Ultrasonography of liver tumors

Cirrhotic liver is characterized by the occurrence of nodules with different sizes and evolution degrees, so that regenerative nodules, dysplastic nodules and even early hepatocellular carcinoma can coexist at some moment during disease progression. There are studies showing that between 59 and 94% of newly diagnosed liver nodules in cirrhotic patients have malignant histology and up to 50% of hyperechoic lesions, with ultrasound appearance of hemangioma, ultimately prove to be hepatocellular carcinoma. Therefore, current practice in many centers considers that any new lesion revealed in a cirrhotic patient should be regarded as malignant until otherwise proven. There are three categories of cirrhotic liver nodules: regenerative, dysplastic (considered as premalignant conditions) and tumoral (HCC).^{[citation needed]}

These lesions are well defined, with isoechoic or hypoechoic appearance and sizes less than 1 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 is different against the general pattern of restructured liver either by different echogenity or by a different size than the majority of nodules. During the arterial phase, the signal is weak or absent. During the portal venous and late phase, the appearance is persistently isoechoic.^{[citation needed]}

Generally, RN is not distinct from the surrounding parenchyma. CEUS examination is useful to exclude an active lesion at the moment of exploration but does not have absolute prognostic value; therefore the patient should be periodically examined at short intervals. Correlation with clinical status and AFP measurements is required.^{[citation needed]}

These lesions have various patterns (hypo or hyperechoic) with at least 1 cm diameter. They are hepatocytes with dysplastic changes, but without clear histological criteria for malignancy. They are divided into low-grade dysplastic nodules, where cellular atypia are mild and high-grade dysplastic nodules with moderate or severe cellular atypia, but without any established signs of malignancy. Occasionally, well-differentiated HCC foci can be identified in high-grade dysplastic nodules (appearance called "nodule in nodule") . Most authors accept the carcinogenesis process as a progressive transformation of DN from low-grade to high-grade and into HCC. The nodule's vasculature changes progressively, correlated with the degree of malignancy, and it is characterized by decrease until absence of portal venous input and by increase of arterial intratumoral input. Neoformation vessels occur with increasing degree of dysplasia. Arterial neovascularization is enhanced in a chaotic and explosive way, while normal, arterial and portal vasculature continues to decline. High-grade dysplastic nodules are hypovascularized both arterial and portal phases, while early HCC nodules may have similar arterial pattern with the surrounding parenchyma or exacerbated, and portal hypovascularization. In moderate or poorly differentiated HCC (classic HCC) tumor nutrition is performed only by neoformation vessels (abundant), the normal arterial and portal vasculature completely disappearing. This behavior of intratumoral vascularization is typical for HCC and is the key to imaging diagnosis.^{[citation needed]}

B-mode ultrasonography is unable to distinguish between regenerative nodules and borderline lesions such as dysplastic nodules and even early HCC. Doppler examination also has a low sensitivity in differentiating dysplastic nodules from early HCC. Doppler signal may be absent in both regenerative and dysplastic nodules. Some authors indicate the presence of venous type Doppler flow which reflects the portal venous nutrition of the nodule 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 variations and 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 after UCAs injection. Dysplastic nodules are hypovascular in the arterial phase. In case of highgrade dysplastic nodule sometimes a hypervascularization can be detected, but without associating "wash out" during portal and late CEUS phases. In these cases, biopsy may clarify the diagnosis.^{[citation needed]}

The suggestive appearance of early HCC on 2D ultrasound examination is that of hypoechoic nodule, with distinct pattern, developed on cirrhotic liver. Hypoechoic appearance is characteristic 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 of differentiation and therefore with slower development. Another common aspect is "bright loop" or "nodule-in-nodule" appearance, hypoechoic nodules in a hyperechoic tumor.^{[citation needed]}

Spectral Doppler characteristics of early HCC overlap those of the dysplastic nodule, as they are 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). The CFM exploration identifies a chaotic vessels pattern.^{[citation needed]}

On CEUS examination, early HCC has an iso- or hypervascular appearance during the arterial phase followed by wash out during portal venous and late phase. There are studies showing that the wash out process is directly correlated with the size and features of neoplastic circulatory bed. Thus, highly differentiated HCC illustrates the phenomenon of late or even very late "wash out" while poorly differentiated HCC has an accelerated wash out at the end of arterial phase. It is therefore mandatory to analyze all these three phases of CEUS examination for a proper characterization of liver nodules. Tumor wash out at the end of the arterial phase allows the HCC diagnosis with a predictability of 89.5%. Some authors consider that early pronounced contrast enhancement of a nodule within 1–2 cm developed on a cirrhotic liver is sufficient for HCC diagnosis. These results prove that for a correct characterization of the lesions it is necessary to extend the examination time to 5 minutes or even longer.^{[citation needed]}

Baseline 2D ultrasound has an important role in surveillance programs for patients at risk to develop HCC. The examination has an acceptable sensitivity which increases with the tumor size. Sensitivity varies between 42% for lesions <1 cm and 95% for tumors larger than 1 cm, and specificity can reach 90%. Optimal time interval for ultrasound screening of “at risk” population is 6 months as it results from clinical 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 by ultrasound every 3 months, as the growth trend is an indication for completion of investigations with other diagnostic procedures; at a size between 10 – 20 mm two concordant imaging procedures are necessary, supplemented if necessary by an ultrasound guided biopsy; at a size over 20 mm one single dynamic imaging technique with characteristic appearance is enough for positive diagnostic. In uncertain cases complementary dynamic imaging techniques or biopsy should be performed. When Doppler 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 of cholangiocarcinomas so complementary diagnostic procedures should be considered.^{[citation needed]}

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 therapy options. The main problem of ultrasound screening is that, in order to be 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 ultrasound examination. The efficiency of such a program is linked to the functional liver parenchyma of the cirrhotic patient. Therefore, some authors argue that screening should be excluded in patients with etiologies that prevent curative treatment or in patients with advanced liver disease (Child-Pugh class C).^{[citation needed]}

After curative therapies (surgical resection, local ablative therapies) continuing ultrasound screening is recommended first at 1 month then at 3 months intervals after the therapy to assess the effectiveness of therapy and to detect other nodules.^{[citation needed]}

Ultrasound exploration can be an effective procedure for the assessment of liver tumors response to treatment. Over the years, different criteria for assessing the effectiveness of curative or palliative therapies have been considered. Now it has been proved that the degree of tumor necrosis is not correlated with tumor diameter, therefore simple measurement of the tumor diameter (RECIST criteria) is not enough for therapy assessment.^{[citation needed]}

Currently, local response to treatment is focused on tumor necrosis diagnosed by contrast dynamic imaging techniques and recognized by the presence of intratumoral non-enhanced areas. Local response to treatment is defined as:^{[citation needed]} a. complete response, defined as complete disappearance of all known lesions (absence of tumor enhanced areas, reflecting total tumor necrosis) and absence of other new lesions determined by two observations not less than 4 weeks apart; b. partial response, defined as more than 50% reduction in total tumor enhancement in all measurable lesions, determined by two observations not less than 4 weeks apart c. stable disease (is not described by a, b, or d) d. progressive disease, defined as 25% increase in size of one or more measurable lesions or 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.^{[citation needed]}

However, it is able to detect the appearance of new lesions and to assess the occurrence of any complications of disease progression (ascites or portal vein thrombosis). Color Doppler ultrasound can be useful sometimes being able to show the presence of intratumoral vasculature as a sign of incomplete therapy or intratumoral recurrence. The absence of Doppler signal does not exclude the presence of viable tumor tissue. CEUS exploration, by its ability to enhance intra-lesion microcirculation, has proved its utility in monitoring therapeutic efficacy. Its indications are defined for HCC ablative treatments (pre, intra and post-therapy), while monitoring of systemic therapies of HCC and metastases are not validated indications at this time, but with proved efficacy in extensive clinical trials (Claudon et al., 2008). CEUS examination cannot completely replace the other imaging diagnostic methods currently in use because of the known limitations of the ultrasound method (operator/ equipment dependent, ultrasound examination limitations). In addition to 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 it provides an overview of tumor extension and it is not limited by bloating or steatosis.^{[citation needed]}

Gadolinium MRI examination is a procedure used more and more often, and its advantages are the absence of irradiation and its high sensitivity in tumor vasculature detection, especially in smaller tumors. However it remains an expensive and not a very accessible procedure, although it has a high specificity. Currently, CEUS and MRI are considered complementary methods to CT scan.^{[citation needed]}

Ablative therapies are considered curative treatments for HCC together with surgical resection and liver transplantation and they are indicated for early tumor stages in patients with good liver function. Also they are successfully applied in the treatment of liver metastases, where surgical resection is contraindicated. They are chemical (intratumoral ethanol injection) or thermal (radiofrequency, laser or microwave ablation). They are applied in order to obtain a full therapeutic response, without affecting liver function. Complete response is locally proved by complete tumor necrosis with a safety margin around the tumor.^{[citation needed]}

2D ultrasound, Doppler ultrasound and especially CEUS can play an important role in pretherapeutic staging, particularly when sectional imaging investigations (CT, MRI) provide uncertain results or are contraindicated. During the interventional procedure, ultrasound allows guidance of the needle into the tumor. CEUS allows guidance in areas of viable tissue and avoids intratumoral necrotic areas. CEUS also allows assessment of therapeutic effect immediately post-procedure (with the possibility of reintervention in case of partial response) . To accurately assess the effectiveness of treatment it is mandatory to compare the tumor diameter before therapy with the ablation area. The volume of damaged tissue must be higher than the initial tumor volume. CEUS appearance is that of central nonenhanced area showing a peripheral homogeneous hyperenhanced rim due to post-procedure inflammation. 24 hours after the procedure the inflammatory peripheral rim is thinning and the necrotic area appears larger than at the previous examination. Thus, a possible residual tumor 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 of the tumor as an eccentric area behaving as the original tumor at CEUS examination, with arterial hyperenhancement and portal and late wash-out. Ultrasound examination 24 hours after the procedure, including CEUS, can show apart from the character of the lesion any potential post-intervention complications (e.g. active bleeding).^{[citation needed]}

In the first days after RFA both CEUS and spiral CT have low sensitivity in assessing therapeutic efficacy. CT sensitivity 24 hours post-therapy is reported to be even lower than CEUS. Difficulties in CEUS examination result from post-lesion hyperemia, presence of intratumoral air, ultrasound limitations (too deep lesion or the presence of fatty liver) or lack of patient's cooperation (immediately after therapy). For this reasons contrast imaging (CT or CEUS) control should be performed one month after ablation to confirm the result of the therapy.^{[citation needed]}

Local recurrence is defined as recurrence of a hyperenhanced area at tumor periphery in the arterial phase, with portal and late wash-out. Sometimes, especially for HCC treated by alcoholization (PEI) hyperenhanced septa or vessels can be shown inside the lesion.^{[citation needed]}

In case of successful treatment, US monitoring using CEUS is performed every three months. Although CE-CT and/or MRI are considered the method of choice in post-therapy monitoring, CEUS can be used in follow-up protocols, its diagnostic accuracy being equivalent to that of CE-CT or MRI.^{[citation needed]}

Transarterial chemoembolization (TACE) is part of palliative therapies for HCC used in intermediate stages of the disease. It consists of selective angiographic catheterization of the hepatic artery and injection of chemotherapeutic agents (usually adriamycin, but other molecules are currently the subject of clinical trials), followed by embolization of hepatic artery with gelfoam, alcohol or metal rings. A similar procedure is transarterial embolization but without chemotherapeutic agents injection, used in the treatment of hypervascular liver metastases. These therapies are based on the predominantly arterial vasculature of HCC and hypervascular metastases, while the remaining liver parenchyma has a dual vascular intake, predominantly portal. Their efficacy is high only for lesions who are hyperenhanced during arterial phase. The role of US is limited in the first few days after the procedure, and refers only to its complications, due to Lipiodol retention mainly intratumoral, but also diffusely intrahepatic. On ultrasound, Lipiodol appears intensely hyperechoic inside the tumor, with significant posterior attenuation which make US examination more difficult. On the other hand, CE-CT is also limited by the presence of Lipiodol (iodine oil), therefore the evaluation of therapeutic efficiency is currently made by indirect assessing Lipiodol binding to the tumor using nonenhanced CT. 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 similar efficacy, even superior, of CEUS compared to CE-CT and CE-MRI for the evaluation of post-TACE treatment results, while other studies have shown the limitations of CEUS especially for deep or small lesions. Given the CEUS limitations, currently some authors consider CT as standard method for the evaluation of TACE and local ablative therapies and CEUS and CE-MRI as complementary methods. Monitoring TACE therapeutic results by contrast imaging techniques is performed as for ablative therapies initially after one month then after every 3 months post-TACE.^{[citation needed]}

Given that TACE is indicated only for hyperenhanced lesions during arterial phase, CEUS plays a very important role in monitoring the dysplastic nodules to identify the moment when changes occur in arterial vasculature, being able to have an early therapeutic intervention in order to limit tumor progression, to increase patient survival, and thus to create a bridge to liver transplantation.^{[citation needed]}

Systemic therapies are procedures based on the affinity of certain molecules to inhibit either tumor cell replication or multiplication of neoplastic vasculature (antiangiogenic therapies).^{[citation needed]}

They are intravenously administered and are indicated in advanced stages of liver tumor diseases, when there are no other effective therapeutic solutions. Among ultrasound techniques, CEUS is the one that brought a significant benefit not only by increasing the sensitivity and specificity of ultrasound in detecting liver metastases, but also by assessing the efficacy of systemic therapy for HCC and metastases. The method has been adopted by oncologists 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 is currently used in large clinical trials aimed at determining the efficacy of different types of anti-angiogenic molecules by quantifying intratumoral perfusion based on the statistical analysis performed using specific software during post-processing in order to assess therapeutic efficacy as early as possible.^{[citation needed]}