Vascular phases in imaging and their role in focal liver lesions assessment

Abstract

The incidental finding of a liver lesion with basic ultrasound is one of the most common clinical issues. Some of the liver lesions which present typical morphological B-mode features (e.g. cysts, typically localized focal fatty sparing/accumulations, hyperechoic hemangiomas) can be easily diagnosed by conventional ultrasound without the need of further diagnostic procedures. Others frequently necessitate further investigation with contrast-enhanced imaging techniques or biopsy in order to differentiate benign from malignant lesions and obtain a final diagnosis. This paper will discuss differences between vascular phases of different cross-sectional contrast-enhanced methods, as well as their subsequent benefits for focal liver lesions (FLLs) assessment, adding also a particular emphasis on small FLLs detection and characterization.

Keywords

Focal liver lesions imaging diagnosis ultrasonography contrast-enhanced ultrasound contrast-enhancedcomputed tomography contrast-enhanced magnetic resonance imaging guidelines

1 Introduction

Conventional B-mode ultrasound (BMUS) as a widely available, non-invasive method is the primary technique for detection and characterization of FLLs [62], but even with the added value of Color Doppler modes, its sensitivity is lower in comparison to contrast-enhanced imaging techniques [4 , 138].

Contrast-enhanced ultrasound (CEUS) has been proved to increase the sensitivity and specificity of BMUS for FLLs assessment [5, 193], that being demonstrated by numerous multicenter studies, such as DEGUM studies [167–169 , 182], French group and Italian group studies [156, 186]. CEUS revealed a high level of concordance with other contrast-enhanced cross-sectional imaging procedures (computed tomography (CT) and magnetic resonance imaging (MRI)) in depicting the contrast enhancement pattern of FLLs, with at least equivalent results [5 , 169], with detailed meta-analyses showing no statistically significant differences between the methods [80, 208]. Even if MRI has the highest reported sensitivity rates, especially for detection and characterization of small and subcentimetric FLLs [22 , 134], still is not the primary modality of choice due to a relative lack of operator expertise, its limited availability, long time of examination procedure, and high costs [24]. CEUS can clarify inconclusive findings generated by BMUS or by CT/MRI/positron emission tomography (PET) or may resolve discrepancies between radiological cross-sectional imaging procedures (CT, MRI, PET) [27]. According to the DEGUM multicenter trial conducted by Strobel [181], CEUS proved an overall diagnostic accuracy of 90.3% for differentiation of FLLs in comparison to a correct final diagnosis based on a combined gold standard, including histology (>75% cases), CT or MRI, with sensitivity, specificity, positive predictive value, and negative predictive value of 95.8%, 83.1%, 95.4%, and 95.7%, respectively. It is true for CEUS that the diagnostic performance is dependent on the observer’s level of experience, with higher diagnostic performance in diagnosing malignancy for experienced users, as compared to inexperienced ones (overall accuracy of 75.9–93.1% for experienced users vs. 63.3–72.8% for inexperienced users) [147]. Intergroup observer agreement (between the group of experienced and the group of inexperienced users) for grading diagnostic confidence was lower (k = 0.47–0.63) as compared to intragroup observer agreement (k = 0.63–0.83), as reported by Quaia et al. [147]. Bartolotta et al. [13] found a good interobserver agreement (k = 0.779) for CEUS in the characterization of indeterminate FLLs incidentally discovered at BMUS. The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) has defined levels of experience [127, 128], and EFSUMB guidelines recommend to gain experience by observing experts in the field performing contrast studies [35, 36].

The purpose of this paper is to discuss differences between cross-sectional contrast-enhanced methods, reflected by different vascular phases timing due to pharmaceutical properties of contrast agents (CAs) used. Also, the subsequent benefits of different vascular phases for the diagnosis of FLLs will be further discussed for each method, adding a particular emphasis on small FLLs assessment.

2 What can we know about focal liver lesions without the use of cross sectional contrast-enhanced imaging techniques

2.1 Conventional B-mode ultrasound and color Doppler techniques

In the situation of a incidentally discovered FLL by ultrasound (US), the sonographic aspects of the lesion including size, uni-/multifocal nature, B-mode/Color Doppler criteria, should be interpreted in the clinical context of the patient, particularly considering the preexistence of a diffuse underlying liver disease or the one of a previously known malignancy [56, 62]. However, the correct diagnosis with BMUS has been reported in the literature in 26% to 35% of benign and in 28% to 39% of malignant lesions [110, 180]. Other reports showed correct differentiation in up to 60% to 68% of the patients [83 , 197]. By means of BMUS, Leen et al. correctly diagnosed liver hemangioma in 36% and focal nodular hyperplasia (FNH) in 31% of the cases, respectively [110]. Correct diagnosis of liver metastases were reported in 67% of the cases by Konopke et al., with a rate of correct detection of number of FLLs of 64% compared to intraoperative findings [104]. In the study of von Herbay et al., from 40 malignant and 27 benign liver lesions, baseline examination including gray-scale, color and power Doppler ultrasound detected 85% of malignant lesions, with a specificity of 30%. Interobserver agreement during baseline imaging was poor, with a weighted Kappa value of 0.469 [192].

3 Contrast enhanced ultrasound

3.1 Guidelines for focal liver lesions characterization by contrast enhanced ultrasound

CEUS is commonly used in Europe and Asia and guidelines have been published for indications and recommendations regarding its use for FLLs assessment. EFSUMB published their first guidelines for liver applications of CEUS in 2004 [3], then they updated in 2008 [34] and in 2012 [35, 36]. Also, comments on guidelines have been published [45 , 52], and illustrations through images are available at EFSUMB website [60]. According to EFSUMB guidelines, CEUS is recommended for characterization of incidental lesions found on BMUS in healthy patients, in patients with a known chronic liver disease/cirrhosis or history of malignancy, as well as in cases without a final diagnosis (contraindicated CT/MRI imaging or vague CT/MRI findings] [35, 36]. Italian Guidelines have recommended CEUS for confirmation and characterization of FLLs detected with other imaging methods in patients with unknown pathology/chronic hepatopathies/oncological patients [68]. Current consensus and guidelines for the use of CEUS in FLLs characterization published by the Korean Association for the Study of Contrast Enhanced Ultrasound recommend the routinely use of CEUS for incidentally detected FLLs on conventional US and for clarifying obscure lesions detected on CT or MRI [91]. Also, CEUS is recommended by the Japanese guidelines on HCC [106, 107].

American guidelines for FLLs assessment (American College of Radiology (ACR) Criteria [131]; American College of Gastroenterology (ACG) Guidelines [121]) does not recommend CEUS and ultrasound contrast agents (UCAs) are not approved for hepatic imaging in the United States. The current AASLD guidelines have been recently discussed in detail [11 , 160] and comments on these guidelines have been also published [51].

The basics of UCAs, essential technical requirements and study procedure of CEUS for FLLs characterization, ultrasonographer training, investigational procedures, guidance on image interpretation, and recommended and established clinical indications have been previously described in the EFSUMB guidelines [3 , 143]. Also, the examiner should keep in mind that just as like any other imaging modality, CEUS also is subjected to possible artifacts and pitfalls. Knowledge of such artifacts helps to avoid uncertain diagnoses and misdiagnoses and they have been explained in details elsewhere [53, 54]. Here we discuss differences between CEUS and other contrast-enhanced cross sectional imaging techniques as regarded vascular phases including timing, assessment and characterization of FLLs. The combined phase and amplitude modification, e.g., using cadence pulse sequencing, exploits best signal to noise and avoids bubble destruction. There is one point we would like to insist on since it has been only seldom described in few papers. It is about the phenomenon of prolonged heterogeneous liver enhancement, which is a rare phenomenon that is similar to the US findings of portal venous gas. This is more likely to occur in the first 2 minutes after contrast agent injection, when high/multiple doses have been administered and may influence FLLs characterization and final diagnosis. This should be known and caution should be taken not to be misdiagnosed as a pathological finding of the liver [42].

3.2 Vascular phases and focal liver lesions assessment (characterization) by contrast enhanced ultrasound

The dynamic enhancement pattern of a lesion is visualized during intermittent or continuous imaging and described during subsequent vascular phases (e.g. arterial phase – 5–25 s postcontrast injection (p.i.), portal-venous phase – 25–60 s p.i., and late phase ->120 s p.i.]. The normal contrast agent enhancement of the liver parenchyma can be evaluated for four to six minutes [3 , 34–36]. UCAs’ vulnerability to high mechanical index can be utilized to repeat the arterial phase during the same injection [3 , 48, 52].

The standardized protocol for liver tumor characterization by CEUS is based on the EFSUMB guidelines [35, 36] and multicenter studies [181] and should assess the following according to our guidelines [35, 36]:

FLL are characterized in comparison to the surrounding liver parenchyma during all vascular phases in a real time–accordingly, the FLL enhancement is characterized as hypoenhancing, isoenhancing, or hyperenhancing.

Enhancement patterns: location of the initial enhancement in the lesion (central, peripheral), enhancement (onset, intensity) during arterial phase and presence (timing of wash-out onset, degree of wash-out during the portal-venous and late phases).

Specific enhancement patterns like rim sign, spoke wheel, nodular enhancement and others.

Particular attention is required in cases of suspected hepatocellular carcionomas (HCCs), for which the diagnostic accuracy of CEUS may increase with prolongation of the examination time till up to 5 minutes after intravenous UCA administration, since the wash-out phenomenon may be slow in early or well-differentiated HCCs [17 , 181]. Liver tumor microvascularization may be quantified by CEUS perfusion analysis through time intensity curves (TICs) and determination of time-to-peak (TTP), regional blood volume (RBV), regional blood flow (RBF), area under the curve, wash-in rate, and peak intensity, continuously measured for a period of 3 minutes. Statistically significant differences between benign and malignant FLLs in values of RBV, RBF, and peak intensity have been proved by the study of Beyer et al., with estimated receiver operating curves (ROC) areas of 0,97, 0.96, and 0.98, respectively [18]. Characteristic of TIC parameters may be displayed on top of the anatomical images as color-coded parametric maps showing cold/hot spots of abnormal perfusion [77]. Jung et al., showed that the combination of contrast enhancement with SonoVue with the quantitative evaluation of contrast-medium dynamics may predict malignancy of hepatic tumors with a positive prognostic value of 93.5% [95]. An EFSUMB paper has been published, providing recommendations and descriptions of CEUS images quantification, including also technical requirements for analysis of time-intensity curves (TICs), as well as methodology for data analysis, and results interpretation [49].

In cases of FLLs which are not visible on BMUS, and thus which cannot be analyzed, nor punctured under conventional guidance, CEUS allows for FLLs visualization and successful biopsies can be performed [161].

3.3 Particular patterns of enhancement of different focal liver lesions by contrast-enhanced ultrasound during vascular phases

FLLs characterized by CEUS can be divided into hypoenhanced, isoenhanced, and hyperenhanced lesions and should be assessed and characterized during each vascular phase previously defined (characteristics of hypervascular lesions using CEUS are illustrated in Fig. 1). Cystic lesions, anechoic in BMUS, show no enhancement in all post injection phases with CEUS [35, 36]. Focal fatty sparing/infiltration zones show exactly the same enhancement pattern as the adjacent liver parenchyma during all phases [82] (Fig. 2) and typically also the central supplying artery [47 , 82]. Abscesses typically show features of rim enhancement in arterial phase, with unenhanced central necrotic areas and enhanced internal septa, although an early lesion may show homogeneous hyperenhancement. The enhancing zones may present as isoenhanced during portal and venous phases, or may show a slowly progressing, mild wash-out [6]. Transient hyperenhanced liver parenchyma around the lesions may be also seen, representing inflammation and congestion of the surrounding liver parenchyma and, if present, it is a valuable indirect sign for the diagnosis of an abscess [66, 113]. Hemangiomas typically have pattern of peripheral discontinuous globular (nodular) arterial enhancement, progressing rapidly or slowly in a centripetal direction to partial or complete fill-in during the portal venous and late phases [35, 36]. FNH and hepatocellular adenoma (HCA) both show arterial phase enhancement, intense and with early onset and rapid progression in a centrifugal manner in FNH, early rapid and homogeneous in (at least smaller <5 cm) HCA. Still, the two benign lesions may be differentiated by analysis of enhancement patterns during early portal venous phase, when FNH is still hyperenhanced in about

95% of cases [87], while most of the HCAs will be isoenhanced then becoming slightly hypoenhanced during later phases since they lack portal vein branches [55, 61]. HCC is typically hyperenhancing, with a chaotic vascular pattern during the arterial phase, then presenting wash-out (hypoenhanced lesion), either during (early) portal phase with mild degree and progression, either and more typically with late phase onset. This sequence of events of arterial uptake followed by washout is highly specific for diagnosis of HCC by imaging. Exception makes the well-differentiated HCC, which may be isoenhancing during portal venous phase as well [35, 36], requiring further investigations by imaging and/or biopsy for diagnosis [151]. Differentiation between HCC and other malignant FLLs can be made by CEUS with Sonovue^® based on wash-out pattern. Cholangiocellular carcinomas (CCCs) present with more pronounced wash-out than HCCs [205], while metastases wash-out completely and very rapidly as compared to HCCs which often present with incomplete and slower wash-out [51]. Uller et al. described a method for improving hypervascularization of HCC. They have evaluated the microcirculation of HCCs by dynamic CEUS after both intravenous and intraarterial UCA application during transarterial chemoembolization using drug-eluting beads, and found improved marginal hypervascularization of HCCs after intraarterial UCA application as compared to intravenous UCA application (p = 0.163) [188]. In the study of Jung et al., early arterial and capillary perfusion was detected in 100% of the HCC lesions with Optison using harmonic imaging, authors considering the method as reliable in detection of tumor foci an appraisal of tumor vascularization [96]. Apart from the extracellular UCA Sonovue^®, which are used only to evaluate the vascular phase, postvascular UCA can be used, such as Sonazoid. With Sonazoid, both the vascular and the postvascular phases can be assessed. Based on Sonazoid’s characteristic following phagocytosis by Kupffer cells, a postvascular Kupffer cell-specific enhancement phase can be assessed starting from 10 min. postinjection [21, 173]. Still, when assessing a FLLs with Sonazoid, attention must be paid in the case of a fatty liver since it has been suggested that the phagocytic ability of Kupffer cells is reduced in fat containing cells as compared to the phagocytic ability of normal liver cells [173]. Even more, the fatty cells may induce narrowing of blood vessels with decreased speed of blood flow containing the injected UCA and even exclusion of some blood vessels in the surrounding liver parenchyma [65 , 137]. This may cause a hyperenhancing FLLs located in a fatty liver to look more hyperenhanced as it would look otherwise in a normal liver [173]. Using Sonazoid, HCCs appear as hypervascular lesions in the arterial phase and hypoenhanced in the postvascular phase, according to the Japanese HCC guidelines [106].

The important clinical problem of the differential diagnosis of well-differentiated HCCs and dysplastic or regenerative nodules in cirrhotic liver is the same for CEUS as it is for CECT and CEMRI, presenting significant overlaps of imaging features. With CEUS, these benign cirrhotic-related liver nodules usually present with the same enhancement as the surrounding liver parenchyma, sometimes with mild arterial hypovascularity, or with slight portal venous hypoenhancement. If the hypoenhancement during the portal phase progressively increases (wash-out), the suspicion of a HCC lesion is high, even in absence of arterial hypervascularity, if the case of a cirrhotic liver [89]. On the other hand, in the settings of cirrhosis, at CEUS, any arterial hypervascularity without typical hemangioma pattern is highly suspicious of HCC, even without presenting with portal venous wash-out [90]. This is not the case of CECT/CEMRI, since with these imaging techniques small arterial enhancing foci with no wash-out are frequently seen in cirrhotic livers, the majority of them not being HCCs [90 , 139].

Other malignant FLLs, such as CCC, lymphoma, and metastases show a variety of patterns of enhancement, still mostly presenting variable enhancement during arterial phase and rapid wash-out during portal and venous phases, usually with earlier onset during portal venous phase or with a more marked degree if present during late venous phase as compared to HCCs [30 , 203]. In patients with HCC other entities have to be encountered [87].

We would like to pay a special attention to liver metastases of neuroendocrine tumors (NETs), since their presence at diagnosis represents the most crucial prognostic factor, irrespective of the primary tumor site (5-years survival of 13–54% if metastases are present at diagnosis, as compared to 75–99% in patients without liver metastases at diagnosis) [123, 155], having also a considerable significance in therapeutic assessment [64]. For diagnosis, a combination of imaging techniques is required, including B-mode US, CEUS, CT and MRI [33]. Still, up till today, the method to be used for assessing the resectability of metastases in grade 1 or grade 2 NETs is the ⁶⁸Gasomatostatin receptor positron emission tomography (PET). It has the highest sensitivity (82–100%) and specificity (67–100% ) for detecting liver metastases of low-grade NETs [71, 159]. A case report of a rare case of NET of gallbladder with liver and retroperitoneal metastases has been recently published, with CEUS playing an important role as well as in diagnosis, and in follow-up [33].

The enhancement pattern of rare FLLs has been described in detail including cholangiocellular adenoma [86], sarcoma [187], sarcoidosis [183], inflammatory pseudotumour [165], actinomycosis [6], rare atypical [32] and pedunculated [8] cases of FNH. Other cases have been published on the EFSUMB website [60]. List with FLLs assessed by CEUS in the literature is provided in Table 1.

In FLLs treated by ablative procedures, CEUS plays an important role also in immediate evaluation of procedure’s efficacy by differentiating necrotic zones from viable residual tumor based on non-enhancement/enhancement as well as in the early postablative evaluation (within the first 30 days post-procedure) (Fig. 3). Attention must be paid to the thin and uniformly enhancing rim which can be visualized during arterial phase at the periphery of the necrotic zone, and which must not be interpreted as being residual viable tumor, primarily based on concentricity and uniform thickness, and also based on the absence of wash-out [35, 36]. Through continuous dynamic evaluation of tumor microcirculation, CEUS has an added value in depicting tumor microvascularization during radiofrequency ablation of malignant FLLs and can be used in combination with CT fluoroscopy as a mean of achieving complete ablation. Intraprocedural CEUS changed management in 59% of cases according to the study of Wiggermann et al., resulting in a number of 17 additional ablation cycles in 18 patients with 22 histologically confirmed malignancies [202]. The same team described the image findings of CEUS after irreversible electroporation performed for treatment of malignant hepatic lesions. They demonstrated a rapid significant centrally and marginally reduction in the microcirculation in the ablation areas, without significant reduction in the macrocirculation [201]. Same authors proved also significant reduction in microcirculation following degradable starch microsphere transarterial chemoembolization of HCC lesions, detectable right after the procedure and during 24 hours follow-up [199], also with the possibility of capillary perfusion quantification [200].

Image fusion of US with CT/MRI may improve FLLs diagnosis and may help therapy control after interventional procedures [37]. CEUS providing tumor vascularization information may be also integrated in the fused images, allowing simultaneous assessment of FLLs with information from CECT/CEMRI [38 , 157]. With its use, ablation of HCCs with poor conspicuity on B-mode US/CEUS/fusion imaging has now become possible [118, 126]. Rennert et al., in a retrospective study of 100 patients, found that image fusion of CEUS with CECT/CEMRI allows a definite localization of FLLs, with additional lesions found in 12 patients, causing a change in the therapeutic management. Also, an improvement in definite diagnosis has been registered, with significant coherency (p < 0.05) among image fusion of CEUS with CECT/CEMRI [153].

The examiner should keep in mind along the images interpretation process that even if enhancement pattern of a FLL depicted by CEUS and CECT/CEMRI are usually similar during the arterial phase (still with a much better temporal resolution for CEUS due to real-time assessment), the enhancement pattern of the same lesion may differ during portal and venous phases between different imaging modalities [108]. This is due to different pharmacokinetics of the contrast agents used, the ones for CEUS being strictly intravascular, while the ones used for CECT/CEMRI are extracellular/hepatobiliary agents which are rapidly cleared from blood pool into the extracellular space/taken up by the liver cells [14–16 , 174].

3.4 Real time assessment

FLLs show characteristic and specific patterns of enhancement during each vascular phase. CEUS is the only imaging modality which allows continuous real-time assessment of the FLLs microvasculature at very high frame rates, providing the best temporal resolution without the need to predefine scan-time-points or to perform bolus-tracking [29 , 193] (Figs. 4, 5). Consequently, there are no drawbacks due to incorrect scanning time. Dynamic contrast enhancement using dynamic vascular pattern analysis is helpful [43 , 72]. By assessing contrast-enhancement patterns obtained at pulse inversion harmonic imaging (PIHI) of FLLs, Kim et al. found that enhancement patterns were associated with specificity of ≥91% for the vascular phase assessment, and of ≥92%, for the delayed phase assessment, concluding that differential diagnosis of FLLs can be made by using this technique, with good results in depicting vascular patterns of HCCs, metastases and hemangiomas [99]. Good results for using PIHI have been reported also by other studies [63 , 204].

Depiction of early arterial phase which is of utmost importance for FLLs characterization is easily done by CEUS due to the physical behavior of UCAs of the second generation during insonation. Because of their characteristics, continuous real-time scanning can be performed without destruction of the microbubbles [163 , 193]. By means of other imaging modalities the early arterial phase is sometimes missed because of lower frame rates [36]. From this point of view, CT may be limited in starting the acquisition at a suitable time point. In addition, CEUS has higher spatial resolution due to its smaller field of view as compared to CT [148]. Moreover, another great CEUS advantage is that multiple UCA injections are allowed, making possible a repetitive observation of tumor enhancement during the same examination [90].

Ultrasound guided biopsies for FLL differentiation has been widely used technique, the overall sensitivity of this method in the tumor diagnosis is 90%. CEUS guided percutaneous biopsy should be applied in large tumors with consistent necrosis (metastasis, HCC, cholangiocarcinoma), including residual tumor after ablative treatment procedures, in hypovascular tumors or in those invisible or poorly visible to conventional ultrasound. An increased accuracy was demonstrated by Sparchez et al. in poorly visible or invisible hepatic lesions and when CEUS was used before biopsy. Mainly this technique is useful for targeting the needle into viable vascularized areas of FLL and avoiding avascular areas (CEUS guidance in comparison with B-mode US for all lesions (100% vs. 86.6%)). The necrotic regions usually present with no enhancement in all vascular phases of CEUS [178]. In 2006, Wu et al. demonstrated the clinical utility of CEUS in percutaneous biopsy of focal liver lesions with success rate in the CEUS group 98.7%, in comparison to US group (91.5% ). The accurate diagnosis rate of malignant lesions ≤2 cm or less in size in the CEUS group was 97.4%, significantly higher than that in the US group (80.6% ) [207].

3.5 Availability and contraindications

In terms of availability, since US is a widely available technique, CEUS may be more approachable and more at hand than other cross-sectional contrast enhanced imaging techniques. In Germany, from more than 2000 hospitals, most could offer the CEUS technique from a technology standpoint. We assume that about 1200 hospitals perform CEUS on a regular basis [44 , 59]. It is important to consider that the same physics principles apply to CEUS as in BMUS, that FLL site should be accessible in various patient habitus (depth) and locoregional anatomy. A lower level of patient collaboration is needed as compared to MRI examination, and it may be performed at bedside in intensive care units and also in the operation room [67]. Even more UCAs may be applied also in patients having decreased renal function, which is not applicable nor for iodinated CT CAs, neither for MRI CAs [79 , 146]. Furthermore, image quality is not influenced by metallic implants or surgical clips which may be the case both for CT, and for MRI examinations. Patients with cardiac peacemakers, cochlea implants or with some ferromagnetic implants which have absolute or relative MRI contraindication may be examined with CEUS without any risks [67].

4 Angiography

Angiography is the first imaging method which had employed post contrast injection imaging vascular phases in the diagnostic of FLLs. Via celiac or selective hepatic angiography early arterial and late arterial phases were observed with gradually fading enhancement in portal phase. Differentiation of hemangiomas, with one sided feeding vessels and regular vessel “cotton-wool” pattern, from metastases and HCC was possible. Latest have irregular, abnormal vascularization with different size of arteries reaching the tumour from different sites. Enhancement of hemangiomas persists 10–15 seconds longer than enhancement of malignant lesions. Since incorporating of novel imaging techniques, angiography was avoided in FLLs diagnostic due its low diagnostic efficiency and its invasive nature. Nowadays, the use of this imaging technique is again spreading due to the growing number of liver tumor embolization procedures. Now the goal of arteriography is to assess anatomical variants of hepatic arteries and to highlight the feeding vessels of FLLs and their collaterals. After selective intravascular positioning, the catheter embolization procedure is monitored till stasis of pathological arteries is accomplished [124 , 150].

5 Role of contrast-enhanced computed tomography

The assessment of the abdomen is one of the main roles of computed-tomography (CT), where the major indication is to detect or exclude and characterize FLLs. And this is especially true in patients with a suspected tumor as well as in ones with a known primary malignancy in order to search for metastases. The diagnosis role of CT for FLLs is to demonstrate the nature of the tumor and its relationship to the surrounding liver tissue and vessels as well as the extrahepatic structures [206].

5.1 Vascular phases and images acquisition

Faster scanning with rapid accurate multiphase imaging with short breath-holding periods improved perfusion imaging and thus, FLLs detection and characterization [206]. While detection of liver lesions relies on creating images that provide optimum liver-to-tumor contrast, characterization of FLLs is determined from contrast enhancement in the arterial and portal venous phases [185, 206]. After injection of CA, FLLs may appear as hypervascular, hypovascular or similar as compared to the surrounding liver tissue [69, 105]. In this regard, image acquisitions, with proper and adapted protocols are of importance. The “early arterial/hepatic arterial phase” is achieved at approximately 20 seconds post injection (p.i.) and it is best for assessing hepatic arterial anatomy including tumours feeding vessels and for detection of arterial-portal venous shunts, but less sensitive for tumor detection (Fig. 6). The best liver-to-tumor contrast in hypervascular FLLs is achieved at 30–35 seconds p.i., during the so called “portal venous inflow/late arterial phase”. 30% of the lesions are detectable exclusively on this phase [69, 105]. For assessing hypovascular tumors, particularly metastases, the best liver-to-tumor contrast is obtained after approximately 60 seconds p.i. when enhancement of the liver parenchyma reaches its maximum. This phase is called “hepatic venous phase” [177, 189]. Images obtained approximately after 2-3 minutes p.i. are suitable for demonstrating slow changes in neoplastic enhancement such as gradual enhancement centrally with a rate and extent depending on the degree of central fibrosis in cholangiocarcinomas (CCC) as well as contrast-material pooling effects or typical fill-in patterns of hemangioma (Fig. 7) and represents the “equilibrium/delayed phase”[105, 206].

Therefore, at least dual phase contrast-enhanced multidetector computed tomography (MDCT) is needed in order to reflect perfusion and vascularization pattern of FLLs [184, 210]. Also, all these considerations point to the importance of time scanning for each vascular phase. If images are incorrectly obtained, some lesions, especially the small ones, can remain indeterminate even after iodinated contrast injection, leading frequently to FLL biopsy or long-term follow-up in order to achieve a definite diagnosis [93 , 166]. These kinds of situations are not infrequently encountered in daily clinical work and poses special problems. Only for hemangiomas, the incidence of atypical patterns of enhancement, with hypoenhancing or even completely unenhancing lesions on dual-phase CT ranges from 8% to 16% [88, 92]. This percentage range is not at all negligible considering that hemangimas are ones of the most frequently encountered FLLs.

For detection and classification of FLLs into benign and malignant, sensitivity, specificity, and diagnostic accuracy reported for CT and CECT are of 66.2% and of 79.0%, respectively [22].

Other characteristic features for each tumor type seen in precontrast scan (such as central scar, presence of fat/calcifications, retraction of liver capsule, cystic components, presence/absence of a capsule, delineation, etc.) and after contrast injection (such as central scan, necrotic areas, hemorrhage) can be helpful in narrowing the differential diagnosis.

Dual source computed tomography (DSCT) as a novel technique has the potential advantage in liver applications. Simultaneous use of two tubes with different kilovoltage (kV) settings and display with water and iodine maps its helpful in differentiation between small solid tumors and cysts and can enhance even subtle lesions in low kV imaging. Despite higher radiation dose (up to 20% in one phase scanning) then in conventional CECT, DSCT has advantage to create virtual native phase from post contrast injection, thus reducing the examination from usual three phases to two. Moreover shifting/switching of kV results in reducing imaging artifacts and depiction of fat or iron deposits in liver parenchyma, with accuracy compared with that of biopsy specimens [12, 212]. Concerning cirrhotic liver this technique is superior in detection of small hypervascular lesions then CECT [75].

6 Role of magnetic resonance imaging

6.1 Magnetic resonance imaging pulse sequences and vascular phases

High-quality liver imaging with high intrinsic soft-tissue contrast is nowadays available due to technical developments of MRI. Automated contrast-detection combined with faster sequences allows reproducible capture of vascular phases [129]. Without the use of ionizing radiation, MRI imaging displays the same lesion contrast enhancement pattern as CT [170 , 175]. However, with MRI a more specific diagnosis of FLLs can be made because of the superior liver-to-tumor contrast, and because the use of liver-specific CAs and newer pulse sequences, such as diffusion-weighted (DWI) and steady-state free precession (SSFP) sequences [130 , 140] (Figs. 8, 9). The combination of enhancement patterns during particular phases of gadolinium-enhanced imaging, altogether with lesion aspect on chemical shift T1-weighted and T2-weighted sequences and also with the added value of diffusion weighted imaging (DWI) has brought MRI to the state of art imaging for FLLs assessment, making it the test of choice for liver masses evaluation. Nowadays, MRI is the best imaging modality in terms of specificity for diagnosing hepatic lesions, particularly when liver-specific CAs are utilized [2].

6.2 Magnetic resonance imaging with Gd-EOB-DTPA and the role of the hepatobiliary phase

Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) (Primovist in Europe and Eovist in the USA) is a liver-specific MRI CA that has up to 50% hepatobiliary excretion in the normal liver. It distributes into the vascular and extravascular spaces during the arterial, portal venous and late dynamic phases and progressively into the hepatocytes and bile ducts during the hepatobiliary phase, improving the detection and characterization of FLLs [191]. Thus, Gd-EOB-DTPA has the properties of both intra- and extravascular CAs. This means that with a single injection of contrast media we can have both a multiphasic MRI (arterial, venous and late phase) and a specific, hepatobiliary phase (at 20 minutes after CA administration). In the study of Hammerstingl et al., the frequency of correctly detected FLLs was higher on MRI using the liver-specific CA Gd-EOB-DTPA as opposed to contrast-enhanced biphasic spiral CT. The differences between the two imaging techniques were significant in the clinical evaluation (10.44%; 95% confidence interval (CI): 4.88, 16.0], while in the blinded regarding there was a trend towards MRI, but without reaching statistical significance (2.14%; 95% CI: –4.32, 8.6]. Also, the differential diagnosis was superior for MRI with Gd-EOB-DTPA (82.1%) as compared to CECT (71.0% ), MRI examination leading to a change in surgical therapy in 14.5% of thepatients [81].

Lesions with no functional hepatocytes, such as HCC, metastases or hemangiomas do not take Gd-EOB-DTPA during the hepatobiliary phase and so they appear dark, with intense hyposignal. Still, by the use of the hepatobiliary phase alone we cannot differentiate benign lesions such as hemangiomas from malignant lesions such as HCC or metastases. They can be differentiated by the use of dynamic, multiphasic MRI and also on the non-contrast examination and on their different behavior on DWI and ADC sequences (Figs. 10, 11).

Another indication for the use of Gd-EOB-DTPA is the differential diagnosis between benign, hypervascular FLLs such as FNH and HCA. Differentiating those lesions is critical because HCAs carry out a risk of hemorrhage and malignant transformation, so they will benefit from imaging surveillance and surgical therapies. In some cases a differential diagnosis can be made on non-enhanced, chemical shift images which can demonstrate the presence of fat or blood, characteristically for HCAs, but absent in FNHs. The uptake of Gd-EOB-DTPA in HCAs is absent in the hepatobiliary phase. FNHs show hypersignal appearance during the hepatobiliary phase (20 minutes from injection), as well as 4 hours from the injection of the CA. This characteristic is due to the presence inside FNH of modified biliary ducts which retain the contrast material. Also, large dimension FNH present a central portion in the hyposignal, corresponding to the central scar. Smaller dimension FNH are, in most of the cases, homogeneous [85, 211]. In contrary, fibrolamellar carcinoma has hypointensive central scar (and sometimes septa) in both T1-weighted and T2-weighted imaging, which sometime is the only feature differentiating this rare type of tumor from FNH [74].

6.3 Pitfalls with magnetic resonance imaging

Still, there are some pitfalls with MRI from which some we considered useful to be highlightened here. Nontumorous arterioportal shunts or obstruction of distal parenchymal portal venous flow may cause transient areas of liver parenchyma enhancement, which will no longer be visible on serial follow-up imaging [40]. In these situations, the diagnosis can be made based on peripheral location, geographic or wedge shape, and no displaced internal vasculature [175]. Also, another pitfall is that treated metastases can exhibit a less aggressive pattern of enhancement with early peripheral rim enhancement and delayed retention of contrast material. This pattern mimics hemangiomas and the differential diagnosis can be based on the aspect of the early rim enhancement which in chemotherapeutically treated metastases is intact, while in hemangiomas it is discontinuous [172, 175]. Another issue would be that hypervascular lesions, such as HCC, enhance less in the arterial phase with the use of Gd-EOB-DTPA in comparison to extracellular gadolinium chelates. Still, there are no studies proving that this weaker burden of contrast material influences the sensitivity and specificity of Gd-EOB-DTPA in the diagnosis of FLLs. The limitation for the use of Gd-EOB-DTPA in the detection of HCC is the diagnostic of well-differentiated HCC nodules because well-differentiated HCC nodules still contain functional hepatocytes so uptake of Gd-EOB-DTPA is present in the hepatobiliary phase, making them undistinguishable from regenerative and dysplastic nodules.

7 The problem of small, subcentimetric focal liver lesons

Even if all imaging techniques have been demonstrated abilities for detection of FLLs larger than 10 mm with different degrees of sensitivities, detection of subcentimetric FLLs is still relatively poor [73, 190]. The issue represents a subject of utmost importance especially in patients with a known primary malignancy for which early detection of liver metastases would allow for their resection with improved survival rates [39, 115].

CECT can properly detect small FLLs but has difficulties in differentiating them, particularly in the case of small, hypovascular lesions. The most useful phase in detecting FLLs is the portal-venous phase. But, in this particular phase, small hemangiomas, biliary cysts and small metastases have pretty much the same appearance. By CECT, hypovascular FLLs which are smaller than 15 mm are considered “too-small-to-be-characterized” (Fig. 12). With the use of dual-energy computed-tomography (DECT), characterization of small liver masses from cysts can be more reliably performed with the use of iodine material and water displays, thus providing complementary information for FLLs characterization [120, 176]. Lv et al. demonstrated that small hepatic hemangiomas, frequently presenting with atypical enhancement pattern, can be accurately differentiated from small HCCs when using a rapid voltage-peak switching DECT, based on lesion’s iodine concentration [117].

MRI has not the same limitation as CECT. Due to recent developments in MRI hardware and software and the availability of novel MRI CAs a significant improvement in small FLLs detection has been obtained [195]. On non-contrast, T2-weighted images, small cysts and hemangiomas have a very intense signal in comparison to the surrounding liver while metastases have only a slightly hyperintense signal. Also their behavior in the DWI and ADC sequences is different. Metastases have, in most cases, high signal on DWI, b-800 or b-1000, sequences and hyposignal on ADC maps (behavior which is called “restricted diffusion”). Benign lesions such as cysts and hemangiomas can have increased signal on DWI, b-800 or b-1000, sequences but they have also hypersignal on ADC maps (behavior which is called T2-shine through).

There are studies suggesting that CEMRI is the most sensitive method for small liver metastases detection, and considering the technique as being the pre-operative standard [112]. Also, there are several studies showing the better conspicuity of Gd-EOB-DTPA enhanced MRI in comparison to gadolinium chelates enhanced MRI or CECT in the detection and characterization of small HCC nodules on the cirrhotic liver. A study published by Kim et al. showed that Gd-EOB-DTPA enhanced MRI is better than CECT in the detection of small (<1 cm) HCC nodules [100]. Another paper showed that 10.7% of HCC nodules are detected only in the hepatobiliary phase [1].

CEUS has shown equal results to MRI for the differential diagnosis of FLLs, this being particularly evident for small lesions [17 , 167]. In cases of small HCCs in cirrhotic liver, CEUS allows visualization in real time of the very early onset of contrast enhancement at the level of the examined lesion. This feature may be missed when other contrast-enhanced cross-sectional imaging techniques are used due to acquisition timing settings (Fig. 13). Strobel et al., in the DEGUM multicenter trial, obtained a sensitivity of 93.3% and a specificity of 75.9% for the characterization by CEUS of FLLs ≤2 cm [181].

High resolution US, combining CEUS with elastography, has been investigated in vitro by Wege et al. in order to assess the role in early detection and characterization of FLLs. In a humanized tumor mouse model, solid FLLs with a diameter of 2–11 mm (mean 3.5 mm) could be detected as areas with higher stiffness at elastography and with no enhancement during late phase at CEUS [196].

8 Liver transplantation imaging

Imaging plays an important role in assessment of complications which may occur in post-transplantation liver tissue [84, 149]. Vascular complications such as ischemia or parenchymal necrosis may also occur and early diagnosis is essential for further management [10, 116]. Due to its accessibility and availability, Doppler technique is a preferred postoperative screening method for evaluation of potential vascular complications [98]. Still, it can measure only blood inflow in large vessels and not in the hepatic parenchyma [213]. CT and MRI also presents with the inability to assess quantitatively hepatocytes damage [158], and CT/MRI angiography has been proved to overestimate hepatic stenosis as compared to conventional angiography [135]. Quantitative evaluation of hemodynamic changed tissue may be assessed by the recently developed perfusion CT. It allows calculation of blood volume/flow, arterial liver/portal venous perfusion, and hepatic perfusion index, providing a quantitative evaluation of the treatment response, as reported by the recent study of Kantarci et al. [98]. First results of Rennert et al., by retrospectively analyzing 23 patients following liver transplantation, showed that CEUS can bring additional clinically relevant information with therapeutic implications as compared with B-mode US, Doppler US, digital subtraction angiography, CT, and MRI [152].

9 Conclusion

Nowadays, cross-sectional imaging for FLLs diagnosis is used with different approach and in various combinations. All contrast-enhanced modalities have their advantages and limitations. All are complementary, each imaging modality bringing its important additional value. Since CEUS has been proven to have similar accuracy in detection of malignant FLLs as CT and MR does and to have higher efficacy than CT for benign FLLs characterization, it may be used as second line imaging technique (after BMUS) in the diagnostic scheme. However, for staging purposes and if disseminated disease is suspected, CT imaging (of whole abdomen and chest) is needed. MR is equally to CEUS in detecting and characterizing FLLs. In doubt liver biopsy and histological examination is mandatory.

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