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Update on ultrasound elastography: Miscellanea. Prostate, testicle, musculo-skeletal
European Journal of Radiology 82 (2013) 1904–1912
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European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Review
Update on ultrasound elastography: Miscellanea. Prostate, testicle, musculo-skeletal J.M. Correas a , E. Drakonakis b , A.M. Isidori c , O. Hélénon a , C. Pozza c , V. Cantisani d,∗ , N. Di Leo d , F. Maghella d , A. Rubini d , F.M. Drudi d , F. D’ambrosio d a
Descartes University & Necker University Hospital, Department of Adult Radiology, Paris, France Nuffield Orthopaedic Centre, Oxford, UK c Sapienza University of Rome, Department of Experimental Medicine, Rome, Italy d Sapienza University of Rome, Department of Radiology, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 17 May 2013 Accepted 20 May 2013 Keywords: Elastosonography Elastography Prostate Testicle Musculo-skeletal Ultrasound
a b s t r a c t Nowadays ultrasound elastosonography is an established technique, although with limited clinical application, used to assess tissue stiffness, which is a parameter that in most cases is associated with malignancy. However, although a consistent number of articles have been published about several applications of elastosonography, its use in certain human body districts is still not well defined. In this paper we write on the use of elastosonography in prostate, testicle and musculo-skeletal apparatus. We report and compare the work of several authors, different type of elastosonography (shear wave, strain elastography, etc.) and instrumental data obtained in the study of both benign and malignant lesions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction When a single examination cannot solve a diagnostic problem, it is usually correct to request cross sectional imaging to achieve an accurate diagnosis. Over time, grey-scale ultrasound equipment has been improved with colour Doppler, power Doppler, software for contrast enhanced studies and more recently also elastography, which is performed for various diagnostic purposes. However, elastography is still a tool with limited clinical application. We therefore decided to add a chapter called “miscellaneous” and include elastography which is still not regularly used in prostate, testicle and musculo-skeletal disorders. 2. Prostate 2.1. Introduction Prostate cancer is a public health issue, because it is the cancer with the highest incidence rate and the second cause of cancer death in men. In addition, prostate cancer is the most commonly diagnosed malignancy in men (besides skin cancer) with an
∗ Corresponding author. Tel.: +39 3471743947. E-mail addresses: [email protected], [email protected] (V. Cantisani). 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.05.031
estimated 790,000 cases in 2012 and 217,730 new cases diagnosed every year in the USA. Despite improvement in diagnosis and therapy, the specific mortality rate started to fall since 2000. 2.1.1. Prostate cancer screening There is no systematic screening in most European countries and United States due to the lack of an effective and simple test to pinpoint men with a risk of cancer high enough to justify continuing the diagnostic procedure with more aggressive tests. For over 30 years, the individual screening for prostate abnormalities has been the combination of digital rectal examination (DRE) and prostate specific antigen (PSA) test for men over 50 without predisposition and after disclosing the benefits and risks of over diagnosis. An abnormal or rising serum PSA level, or an abnormal digital rectal examination, triggers further evaluation, typically with transrectal ultrasound (TRUS)-guided sextant biopsies. Prostate biopsy findings are used to estimate the tumour volume (number of positive samples and length of tumour invasion) and aggressiveness (Gleason score). Due to the dramatic increasing incidence provided by PSA screening and the short mortality reduction, the 5-year survival rate drastically increased by almost 30% in a 25 years, reaching 98% [1]. However, increase of PSA is not specific of prostate cancer and can be related to prostatic hyperplasia, acute and chronic prostatitis, or prostate trauma (caused by cystoscopy, resection, and biopsies). Moreover, there are significant prostate cancers with PSA levels lower than the threshold of 4 ng/ml.
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Fig. 1. Strain elastography: the transducer is used as a compression device and applies alternative cycles of compression and relaxation. A speckle comparison, before and after compression, yields to a colour map of local tissue deformation or strain called elastogram.
2.1.2. Prostate cancer diagnosis The diagnostic tools for prostate cancer diagnosis exhibit some strong limitations. PSA screening leads to a substantial number of unnecessary biopsies in patients with no cancer or with indolent cancer that do not need immediate treatment, with an estimated over-detection rate ranging from 27% to 56% [2]. The false negative rate of prostate biopsy varies from 17% to 21%, in patients with a negative first series of biopsies [3]. The increase in the number of core biopsies improves prostate cancer detection and offers a better estimation of the tumour volume and Gleason score, but even saturation biopsies cannot rule out prostate cancer. It has many limitations including increased cost, morbidity and over diagnosis of microscopic tumour foci [4,5]. Many urologists are now facing a dilemma when patients present with an abnormal level of PSA and negative biopsies: when should one stop and when should one continue carrying out biopsies [4]. Multi-parametric MRI (MP-MRI) combines T2-weighted imaging with functional sequences such as diffusion sequence (including ADC calculation), dynamic contrast-enhanced sequence and spectro-MRI. It has become a major modality for tumour detection and staging [6,7], particularly in candidates to radical prostatectomy [8,9]. However, MRI performance varies depending on which combination of positive features is selected for cancer diagnosis between T2-weighted sequence, diffusion sequence and dynamic contrast-enhanced sequence [10]. If the sensitivity of MP-MRI is high its specificity remains low especially because it is affected by the hypervascularity of the normal inner gland and coexisting benign prostatic hyperplasia (BPH) nodules. Its performance remains low for the detection of small lesions of limited Gleason score (≤6) and there is little information to help distinguish between aggressive and indolent tumours. Additional limitations include cost, limited availability, contra-indication to MRI and contrast agents, and the fact that the very large majority of biopsies are ultrasound guided. Conventional TRUS B-mode imaging is known for its limited sensitivity and specificity in between 40% and 50% for prostate cancer detection, and not significantly improved by colour/power Doppler [11]. Contrast-enhanced ultrasound is still under evaluation and can sensitize prostate biopsy [12,13]. However, the contrast ratio between the cancer and the normal peripheral zone is highly transient (a few seconds).
Prostate TRUS elastography has been developed in order to identify stiff tissues, identified during DRE as prostate cancer is stiffer than normal prostate tissue [14–25]. They are 2 different approaches, the quasi-static (or strain) elastography that was introduced more than 10 years ago [14–17], and the shear wave elastography that became available for prostate examination 3 years ago [18–20]. These techniques are intrinsically limited to stiff cancer, taking into account that all stiff lesions are not cancers.
2.1.3. Technical background and examination procedure 2.1.3.1. Quasi-static/strain elastography (SE). Soft tissues tend to exhibit higher strain (deformation) than stiffer areas when compression is applied, and strain is linked to the stiffness represented by the Young’s modulus E by the following equation, where is the stress applied to the tissue and ε is the resulting strain: E=
ε
Quasi-static ultrasound elastography (or strain elastography, SE) of the prostate is based on the analysis of tissue deformation in a region, generated by inducing a mechanical stress (tissue compression by the transrectal transducer itself); the deformation is then supposed to be uniform in space and intensity. For prostate elastography, the external stress is applied on the patient rectal wall adjacent to the prostate peripheral zone, by using the transrectal transducer as a compression device (Fig. 1). A water filled balloon between the imaging probe and the rectal wall can be used to improve the homogeneity of the deformation [11]. A speckle comparison, before and after compression, yields to a colour map of local tissue deformation or strain called elastogram. The tissue stiffness is estimated by visualizing the differences in strain between adjacent regions. Therefore no quantitative elasticity analysis is available. The stiffness colour scale is automatically distributed from the lowest to the highest strain found in the stiffness box or region-of-interest (ROI), this is why the size and position of the stiffness box may induce artefactual variation of the displayed strain. The ROI should therefore cover the entire gland and the surrounding tissues. Only qualitative images are provided to the clinician. Semi-quantitative information can be derived by measuring strain ratio between two ROIs (usually one considered “normal” in terms of stiffness and one considered “abnormal”). The strain for each
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Fig. 2. Strain elastography in a patient with diffuse Gleason 7 adenocarcinoma. Note the presence of diffuse areas of stiffness.
pixel is colour coded (or grey scale coded) and displayed as overlay on the B-mode image. 2.1.3.2. Shear-wave elastography (SWE). Unlike SE, SWE requires no compression on the rectal wall to produce elastograms. SWE is based on the measurement of shear wave propagating through the tissues. It combines the use of two different ultrasonic waves: one (shear wave) that provides stiffness information and the other (ultrasonic wave) that provides high spatial resolution. SWE offers a real-time quantitative map of the visco-elastic properties of soft tissues expressed in kilo Pascal or in metre s−1 (when shear wave velocities are displayed). SWE basic principle relies on two successive steps: first, a shear wave is remotely induced by the transrectal probe through the rectal wall into the prostate using the acoustic radiation force of a focused ultrasonic beam; second, the shear wave propagation is captured by imaging the prostate at very high frame rate. The shear modulus (i.e. stiffness) is then derived by measuring the shear wave propagation velocity. SWE allows local measurements of prostate tissue stiffness in absolute values. The shear wave speed cs (m/s) or Young’s modulus (kPa) for each pixel is colour coded and displayed as overlay on the B-mode image. 2.1.3.3. Examination procedure. Prostate SE is conducted in a patient lying on its left side, after a complete B-mode and colourDoppler examination conducted in order to evaluate prostate volume, suspicious areas and periprostatic space (including the seminal vesicles). The elastography mode is available on the same transducer used for conventional prostate TRUS. Using SE, slight compressions and decompressions cycles are produced by the transrectal probe. The entire gland as well as suspicious areas is studied for detection of stiff areas typically in the transverse plane. Stiff tissues exhibit a reduced strain colour coded in blue, while soft tissues have an increased strain coded in red (Fig. 2). Hypoechoic lesions with increased stiffness (coded in blue) are highly suspicious to be malignant. With SWE, it is critical to avoid any pressure on the prostate gland applied by the transducer. The entire gland and each suspicious lesion are scanned for detection of stiff areas mainly in the transverse plane using optimized settings (maximized penetration and appropriate elasticity scale from 70 to 90 kPa). Using SuperSonic SWE, the ROI can only cover half of the gland in a transverse plane, so each side of the prostate is scanned separately and stored digitally from base to apex for further review and stiffness
measurements. For each plane, the transducer is maintained in a steady-state position during 2–4 s until stabilization of the signals. Stiff tissues are colour-coded in red, while soft tissues appear in blue. Hypoechoic lesions coded in red are highly suspicious to be malignant. The elasticity values (mean, standard deviation, min and max) can be calculated for each ROI. The ratio between the mean values of two ROIs placed in a suspicious region and in the adjacent normal peripheral zone can be calculated. In young patients without prostate disease, the entire prostate exhibits a similar soft appearance with SW elasticity values below 30 kPa (Fig. 3). In the case of benign prostate hypertrophy, the peripheral zone remains soft and homogeneous, while the central and transition zones become nodular, heterogeneous and hard in the presence of macro-calcifications (Fig. 4). Typical peripheral zone benign nodules are soft (<35 kPa), while cancer nodules are stiffer (>35 kPa). Benign nodules in the peripheral zone, such as focal prostatitis, exhibit low elasticity values, while peripheral cancer nodules are stiff with higher elasticity values. A threshold of 35 kPa is optimal to maximize the negative predictive value. 2.1.4. Performance of prostate elastography Several studies attest the additional value of both prostate SE and SWE. Three main indications can be identified: 1, characterization of an abnormal area detected previously at any imaging technique (B-mode imaging, colour Doppler US, prostate MPMRI); 2, detection of a lesion not seen with any previous imaging technique; 3, biopsy targeting on suspicious lesions. Prostate elastography requires specific training; the learning curve may be longer for strain elastography due to the variability of constraint applied with the transducer. Some of the discrepancies in the literature arise from the earlier versions of SE. However, SWE allows continuous scanning of the prostate from base to apex to detect stiff regions, and provide quantitative elasticity values of nodules and stiffness ratio between nodules and adjacent prostate tissue. SE has been available for a longer period. Most studies report a significant improvement in prostate cancer identification with quasi-static elastography, including guidance for targeted biopsies [21,22]. For example, Brock et al. prospectively investigated in total 229 patients with biopsy proven prostate cancer screened for cancer-suspicious areas and extracapsular extension using greyscale ultrasound and elastography [21]. Among the 1374 sectors evaluated, pathology reported the presence of cancer in 894 (62%) and extracapsular extension in 47 patients. SE correctly detected
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Fig. 3. SWE of a benign nodule corresponding to chronic prostatis at the targeted biopsy. Note the homogeneous encoding of elastography signals in the peripheral zone.
594 (66.4%) and grey-scale ultrasound 215 (24.0%) cancer suspicious lesions. SE sensitivity and specificity were 51% and 72%, respectively, compared to 18 and 90% respectively for grey-scale ultrasound. Elastography identified the largest side specific tumour focus in 68% of patients. The detection of extracapsular extension was also improved compared to B-mode (SE sensitivity 38% vs Bmode sensitivity 15%) with no change in specificity. However, there are still some controversies and some recent studies reported an inability to differentiate prostate cancer from chronic prostatitis [23] or that SE was less accurate than randomized biopsies for identifying prostate cancer [24]. Improvement in biopsy guidance
(targeted biopsy vs systematic biopsies) is often reported in the literature [25], but some well-designed studies did not confirm such results [11,16−24]. For example, Aigner et al. [25] evaluated the cancer detection rate of targeted biopsies (up to 5 cores) to hard suspicious areas detected by strain elastography, compared that of 10-core systematic biopsies in patients with PSA between 1.25 and 4.00 ng/ml and a free-to-total prostate specific antigen ratio less than 18%. Prostate cancer was found in 27 of 94 patients (28.7%). Strain elastography detected cancer in 20 patients (21.3%) and systematic biopsy detected it in 18 (19.1%). Positive cancer cores were found in strain elastography targeted cores in 38 of 158 cases
Fig. 4. Small Gleason 6 adenocarcinoma only detected by SWE.
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(24%) and in systematic cores in 38 of 752 (5.1%) (chi-square test p < 0.0001). The cancer detection rate per core was 4.7-fold greater for targeted than for systematic biopsy. Shear wave elastography is a more recent technique and there are few reports to date. The best stiffness cut-off value to differentiate benign from malignant lesions was found to be 35 and 37 kPa in two independent studies [19,20]. In both of these studies, the lowest performance for shear wave elastography in terms of sensitivity, specificity, positive and negative predictive values, were 63%, 91%, 69.4% and 91%, respectively. The shear wave elasticity ratio performed better, presumably because it takes into account the increased stiffness of the peripheral zone from calcifications and chronic prostatitis. The ratios between the nodule and the adjacent peripheral gland tissue for benign and malignant lesions were 1.5 ± 0.9 and 4.0 ± 1.9 (p < 0.002), respectively [19]. Prostate elastography may be recommended to increase diagnostic confidence in the detection of prostate cancer (characterization of a focal abnormal area, detection of a stiff region not seen with other imaging techniques) and to increase the positive predictive biopsy rate. 2.1.5. Limitations and artefacts SE limitations include the lack of uniform compression over the entire gland, the intra and inter-operator dependency, the penetration issues in large prostate glands, the level of training, and the artefacts due to slippage of the compression plane that can be reduced with training and balloon interposition. SWE limitations include the pressure artefacts induced by the transducer, as the end-fire design of the probe requires bending to image mid prostate and apex, the slow frame rate (1 image per second), the limited size of the ROI (only half of the prostate gland is covered) (Figs. 3 and 4), the delay to stabilize the signals at each acquisition plane and the signal attenuation in large prostates making the evaluation of the anterior transitional zone difficult or impossible. Both techniques are subject to the same intrinsic limitations: not all cancers are stiff, and all stiff lesions are not cancers (calcifications, fibrosis, etc.). Elasticity information must always be combined with the results of the transrectal US B-mode, and when available to the results of other imaging techniques such as MPMRI. 2.2. Future perspective Prostate elastography should become a routine additional US modality for prostate examination in addition to conventional TRUS B-mode and colour-Doppler US. Elastography brings in a new parameter – tissue stiffness – which provides additional information for detecting prostate cancer and guiding biopsies. Elastography improves conventional TRUS sensitivity for detecting prostate cancer and exhibits a high negative predictive value, ensuring that few cancers are missed in the peripheral zone of the prostate. However, this technique does require a learning curve (mainly for SE as the operator is the one inducing tissue deformation by applying alternative pushes with the transducer), so that the user becomes familiar with the characteristics and limitations of the technique, in order to produce a correct diagnosis. Future perspective includes volumetric (3D/4D) prostate elastography with multiplanar reconstruction, and volumetric fusion to MP-MRI. These new modalities should improve guiding capabilities in order to target biopsies to the most suspicious areas. Better detection of prostate cancer and assessment of its aggressiveness remain essential for developing focal therapy in order to improve patients’ quality of life.
3. Testicle 3.1. Introduction Conventional ultrasound (US) is very sensitive for the detection of testicular lesions, but does not provide histological diagnosis. Beside US, several tools have been adopted to improve the sensitivity and specificity of the preoperative characterization of testicular masses, including magnetic resonance and contrast enhanced ultrasonography (CEUS). Sonoelastography (SE) has been recently introduced with the aim of measuring the tissue, showing the degree of deformation or distortion of solid tissue lesions under the application of an external force. This technique is based upon the principle that the softer parts of tissues deform easier than the harder ones under compression, thus allowing a semi-quantitative determination of tissue elasticity. SE evaluation is generally performed during an US examination, using the same real-time instrument and probe, with the intent to track tissue deformation. The strain profile obtained is automatically converted into an elastic modulus image, called an elastogram. The elastogram is generally showed overlaid on the Bmode image. This allows for continuous monitoring of the node in question, checking its inclusion in the scan plane during the procedure. Real-time elastogram, to be trustworthy, must show a firmness of elastography chromaticism for a period of at least 5 s and the operator should exert a constant level of pressure throughout the examination. Tissue stiffness is displayed on the US machine as a colour-coded map, ranging from red to blue, where red indicates the largest strain (the softest tissue) and blue indicates no strain (the stiffest tissue). The areas with average strain are displayed in green. 3.2. Elastosonography for testicular diseases Most focal testicular lesions differ in their consistency from the surrounding parenchyma. For this reason SE could be helpful in differentiating testicular lesions, thus allowing the clinician to choose between a watchful waiting follow-up, in the presence of likely benign lesions, and surgical removal for suspected malignant tumours. On the technical side, involuntary movements, such as those related to tissue perfusion or breathing, that can interfere with the generation of a proper elastogram; however, this limitation is minimal with the testis, making it an ideal tissue to be explored by SE. It is also true that in most cases the testis is readily palpable, allowing a direct examination of large solid masses; the role of elastosonography, therefore, is limited to small-size, non-palpable incidental intratesticular masses. SE has already proved its encouraging potential in the detection and differentiation of nodules in other parenchymal tissues, such as breast, prostate, thyroid gland and lymph nodes, and has been of interest in the evaluation of liver fibrosis and in the exploration of malignant tumours in the cervix. However there are only a few reports available in the literature regarding the efficacy of this technique for scrotal lesions evaluation. At SE evaluation the normal testis show a medium, homogeneous level of elasticity (expressed with a green pattern), and sometimes some linear “red” structures can be seen, related to fluid component (i.e. vessels). Preliminary findings about SE and testicular lesions were reported in 2005 [26], where 15 patients affected by inflammatory and neoplastic diseases were submitted to ultrasound (US) and SE examinations. Authors concluded that SE improved the discovery of testicular nodules, and had the ability to distinguish between testicular lesions and inflammatory changes based on the tissue elasticity.
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Fig. 5. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in seminoma.
Grasso et al. [27] reported their experience in testicular elastosonography, evaluating 41 patients who presented with scrotal pain, painless enlargement of the scrotum or testicular nodules. They concluded that SE could be used as a complement to B-mode assessment in case of solid lesions, smaller than 10 mm, but not alone, because the pattern showed in case of benign and malignant lesions was quite similar. In a series of 88 patients [28] the SE findings of 144 testicular lesions were analysed considering shape, size, elastographic criteria and compared to the histological diagnosis or the benign appearance in the follow-up examinations. Authors assigned an elastographic score (1–5, where a score of 1 indicated even strain for the entire hypoechoic lesion while a higher value of 5 corresponded to absence of strain in the entire hypoechoic lesion or in the surrounding area), according to the distribution and degree of strain as suggested by Itoh et al. [29] for breast lesion classification. In this study nearly 94% of benign lesions showed a complete elastic pattern (scores 1–2), while malignant nodules exhibited a stiff pattern (scores 4–5) in 87.5% of the cases. Authors concluded that SE could be a useful technique in selected cases, i.e. small testicular nodules and pseudo-nodules (in agreement with previous studies), having a good sensitivity and specificity in differentiating malignant from benign lesions. A very recent retrospective study [30] evaluated 50 patients affected by testicular lesions. In 34/50 cases findings from histologic examination and in 16/50 cases finding from clinical and US followup were used as the reference standard. In this series, SE provided additional information in differentiating between malignant and benign lesions, showing a sensitivity of 100% (all testicular cancers appeared as hard regions, characterized by increased tissue stiffness), a specificity of 81% and an accuracy of 94% in the diagnosis of
testicular tumours. Neoplastic lesions were excluded in the absence of increased tissue stiffness (i.e. orchitis, partial infarction, and cysts appeared as “soft”). Authors concluded that this technique could be complementary to conventional US but not a stand-alone imaging modality. Huang et al. [31] reviewed the potential of SE beyond conventional B-mode imaging in the characterization of both benign and malignant intratesticular lesions, confirming the existing data for which “stiff” lesions are more likely to be malignant, and “soft” lesions may suggest benignity. In respect to diagnostic improvement of testicular masses, SE shows a number of limitations: while most malignant lesions appear “stiff” (i.e. seminoma) (Fig. 5), confirming the characteristics already reported in literature, we also noticed this kind of pattern for benign neoplastic lesions (i.e. Leydigioma) (Fig. 6) and for benign, non-neoplastic lesions (i.e. epidermoid cyst) (Fig. 7). The elastography pattern is quite similar in the presence of a focal testicular lesion, probably due to the high and tight cellularity typical of neoplasms. For this reason, in our series the joint use of US and SE showed no significant diagnostic improvement over the use of US and sensitive colour-Doppler findings. On the contrary, application of SE to non-neoplastic cases, might offer greater advantages. A number of scrotal diseases is associated with changes in tissue elasticity (atrophy or sclerosis of seminal tubules, inflammation, traumas); all these clinical conditions could benefit from elastography. These applications are yet unexplored. The principal limitation of SE is related to the manual external compression source by which the tissue is deformed to create the strain. As the driving force is not exactly known, SE may only assess the compressibility ratio of different tissues and consequently their relative elasticity, and not their absolute value.
Fig. 6. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in Leydigioma.
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Fig. 7. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in epidermoid cyst.
Moreover, SE provides only qualitative information whose interpretation may be operator-dependent. Indeed, it should be noted that, after a short training period to acquire the necessary manual skill for a correct execution of the compression, this technique could be applied with a minimal additional time for the operator and without any discomfort for the patient. In conclusion, sonoelastography is a simple, non-invasive diagnostic examination technique that completes the morphological assessment of US, but that, in our opinion, cannot be considered an exclusive imaging modality and should be combined with US conventional imaging for the characterization of testis lesions. A much larger systematic clinical study is required for the characterization of testicular lesions with this newly developed technique, with the purpose to adding a further characterization of non-palpable testicular lesions, especially for benign neoplasms, where follow-up or biopsies are now becoming increasingly requested alternatives to radical surgery.
Finally, sonoelastography might offer greater advantages for the characterization of functional and non-neoplastic testicular disorders; applications that today remain unexplored. 4. Musculo-skeletal Biomechanical research using elastography techniques has proved that diseases of muscles and tendons result in alterations of their mechanical properties [32]. The recent introduction of ultrasound elastography (USE) in commercially available US imaging diagnostic systems has allowed its use in clinical practice and has driven research towards potential clinical applications. Most of the clinical research has focused on the Achilles tendon. Two studies on asymptomatic Achilles tendons have found that normal asymptomatic tendons are either hard (48–93%) or considerably inhomogeneous containing soft areas [33–35] (Fig. 8a). These areas may present either longitudinal bands or spots in the
Fig. 8. (a) Strain elastogram of a 19-year-old volunteer with asymptomatic Achilles tendon. The tendon appears as a stiff structure (green-blue). (b) Strain elastogram of a 23-year-old male with symptomatic Achilles tendinopathy. The tendinopathic area appears as a soft region (red).
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tendon mid-portion not corresponding to any changes in conventional US (12–62%) or discrete soft areas corresponding to asymptomatic degeneration evident also in conventional US imaging (1.3%) [33–35]. Tendons with symptomatic tendinopathy were found to contain discrete or mild softening in 57% and 11% of cases, respectively [34] (Fig. 8b). Surgically repaired Achilles tendons may have a hard and heterogeneous pattern as a consequence of tendon healing [36]. Reproducibility of the method has been found to be good only if the assessment of the elastogram is qualitative [33]. The technique has high sensitivity and specificity compared to clinical findings for the detection of Achilles tendinopathy (93.7% and 99.2%, respectively) [34,37], provided that only discrete soft regions are considered indicative of clinically relevant tendinopathy. The nature of soft areas in asymptomatic tendons has been attributed either to false positive findings or to early preclinical disease [37,38]. Recently, a study on cadavers showed that elastography could detect histologically confirmed Achilles tendon degeneration in all cases whereas B-mode US could detect only 85.7%. Therefore elastography might be more sensitive than Bmode US in detecting early degeneration [39]. Limited data exist on the use of strain USE for other tendons. USE was found to have higher accuracy than conventional US in depicting collateral ligament and fascia involvement in lateral epicondylitis [40]. USE also shows that plantar fascia softens with age and disease; however, the clinical relevance of such findings in not yet established [41]. In trigger finger a study showed increased annular pulley stiffness and reduction after steroid injection [42]. However, these results were not confirmed under carefully controlled experimental conditions, suggesting that substantial technical improvements are required to make USE measurements diagnostically relevant for small tendon disease [43]. Normal skeletal muscle has not been studied in detail using USE; however, strain USE images of normal relaxed muscle show a mosaic of intermediate or increased stiffness with scattered softer areas near muscle boundaries [44,45]. There are differences in stiffness between sexes and for various gaze positions detected in normal masseter and ocular muscles, respectively [46,47]. Interestingly, more data is available about diseased muscle, showing a possible role of strain USE in diagnosing, monitoring and guiding therapy in dystrophic, myopathic and spastic muscle. Strain USE detected early myopathic changes in a case study of congenital Bethlem myopathy and showed changes in muscle stiffness in inflammatory myopathy with good correlation with the levels of serum markers [44,45]. USE has also been employed for the localization and guidance of myofascial trigger point treatment [48], for the depiction of the optimal site for botulinum toxin injection in congenitally spastic muscle [49–52] and for predicting treatment outcomes in congenital muscular torticollis [53]. All studies employing strain USE for musculotendinous disease acknowledge the presence of several limiting factors and the need of training and familiarity with normal appearances and artefacts. The inter and intra observer reproducibility of strain USE for the normal Achilles tendon has been found to be better using qualitative evaluation of the elastogram and in long axis tendon images than using semi-quantitative measurements (strain ratio) and short axis images [33,34]. It may be considerably challenging to produce high quality, artefact-free strain images of tendon and muscle. Several ways have been suggested to minimize technical limitations by acquiring cine-loops instead of static images and by examining overlapping areas of tendons to eliminate border artefacts, by adjusting the size of the elastogram according to specific guidelines and by using stand-off pads or caps and by avoiding the inclusion of gel in the elastogram because it may influence the USE appearance [38]. Familiarity with artefacts encountered in strain imaging of muscle and tendons is also necessary, including fluctuant changes
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into the Achilles tendon and at the edges of the elastogram, soft lines around calcifications, deep in bone and at interfaces between muscles, the characteristic appearance of cysts and mistracking of echoes resulting in artefacts near major pulsating vessels [38]. Shear wave USE provides a promising alternative to USE method due to the lack of manual compression and the potential of quantitative measurements. However, the technique has only recently been assessed on the musculotendinous tissue and there is so far limited experience. Preliminary data is available on normal stiffness values of various muscles and tendons using shear wave USE and ARFI [50,54]. Significant changes in Achilles tendon elasticity depending on the level of stretching and physical activity were documented using a shear wave USE prototype [55]. With the increasing availability of shear wave US ultrasound diagnostic imaging systems, more data on the use of shear wave USE for musculotendinous disease will soon be reported. In conclusion, it seems that USE is a promising method for the evaluation of the musculoskeletal system and could be of value for research in pathophysiology and for early diagnosis and guided treatment of muscle and tendon disease. However, the published literature remains very limited and further research is expected to establish the clinical role of both strain and shear wave USE in the investigation of musculoskeletal diseases. Conflict of interest statement All authors declare that there is no conflict of interest. References [1] American Cancer Society. Cancer facts and figures, 2010. Atlanta, GA: American Cancer Society; 2010. [2] Kelloff GJ, Choyke P, Coffey DS. Challenges in clinical prostate cancer: role of imaging. American Journal of Roentgenology 2009;192:1455–70. [3] Singh H, Canto EI, Shariat SF, et al. Predictors of prostate cancer after initial negative systematic 12 core biopsy. Journal of Urology 2004;171:1850–4. [4] Giannarini G, Autorino R, di Lorenzo G. Saturation biopsy of the prostate: why saturation does not saturate. European Urology 2009;56:619–21. [5] Pepe P, Fraggetta F, Galia A, Grasso G, Aragona F. Prostate cancer detection by TURP after repeated negative saturation biopsy in patients with persistent suspicion of cancer: a case–control study on 75 consecutive patients. Prostate Cancer and Prostatic Diseases 2010;13:83–6. [6] Lemaitre L, Puech P, Poncelet E, et al. Dynamic contrast-enhanced MRI of anterior prostate cancer: morphometric assessment and correlation with radical prostatectomy findings. European Radiology 2009;19:470–80. [7] Lim HK, Kim JK, Kim KA, Cho KS. Prostate cancer: apparent diffusion coefficient map with T2-weighted images for detection—a multireader study. Radiology 2009;250:145–51. [8] Yoshizako T, Wada A, Hayashi T, et al. Usefulness of diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging in the diagnosis of prostate transition-zone cancer. Acta Radiologica 2008;49:1207–13. [9] Ocak I, Bernardo M, Metzger G, et al. Dynamic contrast-enhanced MRI of prostate cancer at 3 T: a study of pharmacokinetic parameters. American Journal of Roentgenology 2007;189:849. [10] Langer DL, van der Kwast TH, Evans AJ, Trachtenberg J, Wilson BC, Haider MA. Prostate cancer detection with multi-parametric MRI: logistic regression analysis of quantitative T2, diffusion-weighted imaging, and dynamic contrastenhanced MRI. Journal of Magnetic Resonance Imaging 2009;30:327–34. [11] Tsutsumi M, Miyagawa T, Matsumura T, et al. Real-time balloon inflation elastography for prostate cancer detection and initial evaluation of clinicopathologic analysis. American Journal of Roentgenology 2010;194:W471–6. [12] Aigner F, Pallwein L, Mitterberger M, et al. Contrast-enhanced ultrasonography using cadence-contrast pulse sequencing technology for targeted biopsy of the prostate. BJU International 2009;103:458–63. [13] Tang J, Yang JC, Li Y, Li J, Shi H. Peripheral zone hypoechoic lesions of the prostate: evaluation with contrast-enhanced gray scale transrectal ultrasonography. Journal of Ultrasound in Medicine 2007;26:1671–9. [14] Aigner F, Pallwein L, Schocke M, et al. Comparison of real-time sonoelastography with T2-weighted endorectal magnetic resonance imaging for prostate cancer detection. Journal of Ultrasound in Medicine 2011;30:643–9. [15] Salomon G, Köllerman J, Thederan I, et al. Evaluation of prostate cancer detection with ultrasound real-time elastography: a comparison with step section pathological analysis after radical prostatectomy. European Urology 2008;54:1354–62. [16] Kamoi K, Okihara K, Ochiai A, et al. The utility of transrectal real-time elastography in the diagnosis of prostate cancer. Ultrasound in Medicine and Biology 2008;34:1025–32.
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[17] Brock M, von Bodman C, Palisaar RJ, et al. The impact of real-time elastography guiding a systematic prostate biopsy to improve cancer detection rate: a prospective study of 353 patients. Journal of Urology 2012;187: 2039–43. [18] Bercoff J, Tanter M, Fink M. Supersonic shear imaging: a new technique for soft tissue elasticity mapping. IEEE Transactions on Ultrasonics, Ferroelectrics and Frequency Control 2004;51:396–409. [19] Correas JM, Khairoune A, Tissier AM, Vassiliu V, Mejean A, Helenon O. Quantitative shear wave elastography of the prostate: correlation to sextant and targeted biopsies. In: Scientific exhibit presented at the European Congress of Radiology. 2012. [20] Barr RG, Memo R, Schaub CR. Shear wave ultrasound elastography of the prostate: initial results. Ultrasound Quarterly 2012;28:13–20. [21] Brock M, von Bodman C, Sommerer F, et al. Comparison of real-time elastography with grey-scale ultrasonography for detection of organ-confined prostate cancer and extra capsular extension: a prospective analysis using whole mount sections after radical prostatectomy. BJU International 2011;108: E217–22. [22] Dudea SM, Giurgiu CR, Dumitriu D, et al. Value of ultrasound elastography in the diagnosis and management of prostate carcinoma. Medical Ultrasonography 2011;13(1):45–53. [23] Kapoor A, Kapoor A, Mahajan G, Sidhu BS. Real-time elastography in the detection of prostate cancer in patients with raised PSA level. Ultrasound in Medicine and Biology 2011;37:1374–81. [24] Walz J, Marcy M, Pianna JT, et al. Identification of the prostate cancer index lesion by real-time elastography: considerations for focal therapy of prostate cancer. World Journal of Urology 2011;29:589–94. [25] Aigner F, Pallwein L, Junker D, et al. Value of real-time elastography targeted biopsy for prostate cancer detection in men with prostate specific antigen 1.25 ng/ml or greater and 4.00 ng/ml or less. Journal of Urology 2010;184:913–7. [26] Pallwein L, Pallwein E, Schurich M, Fischbach V, Steiner H, Frauscher F, Abstract: Sonoelastography of the testicles: preliminary results in the diagnosis of different pathological processes. In: Fourth international conference on the ultrasonic measurement and imaging of tissue elasticity. 2005. [27] Grasso M, Blanco S, Raber M, Nespoli L. Elasto-sonography of the testis: preliminary experience. Archivio Italiano di Urologia, Andrologia 2010;82(September (3)):160–3. [28] Goddi A, Sacchi A, Magistretti G, Almolla J, Salvadore M. Real-time tissue elastography for testicular lesion assessment. European Radiology 2012;22(April (4)):721–30. [29] Itoh A, Ueno E, Tohno E, et al. Breast disease: clinical application of US elastography for diagnosis. Radiology 2006;239(May (2)):341–50. [30] Aigner F, De Zordo T, Pallwein-Prettner L, et al. Real-time sonoelastography for the evaluation of testicular lesions. Radiology 2012;263(May (2)):584–9. [31] Huang DY, Sidhu PS. Focal testicular lesions: colour Doppler ultrasound, contrast-enhanced ultrasound and tissue elastography as adjuvants to the diagnosis. British Journal of Radiology 2012;85(November (Spec. No. 1)): S41–53. [32] Li Y, Snedeker JG. Elastography: modality-specific approaches, clinical applications, and research horizons. Skeletal Radiology 2011;40:389–97. [33] Drakonaki EE, Allen GM, Wilson DJ. Real-time ultrasound elastography of the normal Achilles tendon: reproducibility and pattern description. Clinical Radiology 2009;64:1196–202. [34] De Zordo T, Chem R, Smekal V, et al. Real-time sonoelastography: findings in patients with symptomatic Achilles tendons and comparison to healthy volunteers. Ultraschall in der Medizin 2010;31:394–400. [35] De Zordo T, Fink C, Feuchtner GM, Smekal V, Reindl M, Klauser AS. Real-time sonoelastography findings in healthy Achilles tendons. American Journal of Roentgenology 2009;193:W134–8.
[36] Tan S, Kudas¸ S, Ozcan AS, et al. Real-time sonoelastography of the Achilles tendon: pattern description in healthy subjects and patients with surgically repaired complete ruptures. Skeletal Radiology 2012;41(9):1067–72, http://dx.doi.org/10.1007/s00256-011-1339-4. [37] Klauser AS, Faschingbauer R, Jaschke WR. Is sonoelastography of value in assessing tendons? Seminars in Musculoskeletal Radiology 2010;14:323–33. [38] Drakonaki EE, Allen GM, Wilson DJ. Ultrasound elastography for musculoskeletal applications. British Journal of Radiology 2012;85(November (1019)):1435–45. [39] Klauser AS, Myamoto H, Tamegger M, et al. Achilles tendon assessed with sonoelastography: histologic agreement. Radiology 2013;267(3):837–42, http://dx.doi.org/10.1148/radiol.13121936. [40] Zordo T, Lill SR, Fink C, et al. Real-time sonoelastography of lateral epicondylitis: comparison of findings between patients and healthy volunteers. American Journal of Roentgenology 2009;193:180–5. [41] Wu CH, Chang KV, Mio S, Chen WS, Wang TG. Sonoelastography of the plantar fascia. Radiology 2011;259:502–7. [42] Miyamoto H, Miura T, Isayama H, Masuzaki R, Koike K, Ohe T. Stiffness of the first annular pulley in normal and trigger fingers. Journal of Hand Surgery (American Volume) 2011;36:1486–91. [43] Buck AR, Verstraete N, Li Y, Schweizer A, Snedeker JG, Buck FM. Detection of small tendon lesions by sonoelastographic visualization of strain profile differences: initial experiences. Skeletal Radiology 2012;41:1073–9. [44] Botar-Jid C, Damian L, Dudea SM, Vasilescu D, Rednic S, Badea R. The contribution of ultrasonography and sonoelastography in assessment of myositis. Medical Ultrasonography 2010;12:120–6. [45] Drakonaki EE, Allen GM. Magnetic resonance imaging, ultrasound and real-time ultrasound elastography of the thigh muscles in congenital muscle dystrophy. Skeletal Radiology 2010;39:391–6. [46] Ariji Y, Katsumata A, Hiraiwa Y, et al. Use of sonographic elastography of the masseter muscles for optimizing massage pressure: a preliminary study. Journal of Oral Rehabilitation 2009;36:627–35. [47] Detorakis ET, Drakonaki EE, Tsilimbaris MK, Pallikaris IG, Giarmenitis S. Realtime ultrasound elastographic imaging of ocular and periocular tissues: a feasibility study. Ophthalmic Surgery, Lasers and Imaging 2010;41:135–41. [48] Sikdar S, Shah JP, Gebreab T, et al. Novel applications of ultrasound technology to visualize and characterize myofascial trigger points and surrounding soft tissue. Archives of Physical Medicine and Rehabilitation 2009;90:1829–38. [49] Vasilescu D, Vasilescu D, Dudea S, Botar-Jid C, Sfrângeu S, Cosma D. Sonoelastography contribution in cerebral palsy spasticity treatment assessment, preliminary report: a systematic review of the literature apropos of seven patients. Medical Ultrasonography 2010;12:306–10. [50] Kwon DR, Park GY, Lee SU, Chung I. Spastic cerebral palsy in children: dynamic sonoelastographic findings of medial gastrocnemius. Radiology 2012;263:794–880. [51] Kwon DR, Park GY, Kwon JG. The change of intrinsic stiffness in gastrocnemius after intensive rehabilitation with botulinum toxin a injection in spastic diplegic cerebral palsy. Annals of Rehabilitation Medicine 2012;36:400–3. [52] Park GY, Kwon DR. Sonoelastographic evaluation of medial gastrocnemius muscles intrinsic stiffness after rehabilitation therapy with botulinum toxin a injection in spastic cerebral palsy. Archives of Physical Medicine and Rehabilitation 2012;93:2085–9. [53] Kwon DR, Park GY. Diagnostic value of real-time sonoelastography in congenital muscular torticollis. Journal of Ultrasound in Medicine 2012;31:721–7. [54] Arda K, Ciledag N, Aktas E, Aribas BK, Köse K. Quantitative assessment of normal soft-tissue elasticity using shear-wave ultrasound elastography. American Journal of Roentgenology 2011;197:532–6. [55] Aubry S, Risson JR, Barbier-Brion B, Tatu L, Vidal C, Kastler B. Transient elastography of calcaneal tendon: preliminary results and future prospects. Journal de Radiologie 2011;92:421–7.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
Review
Update on ultrasound elastography: Miscellanea. Prostate, testicle, musculo-skeletal J.M. Correas a , E. Drakonakis b , A.M. Isidori c , O. Hélénon a , C. Pozza c , V. Cantisani d,∗ , N. Di Leo d , F. Maghella d , A. Rubini d , F.M. Drudi d , F. D’ambrosio d a
Descartes University & Necker University Hospital, Department of Adult Radiology, Paris, France Nuffield Orthopaedic Centre, Oxford, UK c Sapienza University of Rome, Department of Experimental Medicine, Rome, Italy d Sapienza University of Rome, Department of Radiology, Rome, Italy b
a r t i c l e
i n f o
Article history: Received 17 May 2013 Accepted 20 May 2013 Keywords: Elastosonography Elastography Prostate Testicle Musculo-skeletal Ultrasound
a b s t r a c t Nowadays ultrasound elastosonography is an established technique, although with limited clinical application, used to assess tissue stiffness, which is a parameter that in most cases is associated with malignancy. However, although a consistent number of articles have been published about several applications of elastosonography, its use in certain human body districts is still not well defined. In this paper we write on the use of elastosonography in prostate, testicle and musculo-skeletal apparatus. We report and compare the work of several authors, different type of elastosonography (shear wave, strain elastography, etc.) and instrumental data obtained in the study of both benign and malignant lesions. © 2013 Elsevier Ireland Ltd. All rights reserved.
1. Introduction When a single examination cannot solve a diagnostic problem, it is usually correct to request cross sectional imaging to achieve an accurate diagnosis. Over time, grey-scale ultrasound equipment has been improved with colour Doppler, power Doppler, software for contrast enhanced studies and more recently also elastography, which is performed for various diagnostic purposes. However, elastography is still a tool with limited clinical application. We therefore decided to add a chapter called “miscellaneous” and include elastography which is still not regularly used in prostate, testicle and musculo-skeletal disorders. 2. Prostate 2.1. Introduction Prostate cancer is a public health issue, because it is the cancer with the highest incidence rate and the second cause of cancer death in men. In addition, prostate cancer is the most commonly diagnosed malignancy in men (besides skin cancer) with an
∗ Corresponding author. Tel.: +39 3471743947. E-mail addresses: [email protected], [email protected] (V. Cantisani). 0720-048X/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejrad.2013.05.031
estimated 790,000 cases in 2012 and 217,730 new cases diagnosed every year in the USA. Despite improvement in diagnosis and therapy, the specific mortality rate started to fall since 2000. 2.1.1. Prostate cancer screening There is no systematic screening in most European countries and United States due to the lack of an effective and simple test to pinpoint men with a risk of cancer high enough to justify continuing the diagnostic procedure with more aggressive tests. For over 30 years, the individual screening for prostate abnormalities has been the combination of digital rectal examination (DRE) and prostate specific antigen (PSA) test for men over 50 without predisposition and after disclosing the benefits and risks of over diagnosis. An abnormal or rising serum PSA level, or an abnormal digital rectal examination, triggers further evaluation, typically with transrectal ultrasound (TRUS)-guided sextant biopsies. Prostate biopsy findings are used to estimate the tumour volume (number of positive samples and length of tumour invasion) and aggressiveness (Gleason score). Due to the dramatic increasing incidence provided by PSA screening and the short mortality reduction, the 5-year survival rate drastically increased by almost 30% in a 25 years, reaching 98% [1]. However, increase of PSA is not specific of prostate cancer and can be related to prostatic hyperplasia, acute and chronic prostatitis, or prostate trauma (caused by cystoscopy, resection, and biopsies). Moreover, there are significant prostate cancers with PSA levels lower than the threshold of 4 ng/ml.
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Fig. 1. Strain elastography: the transducer is used as a compression device and applies alternative cycles of compression and relaxation. A speckle comparison, before and after compression, yields to a colour map of local tissue deformation or strain called elastogram.
2.1.2. Prostate cancer diagnosis The diagnostic tools for prostate cancer diagnosis exhibit some strong limitations. PSA screening leads to a substantial number of unnecessary biopsies in patients with no cancer or with indolent cancer that do not need immediate treatment, with an estimated over-detection rate ranging from 27% to 56% [2]. The false negative rate of prostate biopsy varies from 17% to 21%, in patients with a negative first series of biopsies [3]. The increase in the number of core biopsies improves prostate cancer detection and offers a better estimation of the tumour volume and Gleason score, but even saturation biopsies cannot rule out prostate cancer. It has many limitations including increased cost, morbidity and over diagnosis of microscopic tumour foci [4,5]. Many urologists are now facing a dilemma when patients present with an abnormal level of PSA and negative biopsies: when should one stop and when should one continue carrying out biopsies [4]. Multi-parametric MRI (MP-MRI) combines T2-weighted imaging with functional sequences such as diffusion sequence (including ADC calculation), dynamic contrast-enhanced sequence and spectro-MRI. It has become a major modality for tumour detection and staging [6,7], particularly in candidates to radical prostatectomy [8,9]. However, MRI performance varies depending on which combination of positive features is selected for cancer diagnosis between T2-weighted sequence, diffusion sequence and dynamic contrast-enhanced sequence [10]. If the sensitivity of MP-MRI is high its specificity remains low especially because it is affected by the hypervascularity of the normal inner gland and coexisting benign prostatic hyperplasia (BPH) nodules. Its performance remains low for the detection of small lesions of limited Gleason score (≤6) and there is little information to help distinguish between aggressive and indolent tumours. Additional limitations include cost, limited availability, contra-indication to MRI and contrast agents, and the fact that the very large majority of biopsies are ultrasound guided. Conventional TRUS B-mode imaging is known for its limited sensitivity and specificity in between 40% and 50% for prostate cancer detection, and not significantly improved by colour/power Doppler [11]. Contrast-enhanced ultrasound is still under evaluation and can sensitize prostate biopsy [12,13]. However, the contrast ratio between the cancer and the normal peripheral zone is highly transient (a few seconds).
Prostate TRUS elastography has been developed in order to identify stiff tissues, identified during DRE as prostate cancer is stiffer than normal prostate tissue [14–25]. They are 2 different approaches, the quasi-static (or strain) elastography that was introduced more than 10 years ago [14–17], and the shear wave elastography that became available for prostate examination 3 years ago [18–20]. These techniques are intrinsically limited to stiff cancer, taking into account that all stiff lesions are not cancers.
2.1.3. Technical background and examination procedure 2.1.3.1. Quasi-static/strain elastography (SE). Soft tissues tend to exhibit higher strain (deformation) than stiffer areas when compression is applied, and strain is linked to the stiffness represented by the Young’s modulus E by the following equation, where is the stress applied to the tissue and ε is the resulting strain: E=
ε
Quasi-static ultrasound elastography (or strain elastography, SE) of the prostate is based on the analysis of tissue deformation in a region, generated by inducing a mechanical stress (tissue compression by the transrectal transducer itself); the deformation is then supposed to be uniform in space and intensity. For prostate elastography, the external stress is applied on the patient rectal wall adjacent to the prostate peripheral zone, by using the transrectal transducer as a compression device (Fig. 1). A water filled balloon between the imaging probe and the rectal wall can be used to improve the homogeneity of the deformation [11]. A speckle comparison, before and after compression, yields to a colour map of local tissue deformation or strain called elastogram. The tissue stiffness is estimated by visualizing the differences in strain between adjacent regions. Therefore no quantitative elasticity analysis is available. The stiffness colour scale is automatically distributed from the lowest to the highest strain found in the stiffness box or region-of-interest (ROI), this is why the size and position of the stiffness box may induce artefactual variation of the displayed strain. The ROI should therefore cover the entire gland and the surrounding tissues. Only qualitative images are provided to the clinician. Semi-quantitative information can be derived by measuring strain ratio between two ROIs (usually one considered “normal” in terms of stiffness and one considered “abnormal”). The strain for each
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Fig. 2. Strain elastography in a patient with diffuse Gleason 7 adenocarcinoma. Note the presence of diffuse areas of stiffness.
pixel is colour coded (or grey scale coded) and displayed as overlay on the B-mode image. 2.1.3.2. Shear-wave elastography (SWE). Unlike SE, SWE requires no compression on the rectal wall to produce elastograms. SWE is based on the measurement of shear wave propagating through the tissues. It combines the use of two different ultrasonic waves: one (shear wave) that provides stiffness information and the other (ultrasonic wave) that provides high spatial resolution. SWE offers a real-time quantitative map of the visco-elastic properties of soft tissues expressed in kilo Pascal or in metre s−1 (when shear wave velocities are displayed). SWE basic principle relies on two successive steps: first, a shear wave is remotely induced by the transrectal probe through the rectal wall into the prostate using the acoustic radiation force of a focused ultrasonic beam; second, the shear wave propagation is captured by imaging the prostate at very high frame rate. The shear modulus (i.e. stiffness) is then derived by measuring the shear wave propagation velocity. SWE allows local measurements of prostate tissue stiffness in absolute values. The shear wave speed cs (m/s) or Young’s modulus (kPa) for each pixel is colour coded and displayed as overlay on the B-mode image. 2.1.3.3. Examination procedure. Prostate SE is conducted in a patient lying on its left side, after a complete B-mode and colourDoppler examination conducted in order to evaluate prostate volume, suspicious areas and periprostatic space (including the seminal vesicles). The elastography mode is available on the same transducer used for conventional prostate TRUS. Using SE, slight compressions and decompressions cycles are produced by the transrectal probe. The entire gland as well as suspicious areas is studied for detection of stiff areas typically in the transverse plane. Stiff tissues exhibit a reduced strain colour coded in blue, while soft tissues have an increased strain coded in red (Fig. 2). Hypoechoic lesions with increased stiffness (coded in blue) are highly suspicious to be malignant. With SWE, it is critical to avoid any pressure on the prostate gland applied by the transducer. The entire gland and each suspicious lesion are scanned for detection of stiff areas mainly in the transverse plane using optimized settings (maximized penetration and appropriate elasticity scale from 70 to 90 kPa). Using SuperSonic SWE, the ROI can only cover half of the gland in a transverse plane, so each side of the prostate is scanned separately and stored digitally from base to apex for further review and stiffness
measurements. For each plane, the transducer is maintained in a steady-state position during 2–4 s until stabilization of the signals. Stiff tissues are colour-coded in red, while soft tissues appear in blue. Hypoechoic lesions coded in red are highly suspicious to be malignant. The elasticity values (mean, standard deviation, min and max) can be calculated for each ROI. The ratio between the mean values of two ROIs placed in a suspicious region and in the adjacent normal peripheral zone can be calculated. In young patients without prostate disease, the entire prostate exhibits a similar soft appearance with SW elasticity values below 30 kPa (Fig. 3). In the case of benign prostate hypertrophy, the peripheral zone remains soft and homogeneous, while the central and transition zones become nodular, heterogeneous and hard in the presence of macro-calcifications (Fig. 4). Typical peripheral zone benign nodules are soft (<35 kPa), while cancer nodules are stiffer (>35 kPa). Benign nodules in the peripheral zone, such as focal prostatitis, exhibit low elasticity values, while peripheral cancer nodules are stiff with higher elasticity values. A threshold of 35 kPa is optimal to maximize the negative predictive value. 2.1.4. Performance of prostate elastography Several studies attest the additional value of both prostate SE and SWE. Three main indications can be identified: 1, characterization of an abnormal area detected previously at any imaging technique (B-mode imaging, colour Doppler US, prostate MPMRI); 2, detection of a lesion not seen with any previous imaging technique; 3, biopsy targeting on suspicious lesions. Prostate elastography requires specific training; the learning curve may be longer for strain elastography due to the variability of constraint applied with the transducer. Some of the discrepancies in the literature arise from the earlier versions of SE. However, SWE allows continuous scanning of the prostate from base to apex to detect stiff regions, and provide quantitative elasticity values of nodules and stiffness ratio between nodules and adjacent prostate tissue. SE has been available for a longer period. Most studies report a significant improvement in prostate cancer identification with quasi-static elastography, including guidance for targeted biopsies [21,22]. For example, Brock et al. prospectively investigated in total 229 patients with biopsy proven prostate cancer screened for cancer-suspicious areas and extracapsular extension using greyscale ultrasound and elastography [21]. Among the 1374 sectors evaluated, pathology reported the presence of cancer in 894 (62%) and extracapsular extension in 47 patients. SE correctly detected
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Fig. 3. SWE of a benign nodule corresponding to chronic prostatis at the targeted biopsy. Note the homogeneous encoding of elastography signals in the peripheral zone.
594 (66.4%) and grey-scale ultrasound 215 (24.0%) cancer suspicious lesions. SE sensitivity and specificity were 51% and 72%, respectively, compared to 18 and 90% respectively for grey-scale ultrasound. Elastography identified the largest side specific tumour focus in 68% of patients. The detection of extracapsular extension was also improved compared to B-mode (SE sensitivity 38% vs Bmode sensitivity 15%) with no change in specificity. However, there are still some controversies and some recent studies reported an inability to differentiate prostate cancer from chronic prostatitis [23] or that SE was less accurate than randomized biopsies for identifying prostate cancer [24]. Improvement in biopsy guidance
(targeted biopsy vs systematic biopsies) is often reported in the literature [25], but some well-designed studies did not confirm such results [11,16−24]. For example, Aigner et al. [25] evaluated the cancer detection rate of targeted biopsies (up to 5 cores) to hard suspicious areas detected by strain elastography, compared that of 10-core systematic biopsies in patients with PSA between 1.25 and 4.00 ng/ml and a free-to-total prostate specific antigen ratio less than 18%. Prostate cancer was found in 27 of 94 patients (28.7%). Strain elastography detected cancer in 20 patients (21.3%) and systematic biopsy detected it in 18 (19.1%). Positive cancer cores were found in strain elastography targeted cores in 38 of 158 cases
Fig. 4. Small Gleason 6 adenocarcinoma only detected by SWE.
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(24%) and in systematic cores in 38 of 752 (5.1%) (chi-square test p < 0.0001). The cancer detection rate per core was 4.7-fold greater for targeted than for systematic biopsy. Shear wave elastography is a more recent technique and there are few reports to date. The best stiffness cut-off value to differentiate benign from malignant lesions was found to be 35 and 37 kPa in two independent studies [19,20]. In both of these studies, the lowest performance for shear wave elastography in terms of sensitivity, specificity, positive and negative predictive values, were 63%, 91%, 69.4% and 91%, respectively. The shear wave elasticity ratio performed better, presumably because it takes into account the increased stiffness of the peripheral zone from calcifications and chronic prostatitis. The ratios between the nodule and the adjacent peripheral gland tissue for benign and malignant lesions were 1.5 ± 0.9 and 4.0 ± 1.9 (p < 0.002), respectively [19]. Prostate elastography may be recommended to increase diagnostic confidence in the detection of prostate cancer (characterization of a focal abnormal area, detection of a stiff region not seen with other imaging techniques) and to increase the positive predictive biopsy rate. 2.1.5. Limitations and artefacts SE limitations include the lack of uniform compression over the entire gland, the intra and inter-operator dependency, the penetration issues in large prostate glands, the level of training, and the artefacts due to slippage of the compression plane that can be reduced with training and balloon interposition. SWE limitations include the pressure artefacts induced by the transducer, as the end-fire design of the probe requires bending to image mid prostate and apex, the slow frame rate (1 image per second), the limited size of the ROI (only half of the prostate gland is covered) (Figs. 3 and 4), the delay to stabilize the signals at each acquisition plane and the signal attenuation in large prostates making the evaluation of the anterior transitional zone difficult or impossible. Both techniques are subject to the same intrinsic limitations: not all cancers are stiff, and all stiff lesions are not cancers (calcifications, fibrosis, etc.). Elasticity information must always be combined with the results of the transrectal US B-mode, and when available to the results of other imaging techniques such as MPMRI. 2.2. Future perspective Prostate elastography should become a routine additional US modality for prostate examination in addition to conventional TRUS B-mode and colour-Doppler US. Elastography brings in a new parameter – tissue stiffness – which provides additional information for detecting prostate cancer and guiding biopsies. Elastography improves conventional TRUS sensitivity for detecting prostate cancer and exhibits a high negative predictive value, ensuring that few cancers are missed in the peripheral zone of the prostate. However, this technique does require a learning curve (mainly for SE as the operator is the one inducing tissue deformation by applying alternative pushes with the transducer), so that the user becomes familiar with the characteristics and limitations of the technique, in order to produce a correct diagnosis. Future perspective includes volumetric (3D/4D) prostate elastography with multiplanar reconstruction, and volumetric fusion to MP-MRI. These new modalities should improve guiding capabilities in order to target biopsies to the most suspicious areas. Better detection of prostate cancer and assessment of its aggressiveness remain essential for developing focal therapy in order to improve patients’ quality of life.
3. Testicle 3.1. Introduction Conventional ultrasound (US) is very sensitive for the detection of testicular lesions, but does not provide histological diagnosis. Beside US, several tools have been adopted to improve the sensitivity and specificity of the preoperative characterization of testicular masses, including magnetic resonance and contrast enhanced ultrasonography (CEUS). Sonoelastography (SE) has been recently introduced with the aim of measuring the tissue, showing the degree of deformation or distortion of solid tissue lesions under the application of an external force. This technique is based upon the principle that the softer parts of tissues deform easier than the harder ones under compression, thus allowing a semi-quantitative determination of tissue elasticity. SE evaluation is generally performed during an US examination, using the same real-time instrument and probe, with the intent to track tissue deformation. The strain profile obtained is automatically converted into an elastic modulus image, called an elastogram. The elastogram is generally showed overlaid on the Bmode image. This allows for continuous monitoring of the node in question, checking its inclusion in the scan plane during the procedure. Real-time elastogram, to be trustworthy, must show a firmness of elastography chromaticism for a period of at least 5 s and the operator should exert a constant level of pressure throughout the examination. Tissue stiffness is displayed on the US machine as a colour-coded map, ranging from red to blue, where red indicates the largest strain (the softest tissue) and blue indicates no strain (the stiffest tissue). The areas with average strain are displayed in green. 3.2. Elastosonography for testicular diseases Most focal testicular lesions differ in their consistency from the surrounding parenchyma. For this reason SE could be helpful in differentiating testicular lesions, thus allowing the clinician to choose between a watchful waiting follow-up, in the presence of likely benign lesions, and surgical removal for suspected malignant tumours. On the technical side, involuntary movements, such as those related to tissue perfusion or breathing, that can interfere with the generation of a proper elastogram; however, this limitation is minimal with the testis, making it an ideal tissue to be explored by SE. It is also true that in most cases the testis is readily palpable, allowing a direct examination of large solid masses; the role of elastosonography, therefore, is limited to small-size, non-palpable incidental intratesticular masses. SE has already proved its encouraging potential in the detection and differentiation of nodules in other parenchymal tissues, such as breast, prostate, thyroid gland and lymph nodes, and has been of interest in the evaluation of liver fibrosis and in the exploration of malignant tumours in the cervix. However there are only a few reports available in the literature regarding the efficacy of this technique for scrotal lesions evaluation. At SE evaluation the normal testis show a medium, homogeneous level of elasticity (expressed with a green pattern), and sometimes some linear “red” structures can be seen, related to fluid component (i.e. vessels). Preliminary findings about SE and testicular lesions were reported in 2005 [26], where 15 patients affected by inflammatory and neoplastic diseases were submitted to ultrasound (US) and SE examinations. Authors concluded that SE improved the discovery of testicular nodules, and had the ability to distinguish between testicular lesions and inflammatory changes based on the tissue elasticity.
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Fig. 5. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in seminoma.
Grasso et al. [27] reported their experience in testicular elastosonography, evaluating 41 patients who presented with scrotal pain, painless enlargement of the scrotum or testicular nodules. They concluded that SE could be used as a complement to B-mode assessment in case of solid lesions, smaller than 10 mm, but not alone, because the pattern showed in case of benign and malignant lesions was quite similar. In a series of 88 patients [28] the SE findings of 144 testicular lesions were analysed considering shape, size, elastographic criteria and compared to the histological diagnosis or the benign appearance in the follow-up examinations. Authors assigned an elastographic score (1–5, where a score of 1 indicated even strain for the entire hypoechoic lesion while a higher value of 5 corresponded to absence of strain in the entire hypoechoic lesion or in the surrounding area), according to the distribution and degree of strain as suggested by Itoh et al. [29] for breast lesion classification. In this study nearly 94% of benign lesions showed a complete elastic pattern (scores 1–2), while malignant nodules exhibited a stiff pattern (scores 4–5) in 87.5% of the cases. Authors concluded that SE could be a useful technique in selected cases, i.e. small testicular nodules and pseudo-nodules (in agreement with previous studies), having a good sensitivity and specificity in differentiating malignant from benign lesions. A very recent retrospective study [30] evaluated 50 patients affected by testicular lesions. In 34/50 cases findings from histologic examination and in 16/50 cases finding from clinical and US followup were used as the reference standard. In this series, SE provided additional information in differentiating between malignant and benign lesions, showing a sensitivity of 100% (all testicular cancers appeared as hard regions, characterized by increased tissue stiffness), a specificity of 81% and an accuracy of 94% in the diagnosis of
testicular tumours. Neoplastic lesions were excluded in the absence of increased tissue stiffness (i.e. orchitis, partial infarction, and cysts appeared as “soft”). Authors concluded that this technique could be complementary to conventional US but not a stand-alone imaging modality. Huang et al. [31] reviewed the potential of SE beyond conventional B-mode imaging in the characterization of both benign and malignant intratesticular lesions, confirming the existing data for which “stiff” lesions are more likely to be malignant, and “soft” lesions may suggest benignity. In respect to diagnostic improvement of testicular masses, SE shows a number of limitations: while most malignant lesions appear “stiff” (i.e. seminoma) (Fig. 5), confirming the characteristics already reported in literature, we also noticed this kind of pattern for benign neoplastic lesions (i.e. Leydigioma) (Fig. 6) and for benign, non-neoplastic lesions (i.e. epidermoid cyst) (Fig. 7). The elastography pattern is quite similar in the presence of a focal testicular lesion, probably due to the high and tight cellularity typical of neoplasms. For this reason, in our series the joint use of US and SE showed no significant diagnostic improvement over the use of US and sensitive colour-Doppler findings. On the contrary, application of SE to non-neoplastic cases, might offer greater advantages. A number of scrotal diseases is associated with changes in tissue elasticity (atrophy or sclerosis of seminal tubules, inflammation, traumas); all these clinical conditions could benefit from elastography. These applications are yet unexplored. The principal limitation of SE is related to the manual external compression source by which the tissue is deformed to create the strain. As the driving force is not exactly known, SE may only assess the compressibility ratio of different tissues and consequently their relative elasticity, and not their absolute value.
Fig. 6. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in Leydigioma.
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Fig. 7. Ultrasound showed an hypoechoic lesion, completely anelastic at SE. It was referred to biopsy for histological evaluation, and it resulted in epidermoid cyst.
Moreover, SE provides only qualitative information whose interpretation may be operator-dependent. Indeed, it should be noted that, after a short training period to acquire the necessary manual skill for a correct execution of the compression, this technique could be applied with a minimal additional time for the operator and without any discomfort for the patient. In conclusion, sonoelastography is a simple, non-invasive diagnostic examination technique that completes the morphological assessment of US, but that, in our opinion, cannot be considered an exclusive imaging modality and should be combined with US conventional imaging for the characterization of testis lesions. A much larger systematic clinical study is required for the characterization of testicular lesions with this newly developed technique, with the purpose to adding a further characterization of non-palpable testicular lesions, especially for benign neoplasms, where follow-up or biopsies are now becoming increasingly requested alternatives to radical surgery.
Finally, sonoelastography might offer greater advantages for the characterization of functional and non-neoplastic testicular disorders; applications that today remain unexplored. 4. Musculo-skeletal Biomechanical research using elastography techniques has proved that diseases of muscles and tendons result in alterations of their mechanical properties [32]. The recent introduction of ultrasound elastography (USE) in commercially available US imaging diagnostic systems has allowed its use in clinical practice and has driven research towards potential clinical applications. Most of the clinical research has focused on the Achilles tendon. Two studies on asymptomatic Achilles tendons have found that normal asymptomatic tendons are either hard (48–93%) or considerably inhomogeneous containing soft areas [33–35] (Fig. 8a). These areas may present either longitudinal bands or spots in the
Fig. 8. (a) Strain elastogram of a 19-year-old volunteer with asymptomatic Achilles tendon. The tendon appears as a stiff structure (green-blue). (b) Strain elastogram of a 23-year-old male with symptomatic Achilles tendinopathy. The tendinopathic area appears as a soft region (red).
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tendon mid-portion not corresponding to any changes in conventional US (12–62%) or discrete soft areas corresponding to asymptomatic degeneration evident also in conventional US imaging (1.3%) [33–35]. Tendons with symptomatic tendinopathy were found to contain discrete or mild softening in 57% and 11% of cases, respectively [34] (Fig. 8b). Surgically repaired Achilles tendons may have a hard and heterogeneous pattern as a consequence of tendon healing [36]. Reproducibility of the method has been found to be good only if the assessment of the elastogram is qualitative [33]. The technique has high sensitivity and specificity compared to clinical findings for the detection of Achilles tendinopathy (93.7% and 99.2%, respectively) [34,37], provided that only discrete soft regions are considered indicative of clinically relevant tendinopathy. The nature of soft areas in asymptomatic tendons has been attributed either to false positive findings or to early preclinical disease [37,38]. Recently, a study on cadavers showed that elastography could detect histologically confirmed Achilles tendon degeneration in all cases whereas B-mode US could detect only 85.7%. Therefore elastography might be more sensitive than Bmode US in detecting early degeneration [39]. Limited data exist on the use of strain USE for other tendons. USE was found to have higher accuracy than conventional US in depicting collateral ligament and fascia involvement in lateral epicondylitis [40]. USE also shows that plantar fascia softens with age and disease; however, the clinical relevance of such findings in not yet established [41]. In trigger finger a study showed increased annular pulley stiffness and reduction after steroid injection [42]. However, these results were not confirmed under carefully controlled experimental conditions, suggesting that substantial technical improvements are required to make USE measurements diagnostically relevant for small tendon disease [43]. Normal skeletal muscle has not been studied in detail using USE; however, strain USE images of normal relaxed muscle show a mosaic of intermediate or increased stiffness with scattered softer areas near muscle boundaries [44,45]. There are differences in stiffness between sexes and for various gaze positions detected in normal masseter and ocular muscles, respectively [46,47]. Interestingly, more data is available about diseased muscle, showing a possible role of strain USE in diagnosing, monitoring and guiding therapy in dystrophic, myopathic and spastic muscle. Strain USE detected early myopathic changes in a case study of congenital Bethlem myopathy and showed changes in muscle stiffness in inflammatory myopathy with good correlation with the levels of serum markers [44,45]. USE has also been employed for the localization and guidance of myofascial trigger point treatment [48], for the depiction of the optimal site for botulinum toxin injection in congenitally spastic muscle [49–52] and for predicting treatment outcomes in congenital muscular torticollis [53]. All studies employing strain USE for musculotendinous disease acknowledge the presence of several limiting factors and the need of training and familiarity with normal appearances and artefacts. The inter and intra observer reproducibility of strain USE for the normal Achilles tendon has been found to be better using qualitative evaluation of the elastogram and in long axis tendon images than using semi-quantitative measurements (strain ratio) and short axis images [33,34]. It may be considerably challenging to produce high quality, artefact-free strain images of tendon and muscle. Several ways have been suggested to minimize technical limitations by acquiring cine-loops instead of static images and by examining overlapping areas of tendons to eliminate border artefacts, by adjusting the size of the elastogram according to specific guidelines and by using stand-off pads or caps and by avoiding the inclusion of gel in the elastogram because it may influence the USE appearance [38]. Familiarity with artefacts encountered in strain imaging of muscle and tendons is also necessary, including fluctuant changes
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into the Achilles tendon and at the edges of the elastogram, soft lines around calcifications, deep in bone and at interfaces between muscles, the characteristic appearance of cysts and mistracking of echoes resulting in artefacts near major pulsating vessels [38]. Shear wave USE provides a promising alternative to USE method due to the lack of manual compression and the potential of quantitative measurements. However, the technique has only recently been assessed on the musculotendinous tissue and there is so far limited experience. Preliminary data is available on normal stiffness values of various muscles and tendons using shear wave USE and ARFI [50,54]. Significant changes in Achilles tendon elasticity depending on the level of stretching and physical activity were documented using a shear wave USE prototype [55]. With the increasing availability of shear wave US ultrasound diagnostic imaging systems, more data on the use of shear wave USE for musculotendinous disease will soon be reported. In conclusion, it seems that USE is a promising method for the evaluation of the musculoskeletal system and could be of value for research in pathophysiology and for early diagnosis and guided treatment of muscle and tendon disease. However, the published literature remains very limited and further research is expected to establish the clinical role of both strain and shear wave USE in the investigation of musculoskeletal diseases. Conflict of interest statement All authors declare that there is no conflict of interest. References [1] American Cancer Society. Cancer facts and figures, 2010. Atlanta, GA: American Cancer Society; 2010. [2] Kelloff GJ, Choyke P, Coffey DS. Challenges in clinical prostate cancer: role of imaging. American Journal of Roentgenology 2009;192:1455–70. [3] Singh H, Canto EI, Shariat SF, et al. Predictors of prostate cancer after initial negative systematic 12 core biopsy. Journal of Urology 2004;171:1850–4. [4] Giannarini G, Autorino R, di Lorenzo G. Saturation biopsy of the prostate: why saturation does not saturate. European Urology 2009;56:619–21. [5] Pepe P, Fraggetta F, Galia A, Grasso G, Aragona F. Prostate cancer detection by TURP after repeated negative saturation biopsy in patients with persistent suspicion of cancer: a case–control study on 75 consecutive patients. Prostate Cancer and Prostatic Diseases 2010;13:83–6. [6] Lemaitre L, Puech P, Poncelet E, et al. Dynamic contrast-enhanced MRI of anterior prostate cancer: morphometric assessment and correlation with radical prostatectomy findings. European Radiology 2009;19:470–80. [7] Lim HK, Kim JK, Kim KA, Cho KS. Prostate cancer: apparent diffusion coefficient map with T2-weighted images for detection—a multireader study. Radiology 2009;250:145–51. [8] Yoshizako T, Wada A, Hayashi T, et al. Usefulness of diffusion-weighted imaging and dynamic contrast-enhanced magnetic resonance imaging in the diagnosis of prostate transition-zone cancer. Acta Radiologica 2008;49:1207–13. [9] Ocak I, Bernardo M, Metzger G, et al. Dynamic contrast-enhanced MRI of prostate cancer at 3 T: a study of pharmacokinetic parameters. American Journal of Roentgenology 2007;189:849. [10] Langer DL, van der Kwast TH, Evans AJ, Trachtenberg J, Wilson BC, Haider MA. Prostate cancer detection with multi-parametric MRI: logistic regression analysis of quantitative T2, diffusion-weighted imaging, and dynamic contrastenhanced MRI. Journal of Magnetic Resonance Imaging 2009;30:327–34. [11] Tsutsumi M, Miyagawa T, Matsumura T, et al. Real-time balloon inflation elastography for prostate cancer detection and initial evaluation of clinicopathologic analysis. American Journal of Roentgenology 2010;194:W471–6. [12] Aigner F, Pallwein L, Mitterberger M, et al. Contrast-enhanced ultrasonography using cadence-contrast pulse sequencing technology for targeted biopsy of the prostate. BJU International 2009;103:458–63. [13] Tang J, Yang JC, Li Y, Li J, Shi H. Peripheral zone hypoechoic lesions of the prostate: evaluation with contrast-enhanced gray scale transrectal ultrasonography. Journal of Ultrasound in Medicine 2007;26:1671–9. [14] Aigner F, Pallwein L, Schocke M, et al. Comparison of real-time sonoelastography with T2-weighted endorectal magnetic resonance imaging for prostate cancer detection. Journal of Ultrasound in Medicine 2011;30:643–9. [15] Salomon G, Köllerman J, Thederan I, et al. Evaluation of prostate cancer detection with ultrasound real-time elastography: a comparison with step section pathological analysis after radical prostatectomy. European Urology 2008;54:1354–62. [16] Kamoi K, Okihara K, Ochiai A, et al. The utility of transrectal real-time elastography in the diagnosis of prostate cancer. Ultrasound in Medicine and Biology 2008;34:1025–32.
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