WFUMB Course Book
CONTRAST ENHANCED ULTRASOUND
32. Contrast Enhanced Ultrasound
Gibran T Yusuf, Paul S Sidhu
Keywords: contrast enhanced ultrasound (CEUS), Ultrasound contrast agents,
CEUS liver, CEUS kidney, CEUS trauma
32.1. Ultrasound contrast agents
Ultrasound contrast agents (UCA) are microbubbles of inert gas surrounded by a
phospholipid shell which resonate with low mechanical index ultrasound (US). As
they are the approximate size of a red blood cell, they have stability through the
cardiopulmonary circulation provide accurate assessment of vascularity at a capillary
level. Additional benefits of UCA’s are the lack of nephrotoxicity and excellent safety
profile as well as real time visualisation.
Further benefits are inherent to conventional US including being a bedside, portable,
radiation free means of imaging despite being subject to operator variability.
Contrast enhanced ultrasound (CEUS) has become established for a number of
uses, the most commonly recognised being in liver lesion evaluation. International
guidelines describe and advocate a range of utilities outside the liver.
Remember
• UCA are true intraluminal/blood pool agents allowing real time visualisation
and lesion characterisation
32.2. Liver
CEUS is ideal for focal liver lesion characterisation, as it allows real time evaluation
of the arterial, early and late portal venous phases. Furthermore, SonazoidTM, also
has a Kupffer or post vascular phase, evident 10 minutes after administration. CEUS
has been shown to be more cost effective than CT and MR imaging with similar
diagnostic performance for focal liver lesion characterisation. A critical feature is
portal venous washout, which is a hallmark of malignancy. intravascular nature of the UCA (Fig 32.2).
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32.2.1. Benign focal lesions
32.2.1.1. Haemangioma
Varying types of haemangiomata exist and characteristics are often related to the
size of the lesion. Haemangiomas with typical B-mode appearances do not usually
require CEUS but may appear heterogenous or hypoechoic if there is underlying
liver steatosis. Typical haemangiomas show peripheral nodular enhancement with
gradual infilling, considered pathognomonic. Larger lesions may show central
sclerosis and non-enhancement, whilst smaller lesions may “flash fill” in the arterial
phase. Importantly there is no late phase washout (Fig 32.1).
View enlarged image
Fig 32.1
Simultaneous B-mode
(a) and CEUS image of a
haemangioma. Peripheral
nodular enhancement on
CEUS (b, c), with no late
phase washout (d). The
central aspect of the lesion is
thrombosed and does not fill
32.2.1.2. Focal nodular hyperplasia (FNH)
FNH is the second most common solid benign liver lesion and shows a typical
enhancement pattern on CEUS. There is often (70%) a central feeding artery
leading to a rapid “spoke-wheel” arterialisation from the centre of the lesion to
the periphery, and there remains hyper/isoenhancement in all phases. A small
proportion (approximately 6%) may demonstrate washout in the portal phase and
it is important to distinguish this from malignancy. The central scar (when seen) in
FNH does not enhance, unlike in delayed phase MR imaging, reflecting the pure
WFUMB Course Book
View enlarged image
Fig 32.2a
Simultaneous B-mode
and CEUS image of FNH.
Central filling vessel in an
arterialised lesion
View enlarged image
Fig 32.2b
Simultaneous B-mode
and CEUS image of FNH.
Central filling vessel in an
arterialised lesion
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32. CONTRAST ENHANCED ULTRASOUND
View enlarged image
Fig 32.2c
Simultaneous B-mode
and CEUS image of FNH.
Arterialised lesion with no
late phase washout
32.2.1.3. Hepatocellular adenoma (HCA)
HCA is a rare entity and has been divided into genetic subtypes, some of which
have reported malignant potential. Steroid excess (exogenous and endogenous)
is a risk factor and lesions may be multiple. Typically, HCA have a rapid peripheral
enhancement with central filling. This is distinct from the slower peripheral nodular
filling of a haemangioma and the peripheral to central filling is the opposite of FNH
(often a differential diagnosis).
Portal venous phase and delayed phase imaging appearances are variable including
hyper/iso and hypoenhancement. When there is hypoenhancement, malignancy
must be considered. Areas of haemorrhage or infarction may be present and show
lack of enhancement. Usually for genetic typing histological sampling is needed,
particularly if regression after risk factor removal has been unsuccessful.
WFUMB Course Book 32. CONTRAST ENHANCED ULTRASOUND

32.2.2. Malignant lesions View enlarged image

32.2.2.1. Metastases
Depending on the source of metastases the arterial phase appearances can vary
and include hypo/hyper or rim enhancement. Portal venous phase imaging shows
hypoenhancement and is usually rapid, occurring before 60 seconds (Fig 32.3).
The sensitivity of CEUS often leads to the detection of tiny occult lesions not seen
on B mode imaging.
Fig 32.4a, b
View enlarged image
Simultaneous B-mode
and CEUS image of
cholangiocarcinoma.
Arterialised lesion, although
peripheral and nodular in
nature (a, b)

The development of a regenerative nodule through stages of dysplasia and eventual

HCC means there is some variability in appearances on vascular phases, leading
Fig 32.3 to the belief that all arterialised lesions in a patient with chronic liver disease should
Simultaneous B-mode be considered suspicious.
and CEUS image of liver
metastases with early
pronounced washout

32.2.2.2. Cholangiocarcinoma
CEUS appearances of cholangiocarcinoma are similar to metastatic disease and also View enlarged image

may present as multiple intrahepatic lesions or intraductal lesions. Rim enhancement,

heterogenous/homogenous hyperenhancement and hypoenhancement may all
occur in the arterial phase, with hyper or rim enhancement most common in the
mass forming variant (Fig 32.4) whilst intraductal cholangiocarcinoma tends to be
hypoenhancing. Portal venous phase typically shows early washout prior to 60
seconds, becoming more intense in the late phase.

32.2.2.3. Hepatocellular carcinoma (HCC)

The vast majority of HCC occurs in chronic liver disease, with 5-10% occurring
de novo. As HCC pathologically results in neo-angiogenesis and pseudo-capsule Fig 32.4c
formation, arterialisation is a critical feature and coupled with late phase washout is CEUS image of
the radiological criteria for diagnosis (Fig 32.5). Arterialisation is usually peripheral cholangiocarcinoma - early
in nature before filling centrally in a “basket weave” pattern. pronounced washout

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WFUMB Course Book
View enlarged image
Fig 32.5a
Simultaneous B-mode and
CEUS image of a large
HCC - Arterialised lesion
View enlarged image
Fig 32.5b
Simultaneous B-mode
and CEUS image of a
large HCC - late and mild
washout
HCC washout typically occurs late and is relatively mild, compared to other
malignant lesions, but is dependent on the degree of histological differentiation
(poorly differentiated lesions washout earlier and some well differentiated lesions
may not washout at all).
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32. CONTRAST ENHANCED ULTRASOUND
Approximately 10% of HCC are hypovascular in all phases of imaging. SonazoidTM
has a late post vascular phase in which washout can be detected after 10 minutes
in 50% of cases. CEUS can also detect associated malignant portal venous
thrombus, which shows similar washout to the primary lesion. CEUS LIRADS is a
standardised scoring system to grade the likelihood of a lesion representing HCC
in chronic liver disease.
32.2.2.4. Miscellaneous lesions
Lymphoma has a typical early washout with a “feathery” appearance and variable
arterial phase enhancement.
CEUS is useful to characterise cystic lesions, in particular differentiating solid
components and enhancing septations. Overlap in appearances may occur in
hepatic abscesses and cystic tumours as both may show washout, although an
abscess usually shows rim enhancement and clinical features of infection are
present.
Pseudo-lesions such as focal fatty changes or even regenerative nodules represent
normal tissue and so show symmetrical enhancement to the remaining parenchyma
in all phases.
Remember
• It is important to observe arterial, venous and late phase vascular
characteristics for lesional characterisations
• Portal phase or late phase washout should be considered a malignant
feature of liver lesions
32.3. Gallbladder
Primary gallbladder malignancy is rare, but requires differentiation from polyps,
adenomyosis or atypical appearing calculi. Almost all gallbladder pathology shows
arterial enhancement and is not a differentiator of benign or malignant, however
malignant lesions tend to washout early. Polyps are vascularised (Fig 32.6) and
if over 1cm have a higher risk of malignant transformation, whilst calculi or debris
show no enhancement (Fig 32.7).
WFUMB Course Book
View enlarged image
Fig 32.6
Simultaneous B-mode
and CEUS image of
gallbladder polyp showing
enhancement
View enlarged image
Fig 32.7
Simultaneous B-mode
and CEUS image of
gallstones, thought to be a
cholangiocarcinoma due to
B mode configuration. No
contrast enhancement is
seen
32.4. Renal
32.4.1. Solid renal lesions
Renal CEUS has rapidly become a dominant area of practice. Although differentiation
of benign from malignant solid renal lesions remains controversial, the primary use
of CEUS is to identify pseudo-lesions such as a dromedary hump, by showing
identical enhancement of the area to the remaining renal parenchyma in all phases.
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32. CONTRAST ENHANCED ULTRASOUND
Conversely the vast majority (95%) of solid renal malignancy differs in at least one
phase (Fig 32.8). Necrotic or haemorrhagic areas may also be seen, but is not a
differentiating factor from benign solid lesions. In some cases, renal vein or IVC
thrombus may be seen.
32.4.2. Cystic renal lesions
A leading use of CEUS has been evaluation of renal cysts. Simple cysts require
no additional imaging, however increasing degree of complexity with septations
and solid components can be identified with US and CEUS can provide vascular
assessment of these areas.
The Bosniak classification remains CT based but appears comparable with CEUS
in recent studies. Critical to evaluation is the thickness of vascularised septations as
well as solid components as this correlates with the likelihood of malignancy. A key
utility is in the absence of contrast enhancement for haemorrhagic cysts or those
described as hyperdense on CT. The reassurance of a lesion without malignant
potential ensures no further follow up is needed.
Renal abscesses are usually established from a clinical perspective, with CEUS
showing rim enhancement and potential washout, internal septations or non-
enhancing debris, similar to abscesses seen elsewhere (Fig 32.9).
View enlarged image
Fig 32.8
CEUS images of a renal
cell carcinoma showing
rim enhancement and
disorganised vascularity
with portal phase washout
WFUMB Course Book
View enlarged image
Fig 32.9
Simultaneous B-mode
and CEUS image of a
renal abscess, there is
rim enhancement but no
enhancement of the solid
components seen on
B mode
Remember
• CEUS can define complexity and therefore malignant risk of renal cysts
• At present CEUS cannot distinguish between types of solid renal lesions
but can confirm pseudo-lesions (e.g. dromedary humps)
View enlarged image
Fig 32.10
Simultaneous B-mode
and CEUS image of a
intratesticular lesion shown
on CEUS to have no
enhancement in keeping
with a haematoma
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32. CONTRAST ENHANCED ULTRASOUND
32.4.3. Testicular
It is common for all intratesticular lesions to be considered malignant particularly if
vascular on Doppler US, however Doppler US is reportedly unreliable in paediatric
testis and small lesions. CEUS can confirm the absence of vascularity in lesions
such as intratesticular haematoma (Fig 32.10), infarction, complex cysts and
epidermoid cysts. In rare cases testicular tumours may “burn out” and be avascular.
Testicular tumours otherwise show varying degree of contrast enhancement, and
are not reliably differentiated between cell types except for evidence to suggest
Leydig cell tumours which are typically persistently hyperenhancing (Fig 32.11).
View enlarged image
Fig 32.11
Simultaneous B-mode and
CEUS image of a small
intratesticular lesion with
hyperenhancement which
persists in keeping with a
Leydig cell tumour
Testicular infarction may occur either segmentally or globally and has a number
of underlying causes, including missed torsion and severe epididymitis. CEUS
demonstrates global and focal ischaemia clearly with a complete absence of
enhancement (Fig 32.12).
Typically, arterial infarction results in a wedge-shaped area, whilst venous ischaemia
results in a rounded more central infarct. Epididymal abscess formation may occur
in severe infection and has similar CEUS appearances as elsewhere in the body.
WFUMB Course Book 32. CONTRAST ENHANCED ULTRASOUND

View enlarged image With low mechanical index methods, angiographic type images can be obtained
including delineating stenosis and differentiating from occlusion, as well as defining
thickness of the vessel wall in vasculitis. Specifically, within the carotid arteries
CEUS can identify plaque ulceration and show neovascularisation which presents an
increased risk of rupture and subsequent stroke.

Fig 32.12
Simultaneous B-mode and
CEUS image of a small
unilateral testis shown
on CEUS to have no
enhancement in keeping
with a missed torsion
The aorta is normally easily evaluated on conventional US, however CEUS may be
useful in follow up post endovascular aortic repair (EVAR). Identification of “endoleaks”
usually requires CT but CEUS has been shown to accurately characterise the type
including those previously classified as “endotension” (sac expansion with no source
seen).
Assessing for vascular patency in further vasculature (e.g portal vein) is also easily
performed at the macrovascular level and identifying infarction on a microvascular level.

32.4.4. Pancreas Remember

Adenocarcinoma is a common malignancy and typically shows hypoenhancement
on all phases of imaging. By contrast neuroendocrine tumours are hypervascular
in the arterial phase and show area of necrosis and haemorrhage with increasing
size. Importantly detailed assessment of the mesenteric vasculature can also be
undertaken to evaluate for surgical staging and determine potential for resection.
• CEUS provides detailed macrovascular assessment and can differentiate
occlusion from stenosis
• CEUS can differentiate types of endoleaks with similar and potentially
greater accuracy to CT

Cystic lesions of the pancreas may be either neoplastic or as a sequelae of

pancreatitis (pseudocysts). CEUS is able to characterise the complex cystic lesions
to identify areas of internal or solid enhancement and how thick or vascularised
septations or the wall lining are, and thereby predict the likelihood of mucinous
cystic neoplasia. Simple cystic lesions require no contrast administration.
32.4.5. Vascular
The peripheral vascular system is one of the areas for which the UCA is licensed.
Early utility was as a Doppler US rescue agent, in cases of inadequate assessment
of vascular patency.
32.4.6. Spleen
The spleen has a characteristic enhancement pattern on all modalities and readily
allows for identification of accessory tissue. Although intrasplenic lesions are rare,
CEUS can potentially aid characterisation. Benign lesions such as hamartomas
or haemangiomas typically show persistent late phase enhancement or lack of
enhancement in any phase. Washout in the late phase is not exclusively a malignant
feature and is shown in benign lesions (Fig 32.13). Splenic infarction is readily identified
as a typical peripheral, avascular region. Splenic abscesses, show rim enhancement
and septation with central pus-filled areas and is usually clinically apparent.

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WFUMB Course Book 32. CONTRAST ENHANCED ULTRASOUND

View enlarged image 32.4.8. Bowel

Bowel US has developed recently due to the high-resolution capabilities of US

Fig 32.13
Simultaneous B-mode
and CEUS image of a
focal hepatic cystic lesion
which showed early filling
in the arterial phase post
trauma in keeping with a
pseudoaneurysm
32.4.7. Trauma
allowing visualisation of the 5 sonographic bowel layers. In particular CEUS is of
use in inflammatory bowel disease (IBD) where repeated MR imaging is needed to
assess vascularity, which correlates with disease activity. Degree of enhancement
on CEUS has been show to relate to activity (Fig 32.14), whilst fibrotic strictures
show poor enhancement. In addition, complications of Crohn’s disease include
fistulation and abscess formation both of which can be discerned using CEUS, the
latter showing avascular components. Activity within defined segments affected by
IBD can be monitored but a limitation is the difficulty in ensuring all bowel loops
are visualised.
View enlarged image

Although CT remains the mainstay of polytrauma assessment, CEUS has been

shown to be as similarly effective at identifying solid organ injury, but is not suitable
to perform in a time critical situation. CEUS can be used in solid organ follow
up post trauma or for assessment of low impact blunt abdominal trauma. This is Fig 32.14
particularly important to reduce radiation dose as trauma tends to affect younger Simultaneous transverse
age group, including paediatric patients. Visceral laceration can be seen as an B-mode and CEUS image
avascular plane, whilst pooling of the UCA within these areas can help identify of the terminal ileum in a
active bleeding. Pseudoaneurysm formation is a critical aspect of follow up in solid Crohn’s disease patient
with hypervascularity
organ injury as it represents an unstable point for potential bleeding. CEUS clearly
and neovascularity of
visualises this as a saccular area of arterialisation (usually within a laceration the fat indicating active
plane) and arising from a regional artery. Often the typical “ying-yang” swirling can inflammation
be appreciated on CEUS (Fig 32.13).
As UCA is not excreted by the kidneys it is important to recognise that collecting
system injury cannot be assessed – limiting grading of injury.
32.4.9. Miscellaneous

Remember 32.4.9.1. Intracavity

Intracavity CEUS is a recently developed concept and works in a similar way to
• Rapid assessment of low impact trauma and follow up of solid organ injury
fluoroscopy. UCA are considered true intraluminal agents given the tiny size of the
with CEUS is accurate and can monitor for complications including active
microbubbles. A significantly lower dose of UCA is needed and often diluted in a
bleeding and pseudoaneurysm formation
solute to prevent excessive artefact within the examined area.

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WFUMB Course Book
Assessment of drain/line placement, fistulation and patency are the main uses
and include identification of communicating collections, visceral fistulation and
confirmation of gastrostomy/nephrostomy tube. Relatively little literature exists but
there has been confirmation of similar diagnostic accuracy of CEUS nephrostogram
with fluoroscopic nephrostograms (Fig 32.15). Anecdotal evidence also suggests
ingestion of oral contrast in an effort to identify gastric filling defects, fistulation or
gastroesophageal reflux, is a safe procedure.
View enlarged image
Fig 32.15a
UCA administered through
a nephrostomy tube
demonstrates the renal
pelvis and ureter
View enlarged image
Fig 32.15b
UCA administered through
a nephrostomy tube
demonstrates bladder filling
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32. CONTRAST ENHANCED ULTRASOUND
Dynamic assessment of reflux is now commonly performed using CEUS instead
of fluoroscopic micturating cystourethrograms. This is now considered first line
investigation in suspected vesico-ureteric reflux and is shown to upgrade the degree
of reflux as well as having an excellent safety profile. The investigation is performed
with bladder instillation of UCA followed by repeated imaging pre and post voiding.
Sono-hysterosalpingograms have replaced conventional fluoroscopic
hysterosalpingograms, and utilise saline as a contrast agent owing to the
unnecessary additional cost of UCA in most cases. Rarely UCA may be required in
equivocal cases.
32.4.9.2. Interventional procedures
CEUS lends itself well to intervention, being capable of examining both the macro
and microvasculature as well as intracavity evaluation. The primary use is aiding
lesional visualisation and targeting of significant areas (vascular areas for biopsy
and fluid areas for drainage) (Fig 32.16).
Assessment through intracavity evaluation may also be helpful to confirm needle
position prior to further intervention. Post procedural CEUS can be used to identify
complications including active bleeding and confirm response in cases such as
embolisation or ablation.
View enlarged image
Fig 32.16
Simultaneous transverse
B-mode and CEUS image of
an occult liver lesion lesion
on B mode, which is better
seen on CEUS allowing
targeting of a biopsy
WFUMB Course Book 32. CONTRAST ENHANCED ULTRASOUND

Recommended reading

• Dietrich CF, Nolsøe CP, Barr RG, Berzigotti A, Burns PN, Cantisani V, Chammas
MC, Chaubal N, Choi BI, Clevert DA, Cui X. Guidelines and Good Clinical
Practice Recommendations for Contrast-Enhanced Ultrasound (CEUS) in the
Liver–Update 2020 WFUMB in Cooperation with EFSUMB, AFSUMB, AIUM,
and FLAUS. Ultrasound in medicine & biology. 2020 Jul 24
• Huang DY, Yusuf GT, Daneshi M, Husainy MA, Ramnarine R, Sellars ME,
Sidhu PS. Contrast-enhanced US–guided interventions: improving success
rate and avoiding complications using US contrast agents. Radiographics.
2017 Mar;37(2):652-64
• Nylund K, Maconi G, Hollerweger A, Ripolles T, Pallotta N, Higginson A, Serra
C, Dietrich CF, Sporea I, Saftoiu A, Dirks K. EFSUMB recommendations and
guidelines for gastrointestinal ultrasound.
• Park BK, Kim B, Kim SH, Ko K, Lee HM, Choi HY. Assessment of cystic renal
masses based on Bosniak classification: comparison of CT and contrast-
enhanced US. European journal of radiology. 2007 Feb 1;61(2):310-4.
• Piscaglia F, Bolondi L. The safety of Sonovue® in abdominal applications:
Retrospective analysis of 23188 investigations. Ultrasound in medicine &
biology. 2006 Sep 1;32(9):1369-75.
• Rafailidis V, Huang DY, Yusuf GT, Sidhu PS. General principles and overview
of vascular contrast-enhanced ultrasonography. Ultrasonography. 2020
Jan;39(1):22
• Sidhu PS, Cantisani V, Dietrich CF, Gilja OH, Saftoiu A, Bartels E, Bertolotto
M, Calliada F, Clevert DA, Cosgrove D, Deganello A. The EFSUMB guidelines
and recommendations for the clinical practice of contrast-enhanced ultrasound
(CEUS) in non-hepatic applications: update 2017 (long version). Ultraschall in
der Medizin-European Journal of Ultrasound. 2018 Apr;39(02):e2-44
• Yusuf GT, Fang C, Huang DY, Sellars ME, Deganello A, Sidhu PS. Endocavitary
contrast enhanced ultrasound (CEUS): a novel problem solving technique.
Insights into imaging. 2018 Jun;9(3):303-11

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