Abstract Benign hepatic lesions are relatively common in the general population. The majority of these le 40 Imaging modalities commonly used for non-invasive liver lesion work-up and characterization includes ultrasonography (US), computed tomography ( CT ), magnetic resonance (MR) imaging. The tumor features being evaluated include their cystic or solid appearance; calcifi cations, fat and hemorrhage within the lesion; lesion border and capsule. The use of intravenous contrast agents allows evaluation of lesion vascularity, perfusion, hepatocyte function and biliary excretion. There is a paucity of prospective studies comparing all modalities and their performance in detection and diagnosis of benign hepatic tumors in the literature. Imaging technologies were introduced at different decades with each modality undergoing signifi cant technological advances over time leading to improved lesion conspicuity and characterization. In many cases, studies comparing the imaging fi ndings of a particular modality with lesion histology have not been performed. Comparison with either another modality or following lesion stability over time would be considered the “gold-standard”. Modalities such as US, CT and MR have improved lesion detection and characterization with the introduction of intravascular contrast agents, including selective hepatobiliary MR contrast agents, which have improved liver lesion characterization. Sonographic contrast agents have provided additional diagnostic capability to conventional ultrasonography. However, although these are widely available in Europe, their availability is limited in the US. In this chapter, we will discuss the imaging features of cavernous hemangioma , focal nodular hyperplasia, hepatic adenoma, biliary hamartoma, and provide a preferred modality imaging in diffi cult cases. Cavernous Hemangioma Ultrasonography The ‘typical’ imaging features of a small hemangioma (<2 cm) on ultrasound is uniform hyperechogenicity (66 %), well defi ned margin and posterior acoustic enhancement [ 1 ]. Between 20 and 40 % (mostly larger lesions) can have an ‘atypical’ pattern with an echogenic border either as a thick rind or thin rim with a hypoechoic internal echo pattern or an anechoic/cystic pattern (Fig. 4.1 ) [ 2 , 3 ]. Hemangiomas detected by ultrasound tend to be stable over time with 82 % having similar imaging characteristics. 18 % can show change in their sonographic appearance and they can also grow in size over the time [ 4 ]. The ultrasound appearance of hemangiomas can overlap with those of hepatocellular carcinoma (HCC) and some hypervascular hepatic metastases [ 5 , 6 ]. As a result, patients with chronic liver disease or with a known or suspected extra-hepatic malignancy should undergo a confi rmatory examination such as a contrast enhanced CT or MRI. Computed Tomography Hemangiomas are well demarcated masses that are hypo-attenuating to liver parenchyma and are iso-attenuating to blood pool on noncontrast CT . Dystrophic calcifi cations can be present in approximately 10 % of lesions. With contrast administration, hemangiomas have a typical enhancement S. Thomas and A. Oto 41 pattern with peripheral nodular discontinuous enhancement on the arterial and early portal venous phase with gradual centripetal fi lling on delayed phase images. This enhancement pattern is present in approximately 60 % of all hemangiomas, more commonly present in larger lesions and varies by size: >2 cm (85 %), 1–2 cm (55 %) and <1 cm (23 %) [ 7 ]. Smaller lesions can show diffuse hyper-enhancement, a pattern that can be seen in metastasis. Magnetic Resonance Imaging A typical hemangioma is a well-demarcated homogenous mass that is hypointense on T1-weighted images and hyperintense on T2-weighted images (T2–WI) (Fig. 4.2 ). The very long T2 relaxation of hemangiomas is useful in distinguishing them from malignant hepatic neoplasms. Hemangiomas demonstrate a relative increase in signal intensity on heavily T2–WI sequences compared to moderately T2–WI sequences. In contradistinction, other solid hepatic masses show a relative decrease in signal intensity on more heavily T2–WI [ 8 – 11 ]. Using a 1.5 Tesla MR unit, MRI can characterize lesions as hemangiomas with an accuracy of 84–97 % based on T2 values, morphologic features and tissue homogeneity [ 8 , 10 , 11 ]. However, hypervascular metastasis from pheochromocytoma, carcinoid, and pancreatic islet-cell tumor can also be hyperintense on T2–WI and is a pitfall of this technique [ 12 , 13 ]. Therefore, intravenous administered contrast agent is usually required to make a defi nitive diagnosis of hemangioma. Hemangiomas >4 cm can be heterogeneous in signal due to fi brosis, hemorrhage, thrombosis, hyalinization and cystic degeneration [ 14 , 15 ]. Use of an intravenous gadolinium based contrast agent (GBCA) results in similar enhancement patterns as CT with arterial peripheral nodular or globular enhancement and progressive centripetal enhancement (Figs. 4.3 and 4.4 ). This pattern is seen in hemangiomas >2 cm; small lesions <2 cm may have a homogenous enhancement on early phase and may be indistinguishable from small hypervascular metastasis. Metastasis tends to have a continuous rim enhancement on later phases of imaging [ 12 , 13 , 16 ]. Contrast enhanced MRI is able to distinguish hemangioma from metastasis with an accuracy of 96 % [ 17 ]. Fig. 4.1 Ultrasound of the liver shows a hypoechoic heterogeneous mass within the left lobe of the liver with a hyperechoic rim ( arrow ) 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 42 Strategy for Diffi cult Cases MRI is the modality of choice in cases where the diagnosis is not certain. The use of heavily weighted T2–WI, multi-phasic contrast sequences with the ability to obtain multiple delayed phases without any ionizing radiation can help confi rm the diagnosis of hemangioma. MRI can identify atypical features of hemangiomas, Fig. 4.2 Axial fat saturated T2-weighted MRI shows a welldemarcated T2 hyperintense mass in the left lobe of the liver ( arrow ) Fig. 4.3 Axial fat saturated T1-FSPGR post contrast MRI shows the classic peripheral nodular discontinuous enhancement on early arterial phase of imaging ( arrow ) S. Thomas and A. Oto 43 which include incomplete contrast fi lling, seen in hemangiomas larger than 3 cm due to central scarring. Lesions greater than 5 cm can have “fl ame shaped” discontinuous peripheral enhancement which may dominate or coexist with the typical nodular enhancement [ 18 ]. Hyalinized hemangiomas can be predominately fi brosed with obliterated vascular spaces and may not enhance. They may be only be slightly hyperintense on T2-WI, lack the early enhancement on dynamic contrast enhancement, with slight peripheral enhancement on late phase and may be confi dently diagnosed on MR [ 19 ]. Focal Nodular Hyperplasia Ultrasonography FNH are frequently fi rst identifi ed on US as the modality is commonly used to evaluate the liver and gallbladder. However, FNH echotexture can be quite variable. They can appear hyper, hypo, and isoechoic relative to hepatic parenchyma. Isoechoic lesions may only be detected if they deform the hepatic contour. Frequently, FNH are located in the subcapsular area of the liver and may deform the liver contour or rarely may be exophytic. The central scar, which is an important imaging feature, is only present in about 20 % of cases. Gray scale sonography is unable to reliably distinguish FNH from other neoplastic lesions [ 20 ]. Computed Tomography Detection and characterization of FNH is done using a tri-phasic contrast enhanced CT . On unenhanced CT, FNH is usually a homogenous isoattenuating or hypoattenuating mass. On arterial phase, FNH has marked arterial Fig. 4.4 Axial fat saturated T1-FSPGR post contrast MRI shows the progressive centripetal enhancement on portal phase of imaging with the mass fi lling in and remaining iso-intense to vasculature ( arrow ) 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 44 enhancement that is homogeneous [ 20 – 22 ]. In about 30 % of cases a visible central scar is present which does not enhance on early phases of imaging and can be very small [ 20 , 23 ]. In larger lesions, feeding hepatic arteries, small central and septal arteries, and early draining veins can be present [ 22 , 24 ]. On portal venous and delayed phases, FNHs are iso-attenuating to hepatic parenchyma (Fig. 4.5 ). Enhancement of the central scar can be seen on delayed phases of imaging when it contains myxomatous stroma [ 23 , 25 ]. While no prospective studies exist regarding the accuracy of CT to detect and characterize FNH, a small retrospective series (n = 20) showed that CT had a sensitivity of 70 % and specifi city of 92 % and led to the correct characterization in 78 % of cases [ 26 ]. In a larger series of 86 patients with 99 foci of FNH, CT was able to correctly diagnose FNH in 60.3 % of cases [ 27 ]. Magnetic Resonance Imaging On unenhanced MR, FNH has similar characteristics to hepatic parenchyma on T1- and T2-weighted sequences [ 28 ]. Atypical features include hyperintense appearance on T1-WI due to steatosis, sinusoidal dilatation, or hemorrhage [ 28 ]. The central scar can be present in 25–43 % of lesions and is T1 hypointense and T2 hyperintense (Fig. 4.6 ) due to presence of vascular channels and bile duct ules [ 29 – 32 ]. Using IV GBCA, typically FNH has homogenous arterial enhancement and is isointense to liver on portal venous phase. The central scar can be present in 79 % of FHN and is hyperintense due to enhancement on delayed phase of imaging (Figs. 4.7 and 4.8 ) [ 32 ]. Hepatobiliary contrast agents are unique MR contrast agents in that are taken up by functioning hepatocytes and excreted with bile. Hepatobiliary GBCAs such as Fig. 4.5 Contrast enhanced CT shows a right hepatic lobe mass that is nearly iso-attenuating to the hepatic parenchyma ( arrow ). The lesion has a small hypo-attenuating central scar ( arrow head ) S. Thomas and A. Oto 45 Gd-BOPTA and Gd-EOB-DTPA have properties of an extracellular contrast agent providing dynamic contrast enhancement information and biliary excretion for delayed hepatobiliary imaging performed 20 min after contrast bolus injection. Lesions that contain functioning hepatocytes show contrast uptake. Since FNH contain functioning hepatocytes, on delayed phase of imaging, they are typically hyperintense to isointense to hepatic parenchyma [ 31 , 33 ]. The sensitivity and specifi city of MRI in differentiating FHN from hepatocellular adenoma (HCA) is 96.9 %, and 100 %, and is primarily based on the contrast washout on hepatobiliary phase in hepatic adenomas when using Gd-BOPTA in a prospective study [ 34 ]. Using Gd-EOB-DTPA and the hepatobiliary phase the sensitivity to detect FNH was 96 % with a positive predictive value of 96 % when compared to HCA [ 35 ]. Fig. 4.6 Axial fat suppressed T2 weighted MRI shows a mildly hyperintense mass ( arrow ) with a hyperintense central scar ( arrow head ) Fig. 4.7 Axial fat saturated T1-FSPGR post contrast MRI shows hyper-enhancement of the mass on arterial phase ( black arrow ). The central scar does not enhance ( arrow head ) 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 46 Strategy for Diffi cult Cases MRI using a hepatobiliary specifi c contrast agent may characterize lesions that cannot be otherwise characterized by CT . Atypical FNH lesions may show only mild arterial enhancement, and may be hypointense to liver parenchyma on late dynamic phase. For these lesions adding a hepatobiliary phase and calculating a signal intensity (SI) ratio improves diagnostic yield. Using a cutoff value of 0.87 for the SI ratio during the hepatobiliary phase, the sensitivity and specifi city for differentiating FNH from HCA was 92 % and 91 % respectively [ 36 ]. Hepatocellular Adenoma Ultrasonography HCA have a heterogeneous variable echotexture with 80 % having a mixed echogenicity and 20 % purely hypoechoic [ 37 ]. In a small study of 27 cases of HCA, the lesions were hypoechoic to hepatic parenchyma in 41 %, 30 % are hyperechoic, 22 % are isoechoic, and 7 % are of mixed echogenicity [ 21 ]. The utility of gray scale ultrasound to characterize HCA is limited due the overlap of imaging features with other benign and malignant hepatic lesions. Computed Tomography HCAs have a variable appearance on unenhanced CT images. They may be hypoattenuating due to the presence of intracellular lipid, old hemorrhage or necrosis, or it may be hyperattenuating from acute hemorrhage or large amounts of glycogen [ 37 ]. HCA are sharply marginated – 85 %, nonlobulated – 95 %, sometimes encapsulated – 30 %, and rarely can calcify 5–10 %. Necrosis or hemorrhage can occur in 25 % of lesions [ 38 , 39 ]. HCAs are almost uniformly (80–100 %) hyperattenuating on hepatic arterial phase and have variable appearance on portal venous phase with 31 % remaining hyperattenuating, 44 % Fig. 4.8 Axial fat saturated T1-FSPGR post contrast MRI shows the mass to be iso-attenuating to the liver on portal venous phase ( black arrow ). The central scar now enhances, characteristic of focal nodular hyperplasia ( arrow head ) S. Thomas and A. Oto 47 isoattenuating, and 25 % hypoattenuating [ 39 , 40 ]. On delayed phase CT, HCAs characteristically are hypoattenuating to liver parenchyma with few (6 %) that are hyperattenuating [ 39 ]. The enhancement pattern helps differentiate FNH from HCA, which is important for patient management . HCA however have similar contrast enhancement characteristics as hepatocellular carcinoma (HCC) and differentiation between the lesions can be problematic especially in lesions that have undergone hemorrhage [ 41 ]. Magnetic Resonance Imaging HCAs have a variable appearance on MRI as there are sub-types including infl ammatory, steatotic or those with β-catenin activation. The infl ammatory subtype accounts for 30–50 % of adenomas. These lesions are mildly hyperintense on T2–WI especially in the periphery of the lesion (Fig. 4.9 ), and iso to hypointense on T1–WI with heterogeneous signal intensity. There is characteristic T2 hyperintense rim like band termed the atoll sign in the periphery of the lesion that is isointense to surrounding liver toward the center of the lesion can be seen in 43 % of infl ammatory HCAs [ 42 ]. Infl ammatory HCAs are diffusely hyperintense on arterial enhancement persisting into the portal venous and delayed phases (Figs. 4.10 and 4.11 ). The T2 hyperintensity and persistent enhancement together are 85.2 % sensitive and 87.5 % specifi c for the diagnosis [ 43 ]. The steatotic subtype, shows diffuse signal loss on chemical shift sequence due to homogenous intratumoral fat. These lesions show moderate arterial enhancement not persisting into the portal venous phase [ 43 ]. The presence of intratumoral fat is not specifi c for HCAs as up to 40 % of hepatocellular carcinomas may contain fat [ 44 ]. Fig. 4.9 Axial fat suppressed T2 weighted MRI shows a mildly hyperintense mass ( arrow ) in the right lobe of the liver and larger mass in the left lobe of the liver ( arrow head ) 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 48 Fig. 4.10 Axial fat saturated T1-FSPGR post contrast MRI shows brisk homogenous enhancement of the right hepatic lobe mass ( arrow ) and the larger left hepatic lobe mass ( arrow head ) during arterial phase of imaging Fig. 4.11 Axial fat saturated T1-FSPGR post contrast MRI shows the right hepatic lobe mass ( arrow ) and the left hepatic lobe mass ( arrow head ) remain hyperintense to liver on portal venous phase HCAs with β-catenin activation can have non-specifi c imaging features with strong arterial enhancement and portal venous washout. MRI may not be able to defi nitively characterize these lesions as the imaging features can overlap with HCC [ 43 ]. HCAs with activated β-catenin present a high risk of malignant transformation [ 45 ]. S. Thomas and A. Oto 49 Strategy for Diffi cult Cases Since HCAs can have several subtypes, undergo hemorrhage, and have variable imaging features on conventional MRI, they may not be easily discriminated from FNHs. Using hepatobiliary contrast agents on MR will improve the diagnostic performance of MRI. Delayed hepatobiliary phase images can be used to separate HCA from FNH with the former appearing hypointense to liver (Fig. 4.12 ) [ 34 ]. Follow-up studies have shown that up to 71 % of infl ammatory HCAs can have areas of iso- or hyperintensity to the surrounding liver in the hepatocyte phase [ 46 ]. Biliary Hamartoma Ultrasonography Biliary hamartomas have a variable appearance on ultrasound . They usually present as tiny hypoechoic or hyperechoic foci measuring less that 10 mm scattered through out the liver and may be associated with comet-tail artifacts (Fig. 4.13 ) [ 47 , 48 ]. Their variable appearance on sonography may be mistaken for metastasis. Computed Tomography At unenhanced CT , biliary hamartomas appear as wellmarginated hypo or iso-attenuating lesions of nearly uniform size that do not enhance on contrast administration (Fig. 4.14 ) [ 48 ]. Their imaging features are important to recognize as they may simulate metastases or microabscesses [ 49 , 50 ]. Fig. 4.12 Axial fat saturated T1-FSPGR post contrast MRI performed with a hepatobiliary contrast agent and imaged during the hepatobiliary phase (20 min after injection) shows no retention of contrast in the right hepatic lobe mass compatible with a hepatic adenoma ( arrow ). The left hepatic lobe mass retains contrast and is compatible with focal nodular hyperplasia ( arrow head ) 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 50 Fig. 4.13 Ultrasound of the liver shows increased parenchymal echogenicity of the right lobe with multiple small echogenic interfaces Fig. 4.14 Contrast enhanced CT shows multiple small nearly uniformly hypo-attenuating lesions in the liver ( arrow heads ). No clear enhancing wall is seen Magnetic Resonance Imaging Biliary hamartomas have a characteristic appearance at MRI. They are hypointense on T1–WI, well defi ned and hyper-intense on T2–WI (Fig. 4.15 ). With GBCA they do not have central enhancement but may have a thin rim of peripheral enhancement, which may be from compressed hepatic parenchyma (Fig. 4.16 ) [ 51 ]. S. Thomas and A. Oto 51 Fig. 4.15 Axial T2 weighted MRI shows multiple small nearly uniformly sized T2 hyperintense lesions ( arrow heads ) Fig. 4.16 Axial fat saturated T1-FSPGR post contrast MRI shows multiple small nearly uniformly sized hypointense lesions in the liver. Some have a subtle perceivable wall ( arrow ), which represents compressed hepatic parenchyma Conclusion Focal liver lesions are commonly encountered during routine imaging. While US and CT are able to detect and characterize many lesions, MR imaging with hepatocyte specifi c contrast agents can be used for diffi cult lesions an may be able to 4 Which Diagnostic Modality is best to Assess Benign Hepatic Tumors? 52 defi nitively characterize liver lesions so as to avoid biopsy or surgery . However, for lesions that do not have typical imaging features or those that are complicated by hemorrhage may have to undergo biopsy for accurate diagnosis . References 1. Mirk P, Rubaltelli L, Bazzocchi M, et al. 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Diagnostic Modality is best to Assess Benign Hepatic Tumors?
