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Assessment of the Stiffness of Major Salivary Glands in Primary Sjögren's Syndrome through Quantitative Acoustic Radiation Force Impulse Imaging
Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–9, 2015 Copyright Ó 2015 World Federation for Ultrasound in Medicine & Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.11.009
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Original Contribution ASSESSMENT OF THE STIFFNESS OF MAJOR SALIVARY GLANDS IN PRIMARY € SJOGREN’S SYNDROME THROUGH QUANTITATIVE ACOUSTIC RADIATION FORCE IMPULSE IMAGING SHANSHAN ZHANG,* JIAAN ZHU,* XIA ZHANG,y JING HE,y and JIANGUO LI* * Department of Ultrasound, Peking University People’s Hospital, Beijing, China; and y Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China (Received 23 June 2015; revised 3 November 2015; in final form 9 November 2015)
Abstract—The purpose of the study described here was to evaluate salivary gland stiffness in primary Sj€ ogren’s syndrome (pSS) via acoustic radiation force impulse imaging, including Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). Twenty-one patients with pSS and 11 healthy patients were included, and the paired parotid and submandibular glands of all of the patients were examined using VTQ and VTIQ. Differences between the two groups were compared with independent and paired t-tests. The VTQ value for the parotid in the pSS group was significantly higher than that obtained for the control group (1.33 ± 0.22 and 1.18 ± 0.04 m/s, respectively, p , 0.01). The VTIQ values for the parotid and submandibular gland were both significantly higher in the pSS group than in the control group (p , 0.05). In the pSS group, a positive correlation was observed between the VTQ and VTIQ results for the parotid and submandibular glands. In summary, the stiffness of the major salivary glands in patients with pSS was increased compared with that of patients with normal glands. This finding indicates that VTQ and VTIQ imaging may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of pSS. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Sj€ogren’s syndrome, Salivary glands, Virtual Touch tissue quantification, Virtual Touch tissue imaging quantification, Acoustic radiation force impulse imaging.
significantly to the diagnosis of pSS. The objective methods used for the examination of salivary glands include parotid sialography, salivary scintigraphy and minor salivary gland biopsy (Yazisiz et al. 2009). However, these are all invasive or irradiating procedures that may result in inconvenience and a risk of complications in the patient (Niemel€a et al. 2004). In recent studies, ultrasonography has been reported to be valuable for assessing major salivary gland involvement in pSS (Tzioufas and Moutsopoulos 2008). Four major salivary glands (the paired parotid and submandibular glands) are superficial and suitable for ultrasonic examination. The reported characteristic sonographic findings include inhomogeneity, multiple hypo-echoic areas and multiple hyper-echoic lines (Hocevar et al. 2005). However, the characteristic ultrasonographic changes observed in pSS and the diagnostic accuracy attained are controversial. The greatest limitation is the lack of specificity (Cornec et al. 2013). The features of sonographic images of the major salivary glands observed in pSS may be related to histopathologic changes in the glands, including lymphocytic
INTRODUCTION Primary Sj€ ogren’s syndrome (pSS) is a chronic autoimmune disease that affects exocrine systems, including the salivary and lacrimal glands. Primary Sj€ ogren’s syndrome has a strong female propensity, and its female-to-male ratio varies from as high as 20:1 to 9:1 (Patel and Shahane 2014). Xerostomia and xerophthalmia are the representative clinical features of pSS and can be accompanied by systemic disease manifestation (Maœli~ nska et al. 2015). The salivary glands are the main target organs, and histopathologic analysis reveals focal lymphocytic infiltration, destruction of the glands and fibrosis (Kassan and Moutsopoulos 2004). Among the classification criteria proposed by the American–European Consensus (AEC) group in 2002 (Vitali et al. 2002) and the American College of Rheumatology in 2012 (Shiboski et al. 2012), the evaluation of salivary gland involvement contributes
Address correspondence to: Jiaan Zhu, Department of Ultrasound, Peking University People’s Hospital, 11 Xizhimen South Street, Beijing 100044, China. E-mail: [email protected] 1
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infiltration, destruction of the glands and fibrosis (El Miedany et al. 2004). Because of the correlation that often exists between tissue elasticity and a pathologic state, the pathologic changes in major salivary glands in pSS presumably produce the corresponding elastic changes. Ultrasound elastography is a new non-invasive type of examination that uses the sonographic technique to evaluate tissue stiffness. This technique has proven effective in detecting and assessing many different pathologies (Dewall 2013). There are several types of elastographic examinations (Bamber et al. 2013). Acoustic radiation force impulse imaging (ARFI) is an elastography technique in which a short-duration acoustic radiation force is applied to the region of interest (ROI) to generate localized tissue displacements. The displacements result in propagation of shear waves away from the region of excitation, and the speed of the shear waves can be measured to evaluate the stiffness of the tissue (Matsuzuka et al. 2015). The usefulness of ARFI has been illustrated in many clinical applications, including liver fibrosis staging and lesion detection and classification (e.g., in the breast, thyroid and prostate) (Barr 2014; D’Onofrio et al. 2013; Sporea et al. 2012; Tozaki et al. 2012). Quantitative ARFI imaging includes two modes: Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). Application of a short-duration acoustic radiation force to the ROI induces a shear wave that propagates in the lateral direction. VTQ can calculate the shear wave velocity (SWV) and provide an objective numerical evaluation of tissue stiffness. SWV is expressed quantitatively in meters per second (m/s). Stiffer tissues are associated with a higher SWV (Zhang et al. 2012). VTIQ is a new form of 2-D shear wave imaging that displays a color-coded image and can detect the SWV in multiple locations (Tozaki et al. 2013). In this study, we investigated the usefulness of VTQ and VTIQ in examining the stiffness of major salivary glands (paired parotid and submandibular glands). The VTQ and VTIQ values of the salivary glands were measured to evaluate salivary gland stiffness in patients with pSS and compare it with that in normal salivary glands. METHODS Ethics statement This study was approved by the ethics committee of Peking University People’s Hospital (No. RDC2014-03). All participants provided written consent. Patients Between March and November 2013, 21 patients with suspected pSS were enrolled in this study. The
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inclusion criteria fulfilled the classification criteria proposed by the AEC group in 2002 (Vitali et al. 2002). The AEC criteria include six items: (i) ocular symptoms; (ii) oral symptoms; (iii) ocular signs (i.e., based on Schirmer’s dry eye test and ocular staining score); (iv) biopsy of minor salivary glands; (v) involvement of salivary glands, as proved by sialoscintigraphy, parotid sialography or unstimulated whole salivary flow; and (vi) presence of anti-Sj€ogren’s syndrome-related antigens A (anti-SSA) and B (anti-SSB) antibodies, as determined by Western blot. The patients who met the criteria that ‘‘the presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (histopathology) or VI (serology) is positive; the presence of any 3 of the 4 objective criteria items (i.e., items III, IV, V, VI)’’ were included in this study. The exclusion criteria included the presence of any other associated autoimmune disease, past operations affecting the parotid or submandibular gland and past head and neck radiation treatment. The control group included 11 healthy patients without preexisting autoimmune disease, salivary gland-related disease or symptoms such as xerostomia and xerophthalmia. All patients underwent ultrasonography, and their clinical records, including their age, sex and body mass index (BMI), were collected for analysis. Ultrasonography of the major salivary glands This study employed a Siemens S3000 ultrasound machine (Siemens Medical Solutions, Mountain View, CA, USA) equipped with a 4- to 9-MHz linear transducer and adequate software for performing elastographic examinations in quantitative ARFI mode (VTQ and VTIQ). All patients were examined by the same operator. Gray-scale ultrasonography of the major salivary glands Patients were scanned in the supine position with their necks extended and heads turned to the opposite side. The lengths and widths of the parotid and submandibular glands were measured in the longitudinal plane during ultrasound examination. A previously proposed scoring system (global score: 0–48) (Hocevar et al. 2005) was employed to assess the echostructure of each salivary gland. Five ultrasonography parameters were investigated. (i) Parenchymal echogenicity was evaluated in comparison with that of the thyroid gland or with the surrounding anatomic structures (e.g., muscle structures and subcutaneous fat) in cases of coincident thyroid gland disease. If the echogenicity was comparable to that of the thyroid, the grade was 0, whereas if it was decreased, the grade was 1. (ii) Homogeneity of the parenchyma was graded from 0 to 3. A grade of 0 indicates a homogeneous gland, a grade of 1 indicates mild inhomogeneity, a grade of 2
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indicates evident inhomogeneity and a grade of 3 indicates a grossly inhomogeneous gland. (iii) The presence of hypo-echoic areas was graded from 0 to 3 (grade 0: no areas; grade 1: a few, scattered areas; grade 2: several areas; grade 3: numerous hypo-echoic areas). (iv) Hyper-echogenic reflections were graded from 0 to 3 in parotid glands (grade 0: no reflections; grade 1: a few, scattered reflections; grade 2: several reflections; grade 3: numerous hyper-echogenic reflections) and 0 (absent) and 1 (present) in submandibular glands. (v) The clearness of the salivary gland borders was graded from 0 to 3 (grade 0: clear, regular defined borders; grade 1: partly defined borders; grade 2: illdefined borders; grade 3: borders not visible). The US score was calculated by summing the grades of the five above-described parameters for all four glands. The calculated US score ranged from 0 to 48. Virtual Touch tissue quantification For VTQ measurement, the patient was required to lie in the same position as for the gray-scale ultrasonography examination. The transducer was gently applied together with a sufficient amount of contact gel. VTQ mode was then performed on the long-axis dimension of the parotid and submandibular glands. SWV measurements were performed by placing a pre-defined measurement sample with a fixed size of 5 3 5 mm in the subcapsular parenchyma. In the paired parotid glands, the depth of the subcapsular sample was approximately 1.0 cm, whereas in the paired submandibular glands, the depth of the subcapsular sample ranged from 1.0 to 1.5 cm. Then, VTQ measurements were activated, and the SWV value (expressed in m/s) was displayed on the screen. Subsequently, the measurement sample was moved to the surrounding gland tissue at the same depth, and the procedure was repeated. The measurements were repeated seven times. The highest and lowest values were eliminated, and the mean of the remaining five measurements was calculated and used for the analysis. Virtual Touch tissue imaging quantification The measurement system, patient position, transducer conditions and long-axis dimension scanning for VTIQ were the same as for VTQ. A user-defined ROI that was larger than the salivary glands was positioned, and acoustic radiation force was applied across the ROI. The stiffness, indicated by color-coded 2-D shear wave imaging in the ROI, was then displayed on the screen. The 2-D shear wave image was displayed in four forms: shear wave velocity, shear wave quality, shear wave travel time and shear wave displacement. In the shear wave quality form, the ROIs shown in green color indicate high-quality regions where the SWV estimation was accurate. SWV measurement samples with
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a fixed size of 1 3 1 mm were placed in the subcapsular and central parenchyma. Four to six points at two depth positions (subcapsular and center parenchyma) and three lateral directions were selected in a ROI, and the VTIQ value was defined as the average of these measurements. The VTQ and VTIQ sometimes yield non-numeric results, which are all expressed as X.XX. Three reasons may account for this type of result: (i) Heterogeneous tissues absorb a substantial amount of ultrasound energy, and shear waves cannot be generated and propagated in the target; (ii) the target is so hard that the results exceed the maximum value used by the system; or (iii) possible influencing factors, such as the patient’s respiration and an operator’s inappropriate gesture, could affect the results. Statistical analysis All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, Version 16.0 (SPSS, Chicago, IL, USA). Count data were compared using the c2 test. Non-normally distributed measurement data were compared using the Mann–Whitney U-test. SWV and BMI values, which were measurement data and conformed to a normal distribution, are expressed as means 6 standard deviations (X 6 s). Differences in the VTQ and VTIQ results for the salivary glands between the pSS and control groups were compared with an independent t-test. Differences in the VTQ and VTIQ results between the parotid and submandibular glands of the salivary gland were compared with a paired t-test. Differences between the VTQ and VTIQ results for the salivary gland in the pSS group were compared with a paired t-test, and Pearson’s test was used for correlation analysis; p values , 0.05 were considered to indicate statistical significance. To investigate intra-observer reproducibility, repeated VTQ and VTIQ measurements for the parotid were performed in 10 patients by the same operator within 2 d. The intra-class correlation coefficient was used to evaluate intra-observer agreement. A significance level of p , 0.05 was used in the analysis. RESULTS Characteristics of the patients Table 1 summarizes the study patients’ characteristics. There were no statistically significant differences between the pSS group and control group in terms of age, sex ratio, or BMI. The pSS group had a significantly higher frequency of xerostomia, xerophthalmia, positive Schirmer dry eye test, parotid sialography, salivary scintigraphy, minor salivary gland biopsy, anti-SSA and antiSSB antibodies than the control group (p , 0.01).
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Table 1. General characteristics of the study population Characteristic
pSS group
Healthy control group
Age Female/male ratio Body mass index Xerostomia Xerophthalmia Schirmer’s dry eye test Parotid sialography Salivary scintigraphy Minor salivary gland biopsy Anti-SSA positive Anti-SSB positive
57.6 6 7.7 21/0 22.8 6 1.3 19* 21* 14* 5* 5* 7* 15* 6*
54.1 6 11.2 11/0 23.7 6 2.2 0 0 0 0 0 0 0 0
pSS 5 primary Sj€ ogren’s syndrome; SSA 5 Sj€ogren’s syndromerelated antigen A; SSB 5 Sj€ogren’s syndrome-related antigen B. * p , 0.01: Statistically significant, pSS group versus control group.
Gray-scale ultrasonography of the major salivary glands The length and width of the salivary glands are expressed as means 6 standard deviations in Table 2. No significant difference in the size of the parotid was observed between the pSS group and control group. The length and width of the submandibular gland of the pSS group were both significantly smaller compared with the values obtained for the control group (p , 0.01). In the pSS group, the parotid and submandibular glands exhibited diffuse lesions. According to the 0–48 scoring system, the mean ultrasonography scores for the bilateral parotid glands and bilateral submandibular glands and the mean total for all of the glands in the pSS group were significantly higher than those obtained for the control group (p , 0.01, overall) (Table 2). Comparison of VTQ and VTIQ between the pSS and control groups In the present study, all VTQ and VTIQ measurements produced numerical results, and no X.XX appeared. After excluding possible influencing factors, such as a Table 2. Gray-scale ultrasonography of major salivary glands
Parotid length (mm) Parotid width (mm) Submandibular length (mm) Submandibular width (mm) Parotid scoring Submandibular scoring Total for four glands (0–48)
pSS group (n 5 21)
Healthy control group (n 5 11)
48.1 6 2.9 17.3 6 2.4 28.3 6 3.1* 11.1 6 2.4* 12 (5, 20)y 11 (4, 17)y 23 (10, 34)y
49.5 6 3.5 16.6 6 1.7 35.0 6 3.8 15.4 6 1.5 4 (4, 6) 2 (0, 4) 6 (4, 8)
pSS 5 primary Sj€ ogren’s syndrome. * The length and width of the submandibular gland were both significantly smaller in the pSS group than in the control group, p , 0.01. y Salivary gland scores are expressed as the median (minimum, maximum). p , 0.01, Mann–Whitney test.
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patient’s respiration and an operator’s inappropriate gesture, the value of X.XX m/s is allocated to beyond the range of the VTQ values (between 0.8 and 8.4 m/s) or VTIQ values (between 0.5 and 10.0 m/s). Examples of VTQ and VTIQ measurements are provided in Figures 1 and 2, respectively. The mean VTQ value for the parotid gland in the pSS group (1.33 6 0.22) was significantly higher (p , 0.01) than that obtained for the control group (1.18 6 0.04 m/s). However, the mean VTQ values for the submandibular gland did not significantly differ between the two groups (1.27 6 0.17 and 1.19 6 0.07 m/s, respectively, p 5 0.09). The mean VTIQ values for the parotid (1.36 6 0.19 and 1.25 6 0.05 m/s, respectively, p , 0.05) and submandibular (1.38 6 0.17 and 1.25 6 0.06 m/s, respectively, p , 0.01) glands were both significantly higher in the pSS group than in the control group. The aforementioned findings are illustrated in Figure 3. In the pSS group, the highest SWV value was 1.94 m/s, which was obtained in a patient with serious xerostomia and xerophthalmia. Under gray-scale ultrasonography, the paired parotid glands were observed to be diffusely enlarged and exhibited inhomogeneity and multiple hypo-echoic areas, as illustrated in Figure 4. Comparison of VTQ and VTIQ between the parotid and submandibular glands For the VTQ and VTIQ measurements, no significant difference was observed between the parotid and submandibular glands in the pSS group or control group. Comparison of VTQ and VTIQ in the pSS group In the pSS group, there was no significant difference between the VTQ and VTIQ values for the parotid. However, the VTIQ value for the submandibular gland was significantly higher than the VTQ value (p , 0.05) (see Fig. 3). In the pSS group, there was a positive correlation between the VTQ and VTIQ of the parotid (Pearson’s r 5 0.85, p , 0.01) and submandibular (Pearson’s r 5 0.55, p , 0.05) glands (see Fig. 5). Reproducibility in ARFI elastography Good intra-observer agreement was observed, with intra-class correlation coefficient values of 0.79 (95% confidence interval: 0.36–0.94) for VTQ and 0.94 (95% confidence interval: 0.77–0.98) for VTIQ (both p , 0.01). DISCUSSION Ultrasound elastography comprises a novel set of imaging techniques that are used to evaluate tissue elasticity, and these methods are often referred to as virtual palpation. These techniques have proven effective in
US elastography of major salivary glands d S. ZHANG et al.
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Fig. 1. VTQ measurement for a patient with primary Sj€ ogren’s syndrome (pSS). (a) The VTQ value of the left parotid gland was measured with fixed measurement sample dimensions of 5 3 5 mm. (b) The VTQ value of the left submandibular gland was measured with fixed measurement sample dimensions of 5 3 5 mm. VTQ 5 Virtual Touch tissue quantification.
detecting and assessing many different pathologies because tissue mechanical changes are often correlated with tissue pathologic changes (Dewall 2013). Two major imaging techniques for ultrasound elastography are presently available based on two different types of applied force. The first method is strain elasticity imaging, which requires continuous transducer compression or external mechanical compression to induce strain on tissues. The strain in the ROI and surrounding tissue is measured and analyzed to investigate elasticity. Dejaco et al. (2014) reported the application of the strain elastography method to the assessment of the salivary gland in pSS and indicated that it is a valuable tool in the diagnosis of pSS. However, strain elasticity is easily influenced by several factors, such as operator dependency, poor reproducibility and nonquantitative results (Badea et al. 2013). The second method is acoustic radiation force elasticity imaging, including ARFI imaging. This technique requires no external compression and exploits
short-duration acoustic radiation forces to generate localized tissue displacements. VTQ and VTIQ are two modes of quantitative ARFI imaging (Tozaki et al. 2013). The advantages of quantitative acoustic radiation force elasticity techniques (VTQ and VTIQ) include: The applied force is induced by acoustic radiation force without a subjective bias, and the SWV provides an objective numerical evaluation of tissue stiffness. For the parotid and submandibular glands, it is difficult to apply steady transducer compression because of their irregular shape and location behind the mandible. Moreover, the salivary gland lesions observed in pSS are diffuse, as indicated by our gray-scale ultrasonography results and the literature (Cornec et al. 2013); thus, VTQ and VTIQ are likely more useful for evaluating the stiffness of diffuse salivary gland lesions in pSS. At present, few clinical results obtained using VTQ and VTIQ in investigations of the elasticity of salivary gland have been reported (Matsuzuka et al. 2015); in particular, there is a lack of relevant studies in pSS patients.
Fig. 2. VTIQ measurement of the right parotid gland of a patient with pSS. (a) The shear wave quality form in VTIQ indicated high-quality regions, which are displayed in green. (b) Six measurements with fixed dimensions of 1 3 1 mm were conducted at two depth positions (subcapsular and center parenchyma) and three lateral directions. VTIQ 5 Virtual Touch tissue imaging quantification; pSS 5 primary Sj€ ogren’s syndrome.
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Fig. 3. VTQ and VTIQ values of the parotid and submandibular glands of the pSS and healthy control groups. (i) The mean VTQ value for the parotid gland and the mean VTIQ values for the parotid and submandibular glands in the pSS group were all significantly higher than the corresponding values obtained for the healthy control group (p , 0.01, p , 0.05 and p , 0.01, respectively). (ii) In the pSS group, the VTIQ value for the submandibular gland was significantly higher than the VTQ value (p , 0.05). Boxes 5 values from lower to upper quartiles, central lines 5 medians, dots 5 outliers. SWV 5 shear wave velocity; VTQ 5 Virtual Touch tissue quantification; VTIQ 5 Virtual Touch tissue imaging quantification; pSS 5 primary Sj€ ogren’s syndrome.
The sonographic features of the parotid and submandibular glands of the healthy control and pSS groups detected by gray-scale ultrasonography were similar, and no significant difference in the size of the parotid was observed between the pSS and control groups. The length and width of the submandibular gland of the pSS group were both significantly smaller than the corresponding values obtained for the control group. This finding could be explained by two facts: the symptoms of pSS are nonspecific, and many pSS patients are not diagnosed at the early stage of the disease. It should be noted that all salivary gland sizes were markedly larger than the measurement samples of VTQ (5 mm) and VTIQ (1 mm), indicating that application of VTQ and VTIQ to the assessment of salivary glands is feasible. In our study, no significant difference in stiffness was observed between the parotid and submandibular glands in healthy controls. Matsuzuka et al. (2015) also reported that the stiffness of normal parotid glands is highly similar to that of submandibular glands. In the pSS group, the sonographic features and stiffness of the parotid were consistent with those of the submandibular gland. Hence, it is suggested that all major salivary glands are typically involved, and the lesions are well distributed among these glands in patients with pSS.
Both VTQ and VTIQ values for the parotid in the pSS group were significantly higher than those obtained for the healthy controls. The VTIQ values of the submandibular gland obtained in patients with pSS were significantly higher than those for the control group. These results indicated that the stiffness of the salivary glands in patients with pSS was increased, which may be assumed to be correlated with histopathologic changes, including lymphocytic infiltration, destruction of glands and fibrosis. Similar findings were also obtained in a study of radiation submaxillitis. After radiation therapy, the SWV of the submandibular gland was increased, indicating diffuse histopathologic changes in the salivary glands, including an initial acute inflammatory reaction followed by a chronic hypotrophy (Badea et al. 2013). However, the relationship between the salivary gland stiffness and different durations of pSS or clinical records is not yet known. A study of the application of ARFI in diffuse thyroiditis indicated that shear wave elastography may aid the diagnosis and treatment monitoring of acute, subacute and chronic thyroiditis, as well as the differentiation of the various types of thyroiditis (Ruchala et al. 2012). Thus, our study must be extended to a larger group of patients for further analyses. It is expected that ARFI changes will prove to
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Fig. 4. Images of a 61-y-old female patient with primary Sj€ ogren’s syndrome with the highest SWVof the parotid gland. (a) Gray-scale ultrasonography revealed diffuse lesions that exhibited inhomogeneity and multiple hypo-echoic areas. (b) The SWV was measured with Virtual Touch tissue quantification. (c) The SWV was measured withVirtual Touch tissue imaging quantification. SWV 5 shear wave velocity.
be a valuable adjunct tool for assessing the duration and activity of pSS. In the present study, there was a positive correlation between the VTQ and VTIQ results of the parotid and
submandibular glands. The principles of VTQ and VTIQ are similar, and both involve evaluation of the SWV in a ROI. In the pSS group, the VTIQ value for the submandibular gland was higher than the VTQ value.
Fig. 5. Coefficients of correlation between VTQ and VTIQ of the (a) parotid gland (Pearson’s r 5 0.85, p , 0.01) and (b) submandibular gland (Pearson’s r 5 0.55, p , 0.05) in the primary Sj€ ogren’s syndrome (pSS) group (m/s). VTQ 5 Virtual Touch tissue quantification; VTIQ 5 Virtual Touch tissue imaging quantification.
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The difference between the VTQ and VTIQ values are believed to be because of the different measurement sample sizes. The VTQ technique uses a rather large measurement sample; thus, the data are expressed as the average SWV values. In contrast, the VTIQ technique uses a small measurement sample, and the data are therefore expressed as the local SWV values. Similar results were reported previously; for example, the SWV values measured via VTIQ for breast lesions were higher than the corresponding VTQ values (Tozaki et al. 2013). Possible causes have been suggested: (i) VTIQ enables measurement of the SWV in smaller regions, yielding higher spatial velocity resolution. (ii) The site exhibiting the highest SWV was visually identified using the VTIQ shear wave velocity form, and the SWV may tend to be measured at that site. Researchers have obtained slightly better results using VTIQ than VTQ in differentiating malignant from benign solid breast masses (Tozaki et al. 2013). In our study, the VTIQ values of the submandibular gland obtained in patients with pSS were significantly higher than those in the control group, whereas the VTQ values for the submandibular gland did not differ between the two groups. It was conjectured that VTIQ is more useful. The advantages of VTIQ are as follows: (i) the VTIQ technique includes the shear wave quality form, which contributes greatly to the accuracy of SWV measurements; (ii) the SWV measurement range of VTIQ (0.5–10 m/s) is greater than that of VTQ (0.8–8.4 m/s). (iii) VTIQ is easier to use and provides more conclusive results than VTQ. The acquisition of images is faster with VTIQ, and fewer repeated acquisitions are needed to compare the SWVs from different locations. Our study indicates that VTQ and VTIQ may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of pSS. However, the most important limitations of our study are the small number of patients and the lack of male patients. Because pSS has a strong female propensity, all of our selected pSS cases in this prospective study were female. We hypothesize that further studies involving larger numbers of patients could increase the number of male cases. Moreover, a further large-scale study to validate our results and establish diagnostic threshold values for VTQ and VTIQ should be conducted. Additional studies should also focus on the reliability of quantitative ARFI imaging for the assessment of salivary gland function and during follow-up. Another limitation of this study is the different measurement sample sizes between VTQ and VTIQ imaging. An easy solution would be to make these sizes similar to allow proper comparisons, but the pre-defined measurement sample sizes of VTQ and VTIQ are fixed and cannot be modified. The salivary gland lesions observed in pSS in our study were diffuse, and the sali-
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vary gland sizes were markedly larger than the measurement sample sizes of VTQ and VTIQ, indicating that the application of VTQ and VTIQ imaging to analysis of the salivary gland is feasible. In the future, the measurement sample size will likely be modified to yield a more reasonable size based on the manufacturer’s technical improvement. CONCLUSIONS Virtual Touch tissue quantification and Virtual Touch tissue imaging quantification are useful tools for examining the stiffness of the major salivary glands through quantitative ultrasound elastography. The stiffness of normal salivary glands and of pSS patients was quantitatively determined based on VTQ and VTIQ values. Overall, our study revealed that VTQ and VTIQ do not differ significantly, although better results for the stiffness of salivary gland lesions in pSS were obtained with VTIQ than with VTQ. The stiffness of the major salivary glands in pSS patients was increased compared with that of normal glands. These findings indicate that VTQ and VTIQ may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of primary Sjogren’s syndrome. Acknowledgments—This work was supported by Peking University People’s Hospital Research and Development Funds (Project RDB2014-03).
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tology classification criteria for Sj€ogren’s syndrome: a data-driven, expert consensus approach in the Sjogren’s International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64: 475–487. Sporea I, Sirli R, Bota S, Vlad M, Popescu A, Zosin I. ARFI elastography for the evaluation of diffuse thyroid gland pathology: Preliminary results. World J Radiol 2012;4:174–178. Tozaki M, Isobe S, Sakamoto M. Combination of elastography and tissue quantification using the acoustic radiation force impulse (ARFI) technology for differential diagnosis of breast masses. Jpn J Radiol 2012;30:659–670. Tozaki M, Saito M, Benson J, Fan L, Isobe S. Shear wave velocity measurements for differential diagnosis of solid breast masses: A comparison between Virtual Touch quantification and Virtual Touch IQ. Ultrasound Med Biol 2013;39:2233–2245. Tzioufas AG, Moutsopoulos HM. Ultrasonography of salivary glands: An evolving approach for the diagnosis of Sj€ogren’s syndrome. Nat Clin Pract Rheumatol 2008;4:454–455. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos H, Alexander E, Carsons S, Daniels T, Fox P, Kassan S, Pillemer S, Talal N, Weisman M. Classification criteria for Sj€ogren’s syndrome: A revised version of the European criteria proposed by the American–European Consensus Group. Ann Rheum Dis 2002;61: 554–558. Yazisiz V, Avci AB, Erbasan F, Kiris E, Terzioðlu E. Diagnostic performance of minor salivary gland biopsy, serological and clinical data in Sj€ogren’s syndrome: A retrospective analysis. Rheumatol Int 2009;29:403–409. Zhang YF, Xu HX, He Y, Liu C, Guo LH, Liu LN, Xu JM. Virtual Touch tissue quantification of acoustic radiation force impulse: A new ultrasound elastic imaging in the diagnosis of thyroid nodules. PLoS One 2012;7:e49094.
http://dx.doi.org/10.1016/j.ultrasmedbio.2015.11.009
d
Original Contribution ASSESSMENT OF THE STIFFNESS OF MAJOR SALIVARY GLANDS IN PRIMARY € SJOGREN’S SYNDROME THROUGH QUANTITATIVE ACOUSTIC RADIATION FORCE IMPULSE IMAGING SHANSHAN ZHANG,* JIAAN ZHU,* XIA ZHANG,y JING HE,y and JIANGUO LI* * Department of Ultrasound, Peking University People’s Hospital, Beijing, China; and y Department of Rheumatology and Immunology, Peking University People’s Hospital, Beijing, China (Received 23 June 2015; revised 3 November 2015; in final form 9 November 2015)
Abstract—The purpose of the study described here was to evaluate salivary gland stiffness in primary Sj€ ogren’s syndrome (pSS) via acoustic radiation force impulse imaging, including Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). Twenty-one patients with pSS and 11 healthy patients were included, and the paired parotid and submandibular glands of all of the patients were examined using VTQ and VTIQ. Differences between the two groups were compared with independent and paired t-tests. The VTQ value for the parotid in the pSS group was significantly higher than that obtained for the control group (1.33 ± 0.22 and 1.18 ± 0.04 m/s, respectively, p , 0.01). The VTIQ values for the parotid and submandibular gland were both significantly higher in the pSS group than in the control group (p , 0.05). In the pSS group, a positive correlation was observed between the VTQ and VTIQ results for the parotid and submandibular glands. In summary, the stiffness of the major salivary glands in patients with pSS was increased compared with that of patients with normal glands. This finding indicates that VTQ and VTIQ imaging may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of pSS. (E-mail: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Sj€ogren’s syndrome, Salivary glands, Virtual Touch tissue quantification, Virtual Touch tissue imaging quantification, Acoustic radiation force impulse imaging.
significantly to the diagnosis of pSS. The objective methods used for the examination of salivary glands include parotid sialography, salivary scintigraphy and minor salivary gland biopsy (Yazisiz et al. 2009). However, these are all invasive or irradiating procedures that may result in inconvenience and a risk of complications in the patient (Niemel€a et al. 2004). In recent studies, ultrasonography has been reported to be valuable for assessing major salivary gland involvement in pSS (Tzioufas and Moutsopoulos 2008). Four major salivary glands (the paired parotid and submandibular glands) are superficial and suitable for ultrasonic examination. The reported characteristic sonographic findings include inhomogeneity, multiple hypo-echoic areas and multiple hyper-echoic lines (Hocevar et al. 2005). However, the characteristic ultrasonographic changes observed in pSS and the diagnostic accuracy attained are controversial. The greatest limitation is the lack of specificity (Cornec et al. 2013). The features of sonographic images of the major salivary glands observed in pSS may be related to histopathologic changes in the glands, including lymphocytic
INTRODUCTION Primary Sj€ ogren’s syndrome (pSS) is a chronic autoimmune disease that affects exocrine systems, including the salivary and lacrimal glands. Primary Sj€ ogren’s syndrome has a strong female propensity, and its female-to-male ratio varies from as high as 20:1 to 9:1 (Patel and Shahane 2014). Xerostomia and xerophthalmia are the representative clinical features of pSS and can be accompanied by systemic disease manifestation (Maœli~ nska et al. 2015). The salivary glands are the main target organs, and histopathologic analysis reveals focal lymphocytic infiltration, destruction of the glands and fibrosis (Kassan and Moutsopoulos 2004). Among the classification criteria proposed by the American–European Consensus (AEC) group in 2002 (Vitali et al. 2002) and the American College of Rheumatology in 2012 (Shiboski et al. 2012), the evaluation of salivary gland involvement contributes
Address correspondence to: Jiaan Zhu, Department of Ultrasound, Peking University People’s Hospital, 11 Xizhimen South Street, Beijing 100044, China. E-mail: [email protected] 1
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infiltration, destruction of the glands and fibrosis (El Miedany et al. 2004). Because of the correlation that often exists between tissue elasticity and a pathologic state, the pathologic changes in major salivary glands in pSS presumably produce the corresponding elastic changes. Ultrasound elastography is a new non-invasive type of examination that uses the sonographic technique to evaluate tissue stiffness. This technique has proven effective in detecting and assessing many different pathologies (Dewall 2013). There are several types of elastographic examinations (Bamber et al. 2013). Acoustic radiation force impulse imaging (ARFI) is an elastography technique in which a short-duration acoustic radiation force is applied to the region of interest (ROI) to generate localized tissue displacements. The displacements result in propagation of shear waves away from the region of excitation, and the speed of the shear waves can be measured to evaluate the stiffness of the tissue (Matsuzuka et al. 2015). The usefulness of ARFI has been illustrated in many clinical applications, including liver fibrosis staging and lesion detection and classification (e.g., in the breast, thyroid and prostate) (Barr 2014; D’Onofrio et al. 2013; Sporea et al. 2012; Tozaki et al. 2012). Quantitative ARFI imaging includes two modes: Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). Application of a short-duration acoustic radiation force to the ROI induces a shear wave that propagates in the lateral direction. VTQ can calculate the shear wave velocity (SWV) and provide an objective numerical evaluation of tissue stiffness. SWV is expressed quantitatively in meters per second (m/s). Stiffer tissues are associated with a higher SWV (Zhang et al. 2012). VTIQ is a new form of 2-D shear wave imaging that displays a color-coded image and can detect the SWV in multiple locations (Tozaki et al. 2013). In this study, we investigated the usefulness of VTQ and VTIQ in examining the stiffness of major salivary glands (paired parotid and submandibular glands). The VTQ and VTIQ values of the salivary glands were measured to evaluate salivary gland stiffness in patients with pSS and compare it with that in normal salivary glands. METHODS Ethics statement This study was approved by the ethics committee of Peking University People’s Hospital (No. RDC2014-03). All participants provided written consent. Patients Between March and November 2013, 21 patients with suspected pSS were enrolled in this study. The
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inclusion criteria fulfilled the classification criteria proposed by the AEC group in 2002 (Vitali et al. 2002). The AEC criteria include six items: (i) ocular symptoms; (ii) oral symptoms; (iii) ocular signs (i.e., based on Schirmer’s dry eye test and ocular staining score); (iv) biopsy of minor salivary glands; (v) involvement of salivary glands, as proved by sialoscintigraphy, parotid sialography or unstimulated whole salivary flow; and (vi) presence of anti-Sj€ogren’s syndrome-related antigens A (anti-SSA) and B (anti-SSB) antibodies, as determined by Western blot. The patients who met the criteria that ‘‘the presence of any 4 of the 6 items is indicative of primary SS, as long as either item IV (histopathology) or VI (serology) is positive; the presence of any 3 of the 4 objective criteria items (i.e., items III, IV, V, VI)’’ were included in this study. The exclusion criteria included the presence of any other associated autoimmune disease, past operations affecting the parotid or submandibular gland and past head and neck radiation treatment. The control group included 11 healthy patients without preexisting autoimmune disease, salivary gland-related disease or symptoms such as xerostomia and xerophthalmia. All patients underwent ultrasonography, and their clinical records, including their age, sex and body mass index (BMI), were collected for analysis. Ultrasonography of the major salivary glands This study employed a Siemens S3000 ultrasound machine (Siemens Medical Solutions, Mountain View, CA, USA) equipped with a 4- to 9-MHz linear transducer and adequate software for performing elastographic examinations in quantitative ARFI mode (VTQ and VTIQ). All patients were examined by the same operator. Gray-scale ultrasonography of the major salivary glands Patients were scanned in the supine position with their necks extended and heads turned to the opposite side. The lengths and widths of the parotid and submandibular glands were measured in the longitudinal plane during ultrasound examination. A previously proposed scoring system (global score: 0–48) (Hocevar et al. 2005) was employed to assess the echostructure of each salivary gland. Five ultrasonography parameters were investigated. (i) Parenchymal echogenicity was evaluated in comparison with that of the thyroid gland or with the surrounding anatomic structures (e.g., muscle structures and subcutaneous fat) in cases of coincident thyroid gland disease. If the echogenicity was comparable to that of the thyroid, the grade was 0, whereas if it was decreased, the grade was 1. (ii) Homogeneity of the parenchyma was graded from 0 to 3. A grade of 0 indicates a homogeneous gland, a grade of 1 indicates mild inhomogeneity, a grade of 2
US elastography of major salivary glands d S. ZHANG et al.
indicates evident inhomogeneity and a grade of 3 indicates a grossly inhomogeneous gland. (iii) The presence of hypo-echoic areas was graded from 0 to 3 (grade 0: no areas; grade 1: a few, scattered areas; grade 2: several areas; grade 3: numerous hypo-echoic areas). (iv) Hyper-echogenic reflections were graded from 0 to 3 in parotid glands (grade 0: no reflections; grade 1: a few, scattered reflections; grade 2: several reflections; grade 3: numerous hyper-echogenic reflections) and 0 (absent) and 1 (present) in submandibular glands. (v) The clearness of the salivary gland borders was graded from 0 to 3 (grade 0: clear, regular defined borders; grade 1: partly defined borders; grade 2: illdefined borders; grade 3: borders not visible). The US score was calculated by summing the grades of the five above-described parameters for all four glands. The calculated US score ranged from 0 to 48. Virtual Touch tissue quantification For VTQ measurement, the patient was required to lie in the same position as for the gray-scale ultrasonography examination. The transducer was gently applied together with a sufficient amount of contact gel. VTQ mode was then performed on the long-axis dimension of the parotid and submandibular glands. SWV measurements were performed by placing a pre-defined measurement sample with a fixed size of 5 3 5 mm in the subcapsular parenchyma. In the paired parotid glands, the depth of the subcapsular sample was approximately 1.0 cm, whereas in the paired submandibular glands, the depth of the subcapsular sample ranged from 1.0 to 1.5 cm. Then, VTQ measurements were activated, and the SWV value (expressed in m/s) was displayed on the screen. Subsequently, the measurement sample was moved to the surrounding gland tissue at the same depth, and the procedure was repeated. The measurements were repeated seven times. The highest and lowest values were eliminated, and the mean of the remaining five measurements was calculated and used for the analysis. Virtual Touch tissue imaging quantification The measurement system, patient position, transducer conditions and long-axis dimension scanning for VTIQ were the same as for VTQ. A user-defined ROI that was larger than the salivary glands was positioned, and acoustic radiation force was applied across the ROI. The stiffness, indicated by color-coded 2-D shear wave imaging in the ROI, was then displayed on the screen. The 2-D shear wave image was displayed in four forms: shear wave velocity, shear wave quality, shear wave travel time and shear wave displacement. In the shear wave quality form, the ROIs shown in green color indicate high-quality regions where the SWV estimation was accurate. SWV measurement samples with
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a fixed size of 1 3 1 mm were placed in the subcapsular and central parenchyma. Four to six points at two depth positions (subcapsular and center parenchyma) and three lateral directions were selected in a ROI, and the VTIQ value was defined as the average of these measurements. The VTQ and VTIQ sometimes yield non-numeric results, which are all expressed as X.XX. Three reasons may account for this type of result: (i) Heterogeneous tissues absorb a substantial amount of ultrasound energy, and shear waves cannot be generated and propagated in the target; (ii) the target is so hard that the results exceed the maximum value used by the system; or (iii) possible influencing factors, such as the patient’s respiration and an operator’s inappropriate gesture, could affect the results. Statistical analysis All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, Version 16.0 (SPSS, Chicago, IL, USA). Count data were compared using the c2 test. Non-normally distributed measurement data were compared using the Mann–Whitney U-test. SWV and BMI values, which were measurement data and conformed to a normal distribution, are expressed as means 6 standard deviations (X 6 s). Differences in the VTQ and VTIQ results for the salivary glands between the pSS and control groups were compared with an independent t-test. Differences in the VTQ and VTIQ results between the parotid and submandibular glands of the salivary gland were compared with a paired t-test. Differences between the VTQ and VTIQ results for the salivary gland in the pSS group were compared with a paired t-test, and Pearson’s test was used for correlation analysis; p values , 0.05 were considered to indicate statistical significance. To investigate intra-observer reproducibility, repeated VTQ and VTIQ measurements for the parotid were performed in 10 patients by the same operator within 2 d. The intra-class correlation coefficient was used to evaluate intra-observer agreement. A significance level of p , 0.05 was used in the analysis. RESULTS Characteristics of the patients Table 1 summarizes the study patients’ characteristics. There were no statistically significant differences between the pSS group and control group in terms of age, sex ratio, or BMI. The pSS group had a significantly higher frequency of xerostomia, xerophthalmia, positive Schirmer dry eye test, parotid sialography, salivary scintigraphy, minor salivary gland biopsy, anti-SSA and antiSSB antibodies than the control group (p , 0.01).
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Table 1. General characteristics of the study population Characteristic
pSS group
Healthy control group
Age Female/male ratio Body mass index Xerostomia Xerophthalmia Schirmer’s dry eye test Parotid sialography Salivary scintigraphy Minor salivary gland biopsy Anti-SSA positive Anti-SSB positive
57.6 6 7.7 21/0 22.8 6 1.3 19* 21* 14* 5* 5* 7* 15* 6*
54.1 6 11.2 11/0 23.7 6 2.2 0 0 0 0 0 0 0 0
pSS 5 primary Sj€ ogren’s syndrome; SSA 5 Sj€ogren’s syndromerelated antigen A; SSB 5 Sj€ogren’s syndrome-related antigen B. * p , 0.01: Statistically significant, pSS group versus control group.
Gray-scale ultrasonography of the major salivary glands The length and width of the salivary glands are expressed as means 6 standard deviations in Table 2. No significant difference in the size of the parotid was observed between the pSS group and control group. The length and width of the submandibular gland of the pSS group were both significantly smaller compared with the values obtained for the control group (p , 0.01). In the pSS group, the parotid and submandibular glands exhibited diffuse lesions. According to the 0–48 scoring system, the mean ultrasonography scores for the bilateral parotid glands and bilateral submandibular glands and the mean total for all of the glands in the pSS group were significantly higher than those obtained for the control group (p , 0.01, overall) (Table 2). Comparison of VTQ and VTIQ between the pSS and control groups In the present study, all VTQ and VTIQ measurements produced numerical results, and no X.XX appeared. After excluding possible influencing factors, such as a Table 2. Gray-scale ultrasonography of major salivary glands
Parotid length (mm) Parotid width (mm) Submandibular length (mm) Submandibular width (mm) Parotid scoring Submandibular scoring Total for four glands (0–48)
pSS group (n 5 21)
Healthy control group (n 5 11)
48.1 6 2.9 17.3 6 2.4 28.3 6 3.1* 11.1 6 2.4* 12 (5, 20)y 11 (4, 17)y 23 (10, 34)y
49.5 6 3.5 16.6 6 1.7 35.0 6 3.8 15.4 6 1.5 4 (4, 6) 2 (0, 4) 6 (4, 8)
pSS 5 primary Sj€ ogren’s syndrome. * The length and width of the submandibular gland were both significantly smaller in the pSS group than in the control group, p , 0.01. y Salivary gland scores are expressed as the median (minimum, maximum). p , 0.01, Mann–Whitney test.
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patient’s respiration and an operator’s inappropriate gesture, the value of X.XX m/s is allocated to beyond the range of the VTQ values (between 0.8 and 8.4 m/s) or VTIQ values (between 0.5 and 10.0 m/s). Examples of VTQ and VTIQ measurements are provided in Figures 1 and 2, respectively. The mean VTQ value for the parotid gland in the pSS group (1.33 6 0.22) was significantly higher (p , 0.01) than that obtained for the control group (1.18 6 0.04 m/s). However, the mean VTQ values for the submandibular gland did not significantly differ between the two groups (1.27 6 0.17 and 1.19 6 0.07 m/s, respectively, p 5 0.09). The mean VTIQ values for the parotid (1.36 6 0.19 and 1.25 6 0.05 m/s, respectively, p , 0.05) and submandibular (1.38 6 0.17 and 1.25 6 0.06 m/s, respectively, p , 0.01) glands were both significantly higher in the pSS group than in the control group. The aforementioned findings are illustrated in Figure 3. In the pSS group, the highest SWV value was 1.94 m/s, which was obtained in a patient with serious xerostomia and xerophthalmia. Under gray-scale ultrasonography, the paired parotid glands were observed to be diffusely enlarged and exhibited inhomogeneity and multiple hypo-echoic areas, as illustrated in Figure 4. Comparison of VTQ and VTIQ between the parotid and submandibular glands For the VTQ and VTIQ measurements, no significant difference was observed between the parotid and submandibular glands in the pSS group or control group. Comparison of VTQ and VTIQ in the pSS group In the pSS group, there was no significant difference between the VTQ and VTIQ values for the parotid. However, the VTIQ value for the submandibular gland was significantly higher than the VTQ value (p , 0.05) (see Fig. 3). In the pSS group, there was a positive correlation between the VTQ and VTIQ of the parotid (Pearson’s r 5 0.85, p , 0.01) and submandibular (Pearson’s r 5 0.55, p , 0.05) glands (see Fig. 5). Reproducibility in ARFI elastography Good intra-observer agreement was observed, with intra-class correlation coefficient values of 0.79 (95% confidence interval: 0.36–0.94) for VTQ and 0.94 (95% confidence interval: 0.77–0.98) for VTIQ (both p , 0.01). DISCUSSION Ultrasound elastography comprises a novel set of imaging techniques that are used to evaluate tissue elasticity, and these methods are often referred to as virtual palpation. These techniques have proven effective in
US elastography of major salivary glands d S. ZHANG et al.
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Fig. 1. VTQ measurement for a patient with primary Sj€ ogren’s syndrome (pSS). (a) The VTQ value of the left parotid gland was measured with fixed measurement sample dimensions of 5 3 5 mm. (b) The VTQ value of the left submandibular gland was measured with fixed measurement sample dimensions of 5 3 5 mm. VTQ 5 Virtual Touch tissue quantification.
detecting and assessing many different pathologies because tissue mechanical changes are often correlated with tissue pathologic changes (Dewall 2013). Two major imaging techniques for ultrasound elastography are presently available based on two different types of applied force. The first method is strain elasticity imaging, which requires continuous transducer compression or external mechanical compression to induce strain on tissues. The strain in the ROI and surrounding tissue is measured and analyzed to investigate elasticity. Dejaco et al. (2014) reported the application of the strain elastography method to the assessment of the salivary gland in pSS and indicated that it is a valuable tool in the diagnosis of pSS. However, strain elasticity is easily influenced by several factors, such as operator dependency, poor reproducibility and nonquantitative results (Badea et al. 2013). The second method is acoustic radiation force elasticity imaging, including ARFI imaging. This technique requires no external compression and exploits
short-duration acoustic radiation forces to generate localized tissue displacements. VTQ and VTIQ are two modes of quantitative ARFI imaging (Tozaki et al. 2013). The advantages of quantitative acoustic radiation force elasticity techniques (VTQ and VTIQ) include: The applied force is induced by acoustic radiation force without a subjective bias, and the SWV provides an objective numerical evaluation of tissue stiffness. For the parotid and submandibular glands, it is difficult to apply steady transducer compression because of their irregular shape and location behind the mandible. Moreover, the salivary gland lesions observed in pSS are diffuse, as indicated by our gray-scale ultrasonography results and the literature (Cornec et al. 2013); thus, VTQ and VTIQ are likely more useful for evaluating the stiffness of diffuse salivary gland lesions in pSS. At present, few clinical results obtained using VTQ and VTIQ in investigations of the elasticity of salivary gland have been reported (Matsuzuka et al. 2015); in particular, there is a lack of relevant studies in pSS patients.
Fig. 2. VTIQ measurement of the right parotid gland of a patient with pSS. (a) The shear wave quality form in VTIQ indicated high-quality regions, which are displayed in green. (b) Six measurements with fixed dimensions of 1 3 1 mm were conducted at two depth positions (subcapsular and center parenchyma) and three lateral directions. VTIQ 5 Virtual Touch tissue imaging quantification; pSS 5 primary Sj€ ogren’s syndrome.
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Fig. 3. VTQ and VTIQ values of the parotid and submandibular glands of the pSS and healthy control groups. (i) The mean VTQ value for the parotid gland and the mean VTIQ values for the parotid and submandibular glands in the pSS group were all significantly higher than the corresponding values obtained for the healthy control group (p , 0.01, p , 0.05 and p , 0.01, respectively). (ii) In the pSS group, the VTIQ value for the submandibular gland was significantly higher than the VTQ value (p , 0.05). Boxes 5 values from lower to upper quartiles, central lines 5 medians, dots 5 outliers. SWV 5 shear wave velocity; VTQ 5 Virtual Touch tissue quantification; VTIQ 5 Virtual Touch tissue imaging quantification; pSS 5 primary Sj€ ogren’s syndrome.
The sonographic features of the parotid and submandibular glands of the healthy control and pSS groups detected by gray-scale ultrasonography were similar, and no significant difference in the size of the parotid was observed between the pSS and control groups. The length and width of the submandibular gland of the pSS group were both significantly smaller than the corresponding values obtained for the control group. This finding could be explained by two facts: the symptoms of pSS are nonspecific, and many pSS patients are not diagnosed at the early stage of the disease. It should be noted that all salivary gland sizes were markedly larger than the measurement samples of VTQ (5 mm) and VTIQ (1 mm), indicating that application of VTQ and VTIQ to the assessment of salivary glands is feasible. In our study, no significant difference in stiffness was observed between the parotid and submandibular glands in healthy controls. Matsuzuka et al. (2015) also reported that the stiffness of normal parotid glands is highly similar to that of submandibular glands. In the pSS group, the sonographic features and stiffness of the parotid were consistent with those of the submandibular gland. Hence, it is suggested that all major salivary glands are typically involved, and the lesions are well distributed among these glands in patients with pSS.
Both VTQ and VTIQ values for the parotid in the pSS group were significantly higher than those obtained for the healthy controls. The VTIQ values of the submandibular gland obtained in patients with pSS were significantly higher than those for the control group. These results indicated that the stiffness of the salivary glands in patients with pSS was increased, which may be assumed to be correlated with histopathologic changes, including lymphocytic infiltration, destruction of glands and fibrosis. Similar findings were also obtained in a study of radiation submaxillitis. After radiation therapy, the SWV of the submandibular gland was increased, indicating diffuse histopathologic changes in the salivary glands, including an initial acute inflammatory reaction followed by a chronic hypotrophy (Badea et al. 2013). However, the relationship between the salivary gland stiffness and different durations of pSS or clinical records is not yet known. A study of the application of ARFI in diffuse thyroiditis indicated that shear wave elastography may aid the diagnosis and treatment monitoring of acute, subacute and chronic thyroiditis, as well as the differentiation of the various types of thyroiditis (Ruchala et al. 2012). Thus, our study must be extended to a larger group of patients for further analyses. It is expected that ARFI changes will prove to
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Fig. 4. Images of a 61-y-old female patient with primary Sj€ ogren’s syndrome with the highest SWVof the parotid gland. (a) Gray-scale ultrasonography revealed diffuse lesions that exhibited inhomogeneity and multiple hypo-echoic areas. (b) The SWV was measured with Virtual Touch tissue quantification. (c) The SWV was measured withVirtual Touch tissue imaging quantification. SWV 5 shear wave velocity.
be a valuable adjunct tool for assessing the duration and activity of pSS. In the present study, there was a positive correlation between the VTQ and VTIQ results of the parotid and
submandibular glands. The principles of VTQ and VTIQ are similar, and both involve evaluation of the SWV in a ROI. In the pSS group, the VTIQ value for the submandibular gland was higher than the VTQ value.
Fig. 5. Coefficients of correlation between VTQ and VTIQ of the (a) parotid gland (Pearson’s r 5 0.85, p , 0.01) and (b) submandibular gland (Pearson’s r 5 0.55, p , 0.05) in the primary Sj€ ogren’s syndrome (pSS) group (m/s). VTQ 5 Virtual Touch tissue quantification; VTIQ 5 Virtual Touch tissue imaging quantification.
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Ultrasound in Medicine and Biology
The difference between the VTQ and VTIQ values are believed to be because of the different measurement sample sizes. The VTQ technique uses a rather large measurement sample; thus, the data are expressed as the average SWV values. In contrast, the VTIQ technique uses a small measurement sample, and the data are therefore expressed as the local SWV values. Similar results were reported previously; for example, the SWV values measured via VTIQ for breast lesions were higher than the corresponding VTQ values (Tozaki et al. 2013). Possible causes have been suggested: (i) VTIQ enables measurement of the SWV in smaller regions, yielding higher spatial velocity resolution. (ii) The site exhibiting the highest SWV was visually identified using the VTIQ shear wave velocity form, and the SWV may tend to be measured at that site. Researchers have obtained slightly better results using VTIQ than VTQ in differentiating malignant from benign solid breast masses (Tozaki et al. 2013). In our study, the VTIQ values of the submandibular gland obtained in patients with pSS were significantly higher than those in the control group, whereas the VTQ values for the submandibular gland did not differ between the two groups. It was conjectured that VTIQ is more useful. The advantages of VTIQ are as follows: (i) the VTIQ technique includes the shear wave quality form, which contributes greatly to the accuracy of SWV measurements; (ii) the SWV measurement range of VTIQ (0.5–10 m/s) is greater than that of VTQ (0.8–8.4 m/s). (iii) VTIQ is easier to use and provides more conclusive results than VTQ. The acquisition of images is faster with VTIQ, and fewer repeated acquisitions are needed to compare the SWVs from different locations. Our study indicates that VTQ and VTIQ may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of pSS. However, the most important limitations of our study are the small number of patients and the lack of male patients. Because pSS has a strong female propensity, all of our selected pSS cases in this prospective study were female. We hypothesize that further studies involving larger numbers of patients could increase the number of male cases. Moreover, a further large-scale study to validate our results and establish diagnostic threshold values for VTQ and VTIQ should be conducted. Additional studies should also focus on the reliability of quantitative ARFI imaging for the assessment of salivary gland function and during follow-up. Another limitation of this study is the different measurement sample sizes between VTQ and VTIQ imaging. An easy solution would be to make these sizes similar to allow proper comparisons, but the pre-defined measurement sample sizes of VTQ and VTIQ are fixed and cannot be modified. The salivary gland lesions observed in pSS in our study were diffuse, and the sali-
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vary gland sizes were markedly larger than the measurement sample sizes of VTQ and VTIQ, indicating that the application of VTQ and VTIQ imaging to analysis of the salivary gland is feasible. In the future, the measurement sample size will likely be modified to yield a more reasonable size based on the manufacturer’s technical improvement. CONCLUSIONS Virtual Touch tissue quantification and Virtual Touch tissue imaging quantification are useful tools for examining the stiffness of the major salivary glands through quantitative ultrasound elastography. The stiffness of normal salivary glands and of pSS patients was quantitatively determined based on VTQ and VTIQ values. Overall, our study revealed that VTQ and VTIQ do not differ significantly, although better results for the stiffness of salivary gland lesions in pSS were obtained with VTIQ than with VTQ. The stiffness of the major salivary glands in pSS patients was increased compared with that of normal glands. These findings indicate that VTQ and VTIQ may be valuable adjuncts to gray-scale ultrasonography for the clinical diagnosis of primary Sjogren’s syndrome. Acknowledgments—This work was supported by Peking University People’s Hospital Research and Development Funds (Project RDB2014-03).
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