see also: Salivary Ultrasound and Shear Wave Elastography - Quantitative Salivary Gland Ultrasonography

Salivary gland ultrasound (US) continues to evolve as an increasingly useful tool for both diagnosis and to direct therapy (Hoffman and Pagedar 2018).

This review is designed to addresses the evolving status of US in assessing the impact of radiaton (both radioiodine - I131 and external beam) on salivary gland damage associated with xerstomia - and provides correlates with research addressing Sjogren's syndrome.

Conventional Ultrasound Evaluation of Salivary Glands (without elastography or shear wave analysis)

Definitions (see basic Ultrasound Terminology):

According to Bertin (Bertin 1978):

Qualitative Analysis: "the detection or identification of the constituent elements in a sample"

Semiquantitative Analysis: "the estimation of their approximate concentrations"

Quantitative Analysis: "the accurate determinations of their concentrations"

Hočevar Semiquatitative Scoring System for ultrasound evaluation of structural changes to salivary glands has been cited by others (Law 2020, Elbeblawy 2020). It is one of many systems designed to subjectively assign a numerical score to the obsreved findings - as delineated in the table below which was evaluated in the salivary ultrasound assesment of 28 Sjogren syndreom patients and 29 controls determined to have "good reproducibility" between two blinded observers (one radiologist/one resident in rheumatology) (Hocevar 2007) in grading the parenchyma for echogeneicty, homgeneity, hypoechoic areas, hyperechoci foci and border visibility. Abnormalities consistent with the diagnosis of Sjogren's syndrome were at a level of ≥ 17 on this 48 point scale.

Scoring systems (semi-quantitative) to assess salivary gland findings associated with Sjogren's syndrome and other disease processes include assessment of echogenicity and homogeneity with other characteristics that are less reliably quantified include: size, visibility of posterior border, presence of calcifications, hyperechoic bands, hypoechoic/anechoic areas and abnormal lymph nodes.

Janţă (2021) identified that, due to 'difficulty in differentiating between inflammatory and chronic, fibrotic damages" - "there is not enough data to support the salivary gland ultrasound for monitory and prognostic purposes".

Fisher et al in a study of 52 patients with primary Sjogrens syndrome who had been randomized to treatment with placebo versus rituximab identified greater improvement for the treatment arm at 16 and 48 weeks for a "total ultrasound score" (TUS) which inclued domains of echogenicity, homogeneity, glandular definition,glands involved and hypoechoic foci size (Fisher 2018). Evaluation of each of the domains within the overall TUS - identified that 'glandular definition" was the only domain to show statistically significant improvement wtih rituximab treatment.

Shear Wave Elastography - Acoustic Radiation Force Impulse Imaging (ARFI) - Quantitative Elastography

Definitions:

Ultrasound elastography (Sonoelastography) is a method by which the characters (degree of fibrosis) is assessed by determining the speed of a signal passing a structure in assessment of it stiffness or elasticity. This technique in its rudimentary form (operator dependent and semiquantitative) is accomplished by analyszing changes to the signal of a structure as it is compressed with increasing pressure applied to the ultrasound probe (Li 2021).

Two basic concepts used for Ultrasound Elastography (Elbeblawy 2020)

1. Quasistatic = strain-based: "examination of the strain or defomation fo a tissue due to a force"

2. Dyamic or shear wave-based: "analysis of the propagation speed of a shear wave"

Shear wave: "a transverse wave that occurs in an elastic medium when it is subjected to a periodic shear" (Britannica 2022). "Shear" is further identified as 'the change of shape, without change of volume, of a layer of the substance, produced by a pair of equal forces acting on opposite directison along the two faces of the layer" Shear waves are considered transverse as distinguised from compressional waves that are longitudinal.

Young's Modulus (E) characterizes the stiffness of tissue that correlates with a clinicians perceptions of the firmness determined palpating tissue (Gennsion 2013). It is a measue of the elasticity - the compressive stiffness when a force is applied linthwise to quantify the relationship between stress ( = force per unit area) and axial strain ( = proportional deformation) as determined by the formula E = /  expressed in pascals kPa (Young's Modulus wikipedia). Hooke's law links stress () and strain () via formula:   =E.

Elastography Process wherein an external force is applied to tissue understudy to determine resulting movement - may be done by static, 'quasistatic', and dynamic methods - with 'strain' identifying the dysplacement generated to create a map termed an 'elastogram' (Gennsion 2013).

Dynamic elastography requires complex system to generate shear waves (via ultrasound radiation pressure) and the measure the displacements induced by the shear waves (ultrafast or stroboscopic ultrasound) (Gennsion 2013)

Quantitative asssessment of targetted tissue characteristics through shear wave elastography employs the transmission of successive pulses of acoustic power through the tissue (Sebag 2010)

ARFI (Acoustic Radiation Force Impulse Imaging)

Shear Wave Velocity measurement of periods of time between generation of shear waves and thir crossing of a region of interest (ROI) allows for calcultation of shear wave velocity (SWV in mm/sec) - with the correlate that the stiffer a region in of tissue - the faster the propopagation of the shear wave through the ROI. (Badea 2013)

Ultrasound Analysis of Irradiated Salivary Glands

Simões Lima et al (2020) Analysis of changes to the echotexture of salivary glands following radioiodine therapy via conventional semi-quantitative methods has been reported by Simões Lima et al (2020). These investigators employed experienced ultrasonographers to review salivary ultrasounds done before and then again at least 12 months following I131 treatment ranging from 95.8 mCi to 361 mCi. The analysis focussed on parotid echotexture determined to be either normal (homogeneous) or hetereogeneous - defined by 'irregular features in the parenchyma (with trabeculae apparent)". An ultrasound diagnosis fo chronic sialadenitis after I131 was made when the feature of heterogeneity was identified. 25 patients (31%) showed changes in the echotexture between pre and post I131 treatment with the single ultrasound variable of heterogeneity graded as either present or absent.

Diagnostic Salivary Ultrasound With Contrast Agents (Ultrasound Sialograms)

Definitions

Echogenecity: "The capacity to reflect or transmit ultrasound waves in the context of surrounding tissue" (Hoffman and Pagedar 2018) [see also above]

Contrast agent: Material present in adjacent strutures to enhance differences in radiographic (ultrasound/CT/other) characteristics. Saliva is a an contrast agent that helps discriminate that, when normal, is anechoic and can provided enhanced visualization of salivary ducts when stimulation with ascorbic acid or sour candy fills the ducts with saliva to help discriminate the enlarged fluid-filled ducts from the adjacent soft tissue (Sobrino-Guijarro 2013). Intravenous administration of contrast agents are commonly done for CT (iodine containing radiocontrast) and MRI (gadolinium) and have been reported as "contrast-enhancement ultrasound imaging" through intravenous administration for ultrasound examination of salivary gland tumors (David 2016) 

Microbubble contrast agents: Perflutren lipid microbubbles - "Definity microbubbles (Lantheus Medical Imaging, North Billerica, MA, USA)" usd notes re aquaporin and ultrasound and contrast agents.docx

Therapeutic Salivary Ultrasound with Microbubbles

Definitions

Sonoporation: Use of low frequency acoustic field effect (ultrasound) to allow gene trasfer to the cells of the salivary gland (Passineau 2010)

UAGT = ultrasound-assisted gene transfer - combines plasmid DVA vector and lipid perflutren microbubbles to allow gene trasfer to cells of the salivary gland (Wang 2015) 

As per Lomas et al (Lomas 1996)

"microorganisms on the buccal mucosa may be introaduced retrogradely into the duct system, resulting in gland infection." and "X-ray sialography is contraindicated when a gland infection is already established to avoid any risk of exacerbation."

References

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Sebag F., Vaillant-Lombard J., Berbis J., et. al.: Shear wave elastography: a new ultrasound imaging mode for the differential diagnosis of benign and malignant thyroid nodules. J Clin Endocrinol Metab 2010; 95: pp. 5281-5288.

Badea A.F., Szora A.T., Ciuleanu E., et. al.: AFRI quantitative elastography of the submandibular glands. Normal measurements and the diagnosis value of the method in radiation submaxillitis. Med Ultrason 2013; 15: pp. 173-179.

David E., Cantisani V., De Vincentiis M., et. al.: Contrast-enhanced ultrasound in the evaluation of parotid gland lesions: an update of the literature. Ultrasound 2016; 24: pp. 104-110.

Sobrino-Guijarro B., Cascarini L., Lingam R.K.: Advances in imaging of obstructed salivary glands can improve diagnostic outcomes. Oral Maxillofac Surg 2013; 17: pp. 11-19.

David E., Cantisani V., De Vincentiis M., et. al.: Contrast-enhanced ultrasound in the evaluation of parotid gland lesions: an update of the literature. Ultrasound 2016; 24: pp. 104-110.

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Wikipedia "Young's Modulus" Young's modulus - Wikipedia accessed 92-26-2022

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J Li, R Chow, N Vadivelu, and A Kaye: Ultrasound Fundamentals An Evidence-Based guide for Medical Practitioners. Springer Link 2021

Janţă, I.  The Salivary Glands Chapter pp 237-245 in Q Akram and S Basu: Ultrasound in Rheumatology A Practical Guide for Diagnosis Springer Link 2021 

Fisher BA, Everett CC, Rout J, et al. Effect of rituximab on a salivary gland ultrasound score in primary Sjögren’s syndrome: results of the TRACTISS randomised double-blind multicentre substudy. Ann Rheum Dis. 2018;77:412–6.

Jousse-Joulin S, Devauchelle-Pensec V, Cornec D, et al. Brief report: Ultrasonographic assessment of salivary gland response to rituximab in Primary Sjögren’s syndrome. Arthritis Rheumatol. 2015;67:1623–8.

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Wang X, Fang W, Wei L, Li B, Cheng Y. Clinical and Sialographic Imaging Features of 131I Radiation-induced Submandibular Gland Sialadenitis. J Oral Maxillofac Surg. 2021 Feb;79(2):376-382. doi: 10.1016/j.joms.2020.07.223. Epub 2020 Aug 11. PMID: 32896506.

Atif S, Wahab NA, Ghafoor S, Saeed MQ, Ahmad A. Salivary and imaging-based biomarkers of radiation therapy-induced xerostomia. J Pak Med Assoc. 2021 Mar;71(3):938-942. doi: 10.47391/JPMA.1115. PMID: 34057953.

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