from French teams, established the existence of four subtypes of HCA based on the existence of different altered molecular pathways [25]. Therefore, HCA is no longer to be considered as a unique lesion but as a recollection of different entities sharing common points but most of all separated by different typical morphological aspects. The different HCA subtypes are:
The key-imaging feature of HNF-1␣ inactivated HCAs is the presence of marked and diffuse fat within the lesion. Therefore, they correspond to very homogeneous hyperechoic lesions on ultrasound. It is uncommon to find Doppler signal within the lesion. On CT, they appear as fat containing lesion: strong hypo-attenuation on unenhanced CT scan, absence of marked enhancement and rapid washout on multiphasic examination. The key-imaging feature of telangiectatic/inflammatory HCAs is the presence of telangiectatic components, event if it is not specific of this lesion. Imaging characteristics correspond to those previously described in telangiectatic FNH. On ultrasound examination, the lesion is well-delineated, often hyperechoic and often heterogeneous. Doppler signals are commonly seen and may mimic central arteries found in FNH [10]. On CT, HCAs are hypoattenuating and often heterogeneous. They may contain spontaneously hyperattenuating areas in relation to recent bleeding. The characteristic lesion behavior on multiphasic examination is a strong arterial enhancement (93%) and a persistent enhancement in the delayed phase (96%). The two other subtypes (-Catenin activation and unclassified hepatocellular adenomas) are less characteristic on imaging. They share findings of hepatocellular tumors: hypoechoic on ultrasound examination, spontaneously isoto hypoattenuating on unenhanced CT, arterial enhancement and portal or delayed washout. They may have heterogeneous content.
• HNF1-␣ inactivated HCAs (25—40%) characterized by diffuse steatosis (> 60%) owing to increased fatty acid synthesis and impaired transport of fatty acids resulting in excessive intratumoral lipid accumulation; • -catenin mutated HCAs (5—10%) presenting numerous cytological abnormalities, more frequent in men, and more prompt to malignant transformation [4]; • telangiectatic/inflammatory HCAs (45 — 55%), corresponding to the entity initially described as telangiectatic FNH [1], characterized by an over expression of inflammation proteins such as the C-reactive protein (CRP) and the serum-amyloid associated protein (SAA), and by the presence of inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels without fibrosis. Intratumoral steatosis can be found, sometimes in large amount. Telangiectatic/inflammatory HCAs are associated with obesity, hepatic steatosis (40%), and increased serum levels of acute inflammatory markers such as gammaglutamyl transferase, CRP, SAA. Few of them have an additional -catenin activation (< 10%); • unclassified HCAs, i.e., lesion without HNF1-␣ or catenin mutation and without over expression of inflammatory proteins (5—10%). Prior to the identification of these different subtypes, imaging features of hepatocellular adenomas were non-specific, including heterogeneity, fat containing and hemorrhagic areas. The main issue was to exclude the diagnostic criteria of FNH. Now, it is well established that the different molecular features correspond to distinct phenotypical features [26,27]. MR is the best imaging tool for tumoral characterization, a correct classification being reached in 85% of all cases with good interobserver correlation (0.85) [26].
Contrast-enhanced ultrasound and MR imaging In HNF-1␣ inactivated HCAs, hypervascularization is not very intense on contrast-enhanced ultrasound, and may sometimes be absent. At the portal or delayed phase, a washout can be depicted [28], but given the spontaneous hyperechoic aspect of those HCAs, such washout is better seen with CT or MR. Indeed, MR plays a crucial role in demonstrating the presence of diffuse fat. The striking finding is a diffuse and homogeneous signal dropout on opposed-phase T1-weighted sequences due to the presence of microscopic fat (93%) [26,27]. According to Laumonier et al. and to our experience, this finding has a sensitivity of 87%—91%, and a specificity of 89%—100% [26,27]. It is important to insist on the marked and homogeneous dropout on opposedphase T1-weighted MR sequence required for this diagnosis. Indeed, other subtypes of HCAs may contain fat, but the signal dropout is less intense and rather heterogeneous in such cases. According to Laumonier et al., the association of arterial hypervascularity with centripetal filling, linear vascularities, peripheral rim of sustained enhancement, and central washout in the late venous phase is specific of telangiectatic/inflammatory HCA on CEUS [28]. On MR imaging, telangiectatic/inflammatory HCAs show a strong hyperintense signal on T2-weighted images. On T1weighted sequences, lesion signal intensity is variable isoto hyperintense. If present, the hyperintensity persists on fat suppressed and opposed-phase sequences. Some lesions may contain some heterogeneous fat compared to HNF-1␣
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inactivated HCAs (see above). Considering two imaging findings (markedly hyperintense signal on T2-weighted MR images and persistent enhancement on delayed phase), Laumonier et al. and our experience show that these combined findings have a sensitivity of 85.2%—88.4%, and a specificity of 87.5%—100% [26,27]. Finally, van Aalten et al. recently described a hyperintense peripheral rim-like band on T2-weighted images, with iso-intensity to surrounding liver in the center of the lesion (atoll sign) in nearly 25% of the telangiectatic/inflammatory HCAs [29]. The two other subtypes (-Catenin activation and unclassified hepatocellular adenomas) are less characteristic on imaging, and cannot easily be differentiated from hepatocellular carcinoma. They also share findings of hepatocellular tumors on CEUS and MR: iso- to hypointensity on T1-weighted images, commonly hyperintensity on T2-weighted imaged, arterial enhancement and portal or delayed washout. In our experience, these findings have a sensitivity of 100% and a specificity of 93.3% for
distinguishing these HCAs from the other subtypes but are less accurate to differentiate them from HCC [26]. As for FNH, hepatobiliary contrast agents can be used. Indeed these contrast agents require performing MR sequences at the hepatospecific phase. The enhancement of HCAs is variable [21,30—32]. Most of them are hypointense during the hepatobiliary phase (90—92%). However, some may also take up the contrast agent and appear hyperintense. The different aspects according to the different subtypes have not been described yet. Regarding the telangiectatic/inflammatory HCAs, it seems that the persistent enhancement on delayed phase is less frequently observed, due to the progressive washout of EOB-DTPA. Recently, Thomeer et al. reported that, after gadobenate dimeglumine injection, a majority (71%) of telangiectatic/inflammatory HCAs show areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase, while none of the non telangiectatic/inflammatory HCAs does. In some cases, this hyperintensity can be
Figure 1 MR imaging of a fatty FNH in a 32-year-old female appearing as an atypical lesion, slightly hyperintense to surrounding liver on T2-weighted image (A), iso- to hypointensity to liver on T1-weighted image with signal drop out of the fatty area (B, C). On contrast-enhanced MR, the lesion is lobulated and enhances at the arterial phase with progressive homogenization (D, E). No central scar is visible. The differential diagnosis with a telangiectatic/inflammatory HCA containing fat is difficult. Liver biopsy confirmed the diagnosis of FNH.
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Imaging of hepatocellular benign lesions partially explained by the presence of steatosis or spontaneous hyperintensity on precontrast sequences. Finally, on diffusion-weighted MR images, most HCAs show diffusion restriction slightly higher than the liver and FNHs. [23].
Differentiation FNH from HCAs In young patients without history of cancer, hypervascular lesions developed on a normal liver are considered benign hepatocellular lesions until proven otherwise. The differentiation between FNH and HCA, and the sub-classification of HCAs is possible in the majority of cases using a combination of imaging techniques, as detailed above. Nevertheless, some atypical lesions may be more difficult to characterize. A classical issue is FNH showing absence or unusual appearance of the central scar, and pseudocapsular enhancement on delayed images. The absence of a central scar is the most challenging presentation, frequent in
5 small FNH (< 3 cm) [33]. In these cases, it may be difficult to differentiate atypical FNH from benign or malignant lesions such as hepatocellular carcinoma, fibrolamellar carcinoma, or hypervascular liver metastases, but mostly from HCAs (telangiectatic/inflammatory, -Catenin activation or unclassified). The lesion homogeneity is strongly in favor of FNH. On MR imaging, absence of delayed persistence of contrast uptake (indicative of telangiectatic/inflammatory HCA), or of a washout (indicative of the other HCA subtypes) are important signs. CEUS can be useful, by showing the spoke-wheel aspect and the centrifugal filling [12]. The use of hepatospecific MR contrast agents may also be helpful [17,20,34], by showing hypointensity of most HCAs and an iso- to hyperintense appearance of most FNHs. Liver biopsy should be performed in all cases of uncertain diagnosis and should be systematically completed by immunohistochemistry [35]. Fat depiction is considered a key element in diagnosis and subtyping of HCAs. Nevertheless, fatty FNH are not rare in
Figure 2 MR aspect of a HNF-1␣ inactivated HCA in a 42-year-old female. The subcapsular lesion is slightly hyperintense to surrounding liver on T2-weighted image (A), with homogeneous slight hyperintensity on T1 and dramatic signal drop out on chemical shift sequence (B, C). On contrast-enhanced images, the lesion shows heterogeneous arterial enhancement with portal wash out (D, E).
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pathological descriptions but rarely seen in imaging (Fig. 1). A retrospective series based on surgical specimen of fatty FNH has enabled to differentiate imaging presentations into three groups: • typical FNH with central scar without visible fat on MR; • typical FNH with central scar and visible fat on MR; • atypical lesions, the latter being observed in 50% of the cases [36]. The first two groups are not difficult to diagnose, and the presence of fat should not modify the diagnosis. On the other hand, atypical lesion may be misdiagnosed as HCA, mainly telangiectatic/inflammatory subtype containing fat, and lead to inappropriate surgical resections. In that case, the use of hepatospecific contrast agent has not been evaluated, and liver biopsy is recommended. As seen above, telangiectatic/inflammatory HCAs may also contain fat. In such cases, the two main imaging features (hyperintensity on T2-weighted images, and persistence of enhancement on the delayed phase acquisition) may be absent. According to the amount of intralesional fat, the signal dropout on chemical shift sequence can be
marked and is usually heterogeneous. Therefore the lesion can be misdiagnosed as a fatty FNH or a HNF-1␣ inactivated HCA (Fig. 2). As already mentioned, only the dramatic and homogeneous signal dropout on opposed-phase T1-weighted sequence allows the diagnosis of HNF-1␣ inactivated HCA. The differentiation with a fatty FNH is more difficult. Even if different features have been associated with the different HCA subtypes, CEUS [28] is not very useful for HCA classification. On the other hand, it may be interesting in case of fatty FNH. In patients with liver steatosis, the most common causes of a hypervascular lesion are fatty FNH [36], or telangiectatic/inflammatory HCA [37] (Fig. 3). Signal intensity on T1 and T2-weighted acquisitions is often useful for the diagnosis. However, one has to keep in mind that liver steatosis may also be the sole indication of the presence of a non-alcoholic steatohepatitis. Therefore, the diagnosis of hepatocellular carcinoma should be suggested [38], especially when the lesion harbors washout on portal or delayed phase acquisitions. Multiple FNH are observed in 20 to 30% of the cases. When lesions are typical, the diagnosis is not problematic. However, FNH can be associated with hemangiomas in 20—23%
Figure 3 MR aspect of multiple telangiectatic/inflammatory HCA in a 31-year-old female. Lesions show hyperintensity on T2weighted sequences (A), homogeneous iso-intensity on T1 without fat depiction and signal drop out of the surrounding liver related to marked steatosis (B, C). On contrast-enhanced images, the lesions show a marked arterial enhancement with persistent contrast uptake on delayed phase acquisition. The lesions are well-delineated, and unencapsulated. Note the overweight on the patient.
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Imaging of hepatocellular benign lesions of the cases [39], and more importantly with HCA in about 3.6% [40]. This latter association might not be fortuitous, and requires characterizing each lesion with caution. Multiple HCAs are observed in one-third of the patients [3]. Patients with more than 10 HCAs are subclassified in a so-called liver adenomatosis. Patients with multiple HCAs are predominantly observed in women using OC. The risk of bleeding and of malignant transformation is similar to that in patients with solitary adenoma and is mainly related to the size of tumors [3]. Most of the time, all HCAs share the same subtype, either telangiectatic/inflammatory or, more frequently, HNF-1␣ inactivated one. In case of mixed presentation, the most frequent association is telangiectatic/inflammatory and HNF-1␣ inactivated HCAs. Multiple unclassified HCA are rare, except in patients with underlying metabolic diseases such as type I and III glycogen storage disease. Recently, a new area of research based on the quantification of intrinsic viscoelastic properties of soft tissues has emerged [41]. This approach could be considered to be an interesting complementary tool that may give additional information on the lesion structure, and help in characterizing focal liver lesions. It has been shown that FNHs have significantly higher stiffness values than the other benign lesions, and HCAs in particular [42—45]. Although both FNHs and HCAs contain hepatocytes, numerous differences in tissue architecture could explain the differences in stiffness values. FNH is a normal hyperplastic liver parenchyma subdivided into nodules by fibrous septa that may form stellate scars [5,46], while HCAs are a heterogeneous group of neoplasms containing mildly thickened or irregular liver cell plates and lacking bile ducts or portal triads [47]. Regarding the different HCA subtypes, Frulio et al. recently indicated that telangiectatic/inflammatory HCAs might present with significantly higher stiffness values in comparison with the HNF1- ␣ inactivated ones [48]. These results need to be validated on prospective series of fortuitously discovered lesions. In conclusion, FNH and HCAs subtypes present with specific combinations of imaging features. CEUS and MR imaging, are the best complementary techniques, and lead to the proper diagnosis in the majority of cases. Nevertheless, atypical presentations should be analyzed with great caution, and liver biopsy should be performed when a specific diagnosis cannot be established, to avoid unnecessary invasive treatment.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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Clinics and Research in Hepatology and Gastroenterology (2014) xxx, xxx—xxx
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Imaging of benign hepatocellular lesions: Current concepts and recent updates Maxime Ronot a,∗,b, Valérie Vilgrain a,b a
Department of Radiology, Hôpital Beaujon, Assistance Publique—Hôpitaux de Paris, AP—HP, 100, boulevard du Général-Leclerc, 92110 Clichy, France b INSERM Centre de recherche Biomédicale Bichat-Beaujon, université Paris-Diderot, Sorbonne-Paris-Cité, CRB3 U773, 75018 Paris, France
Summary Focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA) are a variety of solid lesions mostly found in the absence of underlying chronic liver disease in young patients. HCA is no longer to be considered as a unique lesion but as a recollection of different entities sharing common points but most of all separated by different typical morphological aspects. Accurate diagnosis is of clinical importance as the management is most of the time conservative for FNH, whereas HCAs expose patients to hemorrhage and malignant transformation, and may lead to a more invasive treatment, mainly surgical resection. Moreover, the different HCA subtypes expose to different risks of complication. The best imaging techniques for the differentiation between FNH and HCAs and for the subtyping of HCAs are contrast-enhanced ultrasound (CEUS) and magnetic resonance imaging (MRI), as specific combinations of imaging features have been associated with the different lesions. They should be considered as complementary examinations. Atypical or multiple lesions, lesions containing fat or presence of an associated steatosis represent diagnostic challenges. Recently, MR hepatospecific contrast agents have been shown to be useful. Emergent elastography techniques might also be helpful in the near future. Biopsy should always be performed in case of uncertain diagnosis to reach a final diagnosis and avoid unnecessary invasive treatment. © 2014 Elsevier Masson SAS. All rights reserved.
Introduction Benign hepatocellular lesions are rare epithelial solid entities encountered mostly in young women. They are
∗ Corresponding author. Tel.: +33 1 40 87 5358; fax: +33 1 40 87 0548. E-mail address: [email protected] (M. Ronot).
classically divided into two groups that do not share the same pathogenesis or course of evolution and do not expose to the same complications. Focal nodular hyperplasias (FNH) are regenerative polyclonal formations that generally remain asymptomatic and follow a very benign course of evolution, while hepatocellular adenomas (HCA) correspond to neoplastic monoclonal lesions [1,2], subject to hemorrhage and rare malignant transformation [3,4]. Differentiating these two entities has been an issue for many years because management is different for each. Most
2210-7401/$ – see front matter © 2014 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.clinre.2014.01.014
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FNH are managed conservatively and treatments are indicated only for the few symptomatic ones. HCAs, on the other hand, may lead more frequently to an invasive treatment, mainly surgical resection. Final diagnosis relies on pathological analysis performed on biopsy. However, as most of these lesions are discovered fortuitously in young patients and develop on normal liver parenchyma, non-invasive characterization techniques shall be preferred. This is why imaging plays a central role in the diagnosis of these lesions. In the present review, we will detail the imaging features of FNH and HCAs, as recent advances in imaging studies allow an accurate diagnosis in the majority of cases, thus limiting the need for liver biopsies. Pathogenesis and pathological considerations are beyond the scope of the present text.
Focal nodular hyperplasia FNH is the most frequent benign hepatocellular lesion (.9%), with a sex ratio around nine women for one man [5]. They are most of the time asymptomatic, and, when large or pediculated, may result in non-specific abdominal symptoms. In more than half of all cases, hepatic tests are normal. When not, isolated elevation of gammaglutamyl transpeptidase and/or alkalin phosphatases is found.
Ultrasound and computed tomography Most lesions are fortuitously discovered on an ultrasound or CT. At ultrasound, FNH is usually slightly hypoechoic or isoechoic, and may only be detected because they displace the surrounding vessels. Hypoechoic halo or lobulated contours are often observed. The central scar is difficult to visualize at US (20% of the cases) [6]. When visible, it is slightly hyperechoic. Typical findings at color Doppler include the presence of a central feeding artery with a stellate or spokewheel pattern corresponding to the artery running from the central scar to fibrous septa. On CT scans, FNH spontaneously appears as a focal hypoattenuating mass. The central hypoattenuating scar is depicted in only one-third of the cases [6], and calcifications within the central scar, very rare, are observed in only about 1% of the cases [7] At the arterial phase of contrast-enhanced CT, the lesion enhances rapidly in most cases (95—100%) [8]. At the portal venous phase the lesion is either iso- or slightly hyperattenuating relative to normal liver. Furthermore, lesion is homogeneous in 90% of all cases, present with lobulated contour and no capsule. The central feeding artery is visible in the majority of cases [9] and the central element enhances is 89% on the late phase [9].
Contrast-enhanced ultrasound and magnetic resonance imaging A second examination is often required for definite noninvasive diagnosis. It can be achieved with imaging using contrast-enhanced ultrasound (CEUS) or MR imaging, as specific features have been associated with both the techniques [10]. CEUS has been less studied, and imaging features still require prospective validation. This is why MRI
is considered the best imaging tool with a sensitivity of 70% and a specificity of 98% [11]. With ultrasound contrast agents or non-linear continuous imaging, FNH enhances at the very arterial phase, and becomes homogeneously isoechoic after 30 seconds in the vast majority of the cases. They have been associated with two specific features: • a spoke-wheel aspect, encountered in 20—25% of the lesions; • a centrifugal filling, more frequent in lesion smaller than 3 cm [12]. The central scar is detected in around 40% of the lesion, mostly in FNHs larger than 3 cm [9], and appears hypoechoic on both arterial and portal phases. According to Kim et al., by showing centrifugal enhancement with radiated vascularisation, differentiation with adenoma is possible in most cases [13]. Recently, Wang et al. advocated that CEUS should be the first-line imaging technique for the diagnosis of FNH [9]. In our experience, the combination of CEUS and MR imaging is often performed [10]. On MR imaging, one has to remember that the diagnosis of FNH is based on a combination of features, none of them being specific of FNH. There are seven major criteria to assess a proper diagnosis: • lesion not different from the liver before contrast injection, i.e. iso- or hypointense on T1-weighted images (94—100%) and iso- or slightly hyperintense on T2weighted images (94—100%) [14]; • homogeneity apart the central scar; • presence of a central scar, corresponding to a central hypointense area on T1-weighted images and strongly hyperintense on T2-weighted images (78—84%) [15]; • intense enhancement at arterial phase without washout; • no capsule; • lobulated aspect; • absence of underlying chronic liver disease or clinical history of cancer. When all the criteria are present, the diagnostic specificity is close to 100%. One point must be stressed: the prevalence of typical features of FNH in literature ranges from 22—70%, and may be explained by variations in the stringency of the criteria sets used to diagnose FNH, and recruitment bias. Hepatobiliary contrast agents can be used to highlight the hepatocellular origin of the lesions. After injection of Gadolinium-BOPTA (Multihance, Bracco) FNH appears hyperintense in comparison to the surrounding liver [16,17]. After injection of Gadolinium-EOB-DTPA (Primovist/Eovist Schering) most of FNH enhance on the hepatospecific phase, usually homogeneously [18—21]. A rim-like enhancement is also described [22]. Finally, on diffusion-weighted MR sequence, FNHs often show hyperintensity on high-b-values, which could suggest malignancy. Yet, ADC values of FNH are close to the surrounding liver, the vast majority of lesions present with an ADC value 15% inferior to the liver [23].
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Imaging of hepatocellular benign lesions
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HCA are very rare lesions (< 1/1000) that concern mostly young women. They are associated with oral contraception uptake (OC). The risk for developing an HCA increases with the duration and the estrogen content of OC [3]. This tumor can also occur in men receiving anabolic steroids or be associated with diabetes or underlying metabolic diseases: type I and III glycogen storage disease, tyrosinemia, galactosemia. The prevalence of obesity is high in patients with HCA [3] and it was recently described in patients with non-alcoholic steatohepatitis [24]. Although patients with adenoma can present with symptoms, the majority of patients, (80%) are asymptomatic [3]. HCAs can be revealed by an acute abdominal pain in relation with intratumoral bleeding. Lesions also expose to the risk of malignant transformation. Liver function tests are abnormal in two third of cases. When abnormal, they concern cholestatic enzymes (2—10N) and less frequently (one quarter) transaminases (2—8N) [3]. Recent studies, mainly coming from French teams, established the existence of four subtypes of HCA based on the existence of different altered molecular pathways [25]. Therefore, HCA is no longer to be considered as a unique lesion but as a recollection of different entities sharing common points but most of all separated by different typical morphological aspects. The different HCA subtypes are:
The key-imaging feature of HNF-1␣ inactivated HCAs is the presence of marked and diffuse fat within the lesion. Therefore, they correspond to very homogeneous hyperechoic lesions on ultrasound. It is uncommon to find Doppler signal within the lesion. On CT, they appear as fat containing lesion: strong hypo-attenuation on unenhanced CT scan, absence of marked enhancement and rapid washout on multiphasic examination. The key-imaging feature of telangiectatic/inflammatory HCAs is the presence of telangiectatic components, event if it is not specific of this lesion. Imaging characteristics correspond to those previously described in telangiectatic FNH. On ultrasound examination, the lesion is well-delineated, often hyperechoic and often heterogeneous. Doppler signals are commonly seen and may mimic central arteries found in FNH [10]. On CT, HCAs are hypoattenuating and often heterogeneous. They may contain spontaneously hyperattenuating areas in relation to recent bleeding. The characteristic lesion behavior on multiphasic examination is a strong arterial enhancement (93%) and a persistent enhancement in the delayed phase (96%). The two other subtypes (-Catenin activation and unclassified hepatocellular adenomas) are less characteristic on imaging. They share findings of hepatocellular tumors: hypoechoic on ultrasound examination, spontaneously isoto hypoattenuating on unenhanced CT, arterial enhancement and portal or delayed washout. They may have heterogeneous content.
• HNF1-␣ inactivated HCAs (25—40%) characterized by diffuse steatosis (> 60%) owing to increased fatty acid synthesis and impaired transport of fatty acids resulting in excessive intratumoral lipid accumulation; • -catenin mutated HCAs (5—10%) presenting numerous cytological abnormalities, more frequent in men, and more prompt to malignant transformation [4]; • telangiectatic/inflammatory HCAs (45 — 55%), corresponding to the entity initially described as telangiectatic FNH [1], characterized by an over expression of inflammation proteins such as the C-reactive protein (CRP) and the serum-amyloid associated protein (SAA), and by the presence of inflammatory infiltrates, sinusoidal dilatation, and dystrophic vessels without fibrosis. Intratumoral steatosis can be found, sometimes in large amount. Telangiectatic/inflammatory HCAs are associated with obesity, hepatic steatosis (40%), and increased serum levels of acute inflammatory markers such as gammaglutamyl transferase, CRP, SAA. Few of them have an additional -catenin activation (< 10%); • unclassified HCAs, i.e., lesion without HNF1-␣ or catenin mutation and without over expression of inflammatory proteins (5—10%). Prior to the identification of these different subtypes, imaging features of hepatocellular adenomas were non-specific, including heterogeneity, fat containing and hemorrhagic areas. The main issue was to exclude the diagnostic criteria of FNH. Now, it is well established that the different molecular features correspond to distinct phenotypical features [26,27]. MR is the best imaging tool for tumoral characterization, a correct classification being reached in 85% of all cases with good interobserver correlation (0.85) [26].
Contrast-enhanced ultrasound and MR imaging In HNF-1␣ inactivated HCAs, hypervascularization is not very intense on contrast-enhanced ultrasound, and may sometimes be absent. At the portal or delayed phase, a washout can be depicted [28], but given the spontaneous hyperechoic aspect of those HCAs, such washout is better seen with CT or MR. Indeed, MR plays a crucial role in demonstrating the presence of diffuse fat. The striking finding is a diffuse and homogeneous signal dropout on opposed-phase T1-weighted sequences due to the presence of microscopic fat (93%) [26,27]. According to Laumonier et al. and to our experience, this finding has a sensitivity of 87%—91%, and a specificity of 89%—100% [26,27]. It is important to insist on the marked and homogeneous dropout on opposedphase T1-weighted MR sequence required for this diagnosis. Indeed, other subtypes of HCAs may contain fat, but the signal dropout is less intense and rather heterogeneous in such cases. According to Laumonier et al., the association of arterial hypervascularity with centripetal filling, linear vascularities, peripheral rim of sustained enhancement, and central washout in the late venous phase is specific of telangiectatic/inflammatory HCA on CEUS [28]. On MR imaging, telangiectatic/inflammatory HCAs show a strong hyperintense signal on T2-weighted images. On T1weighted sequences, lesion signal intensity is variable isoto hyperintense. If present, the hyperintensity persists on fat suppressed and opposed-phase sequences. Some lesions may contain some heterogeneous fat compared to HNF-1␣
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inactivated HCAs (see above). Considering two imaging findings (markedly hyperintense signal on T2-weighted MR images and persistent enhancement on delayed phase), Laumonier et al. and our experience show that these combined findings have a sensitivity of 85.2%—88.4%, and a specificity of 87.5%—100% [26,27]. Finally, van Aalten et al. recently described a hyperintense peripheral rim-like band on T2-weighted images, with iso-intensity to surrounding liver in the center of the lesion (atoll sign) in nearly 25% of the telangiectatic/inflammatory HCAs [29]. The two other subtypes (-Catenin activation and unclassified hepatocellular adenomas) are less characteristic on imaging, and cannot easily be differentiated from hepatocellular carcinoma. They also share findings of hepatocellular tumors on CEUS and MR: iso- to hypointensity on T1-weighted images, commonly hyperintensity on T2-weighted imaged, arterial enhancement and portal or delayed washout. In our experience, these findings have a sensitivity of 100% and a specificity of 93.3% for
distinguishing these HCAs from the other subtypes but are less accurate to differentiate them from HCC [26]. As for FNH, hepatobiliary contrast agents can be used. Indeed these contrast agents require performing MR sequences at the hepatospecific phase. The enhancement of HCAs is variable [21,30—32]. Most of them are hypointense during the hepatobiliary phase (90—92%). However, some may also take up the contrast agent and appear hyperintense. The different aspects according to the different subtypes have not been described yet. Regarding the telangiectatic/inflammatory HCAs, it seems that the persistent enhancement on delayed phase is less frequently observed, due to the progressive washout of EOB-DTPA. Recently, Thomeer et al. reported that, after gadobenate dimeglumine injection, a majority (71%) of telangiectatic/inflammatory HCAs show areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase, while none of the non telangiectatic/inflammatory HCAs does. In some cases, this hyperintensity can be
Figure 1 MR imaging of a fatty FNH in a 32-year-old female appearing as an atypical lesion, slightly hyperintense to surrounding liver on T2-weighted image (A), iso- to hypointensity to liver on T1-weighted image with signal drop out of the fatty area (B, C). On contrast-enhanced MR, the lesion is lobulated and enhances at the arterial phase with progressive homogenization (D, E). No central scar is visible. The differential diagnosis with a telangiectatic/inflammatory HCA containing fat is difficult. Liver biopsy confirmed the diagnosis of FNH.
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Imaging of hepatocellular benign lesions partially explained by the presence of steatosis or spontaneous hyperintensity on precontrast sequences. Finally, on diffusion-weighted MR images, most HCAs show diffusion restriction slightly higher than the liver and FNHs. [23].
Differentiation FNH from HCAs In young patients without history of cancer, hypervascular lesions developed on a normal liver are considered benign hepatocellular lesions until proven otherwise. The differentiation between FNH and HCA, and the sub-classification of HCAs is possible in the majority of cases using a combination of imaging techniques, as detailed above. Nevertheless, some atypical lesions may be more difficult to characterize. A classical issue is FNH showing absence or unusual appearance of the central scar, and pseudocapsular enhancement on delayed images. The absence of a central scar is the most challenging presentation, frequent in
5 small FNH (< 3 cm) [33]. In these cases, it may be difficult to differentiate atypical FNH from benign or malignant lesions such as hepatocellular carcinoma, fibrolamellar carcinoma, or hypervascular liver metastases, but mostly from HCAs (telangiectatic/inflammatory, -Catenin activation or unclassified). The lesion homogeneity is strongly in favor of FNH. On MR imaging, absence of delayed persistence of contrast uptake (indicative of telangiectatic/inflammatory HCA), or of a washout (indicative of the other HCA subtypes) are important signs. CEUS can be useful, by showing the spoke-wheel aspect and the centrifugal filling [12]. The use of hepatospecific MR contrast agents may also be helpful [17,20,34], by showing hypointensity of most HCAs and an iso- to hyperintense appearance of most FNHs. Liver biopsy should be performed in all cases of uncertain diagnosis and should be systematically completed by immunohistochemistry [35]. Fat depiction is considered a key element in diagnosis and subtyping of HCAs. Nevertheless, fatty FNH are not rare in
Figure 2 MR aspect of a HNF-1␣ inactivated HCA in a 42-year-old female. The subcapsular lesion is slightly hyperintense to surrounding liver on T2-weighted image (A), with homogeneous slight hyperintensity on T1 and dramatic signal drop out on chemical shift sequence (B, C). On contrast-enhanced images, the lesion shows heterogeneous arterial enhancement with portal wash out (D, E).
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pathological descriptions but rarely seen in imaging (Fig. 1). A retrospective series based on surgical specimen of fatty FNH has enabled to differentiate imaging presentations into three groups: • typical FNH with central scar without visible fat on MR; • typical FNH with central scar and visible fat on MR; • atypical lesions, the latter being observed in 50% of the cases [36]. The first two groups are not difficult to diagnose, and the presence of fat should not modify the diagnosis. On the other hand, atypical lesion may be misdiagnosed as HCA, mainly telangiectatic/inflammatory subtype containing fat, and lead to inappropriate surgical resections. In that case, the use of hepatospecific contrast agent has not been evaluated, and liver biopsy is recommended. As seen above, telangiectatic/inflammatory HCAs may also contain fat. In such cases, the two main imaging features (hyperintensity on T2-weighted images, and persistence of enhancement on the delayed phase acquisition) may be absent. According to the amount of intralesional fat, the signal dropout on chemical shift sequence can be
marked and is usually heterogeneous. Therefore the lesion can be misdiagnosed as a fatty FNH or a HNF-1␣ inactivated HCA (Fig. 2). As already mentioned, only the dramatic and homogeneous signal dropout on opposed-phase T1-weighted sequence allows the diagnosis of HNF-1␣ inactivated HCA. The differentiation with a fatty FNH is more difficult. Even if different features have been associated with the different HCA subtypes, CEUS [28] is not very useful for HCA classification. On the other hand, it may be interesting in case of fatty FNH. In patients with liver steatosis, the most common causes of a hypervascular lesion are fatty FNH [36], or telangiectatic/inflammatory HCA [37] (Fig. 3). Signal intensity on T1 and T2-weighted acquisitions is often useful for the diagnosis. However, one has to keep in mind that liver steatosis may also be the sole indication of the presence of a non-alcoholic steatohepatitis. Therefore, the diagnosis of hepatocellular carcinoma should be suggested [38], especially when the lesion harbors washout on portal or delayed phase acquisitions. Multiple FNH are observed in 20 to 30% of the cases. When lesions are typical, the diagnosis is not problematic. However, FNH can be associated with hemangiomas in 20—23%
Figure 3 MR aspect of multiple telangiectatic/inflammatory HCA in a 31-year-old female. Lesions show hyperintensity on T2weighted sequences (A), homogeneous iso-intensity on T1 without fat depiction and signal drop out of the surrounding liver related to marked steatosis (B, C). On contrast-enhanced images, the lesions show a marked arterial enhancement with persistent contrast uptake on delayed phase acquisition. The lesions are well-delineated, and unencapsulated. Note the overweight on the patient.
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Imaging of hepatocellular benign lesions of the cases [39], and more importantly with HCA in about 3.6% [40]. This latter association might not be fortuitous, and requires characterizing each lesion with caution. Multiple HCAs are observed in one-third of the patients [3]. Patients with more than 10 HCAs are subclassified in a so-called liver adenomatosis. Patients with multiple HCAs are predominantly observed in women using OC. The risk of bleeding and of malignant transformation is similar to that in patients with solitary adenoma and is mainly related to the size of tumors [3]. Most of the time, all HCAs share the same subtype, either telangiectatic/inflammatory or, more frequently, HNF-1␣ inactivated one. In case of mixed presentation, the most frequent association is telangiectatic/inflammatory and HNF-1␣ inactivated HCAs. Multiple unclassified HCA are rare, except in patients with underlying metabolic diseases such as type I and III glycogen storage disease. Recently, a new area of research based on the quantification of intrinsic viscoelastic properties of soft tissues has emerged [41]. This approach could be considered to be an interesting complementary tool that may give additional information on the lesion structure, and help in characterizing focal liver lesions. It has been shown that FNHs have significantly higher stiffness values than the other benign lesions, and HCAs in particular [42—45]. Although both FNHs and HCAs contain hepatocytes, numerous differences in tissue architecture could explain the differences in stiffness values. FNH is a normal hyperplastic liver parenchyma subdivided into nodules by fibrous septa that may form stellate scars [5,46], while HCAs are a heterogeneous group of neoplasms containing mildly thickened or irregular liver cell plates and lacking bile ducts or portal triads [47]. Regarding the different HCA subtypes, Frulio et al. recently indicated that telangiectatic/inflammatory HCAs might present with significantly higher stiffness values in comparison with the HNF1- ␣ inactivated ones [48]. These results need to be validated on prospective series of fortuitously discovered lesions. In conclusion, FNH and HCAs subtypes present with specific combinations of imaging features. CEUS and MR imaging, are the best complementary techniques, and lead to the proper diagnosis in the majority of cases. Nevertheless, atypical presentations should be analyzed with great caution, and liver biopsy should be performed when a specific diagnosis cannot be established, to avoid unnecessary invasive treatment.
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
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