| Ultrasonography of liver tumors | |
| Purpose: | detection and characterization of hepatic tumors |
Ultrasonography of liver tumors involves two stages: detection and characterization.[1]
Tumor detection is based on the performance of the method and should include morphometric information (three axes dimensions, volume) and topographic information (number, location specifying liver segment and lobe/lobes). The specification of these data is important for staging liver tumors and prognosis.[2]
Tumor characterization is a complex process based on a sum of criteria leading towards tumor nature definition. Often, other diagnostic procedures, especially interventional ones are no longer necessary. Tumor characterization using the ultrasound method will be based on the following elements: consistency (solid, liquid, mixed), echogenicity, structure appearance (homogeneous or heterogeneous), delineation from adjacent liver parenchyma (capsular, imprecise), elasticity, posterior acoustic enhancementeffect, the relation with neighboring organs or structures (displacement, invasion), vasculature (presence and characteristics on Doppler ultrasonography and contrast-enhanced ultrasound (CEUS).
The substrate on which the tumor condition develops (if the liver is normal or if there is evidence of diffuse liver disease) andthe developing context (oncology, septic) are also added. Particular attention should be paidto the analysis of the circulatory bed. Microcirculation investigation allows for discrimination between benign and malignant tumors. Characteristic elements of malignantcirculation are vascular density, presence of vessels with irregular paths and size, some ofthem intercommunicating, some others blocked in the end with "glove finger" appearance,the presence of arterio-arterial and arterio-venous shunts, lack or incompetence of arterialprecapillary sphincter made up of smooth musculatures.Diagnosis and characterization of liver tumors require a distinct approach for each group ofconditions, using the available procedures discussed above for each of them. The correlationwith the medical history, the patient's clinical and functional (biochemical andhematological) status are important elements that should also be considered.
Benign liver tumors generally develop on normal or fatty liver, are single or multiple (generallypaucilocular), have distinct delineation, with increased echogenity (hemangiomas, benignfocal nodular hyperplasia) or absent, with posterior acoustic enhancement effect (cysts),have distinct delineation (hydatid cyst), lack of vascularization or show a characteristiccirculatory pattern, displace normal liver structures and even neighboring organs (in case oflarge sizes), are quite elastic and do not invade liver vessels. The patient has a good generalstatus, as tumors are often asymptomatic, being incidentally discovered.[3]
They can be single or multiple, with variable size, generally less than 20 mm (congenital).Rarely, sizes can reach several centimeters, leading up to the substitution of a whole liverlobe (acquired, parasitic). They may be associated with renal cysts; in this case the diseasehas a hereditary, autosomal dominant transmission (von Hippel Lindau disease).
The ultrasound appearance is a well defined lesion, with very thin, almost unapparentwalls, without circulatory signal at Doppler or CEUS investigation. The content istransonic suggesting fluid composition. The presence of membranes, abundant sedimentor cysts inside is suggestive for parasitic, hydatid nature. Posterior from the lesion theacoustic enhancement phenomenon is seen, which strengthens the suspicion of fluidmass. They typically displace normal liver vessels but no vascular or biliary invasionoccurs.
It is the most common liver tumor with a prevalence of 0.4 – 7.4%. It is generallyasymptomatic but also can be associated with pain complaints or cytopenia and/oranemia when it is very bulky. It is unique or paucilocular. It can be associated with othertypes of benign liver tumors. Characteristic 2D ultrasound appearance is that of a verywell defined lesion, with sizes of 2–3 cm or less, showing increased echogenity and, whenlocated in contact with the diaphragm, a "mirror image" phenomenon can be seen. Whenpalpating the liver with the transducer the hemangioma is compressible sendingreverberations backwards. Doppler exploration reveals no circulatory signal due to veryslow flow speed. CEUS investigation has real diagnosis value due to the typical behaviorof progressive CA enhancement of the tumor from the periphery towards the center. Theenhancement is slow, during several minutes, depending on the size of hemangioma andon the presence (or absence) of internal thrombosis. During late (sinusoidal) phase, iftotally "filled" with CA, hemangioma appears isoechoic to the liver. Deviations from theabove described behavior can occur in arterialized hemangiomas or those containingarterio-venous shunts. In these cases, differentiation from a malignant tumor is difficultand requires other imaging procedures, follow up and measurements of the tumor atshort time intervals.[4]
It is a tumor developed secondary to a circulatory abnormality with abundant arterialvessels having a characteristic location in the center of the tumor, within a fibrotic scar. Aradial vessels network develops from this level with peripheral orientation. The tumor'scirculatory bed is rich in microcirculatory and portal venous elements. The incidence ishigher in younger women and tumor development is accelerated by oral contraceptivesintake. 2D ultrasound appearance is a fairly well-defined mass, with variable sizes, usuallysingle, solid consistency with inhomogeneous structure. Rarely the central scar can bedistinguished. Spectral Doppler examination detects central arterial vessels and CFMexploration reveals their radial position. CEUS examination shows central tumor filling ofthe circulatory bed during arterial phase and completely enhancement during portal venousphase. During this phase the center of the lesion becomes hypoechoic, enhancing the tumorscar. During the late phase the tumor remains isoechoic to the liver, which strengthens thediagnosis of benign lesion.
It is a benign tumor made up of normal or atypical hepatocytes. It has an incidence of 0.03%.Its development is induced by intake of anabolic hormones and oral contraceptives. Thetumor is asymptomatic but may be associated with right upper quadrant pain in case ofinternal bleeding. 2D ultrasound shows a well-defined, un-encapsulated, solid mass. It mayhave a heterogeneous structure in case of intratumoral hemorrhage. Doppler examinationshows no circulatory signal. CEUS exploration is quite ambiguous and cannot alwaysestablish a differential diagnosis with hepatocellular carcinoma. Thus, during the arterialphase there is a centripetal and inhomogeneous enhancement. During the portal venousphase there is a moderate wash out. During late phase the appearance is isoechoic orhypoechoic, due to lack of Kupffer cells.
Malignant liver tumors develop on cirrhotic liver (hepatocellular carcinoma, HCC) ornormal liver (metastases). They are single or multiple (especially metastases), have avariable, generally imprecise delineation, may have a very pronounced circulatory signal(hepatocellular carcinoma and some types of metastases), have a heterogeneous structure(the result of intratumoral circulatory disorders, consequence of hemorrhage or necrosis)and are firm to touch, even rigid. The patient's general status correlates with the underlyingdisease (vascular and parenchymal decompensation for liver cirrhosis, weight loss, lack ofappetite and anemia with cancer).
It is the most common liver malignancy. It develops secondary tocirrhosis therefore, ultrasound examinationevery 6 months combined with alpha fetoprotein (AFP) determination is an effectivemethod for early detection and treatment monitoring for this type of tumor. Clinically, HCC overlaps with advanced liver cirrhosis(long evolution, repeated vascular and parenchymal decompensation, sometimes bleeding due to variceal leakage) in addition to accelerated weight loss in the recent past and lack ofappetite.
HCC appearance on 2D ultrasound is that of a solid tumor, with imprecise delineation, with heterogeneous structure, uni- or multilocular (encephaloid form). An "infiltrative" type is also described which is difficult to discriminate from liver nodular reconstruction in cirrhosis. Typically HCC invades liver vessels, primarily the portal veins but also the hepatic veins . Doppler examination detects a high speed arterial flow and low impedance index (correlated with described changes in tumor angiogenesis). The spatial distribution of the vessels is irregular, disordered. CEUS examination shows hyperenhancement of the lesion during the arterial phase. During the portal venous phase there is a specific "wash out" of ultrasound contrast agent (UCA) and the tumor appears hypoechoic during the late phase. Poorly differentiated tumors may have a stronger wash out leading to an isoechoic appearance to the liver parenchyma during portal venous phase. This appearance was found in approx. 30% of cases. The described changes have diagnostic value in liver nodules larger than 2 cm.
Ultrasound is useful in HCC detection, stadialization and assessing therapeutic efficacy. In terms of staging related to therapy effectiveness, the Barcelona classification is used which identifies five HCC stages. Curative therapy is indicated in earlystages, which include very early stage (single nodule <2 cm), curable by surgical resection(survival 50-70% five years after surgical resection) and early stage(single nodule of 2–5 cm, or up to 3 nodules <3 cm) which can be treated byradiofrequency ablation (RFA) and liver transplantation. Intermediate stage (polinodular,without portal invasion) and advanced stage (N1, M1, with portal invasion) undergopalliative therapies (TACE and sorafenib systemic therapy) and in the end stage onlysymptomatic therapy applies.
It develops on non cirrhotic liver. 2D ultrasound appearance is uncharacteristic – solid masswith heterogeneous structure, poorly delineated, often with peripheral location and weakDoppler circulation signal. CEUS examination reveals a moderate enhancement of thetumor periphery during arterial phase followed by wash-out during portal venous phaseand hypoechoic appearance during late phase.
US examination is required to detect liver metastases in patients with oncologic history. Inaddition, the method can incidentally detect metastases in asymptomatic patients. Earlyidentification (small sizes, small number) is important to establish an optimal course oftreatment which can be complex (chemotherapy, radiofrequency ablation, surgicalresection) but welcomed. In addition, discrimination of synchronous lesions that have adifferent nature is also important knowing that up to 25–50% of liver lesions less than 2 cmdetected in cancer patients may be benign . US sensitivity for metastasesdetection varies depending on the examiner's experience and the equipment used andranges between 40 and 80% . Sensitivity is conditioned by the size andacoustic impedance of the nodules. For a lesion diameter below 10 mm US accuracy isgreatly reduced, reaching approx. 20%. Other elements contributing to lower USperformance are: excessive obesity, fatty liver disease, hypomobility of the diaphragm, andcertain patterns of hyperechoic or isoechoic metastases that can be overlooked or can mimicbenign conditions. Conventional US appearance of metastases is uncharacteristic, consistingof circumscribed lesions, with clear, imprecise or "halo" delineation, with homogeneous orheterogeneous echo pattern. They can be single (often liver metastases from colonicneoplasm) or multiple. Echogenity is variable. When increased, they can compress the bileducts (which may be dilated) and the liver vessels. Liver involvement can be segmental,lobar or generalized. In this situation a pronounced hepatomegaly occurs. Generally,metastases have non-characteristic Doppler vascular pattern, with few exceptions (carcinoidmetastases). Cyst-adenocarcinoma metastases due to semifluid content may have atransonic appearance. When increasing, they can result in central necrosis. CEUSexamination is a real breakthrough for detection and characterization of liver metastases.
Increased performance is based on identifying specific vascular patterns during the arterialphase and seeing metastases in contrast to normal liver parenchyma during the sinusoidalphase. CEUS increased accuracy is due to the different behavior of normal liver parenchyma(captures CA in Kuppfer cells) against tumor parenchyma (does not contain Kuppfer cells,therefore CEUS appearance is hypoechoic). To this adds the particularities of intratumoralcirculation represented by a reduced arterial bed compared to that of the surroundingnormal liver and the absence of the portal vessels . In terms ofvascularity, metastases can be hypovascular (in gastric, colonic, pancreatic or ovarianadenocarcinomas) with hypoechoic pattern during arterial phase, and similar during portalvenous and late phases, respectively hypervascular (neuroendocrine tumors, malignantmelanoma, sarcomas, renal, breast or thyroid tumors) with hyperechoic appearance duringarterial phase, with washout during the portal venous phase and hypoechoic pattern30 seconds after injection.
Using CEUS examination to detect metastases a sensitivity of 80–95% is obtained, similar tothat of contrast CT and MRI . Intraoperative use ofthe procedure increases its performance even if it does not have a decisive contribution tochange the therapeutic behavior . Limitations of the method are thoserelated to US penetration (pronounced fatty liver disease, deep lesion, excessive obesity) andto the experience of the examiner. To this the risk of confusion between hypervascularmetastases, hepatocellular carcinoma and hemangioma and the confusion betweenhypovascular metastases and small liver cysts is added. Routine use of CEUS examination todetect liver metastases is recommended when conventional US examination is notconclusive, when precise information on some injuries (number, location) is necessary inconjunction with contrast CT/MRI and to assess the effectiveness of treatment when using an antiangiogenic therapy for hypervascular metastases . The methodcannot replace CT/MRI examinations which have well established indications in oncology.
Besides the entities listed above inflammatory masses or even pseudo-masses can occur.Their diagnosis is quite difficult and the criteria used for differentiation are ofteninsufficient, requiring morphologic diagnostic procedures, use of other diagnostic imagingmethods or patient reevaluation from time to time. This includes lesions developed on liverparenchyma reconstruction, as occurs in cirrhosis, steatosis accumulation or in case of acuteor chronic inflammatory diseases.
It consists of localized accumulation of fat-rich liver cells. In some cases this accumulation canmimic a liver tumor. Sometimes the opposite phenomenon can be seen, that is an "island" ofnormal parenchyma in a “shining” liver. In both cases ultrasound examination identifies awell defined, un-encapsulated area, with echostructure and vasculature similar to those ofnormal liver parenchyma. The lesion can have different forms, most cases being oval andlocated in the IVth segment, anterior from the hepatic hilum. It occurs in dyslipidemic or alcohol intake patients with normal physical and biological status. Benign diagnosisconfirmation is made using CEUS examination which proves a normal circulatory bed similarto adjacent liver parenchyma in all three phases of investigation.
Liver abscess have heteromorphic ultrasound appearance, the most typical being that of amass with irregular shapes, fringed, with fluid or semifluid content, with or without air inside.Doppler examination shows the lack of vessels within the lesion. CEUS exploration showshyperenhancement during arterial phase close to the lesion, this being suggestive of a liverparenchymal hyperemia. During venous and sinusoidal phase the pattern is hypoechoic, andthe central fluid is contrast enhanced. CEUS examination is useful because it confirms theclinical suspicion of abscess. In addition, it allows for an accurate measurement of thecollection size and an indication regarding its topography inside the liver (lobe, segment).
Cirrhotic liver is characterized by the occurrence of nodules with different sizes andevolution degrees, so that regenerative nodules, dysplastic nodules and even earlyhepatocellular carcinoma can coexist at some moment during disease progression. There arestudies showing that between 59 and 94% of newly diagnosed liver nodules in cirrhotic patientshave malignant histology and up to 50% of hyperechoic lesions, with ultrasound appearanceof hemangioma, ultimately prove to be hepatocellular carcinoma. Therefore, current practicein many centers considers that any new lesion revealed in a cirrhotic patient should beregarded as malignant until otherwise proven. There are threecategories of cirrhotic liver nodules: regenerative, dysplastic (considered as premalignantconditions) and tumoral (HCC).
These lesions are well defined, with isoechoic or hypoechoic appearance and sizes less than1 cm. They are high in numbers and have a more or less uniform distribution, involving all liver segments. They can crowd resulting in large pseudo tumors. At Doppler examination,these nodules have no circulatory signal. CEUS exploration is indicated when a nodule isdifferent against the general pattern of restructured liver either by different echogenity or bya different size than the majority of nodules. During the arterial phase, the signal is weak orabsent. During the portal venous and late phase, the appearance is persistently isoechoic.
Generally, RN is not distinct from the surrounding parenchyma. CEUS examination isuseful to exclude an active lesion at the moment of exploration but does not have absoluteprognostic value; therefore the patient should be periodically examined at short intervals. Correlation with clinical status and AFP measurements isrequired.
These lesions have various patterns (hypo or hyperechoic) with at least 1 cm diameter. Theyare hepatocytes with dysplastic changes, but without clear histological criteria formalignancy. They are divided into low-grade dysplastic nodules, where cellular atypia aremild and high-grade dysplastic nodules with moderate or severe cellular atypia, butwithout any established signs of malignancy. Occasionally, well-differentiated HCC foci canbe identified in high-grade dysplastic nodules (appearance called "nodule in nodule"). Most authors accept the carcinogenesis process as a progressivetransformation of DN from low-grade to high-grade and into HCC. The nodule'svasculature changes progressively, correlated with the degree of malignancy, and it ischaracterized by decrease until absence of portal venous input and by increase of arterialintratumoral input. Neoformation vessels occur with increasing degree of dysplasia. Arterialneovascularization is enhanced in a chaotic and explosive way, while normal, arterial andportal vasculature continues to decline. High-grade dysplastic nodules are hypovascularizedboth arterial and portal phases, while early HCC nodules may have similararterial pattern with the surrounding parenchyma or exacerbated, and portal hypovascularization.In moderate or poorly differentiated HCC (classic HCC) tumor nutrition isperformed only by neoformation vessels (abundant), the normal arterial and portalvasculature completely disappearing. This behavior of intratumoralvascularization is typical for HCC and is the key to imaging diagnosis.
B-mode ultrasonography is unable to distinguish between regenerative nodules andborderline lesions such as dysplastic nodules and even early HCC. Doppler examinationalso has a low sensitivity in differentiating dysplastic nodules from early HCC. Dopplersignal may be absent in both regenerative and dysplastic nodules. Some authors indicate thepresence of venous type Doppler flow which reflects the portal venous nutrition of thenodule as a characteristic feature of dysplastic nodules and early HCC (Minami & Kudo,2010). Other authors noticed the presence of an arterial flow with small frequency variationsand a normal resistivity index.On CEUS examination both RN and DN may have quite a variable enhancement pattern.Generally, both nodules enhances identically with the surrounding liver parenchyma afterUCAs injection. Dysplastic nodules are hypovascular in the arterial phase. In case of highgradedysplastic nodule sometimes a hypervascularization can be detected, but withoutassociating "wash out" during portal and late CEUS phases. In these cases, biopsy mayclarify the diagnosis.
The suggestive appearance of early HCC on 2D ultrasound examination is that of hypoechoicnodule, with distinct pattern, developed on cirrhotic liver. Hypoechoic appearance ischaracteristic of moderate/poorly differentiated HCC, with low or absent fatty changes.Rarely, HCC may appear isoechoic, consist of a tumor type with a higher degree ofdifferentiation and therefore with slower development. Another common aspect is "brightloop" or "nodule-in-nodule" appearance, hypoechoic nodules in a hyperechoic tumor.
Spectral Doppler characteristics of early HCC overlap those of the dysplastic nodule, as theyare represented by the presence of portal venous signal type or arterial type with normal RI(well differentiated HCC) or increased RI (moderately or poorly differentiated HCC). TheCFM exploration identifies a chaotic vessels pattern.
On CEUS examination, early HCC has an iso- or hypervascular appearance during thearterial phase followed by wash out during portal venous and late phase. There are studiesshowing that the wash out process is directly correlated with the size and features ofneoplastic circulatory bed. Thus, highly differentiated HCC illustrates the phenomenon oflate or even very late "wash out" while poorly differentiated HCC has an accelerated washout at the end of arterial phase. Itis therefore mandatory to analyze all these three phases of CEUS examination for a propercharacterization of liver nodules. Tumor wash out at the end of the arterial phase allows theHCC diagnosis with a predictability of 89.5%. Some authors consider that early pronouncedcontrast enhancement of a nodule within 1–2 cm developed on a cirrhotic liver is sufficientfor HCC diagnosis. These results prove that for a correct characterization ofthe lesions it is necessary to extend the examination time to 5 minutes or even longer.
Baseline 2D ultrasound has an important role in surveillance programs for patients at risk todevelop HCC. The examination has an acceptable sensitivity whichincreases with the tumor size. Sensitivity varies between 42% for lesions <1 cm and 95% fortumors larger than 1 cm, and specificity can reach 90%. Optimal timeinterval for ultrasound screening of “at risk” population is 6 months as it results fromclinical trials that investigated the tumor size doubling time (Bruix, 2005; Maruyama et al.,2008). For a recently developed nodule the dimensional criteria will be taken into account.Thus, for a nodule with a size of less than 10 mm the patient will be reevaluated byultrasound every 3 months, as the growth trend is an indication for completion ofinvestigations with other diagnostic procedures; at a size between 10 – 20 mm twoconcordant imaging procedures are necessary, supplemented if necessary by an ultrasoundguided biopsy; at a size over 20 mm one single dynamic imaging technique withcharacteristic appearance is enough for positive diagnostic. In uncertain casescomplementary dynamic imaging techniques or biopsy should be performed. WhenDoppler exploration is not enough, CEUS examination will be performed. One should always keep in mind the risk of false positive results for HCC in case ofcholangiocarcinomas so complementary diagnostic procedures should be considered.
The effectiveness of screening programs is proved by an increase in detection rate of HCC<2 cm (from <5% in the 90s in Europe to > 30% today in Japan) with curative therapyoptions. The main problem of ultrasound screening is that, in order tobe cost-effective, it should be applied to the general population and not in tertiary hospitals.This raises the importance of the operator and equipment dependent part of the ultrasoundexamination. The efficiency of such a program is linked to the functionalliver parenchyma of the cirrhotic patient. Therefore, some authors argue that screeningshould be excluded in patients with etiologies that prevent curative treatment or in patientswith advanced liver disease (Child-Pugh class C).
After curative therapies (surgical resection, local ablative therapies) continuing ultrasoundscreening is recommended first at 1 month then at 3 months intervals after the therapy toassess the effectiveness of therapy and to detect other nodules.
Ultrasound exploration can be an effective procedure for the assessment of liver tumorsresponse to treatment. Over the years, different criteria for assessing the effectiveness ofcurative or palliative therapies have been considered. Now it has been proved that thedegree of tumor necrosis is not correlated with tumor diameter, therefore simplemeasurement of the tumor diameter (RECIST criteria) is not enough for therapy assessment.
Currently, local response to treatment is focused on tumor necrosis diagnosed by contrastdynamic imaging techniques and recognized by the presence of intratumoral non-enhancedareas. Local response to treatment is defined as:a. complete response, defined as complete disappearance of all known lesions (absence oftumor enhanced areas, reflecting total tumor necrosis) and absence of other new lesionsdetermined by two observations not less than 4 weeks apart;b. partial response, defined as more than 50% reduction in total tumor enhancement in allmeasurable lesions, determined by two observations not less than 4 weeks apartc. stable disease (is not described by a, b, or d)d. progressive disease, defined as 25% increase in size of one or more measurable lesionsor the appearance of new lesions.
The efficiency of 2D ultrasound is low in assessing the effects of HCC or metastasis therapy,as it is unable to differentiate viable tumor tissue from post-therapy tumor necrosis.
However, it is able to detect the appearance of new lesions and to assess the occurrence ofany complications of disease progression (ascites or portal vein thrombosis). Color Dopplerultrasound can be useful sometimes being able to show the presence of intratumoralvasculature as a sign of incomplete therapy or intratumoral recurrence. The absence ofDoppler signal does not exclude the presence of viable tumor tissue. CEUS exploration, byits ability to enhance intra-lesion microcirculation, has proved its utility in monitoringtherapeutic efficacy. Its indications are defined for HCC ablative treatments (pre, intra andpost-therapy), while monitoring of systemic therapies of HCC and metastases are notvalidated indications at this time, but with proved efficacy in extensive clinical trials(Claudon et al., 2008). CEUS examination cannot completely replace the other imagingdiagnostic methods currently in use because of the known limitations of the ultrasoundmethod (operator/ equipment dependent, ultrasound examination limitations). In additionto bloating, in cancer patients post-therapy steatosis occurs, which prevent deep visibility.Spiral CT scan remains the method of choice in monitoring cancer therapies because itprovides an overview of tumor extension and it is not limited by bloating or steatosis.
Gadolinium MRI examination is a procedure used more and more often, and its advantagesare the absence of irradiation and its high sensitivity in tumor vasculature detection,especially in smaller tumors. However it remains an expensive and nota very accessible procedure, although it has a high specificity. Currently, CEUS and MRI areconsidered complementary methods to CT scan.
Ablative therapies are considered curative treatments for HCC together with surgicalresection and liver transplantation and they are indicated for early tumor stages in patientswith good liver function. Also they aresuccessfully applied in the treatment of liver metastases, where surgical resection iscontraindicated. They are chemical (intratumoral ethanol injection) or thermal(radiofrequency, laser or microwave ablation). They are applied in order to obtain a fulltherapeutic response, without affecting liver function. Complete response is locally provedby complete tumor necrosis with a safety margin around the tumor.
2D ultrasound, Doppler ultrasound and especially CEUS can play an important role in pretherapeuticstaging, particularly when sectional imaging investigations (CT, MRI) provideuncertain results or are contraindicated. During the interventional procedure, ultrasound allows guidance of the needle into the tumor. CEUS allows guidance in areas of viable tissueand avoids intratumoral necrotic areas. CEUS also allows assessment of therapeutic effectimmediately post-procedure (with the possibility of reintervention in case of partial response). To accurately assess the effectiveness of treatment it is mandatory tocompare the tumor diameter before therapy with the ablation area. The volume of damagedtissue must be higher than the initial tumor volume. CEUS appearance is that of central nonenhancedarea showing a peripheral homogeneous hyperenhanced rim due to post-procedureinflammation. 24 hours after the procedure the inflammatory peripheral rim is thinning andthe necrotic area appears larger than at the previous examination. Thus, a possible residualtumor may appear more evident. Residual tumor has poorly defined edges, irregular shape,and the tumor diameter is unchanged. Residual tumor tissue is evidenced at the periphery ofthe tumor as an eccentric area behaving as the original tumor at CEUS examination, witharterial hyperenhancement and portal and late wash-out. Ultrasound examination 24 hoursafter the procedure, including CEUS, can show apart from the character of the lesion anypotential post-intervention complications (e.g. active bleeding).
In the first days after RFA both CEUS and spiral CT have low sensitivity in assessingtherapeutic efficacy. CT sensitivity 24 hours post-therapy is reported to be even lower thanCEUS. Difficulties in CEUS examination result from post-lesionhyperemia, presence of intratumoral air, ultrasound limitations (too deep lesion or thepresence of fatty liver) or lack of patient's cooperation (immediately after therapy). For thisreasons contrast imaging (CT or CEUS) control should be performed one month afterablation to confirm the result of the therapy.
Local recurrence is defined as recurrence of a hyperenhanced area at tumor periphery in thearterial phase, with portal and late wash-out. Sometimes, especially for HCC treated byalcoholization (PEI) hyperenhanced septa or vessels can be shown inside the lesion.
In case of successful treatment, US monitoring using CEUS is performed every threemonths. Although CE-CT and/or MRI are considered the method of choice in post-therapymonitoring, CEUS can be used in follow-up protocols, its diagnosticaccuracy being equivalent to that of CE-CT or MRI.
Transarterial chemoembolization (TACE) is part of palliative therapies for HCC used inintermediate stages of the disease. It consists of selective angiographic catheterization of thehepatic artery and injection of chemotherapeutic agents (usually adriamycin, but othermolecules are currently the subject of clinical trials), followed by embolization of hepaticartery with gelfoam, alcohol or metal rings. A similar procedure istransarterial embolization but without chemotherapeutic agents injection, used in thetreatment of hypervascular liver metastases. These therapies are based on thepredominantly arterial vasculature of HCC and hypervascular metastases, while theremaining liver parenchyma has a dual vascular intake, predominantly portal. Their efficacyis high only for lesions who are hyperenhanced during arterial phase. The role of US islimited in the first few days after the procedure, and refers only to its complications, due toLipiodol retention mainly intratumoral, but also diffusely intrahepatic. On ultrasound,Lipiodol appears intensely hyperechoic inside the tumor, with significant posteriorattenuation which make US examination more difficult. On the other hand, CE-CT is alsolimited by the presence of Lipiodol (iodine oil), therefore the evaluation of therapeuticefficiency is currently made by indirect assessing Lipiodol binding to the tumor using nonenhancedCT. CE-MRI is not influenced by the presence of Lipiodol,but it is an expensive method and still difficult to reach. Several studies have proved similarefficacy, even superior, of CEUS compared to CE-CT and CE-MRI for the evaluation of post-TACEtreatment results, while other studies have shown the limitations of CEUS especiallyfor deep or small lesions. Given the CEUS limitations, currently some authors consider CTas standard method for the evaluation of TACE and local ablative therapies and CEUS andCE-MRI as complementary methods. MonitoringTACE therapeutic results by contrast imaging techniques is performed as for ablativetherapies initially after one month then after every 3 months post-TACE.
Given that TACE is indicated only for hyperenhanced lesions during arterial phase, CEUSplays a very important role in monitoring the dysplastic nodules to identify the momentwhen changes occur in arterial vasculature, being able to have an early therapeuticintervention in order to limit tumor progression, to increase patient survival, and thus tocreate a bridge to liver transplantation.
Systemic therapies are procedures based on the affinity of certain molecules to inhibit eithertumor cell replication or multiplication of neoplastic vasculature (antiangiogenic therapies).
They are intravenously administered and are indicated in advanced stages of liver tumordiseases, when there are no other effective therapeutic solutions. Among ultrasoundtechniques, CEUS is the one that brought a significant benefit not only by increasing thesensitivity and specificity of ultrasound in detecting liver metastases, but also by assessingthe efficacy of systemic therapy for HCC and metastases. The method has been adopted byoncologists since 2003 because it involves no irradiation and has no hepatic or renal toxicity,and it is now currently used in tumor therapeutic evaluation. It iscurrently used in large clinical trials aimed at determining the efficacy of different types ofanti-angiogenic molecules by quantifying intratumoral perfusion based on the statisticalanalysis performed using specific software during post-processing in order to assesstherapeutic efficacy as early as possible.