Shear Wave Elastography Materials & Study.docx

Abstract In the past 2 decades, sonoelastography has been progressively used as a tool to help evaluate soft-tissue elasticity and add to information obtained with conventional gray-scale and Doppler ultrasonographic techniques. Recently introduced on clinical scanners, shear-wave elastography (SWE) is considered to be more objective, quantitative, and reproducible than compression sonoelastograph. SWE uses an acoustic radiation force pulse sequence to generate shear waves, which propagate perpendicular to the ultrasound beam, causing transient displacements. The distribution of shearwave velocities at each pixel is directly related to the shear modulus, an absolute measure of the tissue’s elastic properties. Shear-wave images are automatically coregistered with standard B-mode images to provide quantitative colorelastograms with anatomic specificity. Shear waves propagate faster through stiffer contracted tissue, as well as along the long axis of tendon and muscle. There are four main types of sonoelastography techniques: compression sonoelastography (2), transient elastography (2), tension elastography (4), and shear-wave elastography (SWE) (2), each with advantages and disadvantages.

Compression, Transient, and Tension Sonoelastography Compression sonoelastography, which is commercially available on most US machines, provides visualization of different tissue displacements (ie, strain) by comparing US images before and after light freehand transducer compression (ie, stress). With this technique, compressive strain is lower in harder tissues. On most modern US scanners, compression sonoelastography provides a semiquantitative measurement of the strain ratio, which represents an index of the relative elasticity between a chosen region of interest (ROI) in the examined tissue and a

reference ROI, which is usually in the adjacent subcutaneous tissues. However, compression sonoelastography is operator dependent and provides only a qualitative measure of tissue elasticity. As a result, it has limitations with reproducibility and often suffers from the eggshell effect, in which harder tissues on the boundary of a lesion cannot be deformed, limiting the determination of internal strain.

Transient elastography uses low-frequency excitation pulses to generate shear waves and measures only regional tissue elasticity with limited depth. Whereas SWE provides an absolute measure of the shear modulus from just the tissue displacements, transient elastography requires computing tissue strain (ie, the spatial gradient of displacements), which is a noisy mathematical operation and provides only a relative measure of stiffness (soft vs hard). However, transient elastography is easy to perform during real-time imaging of dynamic tissue motion.

Tension elastography is a variation of compression elastography, with tissue strain measured in response to an internally generated tensile stress, which has been validated recently ex vivo. Tensile force is created by voluntary isometric muscle contraction, whereas the generated force is measured externally using a dynamometer and data acquisition system. When compared with compression sonoelastography, tension elastography provides quantitative information related to tissue elasticity (elastic modulus), which is relevant as the primary function of tendons is to transmit tensile force from muscle to bone. Although this technique is not yet commercially available, it holds great promise as a new functional imaging test, which may guide treatment for tendinopathies and other chronic tendon disorders. Basic Physics of SWE

During the past decade, SWE, which is also called dynamic elastography in research and clinical settings, allowing both qualitative and quantitative measurement of tissue elasticity. Shear-wave imaging is now Food and Drug Administration–approved on most state-of-the-art US scanners (including those offered by Philips, GE Healthcare, Siemens

Healthineers, Ultrasonix, and Supersonic Imagine) for diagnostic imaging of the musculoskeletal system. This technique is rapidly evolving for new applications and clinical utility in musculoskeletal imaging. By quantifying mechanical and elastic tissue properties, SWE complements the diagnosis obtained at gray-scale (B-mode) US and power and color Doppler US. To simplify the explanation of the basic physics, the shear wave is a transverse wave that occurs in an elastic medium that is subject to a periodic shear force. Shear is defined as change in the shape of a substance layer without volume change, produced by a pair of equal forces working in opposite directions along the two opposed sides of the layer. After the shear interaction, the initial layer (tissue) will resume its original shape, while the adjacent layers undergo shear, and there will be further shifting of the shear wave, which propagates as a transverse shear wave. shear waves are generated using focused acoustic radiation force from a linear US array, which by itself provides a local stress and generates local displacement in the tissue. Generated shear waves then propagate through the adjacent tissues in the transverse plane, perpendicular to the primary wave that produces the acoustic radiation force, at a much slower velocity, causing shear displacements in tissue. In step 2, fast plane wave excitation is used to track the tissue displacement and shear wave velocities as the shear waves propagate. Tissue displacement is calculated using a speckle tracking algorithm. In step 3, tissue displacement maps are used to calculate shearwave velocity (cs), frequently expressed in meters per second. The distribution of shear-wave velocities at each pixel is directly related to the shear modulus G, which is calculated by a simple mathematical equation and expresses the tissue stiffness and elasticity in units of pressure—normally kilopascals.

The shear modulus is defined as the ratio of stress to strain that is given by G= ρcs2, where ρ is the material density. The Young modulus (E [or λ]) is defined to be E = 3G for isotropic media. The material density for soft tissue is typically estimated on the basis of values published in the literature for the type of tissue being examined, or approximated to be close to that of water (1 g/cm3).Note that there is a direct relationship between the shear and the Young moduli, reported in some studies to be E = 2G(1+ υ), where υ is the Poisson ratio. Because soft tissues with small deformations (ie, quasi-static displacements) are usually assumed to be incompressible (ie, υ = 0.5), G is sometimes converted to E by the simple equation E = 3G for incompressible media.Therefore, although some studies refer to shear-wave values or to G, others report E on the basis of this relationship.

For the colorelastograms, red is usually defined for encoding hard consistency, blue indicates soft consistency, and green and yellow encode intermediate stiffness.

In comparison with compression sonoelastography, SWE is considered to be more objective and reproducible and allows direct assessment of tissue elasticity, with the possibility to obtain quantitative measurements without the need for manual compression. shear waves propagate faster in stiffer and contracted tissues and along the long axis of the tendon A primary limitation of SWE is depth of penetration. Shallow depths may be accommodated by applying a 5-mm layer of coupling US gel as standoff.

The shape and size of the ROI for postanalysis is also limited on some scanners. Most scanners require a timeout of a few seconds before the next acquisition, which prevents real-time dynamic imaging of structures in motion. Additionally, SWE is sensitive to transducer pressure and angle, and the shear modulus depends on the orientation of the probe relative to the examined structures. SWE is an exciting and rapidly evolving US technique that allows quantification of mechanical and elastic tissue properties. It can be used to complement conventional US in the initial characterization and posttreatment follow-up of various traumatic and pathologic conditions of the musculoskeletal system. This may be of great importance in early disease when an abnormality of the musculoskeletal soft tissues cannot be detected or characterized with conventional US methods. It may also prove useful for staging chronic diseases, determining therapeutic response, and monitoring age-related changes, including sarcopenia and clinical frailty syndrome. New methods in SWE, such as continuous-wave and 3D SWE, may add new information not provided by conventional two-dimensional SWE. Finally, future SWE studies that characterize musculoskeletal softtissue masses may reveal yet another application of this evolving technology, which offers much promise as an adjunct to conventional US. MECHANISM OF ACTION: It consists of the generation of a remote radiation force by focused ultrasonic beams, the so-called “pushing beams,” a patented technology called “Sonic Touch.” Several pushing beams at increasing depths are transmitted to generate a quasi-plane shear wave frame that propagates throughout the whole imaging area. After generation of this shear wave, an ultrafast echographic imaging sequence, the Ulmtraast Imaging System, is performed to acquire successive raw radiofrequency dots at a very high frame rate (up to 20,000 frames per second).

Based on Young’s modulus formula, the assessment of tissue elasticity can be derived from shear wave propagation speed. A color-coded image is displayed, which shows softer tissue in blue and stiffer tissue in red. Quantitative information is delivered; elasticity index (EI) is expressed in kilo-Pascal (kPa). Both steps of SWE are achieved using a linear US probe without requiring any intervention (as pressure) by the operator. APPLICATION IN LIVER FIBROSIS: The first ultrasound elastography method became available 13 years ago in the form of transient elastography with Fibroscan. It was the first technique providing non-invasive quantitive information about the stiffness of the liver and hence regarding the amount of fibrosis in chronic liver disease. The innovation was enormous, since a non-invasive modality was finally available to provide findings otherwise achievable only by liver biopsy. In fact, prior to ultrasound elastography, a combination of conventional and Doppler ultrasound parameters were utilized to inform the physician about the presence of cirrhosis and portal hypertension . However, skilled operators were required, reproducibility and diagnostic accuracy were suboptimal, and it was not possible to differentiate the pre-cirrhotic stages of fibrosis. All these limitations were substantially improved by transient elastography, performed with Fibroscan, a technology dedicated exclusively to liver elastography. The technique has been tested in nearly all liver disease etiologies, with histology as the reference standard. Meta-analysis of data, available in many etiologies, showed good performance and reproducibility as well as some situations limiting reliability. Thresholds for the different fibrosis stages (F0 to F4) have been provided by many large-scale studies utilizing histology as the reference standard .

Transient elastography tracks the velocity of shear waves generated by the gentle hit of a piston on the skin, with the resulting compression wave traveling in the liver along its longitudinal axis. The measurement is made in a 4 cm long section of the liver, thus able to average slightly inhomogeneous fibrotic deposition. In 2008 a new modality became available, Acoustic Radiation Force Impulse (ARFI) quantification, and classified by EFSUMB as point shear wave elastography (pSWE), since the speed of the shear wave (perpendicular to the longitudinal axis) is measured in a small region (a "point", few millimeters) at a freely-choosen depth within 8 cm from the skin. This technology was the first to be implemented in a conventional ultrasound scanner by Siemens(®). Although the correlation between Siemens pSWE and transient elastography appeared high, the calculated thresholds for the different fibrosis stages and the stiffness ranges between the two techniques are not superimposable. Interestingly, pSWE appears to provide greater applicability than transient elastography for measuring both liver and spleen stiffness, which is a new application of elastography, of interest for the prediction of the degree of portal hypertension. Nowadays other companies have started producing equipment with pSWE technology, but only very few articles have been published so far, for instance describing the use of Philips(®) equipment, which was the second to provide pSWE. These articles show preliminary good results also in comparison with TE. Not enough evidence is currently available in the literature about the elastographic performance of the products most recently introduced to the market. Furthermore, with some products the shear wave velocities generated by a single ultrasound acoustic push pulse can be measured in a bidimensional area (a box in the range of 2 - 3 cm per side) rather than in a single small point, producing a so-called bidimensional 2D-SWE 1. The stiffness is depicted in color within the area and refreshing of the measurement occurs every 1 - 2 seconds. Once the best image is acquired, the operator chooses a Region Of Interest (ROI) within the color box, where the mean stiffness is then calculated. 2D-SWE can be performed as a "one shot" technique or as a semi-

"real-time" technique for a few seconds (at about 1 frame per second) in order to obtain a stable elastogram. With either technique, there should be no motion/breathing during image acquisition. A bidimensional averaged area should overcome the limitation of pSWE to inadvertently investigate small regions of greater or lesser stiffness than average. A shear wave quality indicator could be useful to provide real-time feedback and optimize placement of the sampling ROIs, a technology recently presented by Toshiba(®)(i. e., transient elastography, pSWE and 2D-SWE), leading to a bidimensional assessment of liver stiffness in real time up to 5 Hz and in larger regions; thus this technique is also termed real-time 2 D SWE. It has been available on the market for a few years, and many articles have been published showing stiffness values quite similar to those of Fibroscan(®); likewise, defined thresholds based on histological findings have appeared in several articles. After this brief summary of the technological state of the art we would like to mention the following critical issues that we believe every user should note prior to providing liver stiffness reports. · The thresholds obtained from the "oldest" techniques for the various fibrosis stages based on hundreds of patients with histology as reference standard cannot be straightforwardly applied to the new ultrasound elastography techniques, even if based on the same principle (e. g. pSWE). In fact, the different manufacturers apply proprietary patented calculation modes, which might result in slightly to moderately different values. It should be kept in mind that the range for intermediate fibrosis stages (F1 to F3) is quite narrow, in the order of 2 - 3 kilopascal (over a total range spanning 2 to 75 kPa with Fibroscan), so that slightly different differences in outputs could shift the assessment of patients from one stage to another. Comparative studies using phantoms and healthy volunteers, as well as patients, are eagerly awaited. In fact, the equipment might not produce linear correlations of measurements at different degrees of severity of fibrosis. As a theoretical example, some equipment might well correlate in their values with an older technique, such as transient elastography, at low levels of liver

fibrosis, but not as well in cases of more advanced fibrosis or vice versa. Consequentely, when elastography data are included in a report, the equipment utilized for the measurement should be clearly specified, and conclusions about the fibrosis stage should be withheld if an insufficient number of comparative studies with solid reference standards are available for that specific equipment.. · Future studies using histology as a reference might be biased in comparison to previous studies, since nowadays fewer patients with chronic hepatitis C or hepatitis B undergo biopsy. In fact, due to wide availability of effective drugs as well as the use of established elastography methods for patients with viral hepatitis, most cases submitted to biopsy today have uncertain etiology or inconsistent and inconclusive clinical data. Therefore, extrapolated thresholds from such inhomogeneous populations applied to more ordinary patients with viral hepatitis might become problematic in the future, although no better solution is currently anticipated. This situation might lead to the adoption of a standard validated elastographic method as reference, but this has to be agreed-upon at an international level.. Ultrasound elastography embedded in conventional scanners usually allows the choice of where to place the ROI within the color stiffness box and whether to confirm or exclude each single measurement when determining the final value. Thus, the operator has a greater potential to influence the final findings than with Fibroscan®, where these choices are not available. This has to be kept in mind to avoid the possibility that an operator could, even inadvertently, tend to confirm an assumption about that specific patient or to confirm the patient's expectations. Ultrasound elastography measures the liver stiffness/elasticity by assessing at least 100 times the proportion of the liver that a biopsy does. Transient elastography (TE) has been validated in multiple studies but shear wave elastography (SWE) may be preferred because unlike transient elastography, which consists of a vibrator

producing shear waves, the latter can perform a conventional ultrasound at the same time. The technique is integrated into an ultrasound system. The principle behind the interpretation of shear wave elastography is that shear waves produced by a focused ultrasound beam are directly related to the stiffness of the liver from where they are generated. SWE is also reportedly more accurate than TE in assessing significant fibrosis (≥ F2).

Focal liver lesion – shear wave elastography shows radical pattern of elasticity in FNH whereas adenomas &hemangiomas are homogenous. Scars from radiofrequency ablation or healed abscess have the highest stiffness values among benign lesion. Cholangiocarcinomas were the stiffest among malignant lesions. Advantages : non invasive, painless & repeatable procedure.

It can evaluate a much larger liver volume than liver biopsy. It can be used for initial assessment, monitoring as well as diagnosis of complication( portal hypertension, esophageal varices). It can help in biopsy planning from stiffest regions to reduced sampling error. Tumor ablation monitoring is also possible real time with this procedure. Limitations : parenchymal thickness < 4 cm under the probe, ascites, severe obesity, absence of intercostal space sufficiently wide for the probe. Male sex, body mass index > 30, metabolic syndrome, acute viral hepatitis increased liver stiffness. The use of shear wave elastography in the diagnosis and staging of liver fibrosis has been increasing. Being a non-invasive technique proves advantageous because repeat measurements can be obtained in patients with chronic progressive liver diseases. However, this non-invasive procedure does have some pitfalls. It is subject to intra- and inter-observer variability, validated cut-offs have mainly only been demonstrated in hepatitis C; Acute hepatitis can have false positives. In patients with a high body mass index, erroneous values may be obtained. A very practical pitfall is confounding factors such as edema, inflammation, cholestasis and congestion. All these must be put in context and a multidisciplinary clinical approach used in the interpretation of the results. Interpretation of liver fibrosis by shear wave elastography in kPa divided the entity into no fibrosis (F0), mild fibrosis (F1), severe fibrosis (F2), significant fibrosis (F3) and cirrhosis (F4).

Automatic median value generated by the ultrasound software was used to establish the elastography grade as follows < 4.6 = F0, 4.6-5.6 = F1, 5.7-7.0 = F2, 7.1-12.0 = F3 and > 12 = F4. here are limitations associated with elastography, including the confounding effects of inflammatory activity, and to a lesser extent, steatosis, on liver stiffness evaluation. There is also reduced accuracy observed in lower fibrosis stages (F0-F2). Furthermore, the incidences of failed and unreliable scans have been reported to be approximately 3% to 16% in transient elastography but less in shear wave elastography (figures not reported yet). A typical liver biopsy covers 1/10000th of the liver while elastography covers a larger area.

APPLICATION IN IDENTIFYING MALIGNANT THYROID NODULE: EI was significantly higher in malignant nodules [150 ± 95 (30–356) kPa] than in benign nodules [36 ± 30 (0–200) kPa] and normal thyroid glands [15.9 ± 7.6 (5–35) kPa] (P < 0.001). The cutoff level of EI for malignancy was estimated as 65 kPa, for a positive predictive value of at least 80%. With this cutoff value, from the ROC curves, the characteristics of EI to predict malignancy were: sensitivity = 85.2% (95% CI, 71.8; 98.6), specificity = 93.9% (95% CI, 89.2; 98.6), positive predictive value = 80% (95% CI, 65.4; 94.6), negative predictive value = 95.9% (95% CI, 92.0; 99.8), and AUC = 93.6 (95% CI, 86.9; 100) SWE was a powerful tool for the diagnosis of malignancy in thyroid nodules. EI was significantly higher in malignant than benign nodules. Using a cutoff level of 65 kPa, the sensitivity and specificity of the technique were 85.2 and 93.9%, respectively. ADVANTAGES:

SWE is operator-independent and more reproducible than static elastography. First, it is quantitative. Second, it provides local elasticity estimation of nodules that is unaltered by the presence of a hard area in the vicinity. This is of major interest in cases of multinodular thyroid. This group of patients may represent up to 40% of all patients referred for thyroid nodules.

DISADVANTAGES: Most cases of multinodulargoiters are not suitable for static elastography because the nodule to be examined with this technique must be clearly distinguishable from other nodules in the thyroid gland. The accuracy of EI measurement may also be altered if nodules are close to the carotid artery because arterial pulsation may create elastographic images and therefore alter the adequate acquisition and accurate interpretation of the data. In nodules with a diameter greater than 3 cm, adequate compression of the whole nodule may not be obtained. Similarly, elastography using external compression was considered unreliable in nodules with calcified shells or rims because the US beam does not cross these macrocalcifications, and no tissue strain is obtained by the probe pressure. In these cases, SWE may offer some advantages over this technique The subtype of thyroid nodules may be the source of variations in EI. CONCLUSION:

The place of SWE in the evaluation of thyroid nodules for potential malignancy needs to be established. Actually, this evaluation is based upon clinical examination, conventional US characteristics, and FNA above all. The lower sensitivity of US characteristics, alone or in association with EI, leads us to support SWE as the first-line procedure in the evaluation of thyroid nodules. When EI is at least 65 kPa, further exploration is needed by FNA or thyroid surgery. For nodules with an EI of less than 65 kPa, careful evaluation of US signs associated with cancer may add useful information for the management of patients. In conclusion, promising results have been obtained with SWE in the evaluation of thyroid nodules.

APPLICATION IN BREAST LESIONS: BASIS OF USE OF ELASTOGRAPHY – Breast cancer tissue is harder than the adjoining normal breast parenchyma due to desmoplastic reaction. Cut off point is taken between 3 & 4 for the malignant lesion, it showed 86.5 % sensitivity, 89.8% specificity & 88.3% accuracy in one study. Simple cyst VS complex cyst – on elastography it gives target or bulls eye appearance with central bright area surrounded by a dark concentric rim. Complex cyst with debris appears as a solid lesion but elastography can help revealing the cystic nature of the lesion with the typical target appearance. Fibroadenoma – in atypical cases of fibroadenoma to elucidate the benign nature of the lesion.

Invasive ductal carcinomas – on sonoelastography it appears darker than the normal tissue or benign lesion. Disadvantage : False negative elastogram in few well defined benign looking masses, masses with tumour necrosis with acoustic enhancement can mimic cysts. Emerging application of SWE in differentiating between reactive & metastatic axillary lymph nodes in breast carcinoma. Cervical elastography in predicting delivery, detecting patients with a high risk of pre term delivery. Transvaginal elastography is helpful in evaluation of benign(polyp/fibroid/erosion/inflammatory) & malignant lesions. Cut off value of strain ratio of 4.53 or higher has been suggested for confident diagnosis of malignancy. It also helps in the detection of endophytic cancers & depth of invasion of stroma which helps in staging. Fibroids VS adenomyosis – elastography shows typical pattern of a soft lesion(green) with central core which is even less stiffer(red) which persist for both focal & diffuse variety however fibroids in comparison are stiffer & shows blue colour on elastogram. Renal transplant assessment – to diagnose chronic allograft injury by monitoring allograft stiffness, so patients with serial increase can be subjected to a biopsy before renal function deteriorates. Disadvantage - Subclincal rejection, infection or recurrence of underlying disease cannot be detected. Cardiovascular application – strain imaging of the myocardium(for ischemia,infarction& scarring)& of atheromatous plaques& the

arterial wall(detection of vulnerable plaques & estimation of arterial wall compliance) Disadvantage – intravascular plaque evaluation is invasive technique. Venous thrombosis: new thrombi are at higher risk for embolization than are more older fibrotic thrombi.(stiffness of a thrombus increases with increasing age). Elastography can visualize components of Skin and soft tissue abscesses. Elastography differentiate between indurated tissue surrounding the abscess cavity which helps to predict progression to bacteraemia or the time to resolution. Asymmetry of the inflammatory changes surrounding the abscess cavities has been associated with a higher rate of failure after standard therapy. Endoscopic ultrasonic elastosonography is used for pancreas which shows uniform, homogenous green colour distribution ( intermediate stiffness) in normal condition & exclude maliganancy. However blue predominant either homogenous or heterogenous favours the diagnosis of the malignant tumour. Disadvantage – inability to control tissue compression by EUS transducer. Motion artifacts by respiratory or heart movments. Large lesions can be under assessed ( portions of the lesion lying out of the field of view), painful lesion leads to discomfort, non axial transducer movments detrimentally affect elastogram.

APPLICATION IN MSK: METHODS USED IN MSK: COMPRESSION ELASTOGRAPHY(M/C) SHEAR WAVE ELASTOGRAPHY ARFI TENDON: NORMAL: NORMAL ACHILIS TENDONS WERE FOUND TO HAVE 2 DISTICNT ELASTOGRAPHY PATTERNS. 1> HOMOGENEOUSLY HARD STRUCTURES 2> INHOMOGENITY WITH SOFT AREAS(LONGITUDINAL BANDS OR SPOTS) TENDINOPATHY: TENDONS SHOWS MARKED SOFTNING/MILD SOFTNING/ NO SOFT AREAS. INCREASED STIFFNESSS OF EXTENSOR TENDON HAS BEEN NOTED IN LATERAL EPICONDYLITIS. MUSCLE: NORMAL:RELAXED MUSCLE GIVES INHOMOGENEOUS APPEARANCE OF INTERMEDIATE/INCREASED STIFFNESS(GREEN/YELLOW OR BLUE COLOUR RESPECTIVELY). EXRCISE:INCREASE IN MUSCLE STIFFNESS IMMIDIATLY AFTER EXERCISE. RHEUMATOL;OGICAL DISORDER: SOFT TISSUE NODULES: HELPS IN DIFFERNTIATION OF RHEUMATIC NODULES FROM TOPHI( NODULES ARE LESS ELASTIC THAN TOPHI) SYNOVITIS: INLAMMATORY SYNOVITIS-INTERMEDIATE STIFFNESS INFECTIOUS SYNOVITIS-SOFTER LIPOMA ABRORESENCE AND PIGMENTED VILLONODULAR SYNOVITIS-SOFT

SOFT TISSUE MASSES: LIPOMA, LOW FLOW VASCULAR MALFORMATIONS AND THYROGLOSSAL CYST- SOFT NEUROGENIC TUMOES, DERMOID OR SEBACEOUS CYSTSSTIFFER MYOFASCIAL PAIN :IDENTIFY ACTIVE TRIGGAR POINT WHICH SHOWS INCREASED HARDNESS. INFLAMMATORY/DYSROPHIC CONDITION INFLAMMATORY MYOSITIS- INCREASES STIFFNESS DUE TO FIBROSIS. CEREBRAL PALSY-ELASTOGRAPHY HELPS TO ESTABLIS SITE OF BOTULINUM TOXIN INJECTION. HYALINE CARTILAGE-EVALUATION OF ELASTICITY OF HYLINE CARTILAGE BEFORE ARTHROSCOPY AND IN MONITORING OF TREATMENT.