INTRODUCTION

Liver cirrhosis

Liver cirrhosis represents the final stage of chronic inflammation through the establishment of necrosis and fibrogenesis up to a total subversion of the hepatic parenchyma and it has systemic repercussions and a fatal outcome in the absence of a liver transplant. Liver cirrhosis is the 14th most common cause of death worldwide[1].

Etiologically, liver cirrhosis recognizes infectious causes (hepatitis B, hepatitis C, schistosoma japonicum), autoimmune (primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis), alcohol abuse, metabolic causes (Wilson disease, hemochromatosis) and vascular or cryptogenic causes[2]. The combination of imaging and serological investigation (transaminases and cholestasis indices) is often sufficient for the diagnosis; however, the gold standard remains the liver biopsy which also allows physicians to identify the noxa that led to the stage of cirrhosis[1]. In the clinical setting, ultrasound (US) allows a morphological assessment of the liver and portal circulation. US also plays a major role as the recommended tool for surveillance every 6 mo at early detection of small hepatocellular carcinoma (HCC)[3].

Imaging characterization of focal lesions in cirrhosis is crucial for appropriate patient management[4,5]. To this end, US is a non-specific technique used to characterize focal liver lesions (FLLs).

Contrast-enhanced ultrasound

At the end of the 1990s, the introduction of contrast agents based on intravenous microbubbles to contrast-specific gray-scale US techniques has enabled contrast-enhanced ultrasonography (CEUS) to represent macro-vascularity and also microcirculation ( vessels up to 40 μm). Starting in the 2000s, the advent of low-solubility gas bubbles (like sulfur hexafluoride) with phospholipid shells for their flexibility has led to a full real time CEUS examination[6].

CEUS, throughout the vascular phase with its blood-pool contrast agent, allows real-time recording with non-invasive assessment of liver perfusion without resorting to expensive and not very common equipment such as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI) that require the use of ionizing radiation or nephrotoxic contrast agents. OF note, when gas microbubbles are injected into the vein, they remain in the intravascular space (blood-pool agents), Only one of marketed contras agents shows a late phase with uptake by hepatic Kupffer cells (Table 1)[7].

CEUS is safe and well tolerated: Renal or pulmonary diseases do not present contraindications for this use and no blood tests are needed to check kidney function. In a study of about 23000 patients, less than 0.01% of the patient population reported a serious adverse event with no death events[8].

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Actually, CEUS is included in the diagnostic work-up of FLLs detected in the healthy population and to study metastases in patients with cancer and to identify HCC in cirrhotic patients, allowing for better management of the disease with effective and advantageous therapies[9-10]. A recent meta-analysis showed that specificity and sensitivity for CEUS in the characterization of FLLs were respectively 87% and 92%[10]. CEUS is gaining an increasing role in the imaging work-up of HCC and many international guidelines are now considering CEUS as a diagnostic tool for HCC as well as CT and MRI with encouraging results and is positive in terms of the cost-benefit analysis[11-12]. Based on literature data and our experience in our center, the recent innovations in the CEUS of FLLs in cirrhotic patients will be presented and discussed.

TECHNICAL NOTE

The US cases illustrated in this article are acquired through various ultrasound equipment provided with multifrequency convex array probes and contrast-specific imaging software: MyLab Twice (Esaote, Genova, Italy), RS80A and RS85A (Samsung Medison, Co. Ltd., Seoul, Korea) and iU22 unit (Philips Ultrasound, Bothell, WA, USA). Before the injection of bolus contrast, a standard exam together with color/power and pulsed Doppler valuation was always performed to optimize lesion images and define the best plane for its visualization. The contrast agent used was composed of gas microbubbles filled with sulfur hexafluoride (SonoVue, Bracco, Milan, Italy) that was injected using a 20- or 22-gauge needle in a cubital vein and a 2.4-mL bolus with a 5-10 ml of saline flush. Low mechanical index (MI) from 0.05 to 0.08 and low frame rate (5 Hz) were used for real-time imaging to avoid microbubble breakdown. The level of the lesion was the focus of examination and the duration of each exam was about 5 min after contrast agent injection.

At CEUS, the typical enhancement pattern of HCC is hyperenhancement in the arterial phase followed by gradual and mild wash-out in the portal venous and/or late phases[10] (Figure 2). Washout is represented as a relatively hypoechoic aspect compared to healthy liver parenchyma in the later stages of the study with any type of contrast-enhancement in the arterial phase. In general, at CEUS, the presence of the wash-out sign is highly suggestive of malignancy. In HCC, washout begins over 60-90 s after injection of contrast agent, whereas metastases or intrahepatic cholangiocarcinoma usually show a rapid washout (＜ 60 s) (Table 2) (Figure 3)[20]. Therefore, in CEUS, an observation period of up to approximately 5 min is required to easily visualize the typically subtle and late (＞ 1 min) washout of HCC (Figure 2).

Basal echogenicity and the dynamic modality of enhancement of each lesion in all vascular phases and among the near liver parenchyma were compared.

CIRRHOTIC NODULES

Liver cirrhosis has been recognized as a major risk factor for the onset of HCC and intrahepatic cholangiocarcinoma (ICC) compared to the non-cirrhotic population, of 30 and 20 times, respectively[13]. In the management of hepatic nodules in liver cirrhosis, early diagnosis and treatment is mandatory. HCC in liver cirrhosis develops as the last step of a complex, multi-step hepatocarcinogenesis process during several molecular and tissue alterations leading to the gradual transformation from regenerative nodule (RN) through low- and high-grade dysplastic nodule (DN) to HCC[14]. Changes of intranodular blood supply is the main transformation for imaging diagnosis: RN show similar blood supply to a normal liver. As a consequence, RNs are typically non-hypervascular. They can be seen as numerous tiny hypoechoic or hyperechoic nodules throughout the liver on grayscale US whereas at CEUS they usually are iso-enhancing to the adjacent liver parenchyma throughout the vascular phase, even if they may show transient hypo-vascularity in the arterial phase[4] (Figure 1).

DN are the next step towards HCC. Often multiple, DNs are classified as low or high grade according to the presence of cytological atypia. These borderline lesions show wide variations of blood supply with overlaps of vascular supply between DN and well-differentiated HCC, with the vast majority of RN and DN being isoechoic to the adjacent liver parenchyma in portal venous and late phase at CEUS[15].

Then there was the dancer, who inflicted12 the wound which has caused me to be here now; she was very violent! My own hair-brush was in love with me, and lost all her hair in consequence

Of note, in a study encompassing 215 FLLs in cirrhotic patients and comparing the CEUS features of RN and DN, 95.1% of RN lesions showed delayed or simultaneous enhancement in the arterial phase in comparison to surrounding liver parenchyma. On the other hand, DN lesions resembled this contrastenhancement pattern only partially, due to the presence of intralesional areas of arterial enhancement followed by a wash out in the late phase. In pathology, these areas of arterial contrast-enhancement within the DN have proven to be early HCC[16]. Hence, any enhancement in the arterial phase within a nodule should be regarded as suspicious for HCC, resembling a “nodule in a nodule” appearance.

MALIGNANT LESIONS

Hepatocellular carcinoma

HCC is the fifth most common cancer in men and the ninth in women showing a greater incidence in developing countries where over 80% of all estimated new cases worldwide occurred in 2012[17].

He saw hanging from its battlements many heads, but it had not the least effect upon him that these were heads of men of rank; he listened to no advice about laying aside his fancy, but rode up to the gate and on into the heart of the city

Almost 90% of HCCs originate through a stepway progression from RN to HCC which may take place in a quite variable period, even though it may take only a few months[18]. On the other hand, the estimated doubling time of HCC ranges between 4 and 6 mo[19].

The digital cine-loops were acquired before and after performing the contrast at different times in the arterial phase (from 10 s to 35 s after the injection), portal phase (from 55 s to 80 s after the injection) and delayed phase (from 235 s to 260 s after the injection).

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Noteworthy, a study showed that arterial enhancement patterns of HCC at CEUS are related to the degree of histologic differentiation: moderately differentiated HCC exhibits a classic behavior after contrast agent injection compared to well-differentiated HCC. Extended observation in the portal phase is important for reporting late washout that in HCC occurs more frequently later than in the portal venous phase[21]. As a caveat, well-differentiated HCC may appear iso-enhancing in the portal-venous or late phase[9].

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On the other hand, in a study by Tada

[22], 63 of 68 (92.6%) small HCCs (＜ 3 cm in size) showed a mainly diffuse and homogeneous enhancement in the arterial-phase whereas large HCCs presented a heterogeneous arterial-phase enhancement pattern mainly related to non-enhancing areas of fibrosis, necrosis or internal hemorrhage.

In general, thanks to the real-time nature of CEUS, its high spatial and temporal resolution, the sensitivity of CEUS in the detection of hypervascularization of cirrhotic nodules was found to be higher compared to CT/MRI[23].

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Overall, CEUS showed a sensitivity of 88.8%, a specificity of 89.2% and a PPV of 91.3% in the characterization of HCC[24].

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Although it is still a matter of debate, several international guidelines are now endorsing the use of CEUS as a first or second-line diagnostic tool for the diagnosis of HCC[12,25]. In 2016, the American College of Radiology included CEUS in its comprehensive Liver Imaging Reporting and Data System (LI-RADS): a unique scoring system for CEUS examinations in patients with increased risk of HCC. A systematic review comparing the cost-effectiveness of CEUS with CT and MRI confirmed that CEUS is cost-effective in the surveillance of patients with liver cirrhosis[11].

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The presence of both ICC and HCC components in the same lesion can make the lesion even more difficult and biopsy may be eventually needed in equivocal cases.

Table 3 shows the main recommendations on the use of CEUS in cirrhotic patients according to the World Federation for Ultrasound in Medicine & Biology[26].

CEUS has shown high sensitivity for the evaluation of portal vein patency and in the differential diagnosis between benign and malignant portal vein thrombosis, this latter occurring in cirrhotic patients at various stages[27]. A thrombus showing hypervascularity in the arterial phase, irrespective of the presence of subsequent washout, is deemed to be malignant[10].

CEUS can also be used with valid results in guidance, response and detection of complications of interventional procedures[28] (Figure 4). CEUS may be of help during or after the interventional procedure[29]. Intraprocedural use of CEUS showed a relevant clinical impact, reducing the number of re-treatments and the related costs per patient[30].

The three-dimensional evaluation through the CEUS of the tumor lesion allows more accurate planning and the treatment with locoregional therapies[31,32] (Figure 5).

Intrahepatic cholangiocarcinoma

Although Focal nodular hyperplasia (FNH) is the second most common benign liver tumor after hemangioma, the report of FNH-like nodules in the cirrhotic liver is only sporadic and imaging appearance is similar to FNH arising in the non-cirrhotic liver[43,49].

At CEUS, hemangioma has a characteristic globular, progressive, peripheral and discontinuous enhancement (Figure 7). However, with progressive cirrhosis, hemangiomas are likely to decrease in size, become more fibrotic and may appear as a hypo vascular lesion with a lack of peripheral globular contrast-enhancement[47,48]. Furthermore, flash filling hemangiomas may pose a diagnostic dilemma with well-differentiated HCC not showing wash-out, thus needing further radiological workup with CT or MRI for the final diagnosis.

In a multicenter study of 1,006 nodules from 848 patients, the use of CEUS LI-RADS criteria for HCC - namely, arterial phase hyperenhancement and late washout (onset ≥ 60 s after contrast injection) of mild degree - was 98.5% predictive of HCC with no risk of misdiagnosis for pure cholangiocarcinoma[39]. To this purpose, contrast-enhanced CT and MRI may provide useful information due to the different contrast agent kinetic. Microbubbles are essentially blood pool agents and remain confined to the vascular space, whereas iodinated contrast agent and gadolinium chelates are essentially extra-cellular contrast agents and progressively accumulate in the fibrotic spaces of ICC[39].

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Metastasis

A wide spectrum of benign lesions may arise in a cirrhotic liver. Hence, it is crucial to avoid the misdiagnosis of benign liver lesions as HCC (

minimize false positives) because this diagnostic interpretation may incorrectly increase the tumor burden[43].

On CEUS, liver metastases show a sharp and early washout within 60 s of contrast administration, irrespective of the contrast enhancement type in the arterial phase (Figure 3)[44]. This latter may present various patterns, such as rim-like, dotted, heterogeneous or even homogeneous, depending on the size and the grade of cellularity, vascularity, fibrosis and necrosis accompanying the development of the lesion.

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BENIGN LESIONS

Metastatic liver deposits are relatively uncommon in the cirrhotic liver. This finding may probably be due to alteration of hemodynamics and the microstructural environment in the liver[40]. In particular, the hepatofugal portal venous flow may prevent neoplastic cells from seeding and flourishing in the liver[41]. Liver metastases from colorectal carcinoma are infrequently reported to spread to the cirrhotic liver[42]. Metastases from non-Hodgkin B-cell lymphoma may also involve the liver in patients with hepatitis C virus and typically consist of multiple small nodules[43].

Generally, at CEUS, a benign lesion presents a progressive and sustained enhancement in all phases of the study[45] (Table 4, Figures 7 and 8). Although tumor lesions may have similar characteristics, a clinical context of oncological or cirrhotic pathology allows differentiating the nature of the lesions[21]. Further aspects that are decisive for the diagnosis are detected by observing the arterial phase[4].

Hemangioma

Hemangioma is seen less frequently in cirrhotic patients than in the general population. In general, imaging features remain similar to those of hemangiomas observed in non-cirrhotic patients[46].

At CEUS, ICC shows heterogeneous contrast enhancement in the arterial phase with a substantially hypoechoic appearance in the extended portal-venous phase[35]. A rim-like contrast-enhancement has been reported but with a quite variable range (8-51% of cases)[9]. The presence and the quantity of fibrotic tissue and necrotic areas may strongly influence the CEUS appearance of ICC. This latter may present at CEUS overlapping features with HCC[36]. At CEUS, a clue suggestive for ICC is the presence of a wash out occurring earlier than 60 s, whereas HCC usually washes out later on (Figure 6)[37,38]. The same temporal difference in wash-out between HCC and other malignancies, including ICC, is also used by the CEUS LI-RADS lexicon for the diagnosis of ICC[10].

Focal nodular hyperplasia

Intrahepatic peripheral cholangiocarcinoma (ICC) constitutes the second most common primary liver malignant tumor in cirrhotic patients and accounts for 1%-3% of newly developed tumors[32,33]. Differentiating ICC from HCC is of clinical relevance since liver transplantation is contraindicated in patients with ICC given poorly reported outcomes[34].

At CEUS, the typical findings of FNH are a centrifugal contrast-enhancement pattern with a spokewheel appearance in the arterial phase followed by sustained contrast-enhancement and iso or hyperechoic appearance in portal-venous and late phase[50] (Figure 8). A central avascular area in the arterial phase is often appreciable in FNH larger than 3 cm with a hypoechoic appearance.

Hepatocellular adenoma

The incidence of hepatocellular adenoma (HA) in the cirrhotic liver is exceedingly rare with a few reports in the literature[51].

At CEUS, a peripheral enhancement with centripetal filling and sustained hypervascularization, suggests the diagnosis of HA[10,52]. However, as a warning, HA may show a hypoechoic appearance in the portal-venous and late phase[52].

Cystic lesions

Simple biliary and peribiliary cysts have similar features in cirrhotic and noncirrhotic livers. They present a homogenous anechoic appearance, a very thin wall and through transmission with posterior acoustic enhancement and no contrast enhancement at CEUS[43]. CEUS may be a problem-solving technique in diagnosing complicated non-anechoic cyst or a rare form of

existence of hepatocellular carcinoma and cystic echinococcosis[53]. Usually, CEUS shows a lack of enhancement of septa separating daughter cysts[54].

Hepatic abscesses, pyogenic, fungal and amebic have similar CEUS features in cirrhotic and noncirrhotic livers. Abscesses do not have a significant internal enhancement after contrast ultrasound administration but septations within the lesion may enhance as well as an irregular peripheral rim[55].

Pseudo lesions

Focal fatty changes or confluent hepatic fibrosis can mimic malignancies. Focal fatty changes are an increase or decrease in fat content in a focal area of the liver parenchyma owing to an aberrant portalvenous vascularization[55].

Confluent hepatic fibrosis is usually shown in patients with alcohol-related cirrhosis. It involves peripheral parenchymal replacement by thick fibrotic bands that appear as focal wedge-shaped areas with thick fibrotic bands causing retraction of the overlying capsule; the presence of inflammation can lead to inhomogeneous arterial phase hyperenhancement[40].

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At CEUS, these pseudo lesions present isoenhanced in comparison with the surrounding liver parenchyma during the extended portal-venous phase[55], furthermore, fibrosis is usually seen in a typical position (medial segment of the left lobe or anterior segment of the right lobe)[40].

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CONCLUSION

A wide spectrum of benign and malignant lesions other than HCC may be found in the cirrhotic liver. More than several years after its release, CEUS is being used for safe diagnostic imaging which enables real-time recognition of enhancement characteristics of focal liver lesions arising in cirrhotic patients. Currently, CEUS is increasingly being performed on a routine basis and is included as a part of the recommended diagnostic work-up of HCC as well as in the follow-up.

FOOTNOTES

Bartolotta TV, Randazzo A, Bruno E and Taibbi A contributed equally to this work; All authors have read and approved the final manuscript.

At the earliest dawn of day Mirlifiche woke me, and made me take many journeys to the stable to bring her word how her unicorn had slept, and how much hay he had eaten, and then to find out what time it was, and if it was a fine day

Tommaso Vincenzo Bartolotta: Lecturer for Samsung.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/Licenses/by-nc/4.0/

Italy

Tommaso Vincenzo Bartolotta 0000-0002-8808-379X; Angelo Randazzo 0000-0001-9558-5248; Eleonora Bruno 0000-0001-6876-2587; Adele Taibbi 0000-0001-6442-744X.

Wang LL

Filipodia

Wang LL

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