Major salivary gland (SG) ultrasonography (US) represents a noninvasive, nonirradiating imaging modality for evaluation of the major SGs in the diagnosis and follow-up of primary and secondary Sjögren syndrome. Structural changes can be visualized as hyperechogenic and hypoechogenic areas, inhomogeneity, and altered echogenicity in general. The reliability of SG-US is poorly investigated, and the definition of US abnormalities varies in previously published studies. Recent studies have shown correlations between SG-US findings and focus score in the minor SGs; however further studies are needed to validate a US criterion in updated classification/diagnostic criteria.
Key points
- •
Salivary gland ultrasonography (SG-US) represents a useful imaging method for detecting structural abnormalities in the major SGs in patients with Sjögren syndrome (SS).
- •
SG-US may serve as a first-line imaging tool in the diagnosis of primary SS (pSS) and should be included in the diagnostic criteria.
- •
Studies are needed to demonstrate the reliability of the US technique and its sensitivity to change in the management of patients with pSS.
Introduction
Primary Sjögren syndrome (pSS) is an autoimmune chronic inflammatory disease predominantly affecting the salivary and lacrimal glands with progressive focal mononuclear cell infiltration ( Fig. 1 ), loss of salivary gland (SG) acinar epithelial tissue, and degenerative changes, such as fibrosis, and giving rise to clinical symptoms, such as oral and ocular dryness (xerostomia and keratoconjunctivitis sicca, respectively). The disease manifestations vary greatly, from very mild symptoms of dryness, to severe extraglandular manifestations of the lung, kidney, liver, neurological, and hematological system. Fatigue is a common feature of pSS, but by far the most severe complication of pSS is lymphoma, most commonly non-Hodgkin lymphoma occurring in 4% to 5% of patients with pSS, with an estimated 16 times increased risk in comparison with the background population.
The diagnosis of pSS is based on 6 items according to the American-European consensus group (AECG) classification criteria for pSS of 2002. According to these criteria, the assessment of SG involvement in SS is based on focal mononuclear cell infiltrates in the minor SGs (see Fig. 1 ), by measures of unstimulated salivary secretion (sialometry) and/or by the detection of morphologic and functional abnormalities of the glands by scintigraphy or sialography, as well as subjective symptoms of oral dryness (xerostomia). In 2012, the American College of Rheumatology (ACR) presented an alternate version of the criteria, based on the Sjögren’s International Collaborative Clinical Alliance(SICCA) cohort, comprising a group of clinical and laboratory investigators, a biorepository, and a data registry. Whereas the AECG 2002 criteria consist of both subjective symptoms, such as dryness of the mouth and eyes, and objective findings of reduced saliva and tear production, the ACR 2012 criteria has weighted the autoimmune and eye components, practically excluding the oral and salivary components, with an exception for minor SG biopsy and sialometry.
A novel set of classification criteria for SS was recently presented, intending to give researchers a single set of consensus measures for the classification of SS, and aiming to replace both the provisional 2012 ACR criteria and the 2002 AECG criteria. The novel criteria are based on 5 objective tests or items, resulting in a total score ≥4, derived from the sum of the weights assigned to each positive test/item. Focus score (FS) ≥1 and positive anti-Ro/SSA serology are proposed to have the highest weighting (3 for each positive test), whereas Ocular Staining Score (OSS) ≥5 on at least 1 eye, Schirmer I-test ≤5 mm/5 minutes on at least 1 eye, and unstimulated whole salivary flow rate ≤0.1 mL/min, will have a weighting of 1 for each positive test. The involvement of SGs is documented by unstimulated sialometry and/or by the minor SG biopsy.
Keeping in mind, classification criteria were essentially developed to classify clinical trial participants, and not for diagnostic purposes. Hence, the diagnostic armamentarium for the SG component in pSS may still count on a broad spectrum of diagnostic tools including sialography ( Fig. 2 ) and scintigraphy. In this scenario, a growing interest has arisen for major SG ultrasonography (SG-US), which has appeared as a valuable, noninvasive, reproducible tool for the diagnosis of SS. SG-US has also been applied to assess SG involvement in secondary Sjögren syndrome (sSS), another condition for which the novel ACR/AECG criteria have not been validated.
The aim of this review was to go through recent literature of SG-US in SS, and to assess its diagnostic and prognostic value in clinical practice as well as in clinical trials.
Introduction
Primary Sjögren syndrome (pSS) is an autoimmune chronic inflammatory disease predominantly affecting the salivary and lacrimal glands with progressive focal mononuclear cell infiltration ( Fig. 1 ), loss of salivary gland (SG) acinar epithelial tissue, and degenerative changes, such as fibrosis, and giving rise to clinical symptoms, such as oral and ocular dryness (xerostomia and keratoconjunctivitis sicca, respectively). The disease manifestations vary greatly, from very mild symptoms of dryness, to severe extraglandular manifestations of the lung, kidney, liver, neurological, and hematological system. Fatigue is a common feature of pSS, but by far the most severe complication of pSS is lymphoma, most commonly non-Hodgkin lymphoma occurring in 4% to 5% of patients with pSS, with an estimated 16 times increased risk in comparison with the background population.
The diagnosis of pSS is based on 6 items according to the American-European consensus group (AECG) classification criteria for pSS of 2002. According to these criteria, the assessment of SG involvement in SS is based on focal mononuclear cell infiltrates in the minor SGs (see Fig. 1 ), by measures of unstimulated salivary secretion (sialometry) and/or by the detection of morphologic and functional abnormalities of the glands by scintigraphy or sialography, as well as subjective symptoms of oral dryness (xerostomia). In 2012, the American College of Rheumatology (ACR) presented an alternate version of the criteria, based on the Sjögren’s International Collaborative Clinical Alliance(SICCA) cohort, comprising a group of clinical and laboratory investigators, a biorepository, and a data registry. Whereas the AECG 2002 criteria consist of both subjective symptoms, such as dryness of the mouth and eyes, and objective findings of reduced saliva and tear production, the ACR 2012 criteria has weighted the autoimmune and eye components, practically excluding the oral and salivary components, with an exception for minor SG biopsy and sialometry.
A novel set of classification criteria for SS was recently presented, intending to give researchers a single set of consensus measures for the classification of SS, and aiming to replace both the provisional 2012 ACR criteria and the 2002 AECG criteria. The novel criteria are based on 5 objective tests or items, resulting in a total score ≥4, derived from the sum of the weights assigned to each positive test/item. Focus score (FS) ≥1 and positive anti-Ro/SSA serology are proposed to have the highest weighting (3 for each positive test), whereas Ocular Staining Score (OSS) ≥5 on at least 1 eye, Schirmer I-test ≤5 mm/5 minutes on at least 1 eye, and unstimulated whole salivary flow rate ≤0.1 mL/min, will have a weighting of 1 for each positive test. The involvement of SGs is documented by unstimulated sialometry and/or by the minor SG biopsy.
Keeping in mind, classification criteria were essentially developed to classify clinical trial participants, and not for diagnostic purposes. Hence, the diagnostic armamentarium for the SG component in pSS may still count on a broad spectrum of diagnostic tools including sialography ( Fig. 2 ) and scintigraphy. In this scenario, a growing interest has arisen for major SG ultrasonography (SG-US), which has appeared as a valuable, noninvasive, reproducible tool for the diagnosis of SS. SG-US has also been applied to assess SG involvement in secondary Sjögren syndrome (sSS), another condition for which the novel ACR/AECG criteria have not been validated.
The aim of this review was to go through recent literature of SG-US in SS, and to assess its diagnostic and prognostic value in clinical practice as well as in clinical trials.
Modalities for salivary gland imaging
Several imaging modalities have been investigated for evaluation of the SG involvement in pSS, with chronic inflammatory changes seemingly occurring in the submandibular glands before the parotid glands. In sialography (see Fig. 2 ), a contrast medium commonly containing iodine is administered to the glandular tissue by a retrograde injection, providing a good illustration of the ductal structures, and been considered the gold standard for showing ductal inflammatory changes. However, due to the partly invasive nature of sialography, it is contraindicated in patients with severe glandular dysfunction, and has in part been replaced by magnetic resonance (MR)-sialography. Nuclear medicine, sialoscintigraphy, provides a quantitative measure of the SG function by imaging the uptake and excretion of a radioactive tracer (99mTc-sodium pertechnetate). In cases in which the labial SG biopsy is insufficient or not possible to perform, there is a potential diagnostic role for sialographic and scintigraphic examination with diffuse sialectasis by parotid sialography (see Fig. 2 ), or salivary scintigraphy showing delayed uptake, reduced concentration, and/or delayed excretion of tracer.
Ultrasonography and Sialography
Sonographic diagnostic criteria for SS were retrospectively investigated in a cohort of patients with previously suspected SS. Ultrasonographic features, such as multiple hypoechoic areas, multiple hyperechoic lines or spots, multiple hypoechoic areas surrounded with hyperechoic lines or spots, and obscuration of the gland configuration were applied. Using logistic regression analysis, valuable sonographic findings were extracted, and sonographic images of a new group of patients investigated prospectively. Experienced observers were able to differentiate patients with SS from negative controls, and findings correlated well with sialographic grading, suggesting that SG-US can be substituted for sialography in screening for SS.
Using indices obtained by texture analyses of US parotid gland images of patients with a clinical suspicion of pSS (n = 132), patients fulfilling the revised Japanese criteria for SS were identified (n = 91) and disease severity assessed. Major SG-US findings (Hurst index) correlated with the degree of destruction of the parotid gland as determined by sialography, whereas the Hurst coefficient of the punctate stage, however, was almost similar to that of the normal stage.
The same group performed quantitative analyses (particle analysis, fractional Brownian motion [fBM] model analysis, 2-dimensional [2-D] fractal analysis) on US images of the parotid SG, and then evaluated whether the obtained indices correlated with the sialographic stage of Rubin-Holt in patients (n = 192) with a clinical suspicion of SS due to sicca symptoms, serologic findings, or neurologic symptoms. Abnormal sialography findings were determined in a little less than half of the patient group. Indices of the parotid glands were entered into a logistic regression analysis to evaluate useful predictors for an abnormal sialographic stage. Significant differences were observed between the normal and abnormal groups in all 5 indices, and abnormal sialographic findings detected by quantitative analysis indicate a potential clinical application.
Consecutive patients (n = 105) were investigated by both high-resolution SG-US and sialography of the parotid glands, and results retrospectively compared with the final diagnosis based on the AECG criteria. Diagnosis of SS was confirmed in 45 patients; pSS (n = 36) and sSS (n = 9), and excluded in 15 subjects. The remaining subjects were excluded from the study due to incomplete records. A decreased and heterogeneous honeycomb pattern of parotid gland ultrasonography was observed in patients with SS, whereas sialography demonstrated a punctate pattern of sialectasis. Sensitivity, specificity, and accuracy for ultrasonography were 84.44%, 73.0%, and 81.6%, respectively, and 77.77%, 86.66%, and 80.0%, respectively, for conventional sialography. Interestingly, the diagnostic difference between the 2 investigations approached significance ( P = .074), but by combining both imaging modalities, sensitivity increased to 91% with 60% specificity and 83.3% accuracy. Although not being able to separate pSS and sSS, high-resolution US was found more sensitive than sialography, and supplementing US with sialography increased accuracy.
Ultrasonography of the parotid and submandibular glands was investigated as an alternative to parotid sialography in patients suspected of SS (n = 360). Patients (n = 188) fulfilled the AECG criteria for pSS (n = 134) and sSS (n = 54), or were classified as non-SS (n = 172). Glands were considered positive for SS if they exhibited peripheral sialectatic changes on sialography and/or hypoechoic areas, echogenic streaks and/or irregular gland margins on SG-US. Images were blindly rated as SS-positive or SS-negative. Average kappa values for the interobserver agreement were 0.81, 0.80, and 0.82 for sialography, parotid, and submandibular US, respectively, thus indicating very good or good agreement. Kappa value for intermodality agreement between sialography and parotid US was 0.81 and between sialography and submandibular US was 0.76, indicating very good and good agreement, respectively. Hence, the diagnostic ability of parotid US was lower than for sialography, but interestingly the diagnostic ability of submandibular US was comparable to that of sialography, prevailing submandibular US as a promising practical alternative to sialography in the classification of SS.
The diagnostic performance of sialography and SG-US for SS was also addressed in a meta-analysis. Findings from 6 existing studies including patients (n = 488) and controls (n = 447) from 2 European and 4 Asian studies indicated that the diagnostic accuracy of SG-US is comparable with sialography in patients with SS.
Ultrasonography and Sialoscintigraphy
Salivary gland US was compared with sialoscintigraphy in the evaluation of SG function in patients diagnosed with SS. In 2 patients with discordant results between sialoscintigraphy and SG-US, a labial biopsy was performed in addition. Abnormal sialoscintigrams were observed in 1 or more of the glands in 17 of 20 patients, and results confirmed by SG-US (n = 15) and labial minor SG biopsy (n = 2). In the remaining 3 patients with SS, both tests showed normal results. The study concluded that parotid and submandibular gland function was better identified by sialoscintigrams as compared with SG-US, as a more sensitive method and better indicating the stage of SS.
US of the parotid and submandibular glands was compared to contrast sialography and scintigraphy in patients fulfilling AECG criteria for pSS (n = 77) and age-matched and sex-matched individuals with sicca symptoms (n = 79). SG-US imaging findings were graded using a score 0 to 16 based on the sum of scores for the parotid and submandibular glands. Sialographic and scintigraphic patterns were classified in 4 different stages. Pathologic SG-US findings were observed in 66 of 77 patients, abnormal sialographic findings in 59 of 77 patients, and abnormal scintigraphic findings in 58 of 77 patients, indicating SG-US as the best screening method, followed by sialography and SG scintigraphy. Adjusting the cutoff score greater than 6 SG-US provided a better ratio of sensitivity (75.3%) to specificity (83.5%), with a likelihood ratio of 4.58, whereas a threshold greater than 8.0 gained test specificity at the cost of sensitivity, with sensitivity 54.5%, specificity 97.5%, and likelihood ratio 21.5.
An SG-US scoring system of the parotid and submandibular glands (scale 0–48) was investigated as a less-invasive alternative to scintigraphy and minor SG biopsy in patients with suspected SS (n = 135), establishing pSS diagnosis (n = 128) according to the AECG criteria. Patients not fulfilling criteria for pSS according to the AECG criteria constituted the control group (n = 28). Patients’ total scintigraphic score (0–12 scale) was determined and the minor SG histopathological changes graded. Major SG-US changes were detected in 98 of 107 patients with SS and in 14 of 28 controls, and SG-US arose as the best diagnostic test, followed by scintigraphy. Setting the SG-US cutoff score at 19 resulted in the best ratio of specificity (90.8%) to sensitivity (87.1%), whereas the scintigraphic cutoff score at 6 resulted in specificity of 86.1% and sensitivity of 67.1%. Among the 70 patients with SG-US score of 19 or higher, a scintigraphic score greater than 6 was recorded in 54 (77.1%) of 70 and positive biopsy findings in 62 (88.5%) of 70 patients.
In a cohort of patients (n = 190), the same group evaluated the diagnostic accuracy of SG-US as an alternative to scintigraphy in the AECG criteria, by testing 3 different sets of 5 diagnostic criteria. Each set combined ocular symptoms, oral symptoms, Schirmer I-test, and anti-Ro/SSA, with SG-US, sialoscintigraphy, or minor SG biopsy. SG-US score was positive in 129 (92%), sialoscintigraphy in 123 (88%), and biopsy in 93 (66%) of 140 patients with pSS. Among the patients with pSS (n = 140), 88 (63%) patients fulfilled the criteria with a positive SG-US, 85 (61%) patients with a positive sialoscintigraphy, and 71 (51%) patients with a positive minor SG biopsy. The non-pSS subjects (n = 50) did not fulfill any of the sets of criteria. Diagnostic accuracy was high for the SG-US, followed by the sialoscintigraphy and the minor SG biopsy.
Taking a different approach, the diagnostic value of SG scintigraphy was investigated in patients (n = 47) with diseases affecting the SGs. All patients were investigated with SG scintigraphy. Patients with chronic obstructive parotitis (n = 25) also underwent SG-US, sialography, and sialoendoscopy; patients with sialolithiasis (n = 12) also underwent SG-US and computed tomography; and patients with SS (n = 10) also underwent SG-US and sialography. Patients with chronic obstructive parotitis showed reduced excretion of tracer by the affected glands, whereas uptake was nearly normal. The patients with sialolithiasis showed reduced excretion by the affected glands, and decreased uptake in 5 patients. In patients with SS, a decrease in both excretion and uptake by the 4 glands was shown.
Novel perspectives
Gray Scale and Color/Power Doppler
Color Doppler, taking into use the principle that the sound pitch increases as the sound moves towards the listener, and decreases as it moves away, enables the imaging of blood flow and allows the clinician to see organ functioning in real time. With the addition of color it is possible to show the direction and rate of blood flow. With power Doppler US, the power in the Doppler signal is encoded in color, a fundamentally different parameter, from the mean frequency shift. The frequency is determined by the velocity of the red blood cells, whereas the power depends on the amount of blood present. Providing an image of a different property of blood flow, power Doppler has shown several key advantages over color Doppler, including higher sensitivity to flow, better edge definition, and depiction of continuity of flow. The combination of gray-scale SG-US and the color/power Doppler technique is suggested to provide more details with regard to soft tissue blood perfusion, and may be of value for narrowing in the number of differential diagnoses.
In pSS, SG-US with color Doppler has been used to evaluate the major SG treatment response in following rituximab treatment. Using B-mode US features, such as parenchymal homogeneity and gland size, and Doppler waveform analysis of the transverse facial artery of parotid glands, patients (n = 16) fulfilling the AECG criteria for pSS were investigated and compared with controls (n = 9). The same US parameters were recorded before and after 12 weeks of intravenous rituximab therapy, and untreated patients had significant SG-US abnormalities in the SG structure and parotid size. Doppler waveform analysis showed significant differences before, but not after, lemon stimulation between untreated patients and controls. Following rituximab treatment, both the parotid and submandibular glands showed significant reduction in size compared with baseline. Doppler resistive indices after lemon stimulation were significantly increased after rituximab treatment.
In a more recent study, the same group investigated SG echostructure and vascularization after rituximab treatment in patients with pSS (n = 28) included in the multicenter, randomized, double-blind, placebo-controlled trial Tolerance and Efficacy of Rituximab in Primary Sjögren’s Syndrome (TEARS). Patients with pSS were examined with SG-US before the first placebo (n = 14) or rituximab infusion (n = 14), and 6 months after. US of the parotid and submandibular glands was performed and parameters echostructure (score 0–4), size of each gland, and vascularization based on the resistive index of the transverse facial artery of the parotid gland before and after lemon juice stimulation. At baseline 5 of 28 patients (3 in the placebo group and 2 in the rituximab group) had bilateral parotid gland enlargement. Parotid parenchyma echostructure improved in 50% of the rituximab-treated patients compared with 7% of the placebo-treated patients ( P = .03). Submandibular gland echostructure also improved in a larger proportion of rituximab-treated patients, although not significantly. Size of the glands and resistive index remained unchanged.
Parotid gland vascularity also has been studied as a diagnostic tool to improve the ultrasonographic diagnosis of SS. Sonographic images of 72 cases of suspected SS, including 43 patients fulfilling the revised Japanese criteria for SS, were analyzed retrospectively for the abnormal vascularity in the parotid gland parenchyma. Vascularity and the results of sialographic, serologic, and histopathologic examinations also were analyzed. The diagnostic accuracy of B-mode only was compared with B-mode plus Doppler-mode. Patients with SS showed significantly higher vascularity; and as the grade of vascularity increased, the rate of non-SS individuals decreased. The initial stage and cavitary-destructive stages showed the highest mean vascular score. Sensitivity and accuracy of B-mode were markedly increased with vascular information, and improving sonographic diagnosis for SS.
Contrast-Enhanced Ultrasonography
In contrast-enhanced SG-US, a contrast medium such as a small air bubble or a more complex structure, influencing the way the sound waves are reflected from interfaces between substances, is used. The technique was applied to distinguish SS from non-SS in a group of patients with sicca syndrome. Patients with sicca syndrome were classified according to the AECG criteria, and fulfilled criteria for pSS (n = 23) and sSS (n = 17). Patients not fulfilling criteria served as controls (n = 20). Contrast-enhanced US imaging of the parotid SGs was performed using a second-generation contrast agent with analysis of time-intensity curves at rest and during salivary stimulation. Sialoscintigraphy and minor labial SG biopsy also were performed. SG-US enhancement values were significantly lower in patients with pSS/sSS compared with individuals without SS, both at rest and during stimulation. Interestingly, in patients with pSS, enhancement values during stimulation were significantly lower compared with sSS. Contrast-enhanced SG-US imaging allowed discrimination of SS from non-SS sicca controls with 87.5% sensitivity, 85% specificity, and 86.7% accuracy, and pSS from sSS with 78.2% sensitivity, 70.5% specificity, and 75.0% accuracy.
Sonoelastography
The US technique real-time sonoelastography (RTS) is commonly used to investigate the elasticity of soft tissues, based on the principle that tissue compression produces strain (displacement) within the tissue that is less pronounced in harder compared with softer tissues. The use of RTS of the major SGs was prospectively investigated for the assessment of glandular damage and diagnosis of pSS. The cohort contained patients with pSS (n = 45) according to the AECG criteria, individuals with sicca complaints (n = 24), and healthy controls (n = 11). Questionnaires, Saxon and Schirmer I-tests, and routine blood tests were carried out in all patients. All patients were investigated with B-mode SG-US and RTS of the parotid and submandibular glands, with abnormal findings graded 0 to 48 and 0 to 16, respectively. Sialoscintigraphy was performed with scores 0 to 12. Patients with pSS had higher B-mode scores compared with the sicca controls. In cases with an inconclusive B-mode SG-US, RTS cutoff score ≥6 provided a sensitive (66.7%) and specific (85.7%) classification of patients and sicca controls. In multivariate regression analysis, impaired SG function was reflected by RTS but not B-mode SG-US, but SG-US results were not related to any of the subjective dryness or discomfort measures. Sialoscintigraphy scores were associated with both B-mode SG-US and RTS results. Reproducibility of B-mode SG-US and RTS was good with intraclass correlation coefficients 0.93 and 0.93, respectively.
SG elasticity also can be measured using Acoustic Radiation Force Impulse (ARFI) US, where local tissue displacement by a brief acoustic radiation induces the emission and propagation of shear waves, which are then digitally recorded. Shear wave velocity (SWV) is measured in meters per second and increases with tissue stiffness. SG-US with ARFI elastometry was performed in healthy controls (n = 15) and patients with pSS (n = 10). Patients were classified according to the ACR criteria. In the parotid glands, mean SWV was significantly higher in the pSS group than in the control group ( P = .001), whereas mean SWV values for the submandibular glands were not significantly different between the patients and controls ( P = .892).
Another recent study also evaluated SG stiffness in pSS using quantitative ARFI imaging, including Virtual Touch tissue quantification (VTQ) and Virtual Touch tissue imaging quantification (VTIQ). VTQ was used to calculate the SWV, providing an objective numerical evaluation of the tissue stiffness, whereas VTIQ, a 2D shear wave imaging displaying a color-coded image, was used to enable the detection of SWV in multiple locations. Patients with pSS (n = 21) according to the AECG criteria and healthy controls (n = 11) were included, and both parotid and submandibular glands were examined using VTQ and VTIQ. The parotid VTQ value was significantly higher in the pSS group than the control group ( P <.01). Interestingly, VTIQ values for both the parotid and submandibular glands were significantly higher in the pSS group than in the control group ( P <.05), and the VTQ and VTIQ results correlated for the parotid and submandibular glands.
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
