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t
1.
2.
3.
t
t
Transmitted
Tissue echo
Microbubble echo
p = Pressuret = time
16 Contrast-Enhanced Ultrasonography: Clinical Applications
Fig. 16.2 The theoretical
background of pulse-inversion
techniques: two pulses are
transmitted rapidly to tissue
and microbubbles. The second
pulse is an inverted copy of
the rst pulse. Tissue
responds with linear echoes,
which summarize results to
zero. Microbubbles show
nonlinear kinetics, resulting in
increased echoes when
summarized
First pulse
p
pulse
333
-linear-
t
t
-non-linear-
t
Inverted pulse
Sum
Table 16.1 Regulatory status of available ultrasound contrast agents
Brand name (manufacturer) Inner gas Outer shell Approved indications Marketed in
Denity/Luminity® (Lantheus Medical
Imaging)
Optison® (GE Healthcare) Perutren Albumin Cardiology USA, Europe
SonoVue®/Lumason® (Bracco
Imaging)
Sonazoid® (GE Healthcare) Perubutane Lipid Liver
a
Only in certain countries
Perutren Lipid Cardiology, liver
Sulfur
hexauoride
Phospholipid Cardiology, breast
vessels
vessels
a
a
a
, breast
a
a
, kidneya,
a
, livera,
t
t
USA, Canada, Europe, Australia,
parts of Asia
USA, New Zealand, Europe, Brazil,
parts of Asia
Japan, South Korea
and countries, with SonoVue® being the leading agent in
general use [4, 17].
16.3 Clinical Applications ofCEUS inHead
able diagnostic pathways or suggestions for using CEUS in
everyday routines.
16.3.1 Salivary Gland Tumors
andNeck Sonography
Tumors of the salivary glands are uncommon and represent
As explained above, CEUS in the head and neck is still an
experimental modality without an international consensus
regarding indications and particular recommendations. The
European CEUS guidelines for extrahepatic indications also
encourage the use of contrast-enhanced sonography for some
indications involving the head and neck. Furthermore,
experts worldwide publish more and more results of CEUS
studies affecting such indications. They often provide valu-
only about 3% of all head and neck neoplasms [18].
Nevertheless, they are a very heterogeneous group. In more
than 80% of all cases, the tumors occur in the parotid gland;
more than 80% of those are benign lesions. The incidence of
malignant tumors is estimated at about 15% [19]. The most
frequent benign salivary gland tumor is pleomorphic adenoma, with 70–80% of all cases, followed by cystadenolymphomas, also known as Warthin’s tumor (5–12%). The most
334
J. Küstermeyer
common malignant tumor is mucoepidermoid carcinoma,
followed by squamous cell carcinoma, acinic cell carcinoma,
lymphoma, and metastases [20]. Detailed pretherapeutic
characterization of those neoplasms is useful for determining
the surgical procedure and choosing the right level of radicality. Histopathological examination is still the gold
standard for conrming the diagnosis of salivary gland
tumors, but some authors report improvement of the differentiation of those heterogeneous pathologies by using CEUS.
Pleomorphic Adenoma
The incidence of pleomorphic adenoma is higher in women
than in men, with a peak in the fth decade and accumulation
in the supercial lobe [20]. Though pleomorphic adenoma is
a benign entity, it can cause some complications. It can create pressure that injures the facial nerve, or it can transform
into a carcinoma. Furthermore, if the capsule is damaged
during surgical excision, there is a high risk of local recurrences, since spreading of the tumor cells leads to a multilocular appearance of pleomorphic adenoma in the primary
location. Hence, a complete resection with clear margins
should be performed as early as possible.
Pleomorphic adenoma shows characteristic perfusion patterns. Qualitative analysis reveals a rich capsular perfusion
with only slight perfusion in the center of the tumor (Fig.16.3
and Video 16.1). Examining the time-intensity curve of a
pleomorphic adenoma shows some specic features when
compared with other entities (Fig.16.4) [21–23].
Fig. 16.3 A pleomorphic adenoma displayed in B-mode sonography
(left) and contrast-enhanced ultrasound (CEUS) (right). B-mode shows
characteristic features including the sharply demarcated border, the
polylobular conguration, posterior acoustic enhancement, and the
Fig. 16.4 A time-intensity curve of a pleomorphic adenoma shows the perfusion intensity dependent on the time after application of the contrast
agent. The time to peak (TTP) is about 17seconds
typical localization inside the lateral parotid lobe. CEUS distinguishes
the hyperperfused capsule, especially in the deep areas of the tumor. In
the center of the tumor, CEUS detects no signs of signicant perfusion
(see also Video 16.1)
16 Contrast-Enhanced Ultrasonography: Clinical Applications
335
Fig. 16.5 A carcinoma ex pleomorphic adenoma in B-mode (left) and
CEUS (right). B-mode shows the same characteristic features as the
pleomorphic adenoma (Fig. 16.3). Qualitative perfusion analysis by
Fig. 16.6 Color-coded duplex sonography of a carcinoma ex pleomor-
phic adenoma after application of a contrast agent shows hypervascularization of the capsule and in the center of the tumor, with B-mode
features similar to those of a benign pleomorphic adenoma
Carcinoma Ex Pleomorphic Adenoma
Malignant transformation into a carcinoma ex pleomorphic adenoma has been reported to occur in 3–4% of all
cases [24]. In B-mode sonography, the malignant tumor
presents almost the same characteristics as the pleomorphic adenoma (see Fig.16.3). Analogous to other malignant tumors, this entity shows increased perfusion, which
can be detected by CEUS (Figs. 16.5, 16.6, and 16.7).
Besides the highly perfused capsule, as in pleomorphic
adenoma, perfusion can also be observed in the center of
the tumor. Quantitatively, the perfusion shows different
properties, with a shorter time to peak (TTP), as discussed
below.
CEUS detects the hyperperfused capsule and, in addition, perfusion in
the center of the tumor. The perfusion originates from the depth and
reaches the central areas of the tumor
Cystadenolymphoma (Warthin’s Tumor)
Cystadenolymphoma is also known as Warthin’s tumor,
named after Aldred Scott Warthin, an American pathologist.
It is the second most common benign tumor entity of the salivary glands, usually occurring in men, with a peak in the
sixth decade. Lesions can be bilateral and multicentric. Cases
of extraglandular tumors have also been described.
Cystadenolymphomas appear most commonly in the parotid
tail region. A relation to cigarette smoking is known [20, 25].
Warthin’s tumors show some characteristic sonographic features that help to differentiate them from other entities
(Figs.16.8 and 16.9 and Video 16.2).
Table 16.2 shows different properties of the two most frequent benign salivary gland tumors.
16.3.2 Inammatory Diseases oftheSalivary
Glands
Besides neoplasms, inammatory diseases of the salivary
glands are prevalent. In most cases, the combination of clinical examination, B-mode sonography, and, if applicable,
color-coded duplex sonography leads to the right diagnosis.
For example, acute parotitis, the most frequent inammatory
alteration of the salivary glands in the elderly, shows very
characteristic features. Some authors have reported studies
using CEUS for obstructive salivary gland diseases. The contrast agent can be applied intraductally to detect sialolithiasis
and monitor the effectiveness of therapeutic procedures [26,
27]. The European CEUS guidelines mention this scope of
application [4].
336
J. Küstermeyer
Fig. 16.7 A time-intensity curve of a carcinoma ex pleomorphic adenoma shows the perfusion intensity dependent on the time after application
of the contrast agent. The time to peak (TTP) is about 20seconds. A steep increase begins after 15seconds
Fig. 16.8 A Warthin’s tumor in B-mode (left) and CEUS (right).
B-mode shows characteristic features including the sharply demarcated
border, a mixed echogenicity with hypoechoic zones, and slight poste-
rior acoustic enhancement. CEUS detects the septal perfusion in the
center of the tumor inside the hyperechoic zones and reveals no perfusion inside the cystic areas (see also Video 16.2)
Sjögren’s Syndrome
Sjögren’s syndrome is an autoimmune disease affecting
primarily the salivary and lacrimal glands; it leads to dryness in the mouth and eyes. Sonographic examination of
the parotid glands typically presents ndings with multiple echoic lesions. Loss of function is characterized by
decreased vascularization and perfusion (Figs.16.10 and
16.11).
16 Contrast-Enhanced Ultrasonography: Clinical Applications
337
Fig. 16.9 A time-intensity curve of a Warthin’s tumor shows the perfu-
sion intensity dependent on the time after application of the contrast
agent. The time to peak (TTP) is about 9seconds. The perfusion analy-
Table 16.2 Characteristics of pleomorphic adenoma and Warthin’s tumor
Parameter Pleomorphic adenoma Warthin’s tumor
Demarcation/outlining Sharply demarcated border; polylobular
Posterior acoustic enhancement +++ +
Vascularization/color-coded duplex
sonography
Contrast-enhanced ultrasound (CEUS) Hyperperfused capsule, low perfusion in the
conguration
Hypervascularized capsule in the depth; seldom
detectable vessels in the tumor’s center
center
sis reveals a higher area under the curve (AUC) compared with pleomorphic adenomas (see Fig.16.4)
Sharply demarcated border; oval, hypoechoic
zones
Septal vascularization mainly in the center inside
hyperechoic zones; vascularized capsule possible
Septal perfusion, cystic areas without perfusion
Fig. 16.10 A parotid gland in B-mode (left) and CEUS (right), with characteristic multiple alterations for Sjögren’s syndrome. B-mode sonogra-
phy typically shows various hypoechoic zones. CEUS demonstrates multiple areas with no perfusion disseminated all over the salivary gland
16.3.3 Quantitative Analysis Based
onTime- Intensity Curves
time (MTT), and intensity changes (∆i). Some studies point
out that in pleomorphic adenoma, the TTP is signicantly
longer than in Warthin’s tumors [24, 28]. Other studies
Besides qualitative analysis, quantitative examinations
based on time-intensity curves (TICs) can be used to assess
perfusion characteristics. The literature describes different
ways to distinguish between pathologies. Most studies
compare various parameters in the TIC, such as the area
under the curve (AUC), time to peak (TTP), mean transit
describe signicant differences of the AUC between benign
and malignant tumors, as well as between pleomorphic
adenoma and Warthin’s tumors (see Figs.16.4, 16.7, and
16.9) [29]. These differences of perfusion can also be
detected by comparing multiple regions of interest inside
the assessed tumors [22].
338
Fig. 16.11 The same parotid gland as in Fig. 16.10, with Sjögren’s
syndrome: color-coded duplex sonography detects intense hypervascularized areas between the hypoechoic zones
Using CEUS to differentiate salivary gland tumors is still
controversial, however. Some authors even see no benet of
distinguishing salivary gland tumors by CEUS [30].
J. Küstermeyer
Fig. 16.12 Color-coded duplex sonography shows a reactive lymph
node after application of a microbubble contrast agent. The vascularized hilum, which spreads centrifugally, can be detected. Further, the
capsule is hypervascularized. The examination of the center reveals no
signs of vascularization independent from the hilar vessels
16.3.4 Lymph Nodes
Lymphadenopathy of unclear etiology is a frequent reason
for consulting a head and neck specialist. Early and accurate diagnosis is crucial for selecting the right therapy and
preventing time delay in cases of malignant entities.
Hence, the question regarding the node’s malignancy is
the central focus. Various studies have analyzed vascular
patterns of lymphadenopathy by using CEUS, with the
aim of distinguishing between benign and malignant
nodes. Their results differ according to the modalities utilized and the parameters examined. Many studies describe
color-coded duplex sonographic examinations that used
microbubble contrast agents [31–37]. Their authors controversially discuss whether the application of contrastenhanced color-coded duplex sonography increases
diagnostic accuracy. Other reports have assessed low
mechanical index B-mode sonography in combination
with microbubbles [38–40].
Perfusion patterns of malignant tumors differ from those
of benign alterations. Malignant tumors secrete angiogenic
factors, which lead to neoangiogenesis. The resulting de
novo vessels differ from physiological vessels. They build
chaotic branches and penetrate the lymph node’s capsule,
and they also create porous vessels with high rates of leakage. CEUS helps to detect those properties by analyzing the
perfusion patterns. Nevertheless, existing guidelines do not
recommend the use of CEUS for routine discrimination
between benign and malignant lymph nodes. Only in particular clinical settings can CEUS increase the diagnostic
benet [4].
Inammatory Reaction
Infectious and inammatory diseases in most cases lead to
collateral reactive lymphadenopathy. Their preserved physiological morphology and vascularization can help to identify
benign lymph nodes. Reactive lymph nodes appear characteristically with sharply demarcated borders and a single hilum
structure, which contains vessels spreading from the center to
the periphery (centrifugal). This vascularization can be
detected by CEUS and contrast-enhanced color-coded duplex
sonography (Figs.16.12 and 16.13 and Video 16.3) [41].
Malignant Lymphomas
Malignant lymphomas represent a category with a vast variety of entities. The polymorphic appearance makes it hard to
differentiate this kind of lymphadenopathy with universal
sonographic features. Furthermore, lymph nodes affected by
a lymphoma have perfusion characteristics quite similar to
those of reactive nodes. Therefore, the differentiation of
benign lymph nodes and malignant lymphomas is not yet
possible with high rates of sensitivity and specicity [4, 39,
41, 42].
Typical sonographic ndings in lymphoma are sharply
demarcated borders and clear, identiable hilum structures.
These are often hypervascularized in color-coded duplex
examinations, with often well-sorted vessels and a centrifugal perfusion. The CEUS shows a homogeneous and intense
hyperperfusion (Figs.16.14 and 16.15).
Carcinoma Metastasis
Compared with benign lymphadenopathies and the formerly
described lymphomas, lymph nodes affected by carcinoma
16 Contrast-Enhanced Ultrasonography: Clinical Applications
339
Fig. 16.13 The same reactive lymph node as shown in Fig.16.12 in
B-mode (left) and CEUS (right): B-mode shows characteristic features
including an oval conguration and a sharply demarcated border. The
Fig. 16.14 Color-coded duplex sonography shows a lymph node,
affected by a non-Hodgkin lymphoma, after application of a microbubble contrast agent. The very prominent hilum is strongly hypervascularized. The detectable ow crosses the node’s entire diameter, with
noticeable branching
metastasis show very characteristic features. Because of the
induced neoangiogenesis, which causes the creation of leaky
and chaotically arranged de novo vessels, necrotic zones typically can be detected (Figs.16.16 and 16.17 and Video 16.4).
Besides qualitative features, some authors describe quantitative markers to distinguish between benign and malignant
alterations. Their analyses of time-intensity curves revealed
a signicantly shorter time to peak (TTP) in malignant lymph
nodes than in reactive ones. Furthermore, the area under the
curve (AUC) as a marker for perfusion intensity was signi-
hilum is not well distinguished because of the low mechanical index
mode. CEUS reveals intense homogeneous enhancement in the whole
lymph node with centrifugal perfusion kinetics (see also Video 16.3)
cantly greater in reactive lymphadenopathy than in malignant alterations [39, 40].
16.3.5 Paragangliomas
Paragangliomas are highly vascularized tumors. Their occurrence is ubiquitous in all body regions. In the head and neck,
paragangliomas appear as glomus caroticum, glomus jugulare, and glomus vagale tumors. Glomus caroticum tumors
are particularly accessible by ultrasound examinations.
Interventional radiologists usually embolize glomus
caroticum tumors prior to a surgical resection, to reduce
intraoperative bleeding. Digital subtraction angiography
(DSA) allows occlusion of feeder vessels under radioscopy.
This modality provides qualitative analysis of perfusion patterns in real time, but the embolization effect is not measured
quantitatively. The disadvantages of DSA for head and neck
specialists are the limited quantitative information about perfusion and the dependence on radiologists to perform the
examination.
Some studies have demonstrated the benet of using
CEUS in the assessment of carotid paraganglioma. In particular, monitoring of the embolization effect with CEUS is a
promising technique. It combines the advantages of noninvasiveness and quantitative analysis, and it is a tool in the hands
of the head and neck specialist (Figs.16.18, 16.19, 16.20 and
16.21 and Video 16.5) [43, 44].
340
J. Küstermeyer
Fig. 16.15 The same lymph node as shown in Fig.16.14, affected by
a non-Hodgkin lymphoma, in B-mode (left) and CEUS (right). B-mode
displays an enlarged lymph node near the mandible. CEUS detects an
Fig. 16.16 A carcinoma metastasis in color-coded duplex sonography
after application of a microbubble contrast agent. The tumor’s extreme
hypervascularization with chaotically arranged vessels is ubiquitous
16.3.6 Dierential Diagnosis ofThyroid
Alterations
Thyroid nodules can be detected in 19–68% of examined
patients with modern ultrasound techniques [45], but only
5% of clinically identied nodules are malignant [46].
Distinguishing between benign and malignant alterations is
thus very important to prevent time delay in the treatment of
thyroid cancer and, furthermore, to reduce potential harm
due to overtreatment.
intense enhancement with a maximum in the depth. Remarkably, the
surrounding tissue shows almost no perfusion, compared with the
lymphoma
The American Thyroid Association (ATA) published
guidelines for the management of thyroid nodules in adults
[45]. These describe ultrasonographic patterns of nodules in
detail concerning B-mode sonography and color-coded
duplex sonography. Scoring of suspicious nodules with an
algorithm system helps to estimate the risk of malignancy
and decide between wait-and-see, ultrasound-guided neneedle aspiration, or surgery. Recommendations for using
CEUS are still missing. Another guideline was created in
2016 by the American Association of Clinical
Endocrinologists, the American College of Endocrinology,
and the Associazione Medici Endocrinologi [47]. It even
advises against the use of CEUS.
Features of high-risk malignant nodules are “a solid
hypoechoic nodule or solid hypoechoic component of a partially cystic nodule with one or more of the following features: irregular margins (inltrative, microlobulated),
microcalcications, taller than wide shape, rim calcications
with small extrusive soft tissue component, evidence of
extrathyroidal extension” [47].
The rst papers about studies using CEUS to improve
diagnostic accuracy in examining thyroid nodules were published in the early 2000s [48–50]. Meanwhile, studies about
contrast-enhanced sonography of the thyroid gland have
been published increasingly, especially in the past few years
[46, 51–59].
16 Contrast-Enhanced Ultrasonography: Clinical Applications
341
Fig. 16.17 The same carcinoma metastasis as shown in Fig.16.16 in
B-mode (left) and CEUS (right). B-mode shows a round, enlarged
lymph node inside the parotid gland. CEUS detects intense, inhomoge-
neous enhancement, including areas without perfusion, corresponding
to necrotic tumor zones (see also Video 16.4)
Fig. 16.18 CEUS examination of a paraganglioma at the carotid bifur-
cation. The tumor shows intense, homogeneous perfusion in all areas.
Because of the hyperperfusion, distinguishing between tumor and
carotid arteries is not possible
Fig. 16.19 CEUS examination of the same paraganglioma as shown in
Fig.16.18, after embolization of a feeder vessel. The tumor now presents inhomogeneous perfusion, especially with a decrease in the supercial areas. The external carotid artery (left circle) and the internal
carotid artery (right circle) are demarcated from the tumor (dotted line)
(see also Video 16.5)
342
J. Küstermeyer
Fig. 16.20 The time-intensity curve of the glomus tumor shown in Fig.16.18. In the early wash-in phase, the perfusion intensity increases by
about 24dB.The time to peak (TTP) is about 15seconds
Fig. 16.21 Time-intensity curve of the same tumor as shown in
Fig.16.19, after embolization of a feeder vessel. The perfusion intensity decreases compared with Fig.16.20. The time-intensity curve conrms the embolization effect. It rises by only about 15dB, and the time
to peak (TTP) is longer, at about 21seconds
Qualitative analysis of thyroid nodules’ perfusion patterns aims at a description (homogeneous, heterogeneous,
hyper-enhancement, hypo-enhancement, and isoenhancement) and a comparison with the surrounding gland
tissue. Some authors conclude that heterogeneous hypo-
Fig. 16.22 Color-coded duplex scan of a thyroid gland with two nod-
ules. The lower left nodule (a thyroid adenoma) is sharply demarcated,
with a surrounding halo sign and homogeneous echogenicity. The
upper right nodule (a thyroid papillary carcinoma) shows no regular
borders, with an irregular ring structure, homogeneous echogenicity,
and hypervascularization compared with the adjacent parenchyma
enhancement of nodules is a criterion for a higher risk of
malignancy [54, 56, 59]. Additional criteria that seem to help
in predicting malignancy are irregular, hyper-enhancement
ring perfusion and no-enhancement ring perfusion
(Figs.16.22, 16.23, and 16.24 and Video 16.6) [56, 59].