Ultrasonography of liver tumors

Ultrasonography of liver tumors involves two stages: detection and characterization.

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.

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 enhancement
effect, 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) and
the developing context (oncology, septic) are also added. Particular attention should be paid
to the analysis of the circulatory bed. Microcirculation investigation allows for discrimination between benign and malignant tumors. Characteristic elements of malignant
circulation are vascular density, presence of vessels with irregular paths and size, some of
them intercommunicating, some others blocked in the end with "glove finger" appearance,
the presence of arterio-arterial and arterio-venous shunts, lack or incompetence of arterial
precapillary sphincter made up of smooth musculatures.
Diagnosis and characterization of liver tumors require a distinct approach for each group of
conditions, using the available procedures discussed above for each of them. The correlation
with the medical history, the patient's clinical and functional (biochemical and
hematological) status are important elements that should also be considered.

Benign liver tumors

Benign liver tumors generally develop on normal or fatty liver, are single or multiple (generally
paucilocular), have distinct delineation, with increased echogenity (hemangiomas, benign
focal nodular hyperplasia) or absent, with posterior acoustic enhancement effect (cysts),
have distinct delineation (hydatid cyst), lack of vascularization or show a characteristic
circulatory pattern, displace normal liver structures and even neighboring organs (in case of
large sizes), are quite elastic and do not invade liver vessels. The patient has a good general
status, as tumors are often asymptomatic, being incidentally discovered.

Liver cysts

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 liver
lobe (acquired, parasitic). They may be associated with renal cysts; in this case the disease
has a hereditary, autosomal dominant transmission (von Hippel Lindau disease).

The ultrasound appearance is a well defined lesion, with very thin, almost unapparent
walls, without circulatory signal at Doppler or CEUS investigation. The content is
transonic suggesting fluid composition. The presence of membranes, abundant sediment
or cysts inside is suggestive for parasitic, hydatid nature. Posterior from the lesion the
acoustic enhancement phenomenon is seen, which strengthens the suspicion of fluid
mass. They typically displace normal liver vessels but no vascular or biliary invasion
occurs.

File:Ultrasonography of a liver cyst.jpg, Liver cyst
File:Ultrasonography of a hydatid liver cyst.jpg, Hydatid liver cyst. Diagnostic criteria are the presence of membranes and sediment inside.

Hemangioma

It is the most common liver tumor with a prevalence of 0.4 – 7.4%. It is generally
asymptomatic but also can be associated with pain complaints or cytopenia and/or
anemia when it is very bulky. It is unique or paucilocular. It can be associated with other
types of benign liver tumors. Characteristic 2D ultrasound appearance is that of a very
well defined lesion, with sizes of 2–3 cm or less, showing increased echogenity and, when
located in contact with the diaphragm, a "mirror image" phenomenon can be seen. When
palpating the liver with the transducer the hemangioma is compressible sending
reverberations backwards. Doppler exploration reveals no circulatory signal due to very
slow flow speed. CEUS investigation has real diagnosis value due to the typical behavior
of progressive CA enhancement of the tumor from the periphery towards the center. The
enhancement is slow, during several minutes, depending on the size of hemangioma and
on the presence (or absence) of internal thrombosis. During late (sinusoidal) phase, if
totally "filled" with CA, hemangioma appears isoechoic to the liver. Deviations from the
above described behavior can occur in arterialized hemangiomas or those containing
arterio-venous shunts. In these cases, differentiation from a malignant tumor is difficult
and requires other imaging procedures, follow up and measurements of the tumor at
short time intervals.

Focal nodular hyperplasia

It is a tumor developed secondary to a circulatory abnormality with abundant arterial
vessels having a characteristic location in the center of the tumor, within a fibrotic scar. A
radial vessels network develops from this level with peripheral orientation. The tumor's
circulatory bed is rich in microcirculatory and portal venous elements. The incidence is
higher in younger women and tumor development is accelerated by oral contraceptives
intake. 2D ultrasound appearance is a fairly well-defined mass, with variable sizes, usually
single, solid consistency with inhomogeneous structure. Rarely the central scar can be
distinguished. Spectral Doppler examination detects central arterial vessels and CFM
exploration reveals their radial position. CEUS examination shows central tumor filling of
the circulatory bed during arterial phase and completely enhancement during portal venous
phase. During this phase the center of the lesion becomes hypoechoic, enhancing the tumor
scar. During the late phase the tumor remains isoechoic to the liver, which strengthens the
diagnosis of benign lesion.

Adenoma

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. The
tumor is asymptomatic but may be associated with right upper quadrant pain in case of
internal bleeding. 2D ultrasound shows a well-defined, un-encapsulated, solid mass. It may
have a heterogeneous structure in case of intratumoral hemorrhage. Doppler examination
shows no circulatory signal. CEUS exploration is quite ambiguous and cannot always
establish a differential diagnosis with hepatocellular carcinoma. Thus, during the arterial
phase there is a centripetal and inhomogeneous enhancement. During the portal venous
phase there is a moderate wash out. During late phase the appearance is isoechoic or
hypoechoic, due to lack of Kupffer cells.

Malignant liver tumors

Malignant liver tumors develop on cirrhotic liver (hepatocellular carcinoma, HCC) or
normal liver (metastases). They are single or multiple (especially metastases), have a
variable, 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 underlying
disease (vascular and parenchymal decompensation for liver cirrhosis, weight loss, lack of
appetite and anemia with cancer).

Hepatocellular carcinoma (HCC)

It is the most common liver malignancy. It develops secondary to
cirrhosis therefore, ultrasound examination
every 6 months combined with alpha fetoprotein (AFP) determination is an effective
method 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 of
appetite.

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 early
stages, 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 by
radiofrequency ablation (RFA) and liver transplantation. Intermediate stage (polinodular,
without portal invasion) and advanced stage (N1, M1, with portal invasion) undergo
palliative therapies (TACE and sorafenib systemic therapy) and in the end stage only
symptomatic therapy applies.

Cholangiocarcinoma

It develops on non cirrhotic liver. 2D ultrasound appearance is uncharacteristic – solid mass
with heterogeneous structure, poorly delineated, often with peripheral location and weak
Doppler circulation signal. CEUS examination reveals a moderate enhancement of the
tumor periphery during arterial phase followed by wash-out during portal venous phase
and hypoechoic appearance during late phase.

Liver metastases

US examination is required to detect liver metastases in patients with oncologic history. In
addition, the method can incidentally detect metastases in asymptomatic patients. Early
identification (small sizes, small number) is important to establish an optimal course of
treatment which can be complex (chemotherapy, radiofrequency ablation, surgical
resection) but welcomed. In addition, discrimination of synchronous lesions that have a
different nature is also important knowing that up to 25–50% of liver lesions less than 2 cm
detected in cancer patients may be benign . US sensitivity for metastases
detection varies depending on the examiner's experience and the equipment used and
ranges between 40–80% . Sensitivity is conditioned by the size and
acoustic impedance of the nodules. For a lesion diameter below 10 mm US accuracy is
greatly reduced, reaching approx. 20%. Other elements contributing to lower US
performance are: excessive obesity, fatty liver disease, hypomobility of the diaphragm, and
certain patterns of hyperechoic or isoechoic metastases that can be overlooked or can mimic
benign conditions. Conventional US appearance of metastases is uncharacteristic, consisting
of circumscribed lesions, with clear, imprecise or "halo" delineation, with homogeneous or
heterogeneous echo pattern. They can be single (often liver metastases from colonic
neoplasm) or multiple. Echogenity is variable. When increased, they can compress the bile
ducts (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 (carcinoid
metastases). Cyst-adenocarcinoma metastases due to semifluid content may have a
transonic appearance. When increasing, they can result in central necrosis. CEUS
examination is a real breakthrough for detection and characterization of liver metastases.

Increased performance is based on identifying specific vascular patterns during the arterial
phase and seeing metastases in contrast to normal liver parenchyma during the sinusoidal
phase. 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 intratumoral
circulation represented by a reduced arterial bed compared to that of the surrounding
normal liver and the absence of the portal vessels . In terms of
vascularity, metastases can be hypovascular (in gastric, colonic, pancreatic or ovarian
adenocarcinomas) with hypoechoic pattern during arterial phase, and similar during portal
venous and late phases, respectively hypervascular (neuroendocrine tumors, malignant
melanoma, sarcomas, renal, breast or thyroid tumors) with hyperechoic appearance during
arterial phase, with washout during the portal venous phase and hypoechoic pattern
30 seconds after injection.

Using CEUS examination to detect metastases a sensitivity of 80–95% is obtained, similar to
that of contrast CT and MRI . Intraoperative use of
the procedure increases its performance even if it does not have a decisive contribution to
change the therapeutic behavior . Limitations of the method are those
related to US penetration (pronounced fatty liver disease, deep lesion, excessive obesity) and
to the experience of the examiner. To this the risk of confusion between hypervascular
metastases, hepatocellular carcinoma and hemangioma and the confusion between
hypovascular metastases and small liver cysts is added. Routine use of CEUS examination to
detect liver metastases is recommended when conventional US examination is not
conclusive, when precise information on some injuries (number, location) is necessary in
conjunction with contrast CT/MRI and to assess the effectiveness of treatment when using an antiangiogenic therapy for hypervascular metastases . The method
cannot replace CT/MRI examinations which have well established indications in oncology.

Pseudotumors and inflammatory masses of the liver

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 often
insufficient, requiring morphologic diagnostic procedures, use of other diagnostic imaging
methods or patient reevaluation from time to time. This includes lesions developed on liver
parenchyma reconstruction, as occurs in cirrhosis, steatosis accumulation or in case of acute
or chronic inflammatory diseases.

Focal steatosis

It consists of localized accumulation of fat-rich liver cells. In some cases this accumulation can
mimic a liver tumor. Sometimes the opposite phenomenon can be seen, that is an "island" of
normal parenchyma in a “shining” liver. In both cases ultrasound examination identifies a
well defined, un-encapsulated area, with echostructure and vasculature similar to those of
normal liver parenchyma. The lesion can have different forms, most cases being oval and
located in the IVth segment, anterior from the hepatic hilum. It occurs in dyslipidemic or alcohol intake patients with normal physical and biological status. Benign diagnosis
confirmation is made using CEUS examination which proves a normal circulatory bed similar
to adjacent liver parenchyma in all three phases of investigation.

Liver abscess

Liver abscess have heteromorphic ultrasound appearance, the most typical being that of a
mass 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 shows
hyperenhancement during arterial phase close to the lesion, this being suggestive of a liver
parenchymal hyperemia. During venous and sinusoidal phase the pattern is hypoechoic, and
the central fluid is contrast enhanced. CEUS examination is useful because it confirms the
clinical suspicion of abscess. In addition, it allows for an accurate measurement of the
collection size and an indication regarding its topography inside the liver (lobe, segment).

Preneoplastic status. Cirrhotic liver monitoring

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 59–94% 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).

Regenerative nodules (RN)

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.

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.

Dysplastic nodules (DN)

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.

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.

Early hepatocellular carcinoma (Early HCC)

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.

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.

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.

The ultrasound value in HCC "screening"

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.

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).

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.

Antitumor therapies

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.

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:
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.

Techniques for evaluating the efficiency of therapy

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 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.

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.

Ultrasound monitoring ablative therapies (alcoholization – PEI, radiofrequency ablation – RFA)

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.

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).

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.

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.

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.

Ultrasound monitoring of TACE therapy (transarterial chemoembolization)

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.

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.

Ultrasound monitoring of systemic therapies

Systemic therapies are procedures based on the affinity of certain molecules to inhibit either
tumor cell replication or multiplication of neoplastic vasculature (antiangiogenic therapies).

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.

References

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Medical ultrasonography
Hepatology
Digestive system neoplasia