Clin Physiol Funct Imaging (2014)
doi: 10.1111/cpf.12199
INVITED REVIEW
Imaging of the major salivary glands Pia Afzelius1, Ming-Yuan Nielsen1, Caroline Ewertsen2 and Klaus Poulsen Bloch1 1
Department of Diagnostic Imaging, North Zealand Hospital, Copenhagen, Denmark, and 2Department of Radiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Summary Correspondence Pia Afzelius, Department of Diagnostic Imaging, North Zealand Hospital, Hillerød, Dyrehavevej 29, DK-3400 Hillerød, Denmark E-mail: [email protected]
Accepted for publication Received 20 June 2014; accepted 18 September 2014
Key words 18
F-FDG positron emission tomography; computed tomography; magnetic resonance imaging; parotid gland; salivary gland scintigraphy; sialography; submandibular gland; ultrasound
The major salivary glands, submandibular, parotid and sublingual glands play an important role in preserving the oral cavity and dental health. Patients with problems of the major salivary glands may present with symptoms such as dry mouth, dysphagia and obstruction of duct, inflammation, severe dental caries or swelling. Imaging plays an important role in visualization of morphology and function, to establish a diagnosis, for treatment, and for surgical planning. There are several options for diagnostic imaging: plain radiography, sialography, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), salivary gland scintigraphy and 18F-FDG positron emission tomography (PET). We present an overview of the modalities in relation to common salivary gland disease.
Introduction The oral cavity is lined with a mucous membrane, which is kept moist by saliva. Saliva protects oral cavity and teeth, and it also facilitates swallowing. The salivary glands produce about one litre of saliva a day. The major salivary glands are the parotid glands, located in front of the ear, the sublingual glands, under the tongue, and the submandibular glands, below the mandible, laterally. In addition, there are several small accessory salivary glands in the oral cavity, paranasal sinuses, larynx and pharynx. The submandibular and sublingual salivary glands constantly produce saliva, while the parotid gland mainly produces saliva in response to meals or by the thought or smell of food. Saliva contains, in addition to mucus and water, enzymes to cleave glycogen, starch and immunoglobulins for defence against infections (Ten Cate’s, 2013). The most common reason for swollen salivary glands is mumps, a viral infection classically affecting the parotid glands. Another reason may be sialolithiasis causing an obstruction of the salivary duct, which may lead to bacterial infection. Frequently, the lymph nodes on the neck will be enlarged and tender. There may be discharge of pus from the infected salivary gland. Untreated infection may lead to impaired or ceased glandular function due to scar tissue. Another cause of swelling may be a tumour. About 70% of
salivary gland tumours arise in the parotid gland. Seventy-five percentage of these are benign. Neoplasms of the salivary glands comprise 3–5% of all head and neck cancers (Laramore et al., 2001) with tumours in the submandibular and sublingual glands having a higher risk of being malignant than tumours in the parotid gland. A tumour in the submandibular or sublingual gland should always be considered malignant until proven benign. The malignant salivary neoplasms are rare, with an overall incidence in the Western world of approximately 25 cases to 30 cases per 100 000 per year (Speight & Barrett, 2002). Cancer of the salivary glands can occur at any age, but is most often seen in people older than 50 years, with almost equal incidence in males and females. The cause of this cancer is unknown, but risk factors may be exposure to ionizing radiation, occupations associated with rubber products manufacturing, asbestos mining, plumbing and some types of woodworking (Scanlon & Sener, 1981; van der Laan et al., 1995; Ellis & Auclair, 1996; Mendenhall et al., 2011). The salivary glands may also be affected in primary Sj€ ogren’s syndrome (SS), which is a chronic progressive autoimmune disease of unknown aetiology. It is characterized by lymphocyte infiltration and the destruction of exocrine glandular tissue, especially in the lachrymal and salivary glands causing xerostomia (Bunim et al., 1964; Johnsson et al., 2005). Secondary SS is associated with other systemic autoimmune
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
1
2 Imaging of the major salivary glands, P. Afzelius et al.
diseases, for example rheumatoid arthritis, systemic lupus erythematosus or scleroderma (Bloch et al., 1965). SS is considered the most common autoimmune disease with a prevalence of 3–4% in a cross-sectional population-based study (Thomas et al., 1998). Patients suffering from SS have a 16- to 40-fold increased risk of developing B-cell lymphoma and patients should be monitored annually (Lazarus et al., 2006; Theander et al., 2006). Ionizing radiation from radiotherapy (Teshima et al., 2010) or adjuvant radioiodine therapy for ablation of residual thyroid after surgery in management of differentiated thyroid cancer (Solans et al., 2001) is another reason for transient or permanent salivary gland dysfunction. To cover this wide range of possible diseases, it is important to choose the best imaging modality regarding cost, radiation, accuracy, reliability and patient satisfaction. We present an overview of the most common methods [plain radiography, sialography, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), salivary gland scintigraphy and 18F-FDG positron emission tomography (PET)] in relation to common salivary gland diseases.
Plain radiography Plain radiography is an inexpensive and simple way of studying sialolithiasis in the salivary glands (Fig. 1). As only onefifth of the ductal sialolithiasis are radiolucent this imaging procedure is today, with other techniques at hand, of limited value. Furthermore, phlebolithiasis, hemangiomas with calcifications or calcified lymph nodes may mimic sialolithiasis on plain radiography. Parotid glands can be visualized in anterior–posterior (AP) projection with extended chin, open mouth and cheeks blown out to show Stensen’s duct lesion. The submandibular gland can be visualized in AP and ipsilateral oblique projections with extended chin, open mouth and the tongue pressed down in the floor of the mouth.
Sialography Conventional X-ray sialography is an old technique described by Carpy in 1902 and later used by Barsony et al. in 1925 as a diagnostic tool (Fig. 2). Later CT sialography with cone-beam CT (see below/page), following injection of contrast agent into the ductal system has been introduced. These sialography techniques allow the demonstration of the ducts, ductules and parenchyma of the salivary gland of interest, or a stricture after introduction of a fat-soluble radiopaque contrast agent in their excretory ducts. Irregular pooling of contrast agent and ductal obstruction without the presence of sialolithiasis may be indirect signs of malignancy. Sialography is rarely used for sublingual imaging because numerous, usually 20, small ducts of Rivinus open directly into the floor of the mouth making an overview difficult. Potential complications associated with sialography include rupture of the ductal system, activation of clinically dormant infection and adverse reactions to contrast agent. Ionizing radiation exposure depends on the operator’s technical skills for quick cannulation of the ductal system, which is not always achievable. The examination is contraindicated in acute sialoadenitis and in cases of former allergic reactions to iodine-containing contrast agent. In such cases, surgical removal of possible sialolithiasis or explorative sialoendoscopy (Hasson, 2010) may be preferred. Technical improvements in the non-invasive procedures such as ultrasound and MRI (see below/page) and the lack of radiation exposure to both patients and staff compared to both conventional sialography and CT sialography have in many institutions made them first choice modalities. MRI is expensive and not always available. Conventional X-ray sialography is usually performed using digital subtraction technique after retrograde intracannular injection of a water-soluble, iodinated, contrast agent in the Stensen’s/Wharton’s duct opening. The goal is a fully opacified ductal system. The gland is allowed to empty for about 5 min, and then, a sialogogue may be administered to
Figure 1 Plain radiograph of the angle of the mandible and parotid region in lateral and lateral oblique projections showing two small calculi (arrow) in the left (L) parotid gland. The right side (R) is normal. Same patient as in Fig. 3. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 3
Figure 2 Conventional X-ray sialography of parotid gland showing a calculus (arrows) in the distal part of the duct. Lateral oblique and AP projections.
promote the secretion of saliva and further emptying of the gland. This procedure has the advantage that the position of head can be optimized during examination.
Ultrasound High-resolution US is in many cases the initial imaging modality for assessment of the salivary glands (Gritzmann, 2011; Carotti et al., 2014). Using high frequency (7–15 MHz) probes, US has a high spatial and temporal resolution, and a high accuracy for delineating benign and malignant lesions, especially superficial lesions (Gritzmann, 1989). US is widely available in Europe, can be used for image guided biopsies, and can be performed in the emergency setting and bedside (Oliveras et al., 2014). US has limitations in evaluating structures behind bone, that is behind the mandible and the deep parts of the parotid gland (Gritzmann, 2011).
US has been evaluated in both benign and malignant conditions. In acute inflammation, US is used to look for sialolithiasis or abscesses (Gritzmann, 2011). It is widely known to have a high sensitivity for detecting sialolithiasis (Fig. 3), and has in many institutions replaced sialography. In a study by Gritzmann, 94% of sialolithiasis were detected with US in 174 patients (Gritzmann, 1989). In a more recent study, the sensitivity for sialolithiasis was only 77% in general, but increased to 94% when looking at sialolithiasis larger than 3 mm. Sialolithiasis was present in 44 glands in the study, which caused some debate as the glands were scanned with rather low frequencies (Terraz et al., 2013; Loizides & Gruber, 2014). Therefore, the sensitivity might be closer to 94%. In acute viral infection for instance with mumps, the symptoms are usually bilateral and the glands are enlarged and
Figure 3 US image showing two calculi (left side of the figure indicated by arrows) in the left parotid gland (same patient as in Fig. 1). There is dilation of Stensen’s duct (arrow) proximal to the calculi (right side of the figure). © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
4 Imaging of the major salivary glands, P. Afzelius et al.
more hypo-echoic due to oedema. Increased vascularization using colour Doppler may be seen. In SS, the salivary glands become enlarged and heterogeneous. These changes are more pronounced in the parotid gland than in the submandibular gland (Takagi et al., 2010). US was compared with contrast sialography and scintigraphy in 77 patients with primary SS in one study, and with sialography and histopathology in 73 patients in another study. Both studies concluded that US was a useful diagnostic tool (Salaffi et al., 2008; Obinata et al., 2010). Scoring systems for determining salivary gland changes were evaluated in three other studies in patients with primary SS. All found characteristic changes in SS compatible with their scoring systems (Hocevar et al., 2005; Cornec et al., 2013; Theander & Mandl, 2013). If a tumour is visible, fine needle aspiration cytology (FNAC) or core needle biopsy (CNB) may be performed. CNB was reported to have a higher sensitivity than FNAC in distinguishing benign from malignant and in providing a final diagnosis (Huang et al., 2012). If a tumour is benign on needle biopsy no further imaging is required. If the tumour affects the deep parotid lobe or potentially extends intracranially, MRI or CT is recommended to delineate the tumour as US does not sufficiently do so (Gritzmann, 2011). The higher grade of vascularity in malignant tumours compared to benign can be demonstrated using colour Doppler US. Elastography, which is a method that depicts tissue stiffness, has also been evaluated for parotid lesions. The interobserver agreement and the correlation between disease and elastographic findings were low, but larger studies are needed to determine the value of this new method (Mansour et al., 2012; Celebi & Mahmutoglu, 2013).
Magnetic resonance imaging MRI is important in evaluation of major salivary gland diseases, especially neoplastic diseases. If there is a strong suspicion of malignancy, MRI is the method of choice (Yousem et al., 2000). If the tumour is large (>3 cm) or located in the
(a)
(b)
deep lobe of the parotid gland, US has limitations in demonstrating and delineating the lesions sufficiently, and MRI (or CT when contraindications to MRI exist) should be performed. MRI provides a large variety of soft tissue signal differences, and multiplanar facilities are helpful in delineating the extent of the tumour, whether located in the submandibular, sublingual or parotid gland. Skull base invasion is often well seen by MRI (Freling, 1994). In case of a large malignant tumour and cranial nerve deficit, MRI should be performed to evaluate the local extent of the lesion and to detect perineural tumour spread and intracranial invasion (Yousem et al., 2000; Freling, 2010). Infiltration into the parapharyngeal space, muscles or bone will strongly suggest malignancy (Freling et al., 1992), or less frequently rupture of the capsule of a pleomorphic adenoma (Fig. 4b). If an infiltrative neoplasm is highly suspected, non-contrast enhanced (NCE) and contrast enhanced (CE) MRI may be superior in demonstrating perineural, meningeal and skull base invasion (Yousem et al., 2000). These problems are not possible to outline with US. MR sialography defines the ductal system of the gland of interest without injection of ductal/intravenous contrast agent by means of highly fluid-sensitive sequences similar to those used for magnetic resonance cholangio-pancreatography (MRCP) (Lomas et al., 1996; Erdogan et al., 2013), where the patient’s own saliva is used as contrast agent. MR sialography can be performed in patients with acute sialadenitis. The administration of a sialogogue may improve ductal visualization in MR sialography by increasing salivary secretion. MR sialography has poor spatial resolution compared to conventional sialography (J€ager et al., 2000), but may be an alternative if x-ray sialography cannot be performed (Uddin, 2011). MR sialography requires sufficient production of saliva. Pacemaker, implanted metals, claustrophobia, long acquisition time and the cost are all disadvantages. Advantages are no ionizing radiation and a non-invasive method. An MRI protocol should consist of axial and coronal T1 spin-echo (SE) and T2 SE weighted images (T1WI and T2WI), fat-saturated CE T1WI axial, coronal and sagittal images. Slice thickness should not exceed 3 mm.
(c)
Figure 4 (a) Coronal T1-weighted spin-echo MR image shows the mass (arrow) to be well demarcated in the parotid gland. The mass has an outer contrast-enhancing rim on this CE, T1-weighted spin-echo MRI and a central non-enhancing component, characteristic for pleomorphic adenoma. (b) In the left parotid gland, a mass (Warthin’s tumour indicated by arrow) was seen on coronal T1-weighted spin-echo (before contrast) MRI. The multiplicity and location in the parotid gland (near the lower mandible) are typical features of the tumour. (c) Coronal T2-weighted spin-echo MR image shows a typical cyst (arrow) in the left parotid gland. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 5
Figure 5 Planocellular carcinoma in left parotid gland (arrow) on MRI (left) and CT (middle). Please note the streak artifacts derived from metallic dental fillings resulting in reduced quality of the CT image, and to lesser extent on MRI. Co-registered 18F-FDG PET and CT (right).
All parotid lesions are well visualized on T1WI because of the hyperintense (fatty) background of the gland (Fig. 4a). The T1WI sequence gives a clear assessment of the margin of the tumour, its depth extent, and its pattern of infiltration (Yousem et al., 2000), whereas fat-saturated CE T1WI is preferred to determine the depth of invasion. Benign and malignant masses exhibit considerable overlap with regard to geographic properties such as margins, shapes and borders (Teresi et al., 1987; Swartz et al., 1989). There is agreement that a hyperintense mass on T2WI is benign (Fig. 4c) and masses of low to moderate signal intensity are malignant (Yousem et al., 2000). Som & Biller (1989) and Sigal et al. (1992) showed a sensitivity of 73% for determination of malignancy with a T2WI. Others have implied that signal intensity on T2WI is useless in determining malignancy (Swartz et al., 1989; Freling et al., 1992). .
Computed tomography CT of the salivary glands is easy, rapid and cheap compared to MRI (Burke et al., 2011), but it involves exposure to ionizing radiation to the head and neck. There are only a few contraindications to contrast enhanced CT (CECT) such as impaired renal function and prior severe allergic reaction to the contrast agent. Artifacts from metal dental fillings often cause diagnostic difficulties (Fig. 5), but iterative correction reduces streak artifacts in the dentoalveolar region (Kondo et al., 2010). Non-contrast enhanced CT (NCECT) can demonstrate sialolithiasis, tissue calcification, gas-formation in the soft tissue, and bony erosion caused by malignant lesions, or infection. Usually, the attenuation of the parotid gland is slightly lower than of the submandibular gland because of a higher content of fat. A decrease in density owing to fatty degenera-
tion can be observed with ageing (Cheng et al., 2011), and also after radioiodine therapy and radiotherapy (Cheng et al., 2011; Nabaa et al., 2012). Cone-beam CT provides a relatively high spatial resolution of high-density structures such as bone, sialolithiasis and contrast agent in sialography with a lower dose of radiation than conventional CT (Miracle & Mukherji, 2009a,b). CECT is useful in acute cases, when MRI is contraindicated, or in cases where the access to MRI is limited. Inflammation in the glands will show as enlarged glands with abnormal attenuation or intensity and clear enhancement. Abscess formation is easily seen on both CECT and MRI. Abscesses can even be seen in the parotid gland on NCECT because of the higher fatty content particularly in ageing (Burke et al., 2011). The inflammatory findings are unspecific and must be held up against the clinical findings, US findings, biopsies and MRI. CECT provides information for staging of salivary gland tumours prior to treatment and when evaluating treatment response. It can assess the intra- and extraglandular location, local extension and invasion into the surrounding tissues; detect regional lymph node metastases and systemic involvement. Dong et al. (2014) have demonstrated significant differences in CT blood perfusion in histologically benign and malignant tumours in the parotid gland. Optimal CT of the salivary glands requires contrast enhanced scan to visualize cysts, abscesses, neoplasms (Fig. 6) and traumatic lesions. Nabaa et al., 2012 have recently demonstrated that routine NCECT screening for recurrence and metastases can also check for possible radiation-induced salivary gland dysfunction by demonstrating altered (decreased) volume and increased attenuation.
Figure 6 NCECT in axial and coronal planes demonstrate a planocellular carcinoma of the left parotid gland (arrows). © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
6 Imaging of the major salivary glands, P. Afzelius et al.
Figure 7 Salivary gland scintigraphy in a patient with Sj€ogren’s disease (left side of the figure) and in a normal individual (right side of the figure). Background corrected time-activity curves for each major salivary gland are shown. Y-axis: Activity in cps. X-axis time in minutes. Lemon juice administration at 1200 s. In the case of SS, both submandibular glands have reduced activity accumulation (parenchymal function) compared to parotids and also reduced response to lemon juice stimulation (excretory function).
The patient is placed in prone position with the arms parallel to the body. A helical scan is performed from above the ears to carina. Image reconstruction is performed using small slice thickness in three planes. In CECT, the contrast agent is injected using bolus tracking and a delay.
Salivary gland scintigraphy Since B€ orner et al., 1965; first introduced 99mTc-pertechnetate for salivary gland scintigraphy; this modality has been used to examine the presence and extent of the oral involvement in SS (Fig. 7) and as follow-up after surgery, radiation therapy and radioiodine therapy. Salivary gland scintigraphy may also be helpful for prediction of the salivary gland function following radiation therapy (Tenhunen et al., 2008). Scintigraphy results correlate with clinical and histopathological features of salivary glands in patients with SS (Daniels et al., 1979; Aung et al., 2001; Tensing et al., 2003; Henriksen & Nossent, 2007; Milic et al., 2009; Vinagre et al., 2009), and are included in the diagnostic study for SS by the European Community Study Group (Vitali et al., 2002). In acute sialoadenitis (of bacterial or viral origin), an increase in radionuclide uptake (hyperactivity) is seen due to hyperaemia and by oedema compressing the intralobar ducts. Scintigraphy cannot be used for differentiation between benign and malignant tumours, nor can it predict the outcome of a surgical procedure.
99m
TcO4- (pertechnetate ion) is distributed similar to Cl in the body and sodium pertechnetate (Na99mTcO4) is used to evaluate salivary gland uptake and function (Fig. 7). 99mTcpertechnetate is accumulated in the lachrymal, salivary and thyroid glands as well as in the gastric mucous membrane and the lactating breast. The method is non-invasive, safe, well tolerated, reproducible and easy to perform. Although this method has been used for almost five decades, there are still no guidelines or consensus on how the procedure should be performed. The lack of consensus about how salivary gland scintigraphy should be performed contributes to difficulties in interpretation and dissemination of the examination, which has made the results less useful for clinicians. The data interpretation is, therefore, qualitative and observer dependent. To refine salivary gland scintigram interpretation and improve the diagnostic accuracy, there has been an increasing interest in quantifying glandular function. A variety of parameters have been proposed over recent decades (Vigh et al., 1997; Loutfi et al., 2003; Shizukuishi et al., 2003; Henriksen & Nossent, 2007; Afzelius & Fuglsang, 2014). Patients are often told to fast and pause smoking (G€ unel et al., 2010) prior to examination. A bolus of 99mTc-sodium pertechnetate is injected intravenously (Becker et al., 1986; Anjos et al., 2006), and dynamic salivary gland scintigraphy is performed to follow accumulation phase of the tracer (Loutfi et al., 2003). A sialagogue is administered to stimulate salivary gland excretion. The excretion and re-accumulation phases are
Figure 8 Co-registered 18F-FDG PET/CT image to the left and 18F-FDG PET to the right, revealing a hypermetabolic mass in the right parotid gland. Both are shown in the axial plane. Biopsy revealed a Warthin’s tumour © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 7
Table 1 Common indications for salivary gland imaging are pain and swelling. If available, US should be preferred as the initial imaging modality.
Function Stone Tumour Infection Sj€ ogren
Sialography
X-ray
++
(+)
Scintigraphy +++
+
(+) +++
MRI
US
CT
+ +++ ++ +
++ + + +
+ ++ ++ +
18
F-FDG
If the result is benign no further examination is required. If the result is malignant, MRI or CECT if MRI cannot be performed, is indicated. FDG PET/CT may be relevant in staging of known malignancy. Not indicated: . Of limited value: (+). Fair: +. Good: ++. Very good: +++.
then followed. A gamma camera with a small field-of-view equipped with a low-energy, high-resolution, parallel-hole collimator is used. The energy window is centred on the 140 keV photo peak of 99mTc. Regions of interests (ROIs) are drawn around parotid and submandibular glands and computer-assisted analysis timeactivity-curves (TACs) for all four salivary glands are generated (Fig. 7). The same applies for background ROIs for subtraction (Aung et al., 2001; Adams et al., 2003; Anjos et al., 2006; Vinagre et al., 2009; G€ unel et al., 2010). Time of administration of the sialogogue is marked on the curves. 18 18
F-FDG positron emission tomography
F-Flurodeoxyglucose (18F-FDG) positron emission tomography (PET) is based on uptake of this glucose analogue in cells having metabolic activity and is combined with CT for an exact anatomical localization (Fig. 8). 18F-FDG is taken up by specific transporters, glucose transporter 1 and 5 (GLUT 1 and GLUT5), of which GLUT1 is over-expressed in salivary gland tumours, but PET cannot, with sufficient certainty differentiate benign from malignant salivary gland tumours (Keyes et al., 1994). As a primary diagnostic tool, its clinical use is limited, but it may have a potential value in staging and restaging of malignant salivary gland tumours (Figs 5 and 8) (Park et al., 2013; Sharma et al., 2013). However, results vary (Jeong et al., 2007; Roh et al., 2007; Razfar et al., 2010; Hadiprodjo et al., 2012; Kim et al., 2012; Sharma et al., 2013). Patients are fasting for at least 6 h before the examination. Blood glucose levels should optimally be
doi: 10.1111/cpf.12199
INVITED REVIEW
Imaging of the major salivary glands Pia Afzelius1, Ming-Yuan Nielsen1, Caroline Ewertsen2 and Klaus Poulsen Bloch1 1
Department of Diagnostic Imaging, North Zealand Hospital, Copenhagen, Denmark, and 2Department of Radiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Summary Correspondence Pia Afzelius, Department of Diagnostic Imaging, North Zealand Hospital, Hillerød, Dyrehavevej 29, DK-3400 Hillerød, Denmark E-mail: [email protected]
Accepted for publication Received 20 June 2014; accepted 18 September 2014
Key words 18
F-FDG positron emission tomography; computed tomography; magnetic resonance imaging; parotid gland; salivary gland scintigraphy; sialography; submandibular gland; ultrasound
The major salivary glands, submandibular, parotid and sublingual glands play an important role in preserving the oral cavity and dental health. Patients with problems of the major salivary glands may present with symptoms such as dry mouth, dysphagia and obstruction of duct, inflammation, severe dental caries or swelling. Imaging plays an important role in visualization of morphology and function, to establish a diagnosis, for treatment, and for surgical planning. There are several options for diagnostic imaging: plain radiography, sialography, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), salivary gland scintigraphy and 18F-FDG positron emission tomography (PET). We present an overview of the modalities in relation to common salivary gland disease.
Introduction The oral cavity is lined with a mucous membrane, which is kept moist by saliva. Saliva protects oral cavity and teeth, and it also facilitates swallowing. The salivary glands produce about one litre of saliva a day. The major salivary glands are the parotid glands, located in front of the ear, the sublingual glands, under the tongue, and the submandibular glands, below the mandible, laterally. In addition, there are several small accessory salivary glands in the oral cavity, paranasal sinuses, larynx and pharynx. The submandibular and sublingual salivary glands constantly produce saliva, while the parotid gland mainly produces saliva in response to meals or by the thought or smell of food. Saliva contains, in addition to mucus and water, enzymes to cleave glycogen, starch and immunoglobulins for defence against infections (Ten Cate’s, 2013). The most common reason for swollen salivary glands is mumps, a viral infection classically affecting the parotid glands. Another reason may be sialolithiasis causing an obstruction of the salivary duct, which may lead to bacterial infection. Frequently, the lymph nodes on the neck will be enlarged and tender. There may be discharge of pus from the infected salivary gland. Untreated infection may lead to impaired or ceased glandular function due to scar tissue. Another cause of swelling may be a tumour. About 70% of
salivary gland tumours arise in the parotid gland. Seventy-five percentage of these are benign. Neoplasms of the salivary glands comprise 3–5% of all head and neck cancers (Laramore et al., 2001) with tumours in the submandibular and sublingual glands having a higher risk of being malignant than tumours in the parotid gland. A tumour in the submandibular or sublingual gland should always be considered malignant until proven benign. The malignant salivary neoplasms are rare, with an overall incidence in the Western world of approximately 25 cases to 30 cases per 100 000 per year (Speight & Barrett, 2002). Cancer of the salivary glands can occur at any age, but is most often seen in people older than 50 years, with almost equal incidence in males and females. The cause of this cancer is unknown, but risk factors may be exposure to ionizing radiation, occupations associated with rubber products manufacturing, asbestos mining, plumbing and some types of woodworking (Scanlon & Sener, 1981; van der Laan et al., 1995; Ellis & Auclair, 1996; Mendenhall et al., 2011). The salivary glands may also be affected in primary Sj€ ogren’s syndrome (SS), which is a chronic progressive autoimmune disease of unknown aetiology. It is characterized by lymphocyte infiltration and the destruction of exocrine glandular tissue, especially in the lachrymal and salivary glands causing xerostomia (Bunim et al., 1964; Johnsson et al., 2005). Secondary SS is associated with other systemic autoimmune
© 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
1
2 Imaging of the major salivary glands, P. Afzelius et al.
diseases, for example rheumatoid arthritis, systemic lupus erythematosus or scleroderma (Bloch et al., 1965). SS is considered the most common autoimmune disease with a prevalence of 3–4% in a cross-sectional population-based study (Thomas et al., 1998). Patients suffering from SS have a 16- to 40-fold increased risk of developing B-cell lymphoma and patients should be monitored annually (Lazarus et al., 2006; Theander et al., 2006). Ionizing radiation from radiotherapy (Teshima et al., 2010) or adjuvant radioiodine therapy for ablation of residual thyroid after surgery in management of differentiated thyroid cancer (Solans et al., 2001) is another reason for transient or permanent salivary gland dysfunction. To cover this wide range of possible diseases, it is important to choose the best imaging modality regarding cost, radiation, accuracy, reliability and patient satisfaction. We present an overview of the most common methods [plain radiography, sialography, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), salivary gland scintigraphy and 18F-FDG positron emission tomography (PET)] in relation to common salivary gland diseases.
Plain radiography Plain radiography is an inexpensive and simple way of studying sialolithiasis in the salivary glands (Fig. 1). As only onefifth of the ductal sialolithiasis are radiolucent this imaging procedure is today, with other techniques at hand, of limited value. Furthermore, phlebolithiasis, hemangiomas with calcifications or calcified lymph nodes may mimic sialolithiasis on plain radiography. Parotid glands can be visualized in anterior–posterior (AP) projection with extended chin, open mouth and cheeks blown out to show Stensen’s duct lesion. The submandibular gland can be visualized in AP and ipsilateral oblique projections with extended chin, open mouth and the tongue pressed down in the floor of the mouth.
Sialography Conventional X-ray sialography is an old technique described by Carpy in 1902 and later used by Barsony et al. in 1925 as a diagnostic tool (Fig. 2). Later CT sialography with cone-beam CT (see below/page), following injection of contrast agent into the ductal system has been introduced. These sialography techniques allow the demonstration of the ducts, ductules and parenchyma of the salivary gland of interest, or a stricture after introduction of a fat-soluble radiopaque contrast agent in their excretory ducts. Irregular pooling of contrast agent and ductal obstruction without the presence of sialolithiasis may be indirect signs of malignancy. Sialography is rarely used for sublingual imaging because numerous, usually 20, small ducts of Rivinus open directly into the floor of the mouth making an overview difficult. Potential complications associated with sialography include rupture of the ductal system, activation of clinically dormant infection and adverse reactions to contrast agent. Ionizing radiation exposure depends on the operator’s technical skills for quick cannulation of the ductal system, which is not always achievable. The examination is contraindicated in acute sialoadenitis and in cases of former allergic reactions to iodine-containing contrast agent. In such cases, surgical removal of possible sialolithiasis or explorative sialoendoscopy (Hasson, 2010) may be preferred. Technical improvements in the non-invasive procedures such as ultrasound and MRI (see below/page) and the lack of radiation exposure to both patients and staff compared to both conventional sialography and CT sialography have in many institutions made them first choice modalities. MRI is expensive and not always available. Conventional X-ray sialography is usually performed using digital subtraction technique after retrograde intracannular injection of a water-soluble, iodinated, contrast agent in the Stensen’s/Wharton’s duct opening. The goal is a fully opacified ductal system. The gland is allowed to empty for about 5 min, and then, a sialogogue may be administered to
Figure 1 Plain radiograph of the angle of the mandible and parotid region in lateral and lateral oblique projections showing two small calculi (arrow) in the left (L) parotid gland. The right side (R) is normal. Same patient as in Fig. 3. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 3
Figure 2 Conventional X-ray sialography of parotid gland showing a calculus (arrows) in the distal part of the duct. Lateral oblique and AP projections.
promote the secretion of saliva and further emptying of the gland. This procedure has the advantage that the position of head can be optimized during examination.
Ultrasound High-resolution US is in many cases the initial imaging modality for assessment of the salivary glands (Gritzmann, 2011; Carotti et al., 2014). Using high frequency (7–15 MHz) probes, US has a high spatial and temporal resolution, and a high accuracy for delineating benign and malignant lesions, especially superficial lesions (Gritzmann, 1989). US is widely available in Europe, can be used for image guided biopsies, and can be performed in the emergency setting and bedside (Oliveras et al., 2014). US has limitations in evaluating structures behind bone, that is behind the mandible and the deep parts of the parotid gland (Gritzmann, 2011).
US has been evaluated in both benign and malignant conditions. In acute inflammation, US is used to look for sialolithiasis or abscesses (Gritzmann, 2011). It is widely known to have a high sensitivity for detecting sialolithiasis (Fig. 3), and has in many institutions replaced sialography. In a study by Gritzmann, 94% of sialolithiasis were detected with US in 174 patients (Gritzmann, 1989). In a more recent study, the sensitivity for sialolithiasis was only 77% in general, but increased to 94% when looking at sialolithiasis larger than 3 mm. Sialolithiasis was present in 44 glands in the study, which caused some debate as the glands were scanned with rather low frequencies (Terraz et al., 2013; Loizides & Gruber, 2014). Therefore, the sensitivity might be closer to 94%. In acute viral infection for instance with mumps, the symptoms are usually bilateral and the glands are enlarged and
Figure 3 US image showing two calculi (left side of the figure indicated by arrows) in the left parotid gland (same patient as in Fig. 1). There is dilation of Stensen’s duct (arrow) proximal to the calculi (right side of the figure). © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
4 Imaging of the major salivary glands, P. Afzelius et al.
more hypo-echoic due to oedema. Increased vascularization using colour Doppler may be seen. In SS, the salivary glands become enlarged and heterogeneous. These changes are more pronounced in the parotid gland than in the submandibular gland (Takagi et al., 2010). US was compared with contrast sialography and scintigraphy in 77 patients with primary SS in one study, and with sialography and histopathology in 73 patients in another study. Both studies concluded that US was a useful diagnostic tool (Salaffi et al., 2008; Obinata et al., 2010). Scoring systems for determining salivary gland changes were evaluated in three other studies in patients with primary SS. All found characteristic changes in SS compatible with their scoring systems (Hocevar et al., 2005; Cornec et al., 2013; Theander & Mandl, 2013). If a tumour is visible, fine needle aspiration cytology (FNAC) or core needle biopsy (CNB) may be performed. CNB was reported to have a higher sensitivity than FNAC in distinguishing benign from malignant and in providing a final diagnosis (Huang et al., 2012). If a tumour is benign on needle biopsy no further imaging is required. If the tumour affects the deep parotid lobe or potentially extends intracranially, MRI or CT is recommended to delineate the tumour as US does not sufficiently do so (Gritzmann, 2011). The higher grade of vascularity in malignant tumours compared to benign can be demonstrated using colour Doppler US. Elastography, which is a method that depicts tissue stiffness, has also been evaluated for parotid lesions. The interobserver agreement and the correlation between disease and elastographic findings were low, but larger studies are needed to determine the value of this new method (Mansour et al., 2012; Celebi & Mahmutoglu, 2013).
Magnetic resonance imaging MRI is important in evaluation of major salivary gland diseases, especially neoplastic diseases. If there is a strong suspicion of malignancy, MRI is the method of choice (Yousem et al., 2000). If the tumour is large (>3 cm) or located in the
(a)
(b)
deep lobe of the parotid gland, US has limitations in demonstrating and delineating the lesions sufficiently, and MRI (or CT when contraindications to MRI exist) should be performed. MRI provides a large variety of soft tissue signal differences, and multiplanar facilities are helpful in delineating the extent of the tumour, whether located in the submandibular, sublingual or parotid gland. Skull base invasion is often well seen by MRI (Freling, 1994). In case of a large malignant tumour and cranial nerve deficit, MRI should be performed to evaluate the local extent of the lesion and to detect perineural tumour spread and intracranial invasion (Yousem et al., 2000; Freling, 2010). Infiltration into the parapharyngeal space, muscles or bone will strongly suggest malignancy (Freling et al., 1992), or less frequently rupture of the capsule of a pleomorphic adenoma (Fig. 4b). If an infiltrative neoplasm is highly suspected, non-contrast enhanced (NCE) and contrast enhanced (CE) MRI may be superior in demonstrating perineural, meningeal and skull base invasion (Yousem et al., 2000). These problems are not possible to outline with US. MR sialography defines the ductal system of the gland of interest without injection of ductal/intravenous contrast agent by means of highly fluid-sensitive sequences similar to those used for magnetic resonance cholangio-pancreatography (MRCP) (Lomas et al., 1996; Erdogan et al., 2013), where the patient’s own saliva is used as contrast agent. MR sialography can be performed in patients with acute sialadenitis. The administration of a sialogogue may improve ductal visualization in MR sialography by increasing salivary secretion. MR sialography has poor spatial resolution compared to conventional sialography (J€ager et al., 2000), but may be an alternative if x-ray sialography cannot be performed (Uddin, 2011). MR sialography requires sufficient production of saliva. Pacemaker, implanted metals, claustrophobia, long acquisition time and the cost are all disadvantages. Advantages are no ionizing radiation and a non-invasive method. An MRI protocol should consist of axial and coronal T1 spin-echo (SE) and T2 SE weighted images (T1WI and T2WI), fat-saturated CE T1WI axial, coronal and sagittal images. Slice thickness should not exceed 3 mm.
(c)
Figure 4 (a) Coronal T1-weighted spin-echo MR image shows the mass (arrow) to be well demarcated in the parotid gland. The mass has an outer contrast-enhancing rim on this CE, T1-weighted spin-echo MRI and a central non-enhancing component, characteristic for pleomorphic adenoma. (b) In the left parotid gland, a mass (Warthin’s tumour indicated by arrow) was seen on coronal T1-weighted spin-echo (before contrast) MRI. The multiplicity and location in the parotid gland (near the lower mandible) are typical features of the tumour. (c) Coronal T2-weighted spin-echo MR image shows a typical cyst (arrow) in the left parotid gland. © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 5
Figure 5 Planocellular carcinoma in left parotid gland (arrow) on MRI (left) and CT (middle). Please note the streak artifacts derived from metallic dental fillings resulting in reduced quality of the CT image, and to lesser extent on MRI. Co-registered 18F-FDG PET and CT (right).
All parotid lesions are well visualized on T1WI because of the hyperintense (fatty) background of the gland (Fig. 4a). The T1WI sequence gives a clear assessment of the margin of the tumour, its depth extent, and its pattern of infiltration (Yousem et al., 2000), whereas fat-saturated CE T1WI is preferred to determine the depth of invasion. Benign and malignant masses exhibit considerable overlap with regard to geographic properties such as margins, shapes and borders (Teresi et al., 1987; Swartz et al., 1989). There is agreement that a hyperintense mass on T2WI is benign (Fig. 4c) and masses of low to moderate signal intensity are malignant (Yousem et al., 2000). Som & Biller (1989) and Sigal et al. (1992) showed a sensitivity of 73% for determination of malignancy with a T2WI. Others have implied that signal intensity on T2WI is useless in determining malignancy (Swartz et al., 1989; Freling et al., 1992). .
Computed tomography CT of the salivary glands is easy, rapid and cheap compared to MRI (Burke et al., 2011), but it involves exposure to ionizing radiation to the head and neck. There are only a few contraindications to contrast enhanced CT (CECT) such as impaired renal function and prior severe allergic reaction to the contrast agent. Artifacts from metal dental fillings often cause diagnostic difficulties (Fig. 5), but iterative correction reduces streak artifacts in the dentoalveolar region (Kondo et al., 2010). Non-contrast enhanced CT (NCECT) can demonstrate sialolithiasis, tissue calcification, gas-formation in the soft tissue, and bony erosion caused by malignant lesions, or infection. Usually, the attenuation of the parotid gland is slightly lower than of the submandibular gland because of a higher content of fat. A decrease in density owing to fatty degenera-
tion can be observed with ageing (Cheng et al., 2011), and also after radioiodine therapy and radiotherapy (Cheng et al., 2011; Nabaa et al., 2012). Cone-beam CT provides a relatively high spatial resolution of high-density structures such as bone, sialolithiasis and contrast agent in sialography with a lower dose of radiation than conventional CT (Miracle & Mukherji, 2009a,b). CECT is useful in acute cases, when MRI is contraindicated, or in cases where the access to MRI is limited. Inflammation in the glands will show as enlarged glands with abnormal attenuation or intensity and clear enhancement. Abscess formation is easily seen on both CECT and MRI. Abscesses can even be seen in the parotid gland on NCECT because of the higher fatty content particularly in ageing (Burke et al., 2011). The inflammatory findings are unspecific and must be held up against the clinical findings, US findings, biopsies and MRI. CECT provides information for staging of salivary gland tumours prior to treatment and when evaluating treatment response. It can assess the intra- and extraglandular location, local extension and invasion into the surrounding tissues; detect regional lymph node metastases and systemic involvement. Dong et al. (2014) have demonstrated significant differences in CT blood perfusion in histologically benign and malignant tumours in the parotid gland. Optimal CT of the salivary glands requires contrast enhanced scan to visualize cysts, abscesses, neoplasms (Fig. 6) and traumatic lesions. Nabaa et al., 2012 have recently demonstrated that routine NCECT screening for recurrence and metastases can also check for possible radiation-induced salivary gland dysfunction by demonstrating altered (decreased) volume and increased attenuation.
Figure 6 NCECT in axial and coronal planes demonstrate a planocellular carcinoma of the left parotid gland (arrows). © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
6 Imaging of the major salivary glands, P. Afzelius et al.
Figure 7 Salivary gland scintigraphy in a patient with Sj€ogren’s disease (left side of the figure) and in a normal individual (right side of the figure). Background corrected time-activity curves for each major salivary gland are shown. Y-axis: Activity in cps. X-axis time in minutes. Lemon juice administration at 1200 s. In the case of SS, both submandibular glands have reduced activity accumulation (parenchymal function) compared to parotids and also reduced response to lemon juice stimulation (excretory function).
The patient is placed in prone position with the arms parallel to the body. A helical scan is performed from above the ears to carina. Image reconstruction is performed using small slice thickness in three planes. In CECT, the contrast agent is injected using bolus tracking and a delay.
Salivary gland scintigraphy Since B€ orner et al., 1965; first introduced 99mTc-pertechnetate for salivary gland scintigraphy; this modality has been used to examine the presence and extent of the oral involvement in SS (Fig. 7) and as follow-up after surgery, radiation therapy and radioiodine therapy. Salivary gland scintigraphy may also be helpful for prediction of the salivary gland function following radiation therapy (Tenhunen et al., 2008). Scintigraphy results correlate with clinical and histopathological features of salivary glands in patients with SS (Daniels et al., 1979; Aung et al., 2001; Tensing et al., 2003; Henriksen & Nossent, 2007; Milic et al., 2009; Vinagre et al., 2009), and are included in the diagnostic study for SS by the European Community Study Group (Vitali et al., 2002). In acute sialoadenitis (of bacterial or viral origin), an increase in radionuclide uptake (hyperactivity) is seen due to hyperaemia and by oedema compressing the intralobar ducts. Scintigraphy cannot be used for differentiation between benign and malignant tumours, nor can it predict the outcome of a surgical procedure.
99m
TcO4- (pertechnetate ion) is distributed similar to Cl in the body and sodium pertechnetate (Na99mTcO4) is used to evaluate salivary gland uptake and function (Fig. 7). 99mTcpertechnetate is accumulated in the lachrymal, salivary and thyroid glands as well as in the gastric mucous membrane and the lactating breast. The method is non-invasive, safe, well tolerated, reproducible and easy to perform. Although this method has been used for almost five decades, there are still no guidelines or consensus on how the procedure should be performed. The lack of consensus about how salivary gland scintigraphy should be performed contributes to difficulties in interpretation and dissemination of the examination, which has made the results less useful for clinicians. The data interpretation is, therefore, qualitative and observer dependent. To refine salivary gland scintigram interpretation and improve the diagnostic accuracy, there has been an increasing interest in quantifying glandular function. A variety of parameters have been proposed over recent decades (Vigh et al., 1997; Loutfi et al., 2003; Shizukuishi et al., 2003; Henriksen & Nossent, 2007; Afzelius & Fuglsang, 2014). Patients are often told to fast and pause smoking (G€ unel et al., 2010) prior to examination. A bolus of 99mTc-sodium pertechnetate is injected intravenously (Becker et al., 1986; Anjos et al., 2006), and dynamic salivary gland scintigraphy is performed to follow accumulation phase of the tracer (Loutfi et al., 2003). A sialagogue is administered to stimulate salivary gland excretion. The excretion and re-accumulation phases are
Figure 8 Co-registered 18F-FDG PET/CT image to the left and 18F-FDG PET to the right, revealing a hypermetabolic mass in the right parotid gland. Both are shown in the axial plane. Biopsy revealed a Warthin’s tumour © 2014 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd
Imaging of the major salivary glands, P. Afzelius et al. 7
Table 1 Common indications for salivary gland imaging are pain and swelling. If available, US should be preferred as the initial imaging modality.
Function Stone Tumour Infection Sj€ ogren
Sialography
X-ray
++
(+)
Scintigraphy +++
+
(+) +++
MRI
US
CT
+ +++ ++ +
++ + + +
+ ++ ++ +
18
F-FDG
If the result is benign no further examination is required. If the result is malignant, MRI or CECT if MRI cannot be performed, is indicated. FDG PET/CT may be relevant in staging of known malignancy. Not indicated: . Of limited value: (+). Fair: +. Good: ++. Very good: +++.
then followed. A gamma camera with a small field-of-view equipped with a low-energy, high-resolution, parallel-hole collimator is used. The energy window is centred on the 140 keV photo peak of 99mTc. Regions of interests (ROIs) are drawn around parotid and submandibular glands and computer-assisted analysis timeactivity-curves (TACs) for all four salivary glands are generated (Fig. 7). The same applies for background ROIs for subtraction (Aung et al., 2001; Adams et al., 2003; Anjos et al., 2006; Vinagre et al., 2009; G€ unel et al., 2010). Time of administration of the sialogogue is marked on the curves. 18 18
F-FDG positron emission tomography
F-Flurodeoxyglucose (18F-FDG) positron emission tomography (PET) is based on uptake of this glucose analogue in cells having metabolic activity and is combined with CT for an exact anatomical localization (Fig. 8). 18F-FDG is taken up by specific transporters, glucose transporter 1 and 5 (GLUT 1 and GLUT5), of which GLUT1 is over-expressed in salivary gland tumours, but PET cannot, with sufficient certainty differentiate benign from malignant salivary gland tumours (Keyes et al., 1994). As a primary diagnostic tool, its clinical use is limited, but it may have a potential value in staging and restaging of malignant salivary gland tumours (Figs 5 and 8) (Park et al., 2013; Sharma et al., 2013). However, results vary (Jeong et al., 2007; Roh et al., 2007; Razfar et al., 2010; Hadiprodjo et al., 2012; Kim et al., 2012; Sharma et al., 2013). Patients are fasting for at least 6 h before the examination. Blood glucose levels should optimally be
