Key words
B-scan - contrast-enhanced ultrasound - elastography - interventional - doppler ultrasonography
Introduction
One reason for the growing importance of ultrasound and the increase in possible applications
is the establishment of new modalities that have shifted in recent years from use
purely for research to use in the clinical routine. In particular, sonoelastography
and contrast-enhanced ultrasound (CEUS) have a number of well-established diagnostic
applications. The development of new ultrasound methods with increasing technological
diversity presents new challenges for radiologists. Diagnostic ultrasound imaging
is an integral part of radiology training. However, it is currently established in
only 78.5 % of radiology departments as a routine diagnostic imaging method, while
contrast-enhanced ultrasound is established in only 26 %. A possible solution here
could be interdisciplinary ultrasound centers. In particular, training and continuing
education can be better organized in combination and the use of high-end devices can
be additionally optimized [2].
Knowledge of the technical principles of new ultrasound modalities, their possible
applications in various organ systems, and their limitations is necessary to ensure
optimal use of diagnostic ultrasound imaging. In addition to purely diagnostic modalities,
local ablative procedures using ultrasound as part of tumor therapy have also become
more diverse in recent years and have been included in guidelines. It is essential
to know the strengths and weaknesses of each local ablative method in order to be
able to select the best method for a particular case. An example of this is the use
of ultrasound-guided microwave ablation (MWA) in large tumor lesions that may not
be able to be sufficiently covered by radiofrequency ablation.
Fusion imaging makes it possible to combine real-time ultrasound examination with
previously acquired CT or MRI datasets. As a result, lesions that are difficult to
access or are very small can be biopsied better under ultrasound guidance or a more
precise differential diagnosis of lesions can be achieved using a multimodal approach.
The various new ultrasound modalities are presented in the following with respect
to their current clinical significance in the individual areas of application.
Contrast-enhanced ultrasound (CEUS)
Contrast-enhanced ultrasound (CEUS)
Technique
Microbubbles are administered intravenously in contrast-enhanced ultrasound (CEUS).
The microbubbles are a few μm in size and oscillate after longitudinal ultrasound
wave excitation in the examination field at a low mechanical index. The oscillating
microbubbles generate nonlinear oscillations. The received contrast signal can be
differentiated from the tissue signal by corresponding contrast agent software. Using
real-time imaging software, organ vascularization can be visualized and also quantified.
In contrast to contrast agents used in CT/MRI, the ultrasound contrast agent primarily
used in Germany(SonoVue®, Bracco, Milano, Italy) is a purely intravascular contrast agent. Thus, the ultrasound
contrast agent primarily used in Germany is not absorbed by body cells [3]. Given the high percentage of gas, the ultrasound contrast agent is primarily eliminated
via the lungs. The small amount of bubble shells is eliminated by the hepatobiliary
system. Therefore, application in patients with limited renal function is possible.
The risk of serious adverse events is very low at less than 0.008 % [4].
Clinical applications
CEUS is most commonly used to examine the organs of the upper abdomen, mainly the
liver and kidneys ([Fig. 1]). While B-mode ultrasound in combination with color Doppler is often sufficient
to characterize simple cysts and typical liver hemangiomas, CEUS can be used to characterize
all other unclear focal and extensive changes in the liver with a sensitivity of over
90 % [5]. Characterization is based on the contrast agent behavior in the arterial phase
(up to approx. 25 seconds after injection), in the portal venous phase (starting approx.
25–45 seconds after injection) and in the late phase (starting 2 minutes after injection).
The type of wash-in and the degree of contrast enhancement in the arterial phase and
the contrast behavior in the venous and the late phase provide important information
regarding the benign/malignant status of a liver lesion and the liver tumor entity.
For example, washout over the course of imaging is an important sign of malignancy.
For example, particularly late washout with significant arterial enhancement and a
chaotic vascular pattern is typical for hepatocellular carcinoma (HCC).
Fig. 1 Giant hemangioma with central thrombosis with typical nodule-like rim enhancement
in contrast-enhanced ultrasound (CEUS).
Cystic renal lesions are common incidental findings on CT and MRI but often cannot
be sufficiently characterized, for example, by single-phase CT. An increase in size
or protein-rich deposits are common even in simple cysts but can result in uncertainty
when interpreting results. The first step to clarify here is B-mode ultrasound and
color Doppler. Vessels should not be visible within a simple renal cyst on color-coded
duplex ultrasound since the presence of vessels indicates solid tissue. CEUS allows
more precise evaluation of possible vascularization and the vascularization pattern,
e. g. in internal septa, in real time allowing better evaluation of the malignancy
risk of cystic as well as solid renal lesions [6]. However, since CEUS is significantly more sensitive than CT with respect to weak
blood flow, e. g. in septa or in the cystic wall, “upgrading” of the Bosniak classification
can occur which then affects the specificity. The high sensitivity of CEUS with respect
to weak blood flow can result in even minimally vascularized papillary renal carcinomas
being better detected with this modality than with CT.
In addition to the organs of the upper abdomen, CEUS can also be used, for example,
in the skeletal musculature to visualize and quantify microperfusion [7]. The studies by Fischer et al. and Doll et al. with a significantly better differentiation
between septic and non-septic impaired fracture healing show an innovative application
of CEUS. The sensitivity and specificity are 85.1 % and 88.7 %, respectively [8]
[9]. As shown by Marcon et al., CEUS is also increasingly important for answering questions
regarding the testicles in testicular trauma, suspicion of testicular torsion, scrotal
infections, or testicular tumors [10]. For example, it allows significantly better differentiation between a simple testicular
cyst and a cystic testicular tumor with partial perfusion. The results of multiple
studies regarding contrast behavior in the differentiation of seminomas from Leydig
cell tumors are not definitive even though fast wash in and washout must be assessed
as a sign of malignancy. In the case of testicular laceration caused by trauma, CEUS
can be used to differentiate areas with better perfusion from those with less perfusion,
thereby contributing to testis-sparing surgery.
In addition, for years CEUS has been an important instrument in endoleak diagnosis
after stent placement in large vessels. In recent years, CEUS has become established
in the detection and characterization of endoleaks in the clinical routine and represents
an important diagnostic method initially and during follow-up. In many cases, it can
replace CT imaging which requires irradiation and nephrotoxic X-ray contrast media
[11].
Microvascular Doppler methods with interference suppression algorithm
Microvascular Doppler methods with interference suppression algorithm
Technique
In contrast to regular color and power Doppler, the latest microvascular Doppler modalities
can be used to visualize even small vessels with low flow rates. The technical approach
is the expanded suppression of interference signals so that weak flow signals can
also be detected and this information can be provided with a high image refresh rate
[12]. Minimal flow can be shown in the form of a color overlay image or based on grayscales
with subtraction of the underlying B-mode image.
Clinical applications
Microvascular Doppler methods with an interference suppression algorithm can be used,
for example, to detect and evaluate the vascularization of parenchymatous lesions
[13] ([Fig. 2]). These methods are primarily used for oncological issues with parallels to CEUS
application areas, e. g., for primary diagnosis or for follow-up during therapy. For
example, Dubinsky et al. show that microvascular Doppler methods are superior to color/power Doppler
for the evaluation of the vascularization of small HCC lesions of the liver (< 2 cm)
[14]. Compared to conventional Doppler modalities, microvascular Doppler methods are
superior with respect to the evaluation of the benign/malignant status of cervical
lymph nodes [15] as well as in the case of renal lesions like renal cell carcinomas [16] or with respect to the vascularization of complex cysts [17].
Fig. 2 Illustration of a typical focal nodular hyperplasia (FNH) in a young female patient
in the different modes. a B-scan display, b contrast-enhanced ultrasound arterial phase (CEUS), c microvascular Doppler technique monochrome), d microvascular Doppler technique color.
There are a number of studies comparing microvascular Doppler methods to regular color/power
Doppler or CEUS. Microvascular Doppler methods and CEUS have comparable sensitivity
with respect to differentiating benign from malignant thyroid nodules. For microvascular
Doppler methods, Gabriel et al. show comparable applicability, sensitivity, and reproducibility
in the diagnosis of endoleaks after “endovascular aneurysm repair” (EVAR) compared
to CEUS and CT angiography [19]. Microvascular Doppler methods performed sequentially in combination with regular
Doppler methods has a diagnostic benefit also in acute diagnosis as in the diagnosis
of acute cholecystitis [20]. However, numerous studies on microvascular Doppler methods also reference application
areas outside of the abdomen: Park et al. showed the superiority of microvascular
Doppler methods compared to conventional Doppler modalities regarding the detection
of the vascularization of breast tumors [21] or in carpal tunnel syndrome [22]. The precise visualization of the smallest vessels by microvascular Doppler methods
– particularly in monochrome mode – was confirmed also in the examination of the testicles
to evaluate vascularization of the parenchyma [23].
There are numerous applications of microvascular Doppler methods in children and especially
in newborns. As an example, microvascular Doppler methods can be used to evaluate
the vascularization of the testicles or to evaluate the perfusion of the brain parenchyma
[12].
A disadvantage of microvascular Doppler methods is that to date there is no quantification
method and the degree of vascularization can only be provided in the form of semiquantitative
scores [24].
Fusion imaging
Technique
For several years, it has been possible to fuse CT or MRI datasets with real-time
ultrasound examinations. A CT or MRI examination stored in DICOM format is imported
to an ultrasound device. After coupling of the datasets with the probe position in
the region of corresponding organ structures on three spatial planes, both the ultrasound
image in real time and the CT/MRI image can be viewed and evaluated in parallel ([Fig. 3]). There are numerous possible applications, particularly in the characterization
of parenchymal lesions as well as during interventions [25]. Ultrasound compensates for the limitations of computed tomography like partial
volume effects, respiratory motion artifacts, and phase-based contrast enhancement.
Fig. 3 Representation of an upper abdominal situs in fusion mode, longitudinal section on
the B-scan and in computed tomography (CT). a Representation of the superimposition of CT and sonography, b Representation on the B-image, c Representation on CT, d Position of the transducer in relation to the trunk.
Clinical applications
Successful image fusion has been discussed in detail in multiple studies: For example,
Ewertsen et al. were able to show that unclear lesions were easier to characterize
via image fusion between ultrasound and CT/MRI and that the benign/malignant status
of a greater number of lesions can then be clarified. In addition to image fusion
with CT and MRI datasets, PET-CT data can also be used [26]. Fusion imaging is primarily used for oncological applications like the detection
and diagnosis of liver lesions in the clinical routine. Particularly in the case of
a small lesion size of less than 10 mm, the use of real time ultrasound-guided fusion
imaging offers advantages with respect to detection on the B-mode image. Okamoto et al. were able to show in this context that smaller parenchymal lesions missed by
regular B-mode ultrasound can be detected by fusion imaging [27]. An advantage of fusion imaging with respect to the detection rate of renal lesions
was also able to be shown [28]. Interventional methods and biopsies represent a further field of application [29]. Fusion imaging expands the possibilities with respect to planning, implementation,
and measurement of results. The most common application in this connection is puncture
or ablation of lesions that are difficult to detect on ultrasound or are very small
and suspicious for tumor [29]
[30]
[31]. Tumor areas that are still vital after intervention, their precise anatomical surroundings,
e. g. adjacent vessels, gas formation during treatment, or subsequent bleeding can
be better detected via fusion imaging. In addition, limitations that can arise as
a result of movement of the liver during respiration can be compensated at least partially
by ultrasound image fusion [32]. A further application area of fusion imaging is the diagnosis of prostate cancer.
As a result of the fusion of MRI and various ultrasound modalities, the accuracy of
targeted transrectal prostate biopsies can be increased and an initial evaluation
of the aggressiveness of prostate cancer can be performed [33].
While image fusion was associated with a significant time requirement in the early
years, technical developments now allow quick application in the clinical routine.
With the establishment of new cross-sectional imaging methods, e. g. PET-MRI, fusion
imaging can be expected to become increasingly important in the future.
Elastography
Technique
In recent years, multiple ultrasound-based elastography methods for noninvasive determination
of tissue elasticity have been developed. Their primary clinical application is the
diagnosis and staging of fibrotic liver diseases and they supplement and sometimes
even replace the results of the current diagnostic gold standard, liver biopsy. The
first method used in this area was transient elastography (TE). Although it has become
established globally as a reliable non-imaging method for determining liver elasticity,
it has various limitations including high dependence on the type of examination [34]. A new generation of elastography methods that do not depend on mechanical impulses
for generating shear waves but rather use high-intensity ultrasound waves is collectively
referred to as point shear wave elastography (pSWE). With similar or even superior
diagnostic precision, the point shear wave methods are more practical than TE and
also yield valid measurements in patients with a high body mass index (BMI) or ascites
[35]. Moreover, as imaging methods they have the advantage that the examiner can use
the anatomical B-mode scan to select a suitable location in the tissue for determining
elasticity [36]. Some point shear wave methods can quantify tissue elasticity indirectly from the
velocity of the induced shear waves. The point shear wave elastography method allows
quantification of the shear wave velocity and is capable of providing a single value
in m/s or kPa in a field selected via B-mode imaging.
Clinical applications
Multiple studies have confirmed that the pSWE technique/virtual TouchTM tissue quantification
(VTQ) is a valid staging method in liver fibrosis: A meta-analysis of eight studies
with the AUROC (area under the receiver operating curve) yielded an accuracy of 0.87
for VTQ for significant liver fibrosis and 0.93 for cirrhosis, with liver biopsy being
used as the reference standard [37]. 2D shear wave elastography (2D SWE) allows a very high frame rate in real-time
images of shear wave propagation in a focused area. The result is a two-dimensional,
color-coded elastogram in which a measurement field can be placed to detect quantitative
data [36]. The most studied 2D-SWE method is the ultrasound shear imaging technique (SSI,
Aixplorer®) [38]. Other manufacturers have increasingly integrated elastography methods in their
ultrasound devices. However, the data currently available regarding the generation
of normal values and cut-off limits for liver stiffness as well as the comparability
with already established methods is often still poor [39]. One current study including 4 different ultrasound devices was able to show high
comparability of shear wave velocities but only in healthy subjects [40] ([Fig. 4]). The determination of tissue elasticity in untreated chronic hepatitis B and C
to rule out significant fibrosis and cirrhosis is currently considered a definite
indication. Liver stiffness typically decreases under antiviral treatment with analogs.
Screening for possible hepatocellular carcinoma and portal hypertension should be
performed in patients with advanced disease regardless of decreasing liver stiffness.
Liver stiffness cannot be used to rule out liver fibrosis or cirrhosis in viremic
patients due to the lack of cut-off values. Moreover, elastography can be used in
non-alcoholic fatty liver disease, alcoholic liver disease, and suspicion of liver
cirrhosis to rule out advanced fibrosis [40]. The significance of liver stiffness in hepatic steatosis has not yet been definitively
clarified. This must be taken into consideration when interpreting the liver stiffness
results in patients with severe steatosis and obesity [41]. When performing elastography, nutritional status, respiration (examination should
not be performed during inspiration), liver values 5 times higher than normal, cholestasis,
liver congestion, and infiltrative liver diseases can affect results. For several
years spleen stiffness measurement particularly for evaluating prognosis in esophageal
varices and as a marker for portal hypertension has increasingly become the focus
of scientific studies [42]
[43]. Due to the contradictory data, spleen elastography cannot yet be categorized as
an established method [44]. Other extrahepatic applications like elastography of the pancreas are currently
the subject of scientific studies [45].
Fig. 4 Shear wave elastography (SWE). 1 Ultrasonic probe (transducer), 2 Push pulses (PI), 3 Shear waves (SW), 4 Horizontal propagation of sound waves, 5 Region of interest (ROI) in which ultrasonic waves measure the propagation speed
of the sound waves, 6 Parallel transmitted image lines (P).
Microwave therapy
Technique
Various local ablative methods are used in tumor therapy [46]:
-
Radiofrequency ablation (RFA)
-
Microwave ablation (MWA)
-
Laser-induced interstitial thermotherapy (LITT)
-
Irreversible electroporation (IRE)
-
Cryoablation.
Microwave ablation (MWA) was developed in the 1980 s from an intraoperative method
for achieving hemostasis [46]. Numerous providers and various types of devices are currently available on the
market. In addition to use in CT, MWA can also be performed under ultrasound guidance.
Compared to other methods, MWA has advantages in large tumor areas and areas close
to large vessels. Microwave energy quickly generates high temperatures with a greater
kinetic energy than RFA [47]. MWA is less susceptible to the heat sink effect caused by adjacent vessels than
the well established RFA method. Microwave ablation (MWA) is based on the emission
of electromagnetic waves whose alternating field causes local water molecules to vibrate.
A spherical ablation area is created around the tip of the probe. Heat is transmitted
to the tissue in a centrifugal fashion around the tip of the probe. This causes denaturation
of the surrounding (tumor) cells resulting in an ablation zone.
Clinical applications
The most common application site is the liver both for primary liver tumors like HCCs
and for secondary liver tumors like metastases [46] ([Fig. 5]). Successful application of MWA for pancreatic neoplasms and renal cell carcinomas
(T1a or smaller T1b) has also been described [48]
[49]. A current meta-analysis examining radiofrequency ablation and microwave ablation
compared to systemic chemotherapy and partial hepatectomy in the treatment of colorectal
liver metastases was able to show an advantage of ablation methods compared to chemotherapy
[50]. To our knowledge, there are currently no studies examining microwave ablation using
ultrasound guidance vs. CT guidance.
Fig. 5 Microwave ablation of hepatocellular carcinoma (HCC). a positioning of the probe in the tumor b local gas formation during ablation c tumor after ablation in the B-scan d monitoring of the ablation area in contrast-enhanced ultrasound.
Conclusion
With their broad spectrum of long established as well as newer modalities, ultrasound
methods are a useful addition to CT and MRI. In particular, contrast-enhanced ultrasound
can greatly expand the diagnostic spectrum in radiology. New microvascular Doppler
ultrasound methods make it possible to eliminate the administration of contrast agent
and the use of ionizing radiation in patients who can be effectively examined with
ultrasound. Sonoelastography methods are additional tools in the diagnostic arsenal
for diagnosing fibrotic liver diseases without the use of invasive methods. Fusion
imaging is currently still a niche method. However, with increasing development of
the technology, image fusion can be expected to become increasingly important in diagnostic
imaging in the future.
Due to the complexity of the new ultrasound methods, they present a growing challenge
in training and continuing education and cannot be sufficiently represented or learned
using current continuing education concepts. The necessary competence can presumably
be better acquired in interdisciplinary ultrasound units. However, these are currently
not sufficiently available.
As a complement to the existing and well established DEGUM level concept, a targeted
change to the Regulation on Continuing Education with the introduction of a corresponding
additional qualification in diagnostic ultrasound imaging could increase the interest
of younger colleagues in ultrasound within radiology. The acquired competences could
also be used for subsequent further professional development.
