Ultrasound elastography in diagnosis and follow-up for patients with chronic recurrent parotitis

Abstract

PURPOSE:

Chronic recurrent parotitis (CRP) is a non-obstructive disease with episodes characterized by painful swelling of the parotid gland. It presents in both a juvenile and an adult form, with no clear information on its actual origin. Diagnosis is based on patient medical history and ultrasound examination but is frequently not correctly identified. Acoustic Radiation Force Impulse Imaging (ARFI) is a novel ultrasound elastography technology that has recently been implemented in the diagnostic work-up of patients with malignancies. This study aimed to answer whether ARFI can reasonably be employed in the initial examination and follow-up during therapy in patients with CRP.

MATERIAL AND METHODS:

Mechanical tissue properties of the salivary glands were analyzed by ARFI in 37 parotid glands of patients with CRP.

RESULTS:

Having integrated ARFI into our diagnostic protocol for CRP, affected parotid glands were found to exhibit lower tissue elasticity compared to both healthy contralateral glands in the same individuals as well as those of healthy individuals. Most importantly, this method enabled us to quantitatively assess the patient benefit of therapy regarding the recovery of the glands’ diseased parenchyma.

CONCLUSIONS:

ARFI provides a quick, easy, and reliable diagnostic tool for the assessment of disease severity and progression in patients with CRP that can be seamlessly implemented into preexisting ultrasound protocols.

Keywords

Chronic recurrent parotitis ultrasound elastography ARFI imaging tissue elasticity

1 Introduction

Chronic recurrent parotitis is a non-obstructive disease with episodes characterized by painful swelling of the gland. It is categorized into a juvenile and an adult form, and there is no clear information on its actual origin. According to a 1997 study, in which 5,000 cases of chronic sialadenitis were evaluated, 27% of these were designated as CRP. The adult form was diagnosed 10 times more frequently than juvenile recurrent parotitis (JCRP) [1]. Specific rates of incidence of the disease in the whole population have not yet been described, but available information suggests that it occurs rather rarely [2 –4]. Following mumps, the juvenile form of CRP is the second most frequent disease of the salivary glands in children [5]. In children it occurs more frequently in boys than in girls [3 –5], while the prevalence in the adult form is more in the female sex [5, 6]. Seifert described an age range for the young CRP from 4 months to 15 years, while most adult patients are between 40 and 60 years old [1]. In most of the affected children the disease heals completely during puberty [7 –9], and almost all young patients are symptom-free by age 22 at the latest [10]. Only in rare cases does juvenile CRP persist in adulthood.

The pathogenesis of CRP has not yet been clarified, although there have been numerous approaches and theories since the turn of the century, which are mainly concerned with the juvenile form [6]. Congenital abnormalities of the salivary gland pathways [10 –13], reduced salivary flow with retrograde infection [2, 10], autoimmune processes [14 –16], genetic predisposition [13], allergic reactions [17] and immunodeficiency as in HIV or hypogammaglobulinemia [3] are described as possible causes or cofactors. In summary, CRP is a chronic inflammation of the duct system of the parotid gland that is associated with changes in the duct epithelium, changes in salivary consistency, and reduced salivary flow [3 , 18].

Although the causes of CRP are not known, the history and clinical findings are predominantly the same in all patients. Typically, a recurring one-sided swelling associated with pain occurs. This appears irrespective of meals and seasons and usually lasts 24 to 48 hours, sometimes even weeks to months. Occasionally, redness and warming of the skin above the salivary gland or fever may occur. Usually, there are symptom-free intervals of varying length from days to years between the acute outbreaks of parotitis. The salivary flow rate is permanently reduced and whitish saliva can be expressed with a fluffy precipitate, presumably from serum proteins that are caused by the chronically inflammatory damage of the duct system. Pus is rarely found [5, 6]. In adults, usually only one gland is affected, whereas in children the symptoms often occur bilaterally but rarely simultaneously [3, 5]. In imaging diagnostics, typical changes in the glandular system of the parotid gland are usually observable. In the juvenile type, the ectasia of the intraglandular ducts is typically, which in the past could be visualized primarily sialographically [3 , 19]; The main duct appears to be affected only in the more severe cases [5, 20]. In approximately 81% of children with jCRP, these typical sialectasia are deteactable by sialogram or sonography [3]. In most cases, both parotid glands exhibit the typical changes of the duct system, even if one of the glands may never show symptoms [5, 6]. Visible with ultrasound, there are round, hypoechoic and echoempty regions in the parotid gland, which correspond to the ectasia of the ducts [3, 6]. In the adult form of CRP, stenoses and dilatations are mainly formed in the distal stenon duct [5, 6]. In both forms, periductal lymphocytic infiltrates are found histologically [10]. In the adult form, the duct epithelium appears in the sialoendoscopy whitish and atrophic and usually without the typical vascular characterization.

The therapy of choice is gland massage and sialagogues, while in more severe cases sialendoscopy together with rinsing of the ducts and instillation of cortisone are indicated. Total parotidectomy remains the last choice and is rarely necessary.

Ultrasound is the first-choice diagnostic tool for diseases of the large salivary glands [21], which in comparison to other imaging methods now promises the highest accuracy in diagnosis. Advantages include fast, non-invasive, cost-effective, user-friendly, and patient-friendly examination with neither radiation exposure nor potential allergic reactions to x-ray contrast agents [22, 23].

Elastography is a technical approach that has been proven to be useful for the evaluation of malignant tumors, thyroid pathologies, and liver fibrosis [24 –26]. Acoustic Radiation Force Impulse Imaging (ARFI) represents a novel ultrasound elastography technology that can be integrated into conventional real-time ultrasound equipment and thereby be performed along with B-mode imaging. In ARFI, short duration acoustic pulses are emitted into the tissue under investigation. Subsequently, the impulses induce localized micro-shifts within the tissue, which allow transverse waves to spread centrifugally from the center of excitation. The shear wave velocity, which can be measured using ultrasound waves, provides an indication of the tissue‘s elasticity.

Using ARFI, we have recently demonstrated that healthy parotid glands exhibit lower tissue elasticity compared to healthy submandibular glands [27]. In the present study, we sought to evaluate the employment of this technique in both the initial examination as well as follow-up therapy of patients suffering from CRP.

2 Material and methods

2.1 Study design and study population

This prospective study was performed at the Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Munich, Germany. The local ethics committee has examined the study, and the patients were informed about the investigation.

Between 2014 and 2016, patients with ongoing diseases affecting one or more salivary glands were recruited by the employees of the Department of Otorhinolaryngology and underwent a routine ultrasound examination. Subsequently, patients diagnosed with CRP were referred for elastography and had to complete a standardized questionnaire on their complaints. As follow-up, ultrasound and elastography examinations as well as the completion of a standardized questionnaire by the patient were repeated after the end of successful therapy.

Patients with recurrent swelling of their parotid glands and ultrasound findings documenting the typical sights of CRP were included in the study. For elastography analyses, five regions of interest were chosen in each of the parotid glands.

2.2 Exclusion criteria

There were no exclusion criteria because the elastography measurement is considered to be a safe standard ultrasound technique.

2.3 Ultrasound imaging

Conventional ultrasound examinations were performed on a Siemens ACUSON S 2000 (Siemens Medical Systems, Erlangen, Germany) using a linear 9 MHz multi-frequency transducer. The examination consisted of a conventional B-scan followed by color-coded duplex sonography. The color gain mode was employed only to the extent necessary to avoid obscuring artefacts. Additionally, automatic image gain optimization (TEQ) was performed. For elastography analyses, elastography ARFI software was used to measure the velocity of shear waves.

“Virtual Touch TM Tissue Quantification” allows for the tracking of a shear wave within the region of interest as it travels perpendicularly to the transmitted longitudinal push pulse. Subsequently, “Time to Peak analysis” allows for the computation of a numerical value of the shear wave velocity obtained over the region of interest and expressed in meters per second (m/s). The stiffer the tissue, the higher the share wave velocity [14, 36]. Thus, the measurements provide quantitative information about tissue elasticity. The ultrasound device features a high performance processor and provides output documentation as dynamic image sequences in cine mode by a digital frame buffer.

2.4 Data and statistical analysis

Data analysis from digitally stored video sequence data sets was performed using a statistical software package (SigmaStat for Windows, Jandel Scientific, Erkrath, Germany). After testing for normality of data (Shapiro-Wilk test), the t-test (2 groups) was used for the estimation of stochastic probability in intergroup comparisons. Mean values and standard deviations are given. P values <0.05 were considered significant.

3 Results

3.1 Study population

The elastograph values of a total of 37 glandulae parotideae with chronic recurrent parotitis of 25 patients were used for this study. Nine of the 25 patients were children aged two to 15 years (36%) with a gender distribution of 56% girls and 44% boys with the remaining 16 adult patients (64%) aged 28 to 75 years with 88% women and 12% men. In twelve patients (48%) both glandulae parotidea were affected by CRP, while in thirteen patients (52%) only on side was involved.

3.2 Effect of CRP on tissue elasticity

As a measure of tissue elasticity, ARFI analyses were performed in individuals with CRP of their salivary glands. The elastography values of the 37 parotid glands with chronic recurrent parotitis of 3.25±1.73 m/s for the average shear wave velocity showed statistically significant higher values in comparison with the twelve healthy glands of the opposite side of the patient with an average shear wave velocity of 2.19±0.60 m/s (p = 0.023). A significant increase in elastography values of the patients with CRP was also shown in comparison with the values of parotid glands of normal collective with average shear wave velocity of 2.63±0.59 m/s (p = 0.008; Fig. 1).

Fig.1

ARFI shear wave velocity values of parotid glands in patients with CRP or in healthy individuals (mean±SD; p = 0.008 for diseased vs. healthy glands).

3.3 Comparison of adults and children with CRP

On re-examination by grouping into adults and children with CRP, it was found that the elastography values of the thirteen affected juvenile parotid glands at an average shear wave velocity of 3.18±1.99 m/s were not significantly increased (p contralateral side = 0.168; p healthy volunteers = 0.376). The average shear wave velocity of the five non-affected glands was 1.89±0.48 m/s and the average shear wave velocity of healthy volunteers was 2.36±0.51 m/s (Fig. 2). However, in the case of the 24 affected glands of the 16 adults, a significant increase in the average shear wave velocity of 3.29±1.62 m/s was found in comparison to the nine contralateral sides with an average shear wave velocity of 2.36±0.57 m/s and 2.36±0.51 m/s for healthy volunteers (p contralateral side = 0.045, p healthy volunteers = 0.03; Fig. 3). No statistically significant difference was found between the average shear wave velocities of the adults of 3.18±1.99 m/s and those of the children at 3.29±1.62 m/s (p = 0.272).

Fig.2

ARFI shear wave velocity values of parotid glands in children with CRP or in healthy individuals (mean±SD; p = 0.376 for diseased vs. healthy glands).

Fig.3

ARFI shear wave velocity values of parotid glands in adult patients with CRP or in healthy individuals (mean±SD; p = 0.030 for diseased vs. healthy glands).

3.4 Effect of successful therapy on tissue elasticity of diseased glands

The effect of successful therapy (sialendoscopy, prednisolone installation) on tissue elasticity of diseased glands was determined after the patient was symptom free more than two months after therapy. After therapy, ARFI shear wave velocity values in parotid glands decreased to values not significantly different from other unaffected contralateral glands or those of healthy volunteers. As follow-up, elastography values confirmed successful therapy in all investigated cases.

After treatment, the elastography values of the treated glands were no longer statistically significantly different values from those of healthy glands. In particular, the average shear wave velocity measured was 2.49±0.34 m/s in the treated glands, 2.05±0.30 m/s in two unaffected glands of the opposite side and 2.63±0.59 m/s in glands of the healthy volunteers (p opposing side = 0.12; 0.323 healthy volunteers; Fig. 4). The direct comparison of the affected glands showed a significantly decreased value; the average shear wave velocity before treatment was 3.72±2.04 m/s in comparison to 2.49±0.34 m/s at least two months after therapy (p = 0.006).

Fig.4

ARFI shear wave velocity values of parotid glands in adult patients with CRP >2 months after therapy or in healthy individuals (mean±SD; p = 0.323 for formerly diseased vs. healthy glands).

3.5 Association of subjective parameters and tissue elasticity measurements

Symptoms of the individuals with CRP of their salivary glands were assessed using a standardized questionnaire. A comparison of glands with chronic verses short-term complaints was made with a threshold of one year with 17 parotid glands with short-term patient complaints of twelve months or less and 18 glands with chronic symptoms of more than one year. The average shear wave velocity was 2.54±0.80 m/s for the short-term group in comparison to 3.93±2.16 m/s in the chronic patient group. These measurements indicate a statistically significant difference between the elastography values of the two groups (p = 0.013; Fig. 5). No significant differences in ARFI shear wave velocity values of affected salivary glands were detected between patients with infrequent (<50) or frequent (>50) episodes, low (visual analogue scale (VAS) 0 –5) or high (VAS 6 –10) intensity of gland pain (data not shown).

Fig.5

ARFI shear wave velocity values of parotid glands in CRP patients with a duration of symptoms for less or more than 12 months (mean±SD; p = 0.013 for <12 vs. >12 months).

4 Discussion

In chronic sialadenitis, the affected parenchyma can become fibrotic, ultimately leading to the loss of the gland’s secretory function. Due to emerging knowledge about the salivary glands’ potential to recover after therapy, the treatment of CRP shifted in the past decades from ablative surgical techniques to minimal-invasive therapeutical strategies [28 –31]. In order to evaluate the effect of these therapeutic modalities on the recovery of the salivary glands’ parenchyma, different technical means including scintigraphic, sialographic, and echostructural analyses as well as questionnaire-based approaches have been employed –all with more or less unsatisfying results regarding their usefulness in clinical routine [32 –35].

Recently, ARFI has been implemented in the diagnostic work-up of different pathological entities such as malignant tumors, thyroid pathologies, and liver fibrosis [24 –26]. Our previous research indicates that this technical approach serves as a valid method to determine the tissue elasticity of salivary glands [27]. Consequently, ARFI might be useful as a clinical routine to objectively measure structural alterations in the parenchyma of salivary glands in patients with CRP.

Based on our previous findings [27], we routinely employed ARFI elastography in both the initial examination and follow-up therapy of patients with CRP.

Around a third of the 25 patients in this study with CRP were children. This is an unusually high proportion of children, as CRP has been found to be about ten times more likely to occur in adults according to a publication by Seifert in 1997 [1]. On average, more boys than girls are affected. The proportion of women with 88% was dominant in the adult population, confirming the results of previous publications on the epidemiology of CRP [3 , 6].

As a measure of tissue elasticity, the elastography values of the 37 parotid glands with chronic recurrent parotitis showed statistically significant higher values in comparison with the values of parotid glands of normal collective.

A correlation was found between the first appearance of disease-specific symptoms on the affected gland and the elastography values. The values were significantly higher in the patients who indicated that they had had symptoms for more than a year. In this case the fibrosis of the glandulae parotideae, which could be demonstrated elastographically, appeared with the duration of untreated chronic inflammation.

However, the dependence of the elastography values on the frequency and intensity of pain and swelling in the affected glands could not be ascertained in contrast to the duration of the disorder.

In addition to the initial patient examination, we also sought to evaluate the effect of our therapeutic interventions on the salivary glands’ tissue elasticity in follow-up visits. At least two months after the therapy, the elastograph values of meanly symptom-free glands were again similar to the normal values, measured on the contralateral side and the healthy volunteers. Also, a statistically significant difference between the pretherapeutic elastography values and the values two months after therapy could be calculated; The values had declined significantly. Obviously the glandular tissue had regenerated after the therapy. Thus, ARFI also appears to be useful for monitoring the patient’s benefit of therapy regarding tissue recovery.

In the case of a separate examination of the elastography values of children and adults with CRP, it could be observed that the affected glands did not significantly differ. It is obviously not relevant to the fibrosis of the chronically inflamed glands, whether it is the juvenile or adult form of the CRP. There was also no statistically significant difference in the comparison of the non-affected glands of children with those of the adults, although the elastography values of the healthy glands of the adults were somewhat higher in our studies than those of the children. However, a statistically significant age-dependent difference in the elastography of healthy glands could not be determined. Furthermore, it was noteworthy that only the diseased parotid glands of the examined adults were significantly higher in their elastography than the healthy contralateral side or the healthy volunteer glands. In the affected childrens’ glands, however, no statistically significant increase in elastography compared to healthy glandulae parotideae could be observed, although the values of the glands affected by CRP tended to be higher and also had a larger standard deviation. Possibly, the number of subjects was too small to show significance, or the disease interval of the children was shorter.

Unfortunately, there are no publications on elastography of parotid glands with CRP in the literature; thus, no comparison is possible.

In conclusion, the results of our study demonstrate that ARFI elastography shows promise as a valuable diagnostic tool for assessing disease severity, progression and the treatment response. The method is easy to use, not time consuming, and can be easily and seamlessly integrated into preexisting ultrasound examination protocols.

Footnotes

Acknowledgments

This study is part of the doctoral thesis of T.V.

References

Seifert

, Aetiological and histological classification of sialadenitis, Pathologica89(1) (1997), 7–17.

Chitre

V.V.

and Premchandra

D.J.

, Recurrent parotitis, Archives of Disease in Childhood77 (1997), 359–363.

Leerdam

C.M.

, Martin

H.C.O.

and Isaacs

, Recurrent parotitis of childhood.pdf, J Paediatr Child Health41 (2005), 631–634.

Saarinen

, et al., The clinical picture of juvenile parotitis in a prospective setup, Acta Paediatr102(2) (2013), 177–181.

Baurmash

H.D.

, Chronic recurrent parotitis: A closer look at its origin, diagnosis, and management, Journal of Oral and Maxillofacial Surgery62(8) (2004), 1010–1018.

Zenk

, et al., Chronic recurrent parotitis, HNO58(3) (2010), 237–243.

Geterud

, Lindvall

A.M.

and Nylen

, Follow-up study of recurrent parotitis in children, Ann Otol Rhinol Laryngol97(4 Pt 1) (1988), 341–346.

Kolho

K.L.

, et al., New insights into juvenile parotitis, Acta Paediatr94(11) (2005), 1566–1570.

Wang

, et al., Classification and management of chronic sialadenitis of the parotid gland, J Oral Rehabil36(1) (2009), 2–8.

10.

Ericson

, Zetterlund

and Ohman

, Recurrent parotitis and sialectasis in childhood. Clinical, radiologic, immunologic, bacteriologic, and histologic study, Ann Otol Rhinol Laryngol100(7) (1991), 527–535.

11.

Konno

and Ito

, A study on the pathogenesis of recurrent parotitis in childhood, Ann Otol Rhinol Laryngol Suppl88(6 Pt 4 Suppl 63) (1979), 1–20.

12.

Zou

Z.J.

, et al., Recurrent parotitis in children. A report of 102 cases, Chin Med J (Engl)103(7) (1990), 576–582.

13.

Wittekindt

, et al., Chronic recurrent parotitis in childhood in monozygotic twins. Magnetic resonance sialography, Hno48(3) (2000), 221–225.

14.

Andrade

R.E.

, Hagen

K.A.

and Manivel

J.C.

, Distribution and immunophenotype of the inflammatory cell population in the benign lymphoepithelial lesion (Mikulicz’s disease), Hum Pathol19(8) (1988), 932–941.

15.

Bowling

D.M.

, et al., Intraductal tetracycline therapy for the treatment of chronic recurrent parotitis, Ear Nose Throat J73(4) (1994), 262–274.

16.

Morales-Bozo

, et al., Association between the occurrence of matrix metalloproteinases 2 and 9 in parotid saliva with the degree of parotid gland damage in juvenile recurrent parotitis, Oral Surg Oral Med Oral Pathol Oral Radiol Endod106(3) (2008), 377–383.

17.

Marsman

W.A.

and Sukhai

R.N.

, Recurrent parotitis and isolated IgG3 subclass deficiency, Eur J Pediatr158(8) (1999), 684.

18.

Nahlieli

, et al., Management of chronic recurrent parotitis: Current therapy, Journal of Oral and Maxillofacial Surgery62(9) (2004), 1150–1155.

19.

Miziara

I.D.

and Sousa

V.E.

, Campelo, Infantile recurrent parotitis: Follow up study of five cases and literature review, Rev Bras Otorrinolaringol71(5) (2005), 570–575.

20.

Shacham

, et al., Long-term experience with endoscopic diagnosis and treatment of juvenile recurrent parotitis, J Oral Maxillofac Surg67(1) (2009), 162–167.

21.

Vogl

T.J.

, et al., Updated S2K AWMF guideline for the diagnosis and follow-up of obstructive sialadenitis–relevance for radiologic imaging, Rofo186(9) (2014), 843–846.

22.

Mehanna

, et al., Salivary Gland Swellings, Clinical Otolaryngology38 (2013), 58–65.

23.

Iro

, Zenk

and Koch

, Modern concepts for the diagnosis and therapy of sialolithiasis, HNO58(3) (2010), 211–217.

24.

Trottmann

, Marcon

, D’Anastasi

, et al., Shear-wave elastography of the testis in the healthy man - determination of standard values, Clinical Hemorheology and Microcirculation62 (2016), 273–228.

25.

Cantisani

, Lodise

, Grazhdani

, et al., Ultrasound elastography in the evaluation of thyroid pathology. Current status, European Journal of Radiology83 (2014), 420–428.

26.

Sporea

, Sirli

, Popescu

, et al., Acoustic Radiation Force Impulse (ARFI)–a new modality for the evaluation of liver fibrosis, Medical Ultrasonography12 (2010), 26–31.

27.

Zengel

, Schrotzlmair

, Schwarz

, et al., Elastography: A new diagnostic tool for evaluation of obstructive diseases of the salivary glands; primary results, Clinical Hemorheology and Microcirculation50 (2012), 91–99.

28.

Koch

, Zenk

and Iro

, Algorithms for treatment of salivary gland obstructions, Otolaryngologic Clinics of North America42 (2009), 1173–1192.

29.

Rahmati

, Gillespie

M.B.

and Eisele

D.W.

, Is sialendoscopy an effective treatment for obstructive salivary gland disease?, The Laryngoscope123 (2013), 1828–1829.

30.

Thomas

B.L.

, Brown

J.E.

and McGurk

, Salivary gland disease, Frontiers of Oral Biology14 (2010), 129–146.

31.

Witt

R.L.

, Iro

, Koch

, et al., Minimally invasive options for salivary calculi, The Laryngoscope122 (2012), 1306–1311.

32.

Anjos

D.A.

, Etchebehere

E.C.

, Santos

A.O.

, et al., Normal values of [99mTc]pertechnetate uptake and excretion fraction by major salivary glands, Nuclear Medicine Communications27 (2006), 395–403.

33.

Hermann

G.A.

, Vivino

F.B.

, Shnier

, et al., Variability of quantitative scintigraphic salivary indices in normal subjects, Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine39 (1998), 1260–1263.

34.

Yoshimura

, Morishita

and Sugihara

, Salivary gland function after sialolithiasis: Scintigraphic examination of submandibular glands with 99mTc-pertechnetate, Journal of Oral and Maxillofacial Surgery: Official Journal of the American Association of Oral and Maxillofacial Surgeons47 (1989), 704–710.

35.

Zhang

, Escudier

, Brown

, et al., Long-term outcome after intraoral removal of large submandibular gland calculi, The Laryngoscope120 (2010), 964–966.

36.

Yang

Y.P.

, Xu

X.H.

, Bo

X.W.

, Liu

B.J.

, Guo

L.H.

, Xu

J.M.

, Sun

L.P.

and Xu

H.X.

, Comparison of Virtual Touch Tissue Imaging & Quantification (VTIQ) and Virtual Touch Tissue Quantification (VTQ) for diagnosis of thyroid nodules, Clin Hemorheol Microcirc65(2) (2017), 137–149.