Sonoelastographic Modalities in the Evaluation of Salivary Gland Characteristics in Sjögren's Syndrome

Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–10, 2016 Copyright Ó 2016 World Federation for Ultrasound in Medicine and Biology Printed in the USA. All rights reserved 0301-5629/$ - see front matter

http://dx.doi.org/10.1016/j.ultrasmedbio.2016.04.011

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Original Contribution SONOELASTOGRAPHIC MODALITIES IN THE EVALUATION OF SALIVARY € GLAND CHARACTERISTICS IN SJOGREN’S SYNDROME BENEDIKT HOFAUER,* NAGLAA MANSOUR,* CLEMENS HEISER,* CONSTANZE GAHLEITNER,* KLAUS THUERMEL,y MURAT BAS,* and ANDREAS KNOPF* * Otorhinolaryngology/Head and Neck Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany; and y Rheumatology, II. Medizinische Department, Klinikum rechts der Isar, Technical University, Munich, Germany (Received 26 August 2015; revised 23 February 2016; in final form 11 April 2016)

Abstract—The purpose of this study was to investigate salivary tissue assessment with various sonoelastographic modalities (real-time tissue elastography, Virtual Touch imaging and quantification) in patients with Sj€ ogren’s syndrome as compared with an appropriate control group. The sonoelastographic modalities were evaluated in 50 patients with primary Sj€ogren’s syndrome (pSS). Patients underwent high-resolution ultrasonography of the submandibular and parotid glands. Results of B-mode, real-time tissue elastography, Virtual Touch imaging— each graded with the appropriate scoring system—and Virtual Touch quantification were compared with those for 50 patients with sicca symptoms who did not fulfill the American–European consensus group criteria. In B-mode, 34 of 50 parotid glands in patients with pSS and 8 of 50 in the control group had abnormal findings (p , 0.001). Compared with 9 of 50 control patients, 38 of 50 patients with pSS had abnormal findings in submandibular gland B-mode (p , 0.001). With real-time tissue elastography, there was a trend toward higher scores for parotid glands in the pSS group (p 5 0.238), whereas scores for submandibular glands in the control group were higher (p 5 0.107). Virtual Touch imaging did not indicate any difference (p 5 0.647 and p 5 0.658). In Virtual Touch quantification, values for parotid (mean: 2.99 m/s) and submandibular glands (mean: 2.54 m/s) in the pSS group were higher than those for parotid (mean: 2.16 m/s) and submandibular (mean: 2.04 m/s) glands in the control group (p , 0.001 and p 5 0.008). Glandular stiffness, measured by Virtual Touch quantification, was significantly higher in patients with Sj€ ogre ns syndrome than in patients with sicca symptoms. (E-mail: [email protected]) Ó 2016 World Federation for Ultrasound in Medicine and Biology. Key Words: Ultrasonography, Salivary gland disease, Elastography, Virtual Touch imaging, Virtual Touch quantification, Sjogren’s syndrome, Shear wave.

Consensus Group (AECG) criteria for the classification of SS, which were proposed in 2002 (Vitali et al. 2002), or the classification criteria set by the American College of Rheumatology (ACR) (Knopf et al. 2011; Shiboski et al. 2012). According to these classification criteria, different modalities are suitable for the evaluation of salivary gland involvement in suspected Sj€ogren’s syndrome. However, these well-established modalities are being reconsidered because of different disadvantages. According to the AECG criteria, unstimulated whole salivary flow, salivary scintigraphy and parotid sialography represent the alternatives for the objective evaluation of the oral component in SS (Vitali et al. 1994, 2002). Measuring unstimulated whole salivary flow is under criticism because of its great variation over time in a single patient and its limited sensitivity and specificity (Cornec et al. 2013;

INTRODUCTION Sj€ ogren’s syndrome (SS) is a chronic autoimmune disorder that affects primarily the salivary and lacrimal glands. Therefore, xerostomia, keratoconjunctivitis sicca and parotidomegaly represent the cardinal symptoms. Primary SS (pSS) can be classified in the absence of another rheumatologic disease, whereas secondary SS is associated with another rheumatologic disease such as rheumatoid arthritis, systemic sclerosis or systemic lupus erythematosus (Cornec et al. 2015b; Hofauer et al. 2013). Diagnosis is usually based on the American–European

Address correspondence to: Benedikt Hofauer, Otorhinolaryngology/Head and Neck Surgery, Klinikum rechts der Isar, Technical University Munich, Ismaningerstrasse 22, 81675 Munich, Germany. E-mail: [email protected] 1

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Hocevar et al. 2005). Parotid sialography has high specificity, but low sensitivity, especially in early stages of the disease (Kalk et al. 2002). In some patients, the examination cannot be conducted because of anatomic or allergic contraindications. Further disadvantages of this procedure are its invasiveness and exposure to radiation (Cornec et al. 2013; Makula et al. 1996). Salivary scintigraphy has proved to be very sensitive and of potential prognostic value, particularly in early stages of the disease; on the other hand, its specificity is limited (Salaffi et al. 2008). Further disadvantages are its limited availability and, again, exposure to radiation (Cornec et al. 2013). The implementation of major salivary gland ultrasound (SGUS) to increase sensitivity and specificity or to replace other diagnostic modalities of the AECG/ ACR criteria is part of ongoing discussions (Bootsma et al. 2013; Cornec et al. 2013, 2014, 2015a; De Vita et al. 1992; Takagi et al. 2014). The aim of recent investigations was to evaluate the change in diagnostic accuracy of the AECG or ACR criteria after replacement of sialoscintigraphy, sialography (both part of the AECG criteria) or minor salivary gland biopsy (MSGB) with SGUS. Various ultrasonographic methods have been investigated so far (Gritzmann et al. 2003). Most studies focused on the B-mode ultrasonographic alterations of parotid and submandibular glands in patients with SS, as compared with different control groups, and on the possible beneficial effect on the established classification criteria. Lately, color-coded duplex sonography and contrast-enhanced ultrasonography have been brought into focus (Carotti et al. 2001; Giuseppetti et al. 2005; Jousse-Joulin et al. 2007). Although there is increasing evidence of the impact of SGUS, sonography is not part of any classification criteria (Chikui et al. 2006; Cornec et al. 2013, 2014, 2015a). During the past few years, there has been a major improvement in ultrasonographic modalities such as real-time tissue elastography (RTTE), Virtual Touch imaging (VTI) and Virtual Touch quantification (VTQ), enabling the provision of qualitative and quantitative information on the mechanical stiffness of the examined tissue or region (Benson and Fan 2012; Bhatia et al. 2010, 2012; Westerland and Howlett 2012). These new modalities could find their way into the daily clinic routine for various indications in several clinical specialties and, meanwhile, are part of the assessment of the thyroid gland or mammary lesions (Wojcinski et al. 2013; Zhang et al. 2015). The reliability of sonographic tissue evaluation has proved to be high enough to replace histologic examinations in indications such as grading of liver fibrosis (Corpechot et al. 2012; Zhang et al. 2014). The aforementioned

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techniques could also gain importance in the preoperative evaluation of parotid and submandibular gland lesions (Mansour et al. 2012). Our study group had already conducted an examination on the reliability, sensitivity and specificity of VTQ in the diagnostic pathway to pSS, particularly with respect to early stages of the disease (Knopf et al. 2015). The aim of this study was to evaluate sonographic salivary tissue assessment using B-mode ultrasonography, RTTE, VTI and VTQ in patients with SS and to uncover differences in comparison to an appropriate control group. METHODS Study group Fifty patients with xerostomia and keratoconjunctivitis sicca who were referred to our department between June 2011 and June 2013 and diagnosed with pSS were included in this study. Classification was done according to the AECG criteria (Vitali et al. 2002). Patients with past head and neck radiation, hepatitis C infection, AIDS, pre-existing lymphoma, sarcoidosis or graftversus-host disease and patients using anticholinergic drugs were excluded. Subjective complaints (xerostomia, keratoconjunctivitis sicca, parotidomegaly) were evaluated with visual analogue scales. Ocular signs and salivary gland involvement were further assessed with the Schirmer I and Saxon tests. Antibodies to Ro (SS-A) and La (SS-B) antigens were detected. If necessary, MSGB was performed through a vertical incision of normal-appearing mucosa of the lower lip. A minimum of five minor salivary glands had to be obtained, and histopathology was evaluated with the score proposed by Chisholm and Mason (1968). For the control group, we chose 50 patients who had also been referred to the Department of Otorhinolaryngology complaining of xerostomia and keratoconjunctivitis sicca, but who did not fulfill the AECG criteria. Ultrasonographic examinations All ultrasonographic examinations were performed simultaneously with the other diagnostic evaluation by two experienced sonographers. Ultrasonographic studies were performed using an Acuson 2000 (Siemens Healthcare, Erlangen, Germany) equipped with a linear transducer (9 L4, Siemens Medical Solutions). B-Mode ultrasonography (BMUS), RTTE, VTI and VTQ were performed on the right parotid and submandibular glands (Table 1). In VTQ, every examination consisted of 10 single measurements taken at a depth of 1.0 cm in the center of the caudal pole of the parotid gland and the center of the submandibular gland (to guarantee a maximum distance to the jawbone or adjacent blood vessels) within a preferably homogeneous area of the gland. The mean

Salivary gland characteristics in Sj€ogren’s syndrome d B. HOFAUER et al.

Table 1. Explanation of the sonographic techniques used Technique

Explanation

Real-time tissue elastography

The elastogram is created by computing relative tissue displacement and displaying the information within a region of interest. Tissue displacement can be generated by adjacent vessel pulsation or pressure generated by the sonography probe. To generate the elastogram, an acoustic push pulse is transmitted to compress the tissue, and detection pulses are used to track the degree of compression. Within a selected region of interest an acoustic push pulse is applied. Tracking beams are used to measure the shear wave velocity within that region of interest, and quantitative assessment of tissue stiffness is thus enabled.

Virtual Touch imaging Virtual Touch quantification

value of the 10 single measurements was calculated and used for further analysis. Measurements were made with moderate transducer pressure timed to the absence of swallowing maneuvers. To avoid circadian variation, all examinations were performed at the same time during the morning. Patients were asked not to eat, drink or smoke for 2 h before the examination. The echostructure of the parotid and submandibular glands in BMUS was graded on a scale of 0 to 4 according to a previously published scoring system (Makula et al. 1996): grade 0 5 normal, homogeneous gland; grade 1 5 mild parenchymal inhomogeneity (PIH), hypo-echoic areas ,2 mm; grade 2 5 evident PIH, hypo-echoic areas of 2–6 mm; grade 3 5 gross PIH, hypo-echoic areas .6 mm; grade 4 5 adipose degeneration of the gland, adipose tissue echogenicity and parenchymal atrophy. The BMUS result was scored as abnormal if the score was $2 or higher, which had proved to be the optimal cutoff in previous studies (Makula et al. 2000). RTTE generates color-coded elastogram maps (ranging from purple 5 soft over blue and green to red 5 hard) and was graded on a scale of 1 to

3

3. This scoring system had been adapted from a similar scoring system used in patients with liver fibrosis (Morikawa et al. 2011; Paparo et al. 2014): pattern 1 5 diffuse soft pattern, homogeneously spread, lightgreen color; pattern 2 5 intermediate pattern, partially mottled, dotted image with blue spots on a light green background; pattern 3 5 patchy hard pattern, mixed images with patchwork effect of light green, red and blue. RTTE results were rated as abnormal if the score was $2. The quality factor in RTTE had to be larger than 75%. VTI generates gray scale-coded elastogram maps (ranging from white 5 soft over increasing gray levels to black 5 hard) and was also graded on a scale of 1 to 3: pattern 1 5 homogeneously spread, white or light gray pattern: pattern 2 5 intermediate, partially mottled, gray pattern; pattern 3 5 patchy, mixed images with mostly darker gray and black pattern. VTI results were rated as abnormal if the score was $2. The scoring systems are summarized in Table 2. In VTQ, absolute values are generated; therefore, no additional scoring is required. Sonographic images representing the average echogenicity of the examined salivary gland were archived. Every ultrasound scan was scored independently by three experienced sonographers blinded to the clinical diagnosis (static imaging grading). Every scan was scored twice by every sonographer at an interval of 2 wk to evaluate intra-rater reliability. Statistical analysis Version 16.0 of the Statistical Package for the Social Sciences software for Windows (SPSS, Chicago, IL, USA) was used. Data are reported as the mean (standard deviation [SD]) if not otherwise stated. Data of patients and controls were compared using the Mann–Whitney U-test for metric data and the c2-test for ordinal data. Cronbach’s a was used for the analysis of inter- and intra-rater reliability (.0.9 5 excellent, .0.8 5 good, .0.7 5 acceptable, .0.6 5 questionable,

Table 2. Scoring systems for BMUS, RTTE and VTI Score/pattern 0 1 2

B-Mode ultrasound Normal, homogeneous gland Mild PIH, hypo-echoic areas ,2 mm Evident PIH, hypo-echoic areas of 2–6 mm

3

Gross PIH, hypo-echoic areas .6 mm

4

Adipose degeneration of gland, adipose tissue echogenicity and parenchymal atrophy PIH 5 parenchymal inhomogeneity.

Real-time transient elastography Diffuse soft pattern, homogeneous spread, light-green color Intermediate pattern, partially mottled, dotted image with blue spots on light green background Patchy hard pattern, mixed images with patchwork effect of light green, red and blue

Virtual Touch imaging Homogeneous spread, white or light gray pattern Intermediate, partially mottled, gray pattern Patchy, mixed images with mostly darker gray and black pattern

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.0.5 5 weak, #0.5 5 not acceptable). Spearman’s rank correlation coefficient (r) was used for analysis of correlations (0.8–1.0 5 very strong correlation, 0.6– 0.79 5 strong correlation, 0.40–0.59 5 moderate correlation, 0.20–0.39 5 weak correlation, 0.00–0.19 5 very weak correlation). Receiver operating characteristic (ROC) analysis was conducted for each method to determine the optimal cutoff producing the best combination of sensitivity and specificity for each technique. p # 0.05 was considered to indicate statistical significance. The local ethics committee (Fakult€at f€ ur Medizin, Ethikkommission, Technische Universit€at M€ unchen) approved this study. Informed consent was obtained from every patient.

RESULTS Study group The total number of patients in this study was 100, among which pSS was diagnosed according to AECG criteria in 50 patients (male/female ratio: 3/47, mean age: 61 y, range: 23–89 y). Fifty patients did not fulfill the AECG criteria and were therefore assigned to the control group (male/female ratio: 8/42, mean age: 58 y, range: 28–89 y). The demographic characteristics of the patients in the SS and control groups are summarized in Table 3. The groups were comparable with respect to age and gender. Significant differences could be observed regarding the frequency of oral (p , 0.001) and ocular (p 5 0.004) symptoms. There were significantly more positive Schirmer I tests, Saxon tests and detection of anti-Ro or anti-La antibodies in the SS group (p , 0.001, respectively). MSGB was performed in 32 patients in the SS group and 25 patients in the control group. Significantly more biopsies with a Chisholm and Table 3. Demographic characteristics of patients and controls Characteristic

Patients (n 5 50) Controls (n 5 50)

Males/females 3/47 Age, mean (SD) 61.3 (16.4) Age range 23–89 Ocular symptoms 39/50 (78%) Oral symptoms 46/50 (92%) Schirmer I test* 26/50 (52%) 30/32 (93.75%) MSGBy 42/50 (84%) Saxon testz Ro antibody 29/50 (58%) La antibody 22/50 (44%)

8/42 58.2 (15.5) 28–89 25/50 (50%) 29/50 (58%) 3/50 (6%) 10/25 (40%) 20/50 (40%) 6/50 (12%) 2/50 (4%)

MSGB 5 minor salivary gland biopsy. * Positive if #5 mm in 5 min. y Positive if Chisholm and Mason score $3. z Positive if #2.5 g in 2 min.

p value 0.112 (n.s) 0.372 (n.s.) 0.004 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001

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Mason score of at least 3 were performed in the SS group (p , 0.001). B-Mode ultrasound of salivary gland In the SS group, abnormal findings were detected in 34 of 50 parotid glands (68%) and 38 of 50 submandibular glands (76%). In the control group, abnormal findings were detected in 8 of 50 parotid glands (16%) and 9 of 50 submandibular glands (18%). The mean BMUS score for parotid glands was 2.1 (SD: 0.9) in the SS group and 1.2 (SD: 0.7) in the control group (p , 0.001). The mean BMUS score for submandibular glands was 2.4 (SD: 1.0) in the SS group and 1.1 (SD: 0.7) in the control group (p , 0.001). At a Cronbach a of 0.895, a good inter-rater reliability between the three examiners could be reached. Cronbach’s a values for intra-rater reliability of individual examiners were 0.927 (examiner 1), 0.771 (examiner 2) and 0.93 (examiner 3) and, therefore, between acceptable and excellent levels (Fig. 1). BMUS scores for parotid glands moderately correlated with the Saxon test (p 5 0.032, r 5 20.313), Schirmer I test (p 5 0.016, r 5 20.354), Ro Ab (p 5 0.006, r 5 0.416), La Ab (p 5 0.013, r 5 0.376) and histopathology grading (p 5 0.041, r 5 0.375). The ideal cutoff score for BMUS of parotid glands was $2 and was associated with a sensitivity of 70.2% and a specificity of 83.4%. The area under the curve (AUC) was 0.785 (p , 0.001, 95% confidence interval [CI]: 0.689–0.881) (Fig. 2). BMUS scores for submandibular glands moderately correlated with the Saxon test (p 5 0.009, r 5 20.394), Ro Ab (p 5 0.001, r 5 0.497) and La Ab (p 5 0.039, r 5 0.327); a strong correlation with BMUS parotid gland scores could be observed (p , 0.001, r 5 0.671). The ideal cutoff score for BMUS of submandibular glands was $2 and was associated with a sensitivity of 78.7% and a specificity of 79.1%. The AUC was 0.834 (p , 0.001, 95% CI: 0.751–0.917). All sonographic results are summarized in Table 4. Real-time tissue elastography In the SS group, abnormal findings were detected in 47 of 50 parotid glands (94%) and 42 of 50 submandibular glands (84%). In the control group, abnormal findings were detected in 41 of 50 parotid glands (82%) and 40 of 50 submandibular glands (80%). The mean RTTE score for parotid glands was 2.3 (SD: 0.5) in the SS group and 2.2 (SD: 0.5) in the control group (p 5 0.238). The ideal cutoff score for RTTE of parotid glands was $2 and was associated with a sensitivity of 32.6% and a specificity of 79.1%. The AUC was 0.557 (p 5 0.356, 95% CI: 0.437–0.677) (Fig. 2). The mean RTTE score for submandibular glands was 1.9 (SD: 0.4) in the SS group and 2.1 (SD: 0.5) in the control group (p 5 0.107). The ideal

Salivary gland characteristics in Sj€ogren’s syndrome d B. HOFAUER et al.

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Fig. 1. B-Mode ultrasound images of salivary gland alterations in different patients graded according to the criteria in Table 2. (A1–A5) Parotid glands. (B1–B5) Submandibular glands. The section of the sonogram was adapted with a focus on the salivary gland. Performance of examinations in a linear or sector view depended on the sonographer.

cutoff score for RTTE of submandibular glands was $2 and was associated with a sensitivity of 87.0% and a specificity of 7.0%. The AUC was 0.429 (p 5 0.250, 95% CI: 0.310–0.548). At a Cronbach a of 0.751, an acceptable inter-rater reliability between the three examiners could be reached. Cronbach’s a values for intra-rater reliability of individual examiners were 0.916 (examiner 1), 0.826 (examiner 2) and 0.815 (examiner 3) and, therefore, between good and excellent levels (Fig. 3).

Virtual Touch imaging In the SS group, abnormal findings were detected in 43 of 50 parotid glands (86%) and 38 of 50 submandibular glands (76%). In the control group, abnormal findings were detected in 46 of 50 parotid glands (92%) and 43 of 50 submandibular glands (86%). The mean VTI score for parotid glands was 2.4 (SD: 0.7) in the SS group and 2.4 (SD: 0.6) in the control group (p 5 0.647). The ideal cutoff score for VTI of the parotid glands was $2 and was

Fig. 2. Receiver operating characteristic curves for (a) B-mode ultrasound imaging, (b) real-time tissue elastography, (c) Virtual Touch imaging, and (d) Virtual Touch quantification of parotid and submandibular glands.

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Table 4. Summary of all sonoelastographic methods used Sonographic method B-Mode ultrasound Parotid gland Submandibular gland Real-time tissue elastography Parotid gland Submandibular gland Virtual Touch imaging Parotid gland Submandibular gland Virtual Touch quantification Parotid gland Submandibular gland

Patients

Controls

p value

AUC

Sensitivity

Specificity

2.1 (0.9) 2.4 (1.0)

1.2 (0.7) 1.1 (0.7)

,0.001 ,0.001

0.785 0.834

70.2% 78.7%

83.4% 79.1%

2.3 (0.5) 1.9 (0.4)

2.2 (0.5) 2.1 (0.5)

0.238 0.107

0.557 0.429

32.6% 87.0%

79.1% 7.0%

2.4 (0.7) 2.0 (0.7)

2.4 (0.6) 2.1 (0.6)

0.647 0.658

0.525 0.467

58.1% 27.9%

48.8% 74.4%

2.99 (0.96) 2.54 (0.76)

2.16 (0.71) 2.04 (0.40)

,0.001 0.008

0.759 0.555

77.0% 63.0%

57.8% 46.2%

AUC 5 area under the curve.

associated with a sensitivity of 58.1% and a specificity of 48.8%. The AUC was 0.525 (p 5 0.685, 95% CI: 0.402– 0.649) (Fig. 2). The mean VTI score of submandibular glands was 2.0 (SD: 0.7) in the SS group and 2.1 (SD: 0.6) in the control group (p 5 0.658). The ideal cutoff score for VTI of submandibular glands was $2 and was associated with a sensitivity of 27.9% and specificity of 74.4%. The AUC was 0.467 (p 5 0.595, 95% CI: 0.344–0.590). At a Cronbach a of 0.787, an acceptable inter-rater reliability between the three examiners could be reached. Cronbach’s a values for intra-rater reliability of individual examiners were 0.848 (examiner 1), 0.765 (examiner 2) and 0.901 (examiner 3) and, therefore, between acceptable and excellent levels (Fig. 4). Virtual Touch quantification The mean VTQ value for parotid glands was 2.99 m/s (SD: 0.96) in the SS group and 2.16 m/s (SD: 0.71) in the control group (p , 0.001). The ideal cutoff score for VTQ of parotid glands was $2.34 m/s and was associated with a sensitivity of 77.0% and a specificity of 57.8%. The AUC

was 0.759 (p , 0.001, 95% CI: 0.729–0.789) (Fig. 2). The standard deviation for the 10 single measurements in every patient was calculated as 0.17 on average for parotid glands. The mean VTQ value for submandibular glands was 2.54 m/s (SD: 0.76) in the SS group and 2.04 m/s (SD: 0.40) in the control group (p 5 0.008). The ideal cutoff score for VTQ of submandibular glands was $1.95 m/ s and was associated with a sensitivity of 63.0% and a specificity of 46.2%. The AUC was 0.555 (p 5 0.004, 95% CI: 0.518–0.593). The standard deviation for the 10 single measurements in every patient was calculated at 0.16 on average for submandibular glands. There was moderate correlation between the VTQ for parotid glands and the VTQ for submandibular glands (p 5 0.042, r 5 0.291). Figure 5 illustrates the application of all sonographic modalities used in one single patient. DISCUSSION Various sonographic techniques are being investigated with respect to their potential for evaluating

Fig. 3. RTTE images of salivary gland alterations in different patients graded according to the criteria in Table 2. RTTE generates color-coded elastogram maps (ranging from purple 5 soft over blue and green to red 5 hard). (A1–A3) Parotid glands. (B1–B3) Submandibular glands. The corresponding B-mode ultrasound image is to the left of each RTTE image. RTTE 5 real-time tissue elastography.

Salivary gland characteristics in Sj€ogren’s syndrome d B. HOFAUER et al.

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Fig. 4. VTI images of salivary gland alterations in different patients graded according to the criteria Table 2. VTI generates gray scale-coded elastogram maps (ranging from white 5 soft over increasing gray levels to black 5 hard). (A1– A3) Parotid glands. (B1–B3) Submandibular glands. The corresponding B-mode ultrasound image is to the left of each VTI image. VTT 5 Virtual Touch imaging.

salivary gland involvement in patients with SS. Besides B-mode sonography, color-coded duplex sonography has been under further examination and has proved to be a useful technique for the analysis of abnormalities in vascularization, of course, but also changes in vascularization before and after stimulation of salivary secretion. Color-coded duplex sonography might be used for monitoring response to local or systemic treatments (Carotti et al. 2001; Jousse-Joulin et al. 2007). Furthermore, Giuseppetti et al. (2005) reported that contrastenhanced ultrasound can provide additional information

in morphologic and functional parotid imaging. Most of the previous studies on salivary gland ultrasound in SS deal with the contribution of B-mode sonography to diagnosis and focus on different scoring systems or the potential to replace the aforementioned established modalities, which are part of different classification criteria (Cornec et al. 2013, 2014; Hocevar et al. 2005; Kawamura et al. 1990; Milic et al. 2012; Niemela et al. 2004; Takashima et al. 1992; Wernicke et al. 2008; Yonetsu et al. 2002). Meanwhile, there are various validated scoring systems for B-mode sonography, with just marginal differences

Fig. 5. Results from all sonographic modalities used in one patient. Dotted lines delineate the contours of the glands. (A1, B1) B-Mode ultrasound images of the parotid gland (grade 2) and submandibular gland (grade 2). (A2, B2) Real-time tissue elastography images of the parotid gland (pattern 3) and submandibular gland (pattern 3). (A3, B3) Virtual Touch images of the parotid gland (pattern 2) and submandibular gland (pattern 3). (A4, B4) Virtual Touch quantification images of the parotid gland (velocity 5 2.51 m/s, depth 5 1.0 cm) and submandibular gland (velocity 5 1.72 m/s, depth 5 1.0 cm).

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regarding the evaluation of salivary gland echostructure, which seems to be the most characteristic alteration. If parotid and submandibular glands are considered together, 72% of findings were abnormal in the SS population and 17% were abnormal in the control group. These results are comparable to the original results of Niemela et al. 2004: 78% and 7%, respectively. Makula et al. (1996) used a very similar scoring system, distinguishing between four different grades (0–3), which were identical to our grades apart from a missing grade 4 (adipose degeneration). They observed evident and gross PIH (in each scoring system grade 2 and 3) in 72%, which corresponds well to our observation. Carotti et al. (2001) also used a scoring system with similar criteria and found abnormalities in 86.6% of SS patients and 30% of controls. The application of elastographic techniques, such as RTTE and VTI, which provided promising results, for example, in the non-invasive evaluation of liver fibrosis or mammary lesions, seems to be partly inconsistent and non-significant with respect to the evaluation of salivary glands in SS. Although RTTE exhibited a trend toward higher grades in the evaluation of parotid glands in the SS population, the submandibular glands exhibited a trend toward higher grades in the control group, without reaching a level of significance. In VTI, a trend toward higher scores in submandibular glands in the control group was seen, but, again, a level of significance was not reached. No differences were seen in parotid glands. Therefore, RTTE and VTI do not add further information to B-mode sonography in the evaluation of salivary gland involvement in patients with suspected SS. An explanation for this might be that RTTE and VTI can be influenced in two different ways. On the one hand, variation in elastogram generation can influence the reproducibility (5 inadequate elastogram acquisition, e.g., caused by various amounts of applied pressure or patient movement during generation of the elastogram); on the other hand, the generated elastogram has to be interpreted, which leaves further room for variation (5 inaccurate interpretation). The scoring system used might also have an effect. No comparable studies have yet been published. Virtual Touch quantification did show promising results, as the values for the parotid and submandibular glands in the SS population were significantly higher than the values for the parotid and submandibular glands in the control group. A significant advantage of this modality is the generation of absolute values, which makes the application of an additional scoring system obsolete and makes this technique more objective and examiner independent. However, examiners must be aware of the fact that there is variability in the generation of VTQ images because there are various influencing factors.

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Pre-compression of the investigated tissue is consistently reported to influence the generation of VTQ imaging in all organs (Mantsopoulos et al. 2015; Wojcinski et al. 2013). This means that application of different amounts of pressure by the sonography probe during the examination can lead to different results in VTQ. Swallowing or speaking by the patient during the examination can also influence VTQ measurements. With the implementation of a standard operating procedure, reliable inter- and intra-rater reliability could be achieved (Knopf et al. 2015). Knopf et al. reported VTQ values for healthy glandular tissue comparable to previous reports in the literature. VTQ values in patients with pSS were significantly higher than those in the control group. Results of VTQ measurements are comparable to the results of this study, with both populations partly overlapping. A very similar ideal cutoff for VTQ in parotid glands of 2.395 m/s could be defined. In addition a characteristic discrepancy in VTQ values between the parotid and submandibular glands was observed, which led back to the different histologic compositions of these glands. VTQ was concluded to be the most important diagnostic tool—next to histologic examination—in identifying early stages of pSS (Knopf et al. 2015).

CONCLUSIONS We were able to illustrate that examiner-dependent sonoelastographic modalities, such as real-time tissue elastography and Virtual Touch imaging, do not add further information to B-mode sonography in the evaluation of salivary gland involvement in Sj€ogren’s syndrome. The significance of B-mode sonography in the evaluation of salivary gland characteristics in Sj€ogren’s syndrome was again highlighted. Most promising, though, are the results of Virtual Touch quantification, which seems to provide an examiner-independent modality for the evaluation of salivary gland stiffness. Studies on its possible qualification as a monitoring tool for the evaluation of local or systemic treatment should follow.

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