Development and Application of a Technique for Three-Dimensional Sialography

Using Cone Beam Computed Tomography

By

Fatima M. Jadu BDS, MSc

A thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy

Oral Radiology

Graduate Department of Dentistry

University of Toronto

© Copyright by Fatima M. Jadu BDS, MSc 2012 Development and Application of a Technique for Three-Dimensional Sialography

Using Cone Beam Computed Tomography

Fatima M. Jadu BDS, MSc

Doctor of Philosophy

Graduate Department of Dentistry

University of Toronto

2012

ABSTRACT

Introduction: Salivary gland obstructive conditions are common and may necessitate imaging of the glands for diagnosis and management purposes. Many imaging options are available but all have limitations. Sialography is considered the gold standard for examining obstructive conditions of the parotid and submandibular glands but it is largely influenced by the imaging technique to which it is coupled. Cone beam computed tomography (cbCT) is a relatively new and very promising imaging modality that has overcome many of the inherent limitations of other imaging modalities used in the past for sialography. Materials and methods: A RANDO®Man imaging phantom was used to determine the effective radiation doses from the series of plain film images that represent the current standard of practice for sialography. Similar experiments were then undertaken to determine the effective radiation doses from cbCT when varying the field-of-view (FOV) size and center, x-ray tube peak kilovoltage (kVp) and milliamperage

(mA). Next, cbCT image quality, measured using the signal-difference-to-noise-ratio

(SDNR) was used to determine those technical factors that optimized image quality.

ii

Finally, using the optimized image acquisition parameters, a prospective clinical study was conducted to test the diagnostic efficacy of cbCT sialography compared to plain film sialography. Results: Effective radiation doses were comparable between the plain film image series and cbCT examinations of the parotid and submandibular glands when a 6” FOV was chosen, and when the x-ray tube was operating at 80 kVp and 10 mA. We also found that these exposure settings optimized the image SDNR. Finally, we demonstrated that the diagnostic capabilities of cbCT sialography were superior to plain film sialography with regards to detecting sialoliths and strictures, and when differentiating normal salivary glands from those with changes secondary to inflammation. Conclusion: We have successfully developed a three dimensional (3D) sialography technique for imaging the parotid and submandibular salivary glands using cbCT that balances radiation effective dose with image quality. We also demonstrated the superior diagnostic capabilities of the new technique in a clinical setting.

iii

ACKNOWLEDGEMENT

I would like to express my sincere gratitude to my supervisor Dr. EWN Lam for his unwavering support and for trusting me to be his first PhD student.

A special thanks to my research committee members Drs. Pharoah, Yaffe and Jokstad for their constructive criticism and insightful comments.

My sincere thanks also go to Dr. Baghdady, Perschbacher and Petrikowski for kindly volunteering their time and expertise to this project.

To my best friends Susanne and Mariam, thank you for being my personal cheer squad.

I am indebted to the residents in the Oral and Maxillofacial Radiology graduate program for helping with this project, Drs. Alsufyani, Madhavji, Khalifa, Chan, Lukat and Amintavakoli. Thank you for being amazing stimulating students. I especially wish to thank Dr. Madhavji for putting his computer genius to my service.

I am grateful to the support staff in the oral radiology department for always, always helping me out.

Lastly, and most importantly, I wish to thank my husband Ahmed for encouraging me to soar high in the skies of graduate education and research, and my parents who instilled in me the love of knowledge.

I dedicate this PhD to my lovely children Saeed, Yousef and Maryam…I hope this experience was a lesson in the rewards of hard work and dedication.

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TABLE OF CONTENT

Abstract ...... ii

Acknowledgement ...... iv

Table of content ...... v

List of Tables ...... viii

List of Figure ...... ix

List of Appendices ...... xi

1 Introduction ...... 1

1.1 Review of the literature ...... 1

1.1.1 Development of the salivary glands ...... 1

1.1.2 Anatomy of salivary glands ...... 4

1.1.3 Histology of salivary glands ...... 8

1.1.4 Physiology of salivary glands ...... 11

1.1.5 Diseases of salivary glands ...... 15

1.1.6 Imaging of salivary glands ...... 25

1.1.7 Cone beam computed tomography ...... 34

1.2 Summary ...... 41

1.3 Statement of the problem ...... 42

1.4 Aims ...... 42

1.5 Hypotheses ...... 43

1.6 Null hypotheses ...... 43

v

2 A comparative study of the effective radiation doses from cone beam computed tomography and plain radiography for sialography...... 44

2.1 Introduction ...... 44

2.2 Objectives ...... 45

2.3 Null hypotheses ...... 45

2.4 Materials and methods ...... 46

2.5 Results ...... 50

2.6 Discussion ...... 54

3 Optimization of exposure parameters for cone beam computed tomography sialography ...... 62

3.1 Introduction ...... 62

3.2 Objectives ...... 64

3.3 Null hypotheses ...... 65

3.4 Materials and methods ...... 65

3.5 Results ...... 71

3.6 Discussion ...... 75

4 a comparative study of the diagnostic capabilities of 2d plain radiography and 3d cone beam computed tomography for sialography ...... 80

4.1 Introduction ...... 80

4.2 Objectives ...... 82

4.3 Null Hypothesis ...... 82

4.4 Materials and methods ...... 83

4.5 Results ...... 88

vi

4.6 Discussion ...... 97

5 General Discussion ...... 104

5.1 Conclusion ...... 120

5.2 Future directions ...... 122

References ...... 124

Copyright Acknowledgement ...... 135

vii

LIST OF TABLES

Table 1: Summery of functions of saliva...... 14

Table 2: The selected locations for measuring the absorbed radiation dose in the head and neck of the RANDO®Man phantom...... 47

Table 3: Reproducibility of the thermoluminescent dosimeter (TLD) chips measurements...... 53

Table 4: The different combinations of operational parameters that were used for the cbCT scans...... 68

Table 5: The effective radiation doses that were used to calculate the figure-of-merit

(FOM) for the different technique combinations...... 71

Table 6: List of the radiographic features and findings that were reviewed...... 86

Table 7: Radiologic interpretation and identification of features as determined by the reviewers...... 91

Table 8: Overall percent agreement and positive and negative percent agreements for cone beam CT and plain imaging sialography...... 95

viii

LIST OF FIGURE

Figure 1: Photomicrograph of a developing salivary gland...... 3

Figure 2: Diagram of the anatomy of the parotid gland...... 7

Figure 3: Diagram of the anatomy of the submandibular and sublingual glands...... 7

Figure 4: Diagram of the different terminal end pieces found in histologic sections of salivary glands...... 10

Figure 5: Plain films for imaging the major salivary glands...... 31

Figure 6: Ultrasound (US) image of the right parotid gland...... 31

Figure 7: Computed tomography (CT) images of the left submandibular gland...... 32

Figure 8: Magnetic resonance images (MRI) of the left parotid gland...... 32

Figure 9: Lateral skull radiograph of a left submandibular gland sialogram using plain film...... 33

Figure 10: Scintigraphy of the major salivary glands...... 33

Figure 11: Illustration demonstrating the basic principle of cbCT...... 35

Figure 12: Variation of effective radiation dose (E) for the parotid gland...... 51

Figure 13: Variation of effective radiation dose (E) for the submandibular gland...... 52

Figure 14: Sialogram of left submandibular gland...... 61

Figure 15: Photograph (a) and axial cbCT image (b) of the imaging phantom...... 67

Figure 16: Four example cbCT images...... 69

Figure 17: Cone beam CT image showing the regions-of-interest (ROI)...... 69

Figure 18: Variation of pixel signal-difference-to-noise ratio (SDNRp) with different kVp and mA settings...... 72

ix

Figure 19: Variation of pixel signal-difference-to-noise-ratio (SDNRp) relative to iodine concentrations in the phantom...... 73

Figure 20: Calculated figure-of-merit (FOM)...... 74

Figure 21: Plain and cbCT images of a left submandibular gland sialogram...... 98

Figure 22: Plain and cbCT images of a left parotid gland sialogram...... 100

x

LIST OF APPENDICES

Appendix 1: Research ethics board approval letter ...... 136

Appendix 2: Patient consent form ...... 137

xi

1 INTRODUCTION

1.1 REVIEW OF THE LITERATURE

The salivary glands are exocrine glands that play an important role in

maintaining the well-being of the oral cavity through the function of producing

saliva.1 There are three pairs of major salivary glands: parotid, submandibular, and

sublingual.1 These are located outside the oral cavity but have ductal systems that

deliver their salivary secretions into the oral cavity.1 As well, the minor salivary

glands are numerous and scattered throughout the oral submucosa.1

An array of disorders can affect the salivary glands and many require

imaging for the purposes of diagnosis, management, and follow up. The choice of

imaging depends on the clinical presentation and the provisional diagnosis, and

this may include one or more of the following techniques: projection radiography

(i.e. plain imaging), computed tomography (CT), magnetic resonance imaging

(MRI), sialography, and scintigraphy. As well, a variant of CT, cone beam

computed tomography (cbCT), has been recently used to image the salivary

glands.

1.1.1 DEVELOPMENT OF THE SALIVARY GLANDS

The parotid glands are the first of the major salivary glands to develop at

four to six weeks in utero. They are followed by the submandibular glands which

develop late in the sixth week and the sublingual glands which develop at seven

to eight weeks.1,2 The minor salivary glands develop later during the 12th week of

intrauterine life.1,2 Development of all salivary glands follows the same process

1 which starts with a focal thickening of oral epithelium. This epithelium proliferates into the underlying ectomesenchyme forming an epithelial bud.1 Proliferative condensation of the underlying ectomesenchyme around the epithelial bud is a vital step in the development process because it will promote the differentiation of the oral epithelium to glandular epithelium (Figure 1).1 During this time, the epithelial bud remains connected to the surface epithelium via an epithelial cord and undergoes further clefting to form more buds. This process of clefting and continued bud formation is termed branching morphogenesis .1

With time, the epithelial cord undergoes canalization to develop a lumen.

The process of canalization occurs as a result of differential mitotic activity between the outer cell layers of the cord which are rapidly dividing and the more slowly dividing inner cell layers.1,2 Lumen development starts in the distal portion of the cord, then in the proximal portion and finally in the central portion. When luminal development approaches the terminal buds, they subdivide into two cell thick terminal end pieces.1,2 The innermost layer of the terminal end piece differentiates into secretory cells and the outermost layer differentiates into contractile myoepithelial cells.1

The major salivary glands undergo a further developmental step; that of encapsulation with fibroconnective tissue.2 The connective tissue not only surrounds and supports the gland but it also forms the septa between its lobes and lobules, and carries the nerve, vascular, and lymphatic supply to and from the parenchyma of the gland.1,2 Interestingly, encapsulation of the parotid gland occurs after the submandibular and sublingual glands, but before the

2 development of the lymphatic system.2 This discrepancy in timing leads to entrapment of lymph tissue (nodes and channels) in the parotid but not in the submandibular and sublingual glands.2 Approximately ten lymph nodes are usually found in close association with the parotid gland, most of which are found in the superficial lobe.2 These nodes drain the ipsilateral upper and midface skin and the palatine tonsils, and in turn drain into the internal jugular chain of lymph nodes.1

Figure 1: Photomicrograph of a developing salivary gland. The image demonstrates the proliferation of the surface oral epithelium (arrowheads) into the underlying mesenchyme (MES) which, in response, is condensing around it.1 (Copied with permission from Oral Histology: development, structure, and function. Mosby, St. Louis, MO)

3

1.1.2 ANATOMY OF SALIVARY GLANDS

The paired parotid glands are the largest salivary glands, weighing

between 14 and 28 grams each (Figure 2).1,2 The facial nerve (cranial nerve VII)

which exits the skull through the stylomastoid foramen, pierces the posterior

surface of the parotid gland and courses through its parenchyma in an anterior

and inferior direction lateral to the retromandibular vein.2 While still in the

parenchyma of the gland, the nerve then divides into its five terminal branches

(temporal, zygomatic, buccal, mandibular, and cervical).1-3 Traditionally, the

plane of the facial nerve and its five terminal branches marks the anatomic plane

that divides the parotid gland into superficial and deep lobes. Glandular tissue

located lateral to this plane is considered to be part of the superficial lobe and

any glandular tissue medial to the plane is considered to be part of the deep

lobe.2 Som et al believe that this landmark is anatomically incorrect. Rather, they

believe the posterior border of the mandibular ramus to be a more accurate

dividing line.2 Using this definition, the larger superficial lobe of the parotid gland

lies lateral to the mandibular ramus and masseter muscles, anterior and inferior

to the external auditory meatus extending from approximately the zygomatic arch

superiorly to the angle of the mandible inferiorly.2 In contrast, the smaller deep

lobe of the parotid gland lies posterior and medial to the mandibular ramus but

anterior to the styloid process and the carotid sheath.2 Both anatomic landmarks

for dividing the parotid lobes are currently in use.2

The parotid duct (Stensen’s) leaves the anterior border of the superficial

lobe and runs an anterior course that is inferior to the zygomatic arch and

4 superficial to the lateral surface of the masseter muscle.1,3 At the anterior border of the masseter muscle the duct turns sharply medially, pierces the buccal fat pad and buccinator muscle to open into the oral cavity opposite the maxillary second molar.1,3 Stensen’s duct measures approximately 6 mm to 7 mm in length with a lumen caliber of 1 mm to 2 mm.2 Accessory parotid tissue is present in approximately 20% of the population and is usually found anterior to the superficial lobe and superior to Stensen’s duct.2

Parasympathetic innervation of the parotid gland which regulates secretion, is received from the glossopharyngeal nerve (cranial nerve IX) which has a synapse in the otic ganglion and reaches the gland via the auriculotemporal nerve (branch of the mandibular division of the trigeminal nerve, cranial nerve X).1,3 Sympathetic innervation which regulates vasoconstriction, is derived from the sympathetic plexus on the carotid artery.2 Blood supply is provided by branches from the external carotid artery.2,3

The submandibular gland is the second largest salivary gland, weighing between 10 and 15 grams (Figure 3).1 It is divided into two lobes by the posterior free border of the mylohyoid muscle.3 The larger superficial lobe is located in the submandibular triangle between the mylohyoid muscle and the mandibular fossa on the medial aspect of the posterior mandibular body.2,3 The smaller deep lobe, on the other hand, lies superior to the mylohyoid muscle in the posterior floor of the mouth, medial to the mandibular body.3 The submandibular duct (Wharton’s) emerges from the deep lobe and courses anteriorly and superiorly between the sublingual gland laterally and the genioglossus muscle medially to open

5 immediately lateral to the lingual frenum.2,3 Wharton’s duct is approximately 5 mm long with a lumen caliber that ranges between 1 mm and 3 mm.2 The gland receives parasympathetic innervation from the chorda tympani branch of the facial nerve (cranial nerve VII) through the lingual nerve and the submandibular ganglion.2,3 It receives its sympathetic innervation from the sympathetic plexus around the carotid artery like the parotid gland.2,3 Blood supply to the submandibular gland is provided by the external maxillary and lingual arteries.2

The smallest of the major salivary glands is the sublingual weighing approximately 2 to 4 grams (Figure 3).1,2 It is located in the anterior floor of the mouth between the sublingual fossa on the medial aspect of the anterior mandibular body laterally and the genioglossus muscle medially.3 It is separated from the genioglossus muscle by the lingual nerve and Wharton’s duct.2 Saliva is secreted into the oral cavity though a number of ducts (the ducts of Rivinus) that open like pores upwards into the sublingual fold.1-3 Occasionally, these ducts fuse and form Bartholin’s duct which opens into Wharton’s duct.2 Nerve supply to the sublingual gland is identical to the submandibular gland but the blood supply is provided by the sublingual artery.3

The minor salivary glands are many, estimated to be between 600 and

1000 aggregates scattered throughout the oral submucosa with the exception of the anterior hard palate and gingiva.1 They are also found in the submucosa of the paranasal sinuses, pharynx, larynx, trachea, and bronchi.2 Depending on their location, they receive autonomic secretory innervations from several ganglia including the pterygopalatine, otic, and submandibular.2

6

Figure 2: Diagram of the anatomy of the parotid gland. (Copied with permission from Head and Neck Imaging. Elsevier, St. Louis, MO)

Figure 3: Diagram of the anatomy of the submandibular and sublingual glands. (Copied with permission from Head and Neck Imaging. Elsevier, St. Louis, MO)

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1.1.3 HISTOLOGY OF SALIVARY GLANDS

The structure of any salivary gland follows the same general pattern; a

main excretory duct which branches into smaller lobar ducts, even smaller

interlobular ducts, and finally intralobular ducts.4 The intralobular ducts consist of

the larger striated ducts and the smaller intercalated ducts.1 The lumen of

intercalated ducts is continuous with the blind terminal secretory end pieces or

acini which are either spherical (serous) or tubular (mucous) in shape.1

Surrounding the terminal end pieces and intercalated ducts are contractile

myoepithelial cells.1 These cells are stellate in shape around the acini to help

expel saliva from the acini and fusiform in shape around the ducts to help

maintain the patency of the duct lumens.1 Myoepithelial cells are also believed to

have other functions such as producing antiangiogenic factors and proteins with

tumour suppressor activity.1 The basic histologic structure of a salivary gland is

presented in Figure 4.

For all salivary glands, the main excretory duct is lined with epithelium that

ranges from stratified squamous near the oral cavity to pseudostratified columnar

near the lobar ducts with scattered mucous (goblet) cells.1 The lobar ducts are

lined with epithelium that ranges from high columnar to stratified cuboidal while

interlobular ducts are lined with high columnar epithelium.4

The intralobular ducts and terminal end pieces differ for each salivary

gland. The terminal end pieces of the parotid glands are all spherical and of the

serous type.1 This type of acinus is made up of pyramidal cells that have

spherical basal nuclei, abundant secretory granules, and surround small central

8 lumens (Figure 4).1 Intercalated ducts are numerous and long in the parotid glands and they are lined with cuboidal epithelium with round central nuclei and sparse cytoplasm.1 Striated ducts, however, are lined with columnar epithelium with centrally located nuclei.1

In the submandibular glands, most of the terminal end pieces are serous, like the parotid gland.1,2 The remainder of the terminal end pieces are mixed units with mucous tubules capped by serous demilunes (Figure 4).1 In comparison to serous acini, mucous tubules have larger lumens surrounded by pyramidal cells with flat basal nuclei (Figure 4).1 Serous demilunes are similar in structure to serous acini but they empty their secretions into small intercellular canaliculi that form finger like projections between the cells of the mucous tubule

(Figure 4).1 The submandibular intercalated and striated ducts are structurally similar but less numerous than those found in the parotid gland.1

The sublingual gland, like the submandibular gland, is considered a mixed gland with regard to its terminal end pieces because it is made up of mucous tubules (these are the most abundant) and mucous tubules capped with serous demilunes.1 Serous acini are rare in the sublingual gland.1 Both intercalated and striated ducts are fewer and shorter than in the parotid and submandibular glands.1

The minor salivary glands are made up of predominantly mucous terminal end pieces, few of which are capped with serous demilunes.1 The exception to this rule are the minor salivary glands found in the troughs around the circumvallate papillae on the dorsum of the tongue and the foliate papillae on the

9

sides of the tongue. These are made-up of purely serous acini.1 The ducts of

minor salivary glands are generally less well developed than those of the major

salivary glands.1

Figure 4: Diagram of the different terminal end pieces found in histologic sections of salivary glands.

(Copied with permission from Head and Neck Imaging. Elsevier, St. Louis, MO)

10

1.1.4 PHYSIOLOGY OF SALIVARY GLANDS

The main function of salivary glands, both major and minor, is to produce

saliva.1 However, the contribution and composition of saliva differs between

glands.

Parotid glands are the largest salivary glands and therefore they produce

a significant amount of the total saliva volume (approximately 45% or 450 to 675

mL/day).2 Their secretion is mostly serous, rich in amylase and glycoproteins.1

Submandibular glands are the second largest salivary glands and they also

secrete approximately 45% of the total saliva volume. Submandibular gland

secretions are more mucinous in nature due to some of their terminal end pieces

being mucous tubules with serous demilunes.1,2 Sublingual glands contribute 5%

of the total saliva volume (50 to 75 mL/day) and secrete saliva that is more

viscous because most of their terminal end pieces are mucous tubules. Minor

salivary glands also contribute about 5% of the total saliva volume but their saliva

is purely mucinous and rich in secretory immunoglobulin A (IgA).1,2 A minority of

minor salivary glands, as mentioned earlier, are made up of serous acini and

secrete serous saliva.1 Therefore, the saliva found in the oral cavity is termed

mixed or whole saliva because it is composed of differing amounts of all these

saliva types plus desquamated oral epithelial cells, microorganisms and their

products, serum components and inflammatory cells.1

Production of saliva takes place in the acini. This primary saliva is isotonic,

high in sodium and low in potassium.2 Saliva then undergoes modification in the

striated ducts where sodium is reabsorbed and potassium is excreted, making it

11 hypotonic.1,2 Saliva is predominantly made up of water (99.5%) with a specific gravity of 1.002 to 1.012.2 The production of saliva, especially from the major salivary glands, is under the control of the autonomic nervous system and is prompted by stimulation.4 Therefore, more saliva is produced during the day when there is more chemical, mechanical, and olfactory stimulation with a total of approximately 1 to 1.5 L of saliva produced in 24 hours.1

Saliva has many functions (Table 1).1 It protects the oral tissues by mechanically washing away nonadherent bacteria and other debris, and its mucin content forms a barrier that protects the delicate oral mucosa from microbial and mechanical trauma.1 Saliva also has buffering capabilities. It contains ions such as bicarbonate and phosphate that neutralize the acids produced by cariogenic bacteria, and protects the enamel from demineralization.1

Saliva also contains urea and ammonia, byproducts of bacteria in the oral cavity, both of which contribute to increasing the pH in the oral cavity and creating an environment unfavorable for cariogenic bacteria to grow.1

The major immunoglobulin in saliva is secretory IgA which prevents certain pathologic bacteria from adhering to the oral tissues by causing them to agglutinate.1 Several proteins in saliva exhibit antimicrobial properties.1

Lyzoymes and peroxidases are two examples of salivary proteins with antibacterial properties that prevent the growth of cariogenic bacteria.5 Histatins are another example of salivary antimicrobials but they are potent antifungals that restrict the growth of opportunistic fungal infections.5 Saliva also plays a major role in the post-eruption maturation of the crystalline structure of enamel

12 because it contains vital ions such as calcium, phosphorus, and fluoride that diffuse into the enamel structure rendering it harder and more resistant to demineralization.1 The process of ion diffusion from saliva to the structure of enamel also allows the remineralization of early caries lesions.1

Dissolving food substances and presenting them to the taste receptors on taste buds is another function of saliva.1 Saliva also plays a role in maintaining the healthy well-being of taste buds.1 For digestion, saliva’s water and mucin content help form the food bolus.1 Saliva also contains amylase and lipase which start the process of digesting starches and triglycerides respectively.1 Although not yet confirmed, the growth factors and trefoil proteins present in saliva are believed to play a role in hastening clot formation and in advancing wound repair.1

13

Table 1: Summary of functions of saliva.1,5

Function Effect Active substance

Mechanical washing Water Protection Barrier Mucin

Neutralize acids Bicarbonate and phosphate Buffering Increase the pH Urea and ammonia

Barrier Mucin

Antibodies Secretory IgA Antimicrobial Antibacterial Lysozyme, peroxidase

Antifungal Histatin

Enamel maturation Calcium, phosphate Tooth integrity Enamel remineralization Fluoride

Dissolve substances Water, lipocalins

Taste Maintain taste buds Epidermal growth factor,

carbonic anhydrase VI

Form food bolus Water, mucin Digestion Digest starch and triglycerides Amylase, lipase

Promote wound healing and clot Growth factors Tissue repair formation Trefoil proteins

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1.1.5 DISEASES OF SALIVARY GLANDS

Pathologic conditions of the salivary glands are many but they are broadly

categorized into inflammatory conditions, non-inflammatory conditions, and

space occupying masses.6 Inflammatory conditions are the most common

abnormalities to affect the salivary glands, and may involve the parenchyma of

the gland (sialadenitis),or the ductal structures (sialodochitis), or both.6 An array

of causes result in inflammation of the salivary glands but infections (bacterial or

viral) are the most common cause of acute inflammation.1,2 Bacterial infections of

the salivary glands are more often than not the result of a retrograde infection

from the oral cavity by one of the following organisms: Staphylococcus aureus,

Streptococcus viridans, Streptococcus pneumoniae, Haemophilus influenzae,

Streptococcus pyogenes, and Escherichia coli.2 Retrograde infections are the

direct result of a decrease in salivary flow which is a serious consequence of

many conditions including dehydration, bulimia, salivary gland obstruction,

therapeutic radiation to the head and neck, certain systemic diseases (diabetes

mellitus, Sjögren syndrome) and some medications (diuretics, antihypertensives,

antidepressants).2 These infections more commonly involve the parotid glands

because Stensen’s duct orifice is larger than Wharton’s duct orifice, and the

saliva produced by the parotid glands is more serous in nature as opposed to the

more viscous mucinous saliva produced by the submandibular and sublingual

glands. Mucin rich saliva contains antibacterial substances such as IgA

antibodies and lysosomes that agglutinate bacteria and prevent their adherence

to the epithelial cells of the ducts.1 The typical clinical presentation of acute

15 inflammation due to bacterial infection is tender swelling of the infected salivary gland, swelling of the adjacent lymph nodes, and pus at the orifice of the gland.2

Treatment of choice is antibiotics but caution must be exercised because inadequate or delayed treatment may result in formation of intraglandular abscesses which may requires more extensive management and surgical drainage.2

Many viral agents can infect the salivary glands but mumps is by far the most common.2 It is considered the most common condition to affect the salivary glands in children.7-9 Mumps is caused by a ribonucleic acid (RNA) virus of the paramyxovirus group that usually affects the parotid glands bilaterally although the submandibular and sublingual glands may be infected as well.2 Mumps produces acute painful swelling of the infected glands and some cases of mumps may be preceded by a prodromal period of general malaise.2 Some cases of mumps may be subclinical, and a few cases may develop complications such as thyroiditis.2 Viral infections generally are self-limiting and their management is supportive rather than curative.

Obstruction is not only the most common cause of chronic inflammation of the salivary glands but is also the most common condition to affect them.7,9

Obstruction affects nearly 1% of the general population with a peak incidence during the fourth to sixth decade of life.7-9 Primary causes of obstruction include sialoliths, ductal strictures, and mucous plugs. In contrast, secondary causes of obstruction include trauma to the ductal structures and space occupying masses that impinge on the ductal system. Sialoliths are the most common cause of

16 salivary gland obstruction, accounting for approximately 66% to 73% of all cases of obstruction.7,9 The mechanism of sialolith development is not fully understood but is thought to start by the presence of an intraductal inorganic nidus, on which layers of organic (carbohydrates and amino acids) and inorganic substances

(calcium phosphate, ammonium, carbonate) from the saliva are deposited.2,10

Even though sialoliths can affect both the major and minor salivary glands they are most common in the submandibular glands.2 This is due to several factors; the narrower orifice of Wharton’s compared to Stensen’s duct, the upward sloping of Wharton’s duct, and the thicker mucinous saliva produced by the submandibular glands.2 Additionally, the saliva produced by the submandibular glands is rich in hydroxyapatite and phosphate and has a higher pH which helps facilitate their precipitation around the nidus.2 Management of sialoliths depends on many factors including their number, location, and the effects they have exerted on the gland structure. It ranges from non-invasive, radiologically guided basket retrieval of the stone to complete excision of the gland and its ductal systems.2,11 Lithotripsy of sialoliths was attempted in the early 1990s but the results were variably successful and therefore this modality is no longer considered a management option.2

Non-inflammatory conditions of the salivary glands include any non- inflammatory, non-neoplastic condition of the salivary glands.6 Most of these conditions result in secretory abnormalities, namely xerostomia.12 Xerostomia is the subjective feeling of dry mouth that results from a decrease in the quantity of saliva.13 It is believed to affect between 17% and 29% of the population with a

17 female predilection.13 The three most common causes of xerostomia are medications, Sjögren syndrome, external beam radiation therapy to the head and neck and radioactive iodine treatment.13 The classes of medications that induce xerostomia as a side effect is extensive and includes antihypertensives, antidepressants, diuretics, and antihistamines, to name a few.13 Patients with xerostomia usually complain of a burning sensation or soreness in the mouth, loss or altered taste, and difficulty swallowing.13 Upon intraoral examination, the oral tissues are found to be erythematous, the tongue fissured, and the salivary glands difficult to milk.13 An increased incidence of cervical caries and candidiasis (caused by the opportunistic fungus Candida albicans) are also noted.13 Objectively, the diagnosis of xerostomia is made if the amount of unstimulated whole saliva collected in 15 minutes is less than 1.5mL or the amount of stimulated whole saliva collected in one minute is less than 0.1 mL.13

Normal flow rates for unstimulated whole saliva range between 0.3 and 0.5 mL/minute and for stimulated whole saliva the range is 1 to 2 mL/minute.14

Salivary gland scintigraphy has also been used to assess salivary gland function and to confirm the diagnosis of xerostomia based on a delayed uptake, reduced concentration, and/or delayed excretion of the intravenously injected radiopharmaceutical technetium-99m (99mTc) pertechnetate (TPT).2,13

Scintigraphy of the salivary glands will be discussed in detail in the next section on salivary gland imaging. Management of xerostomia involves managing the underlying cause and alleviating the patient’s symptoms.13 If the cause of xerostomia is drug induced then an alternate drug may be recommended or the

18 drug dose may be modified.13 Parasympathomimetic drugs such as pilocarpine hydrochloride have effectively been shown to stimulate salivary secretion in patients with xerostomia caused by Sjögren syndrome and radiation therapy to the head and neck.13 Palliative measures to manage xerostomia include frequent sipping of water and the use of saliva substitutes which are available commercially in a multitude of formulas such as chewing gum and mouth rinses.13 To prevent the complication of dental caries, patients with xerostomia must adhere to a rigorous oral hygiene program, restrict their dietary intake of sugar, and apply topical fluoride at regular intervals.13 Candidiasis in xerostomic patients is managed with oral or systemic antifungals.13

Three conditions of the salivary glands, sialadenosis, Sjögren syndrome, and post-irradiation sialadenitis are of particular interest to us because patients with these conditions are often referred for sialography. Sialadenosis, also known as sialosis, is a non-inflammatory, non-neoplastic, non-tender, chronic or recurrent enlargement of primarily the parotid glands.6 The condition may present itself in other major salivary glands and is usually bilateral in distribution.2 A variety of endocrine diseases, especially diabetes mellitus, can cause sialadenosis, and parotid enlargement is sometimes the first presentation of the underlying disease.2 Sialadenosis is associated with a number of nutritional abnormalities but most commonly it is associated with chronic alcoholism and alcoholic cirrhosis.2 Some medications cause sialadenosis including non- steroidal anti-inflammatory drugs (NSAID) and certain antibiotics.2 The enlargement noted in sialadenosis is due to hypertrophy of the salivary gland

19 acini, and this may result in xerostomia. The xerostomia can resolve completely if the underlying cause is managed before fatty atrophy of the gland parenchyma has taken place.2 As such, imaging the enlarged gland with CT or MRI reveals nonspecific enlargement with fibrous or fatty changes, depending on the stage of the condition.2 In contrast, sialographic changes noted in sialadenosis are specific and significantly different from those found in cases of sialadenitis and

Sjögren syndrome and allow a definitive interpretation to be made confidently.2

These sialographic changes of sialadenosis are a normal ductal system that may be slightly splayed due to glandular enlargement and normal parenchymal blush.2

Sjögren syndrome is the second most common systemic autoimmune condition after rheumatoid arthritis.2 It is a disease of the exocrine glands that primarily affects the salivary and lacrimal glands and predominantly affects females (90% to 95% of patients diagnosed with the syndrome are females between the fourth and sixth decade of life).2 There are two forms of the syndrome, a primary form that occurs alone (also known as sicca syndrome) and a secondary form that is associated with other autoimmune connective tissue diseases.2 The most common of the connective tissue diseases to be associated with Sjögren syndrome is rheumatoid arthritis but others including systemic lupus erythematosus (SLE), progressive systemic sclerosis, and polymyositis may also occur.2 Histopathologically, Sjögren syndrome is characterized by a periductal

CD4-positive T-lymphocytic infiltrate that destroys the acini of the exocrine glands and reduces their secretion resulting in dryness.2 The lymphocytic

20 infiltrate may form localized solid or cystic masses in the parenchyma of major salivary glands that are known as benign lymphoepithelial lesions (BLEL).2 It must be noted, however, that BLEL can occur in the major salivary glands independent of the autoimmune condition.2 The criteria for diagnosing Sjögren syndrome are:

1. Clinical symptoms of dry mouth (xerostomia) and these were discussed

earlier.2

2. Clinical symptoms of dry eyes (xerophthalmia).2 Patients with xerophthalmia

usually complain of dry eyes, grittiness in the eyes, or the need to frequently

use ocular lubricants.2

3. Clinical signs of xerostomia.2 Confirmation of xerostomia was discussed

earlier but for Sjögren syndrome specifically, one must add the

pathognomonic sialographic changes of homogenous collections of contrast

material distributed throughout the parenchyma without evidence of

obstruction.2,6

4. Clinical signs of xerophthalmia. Objective tests for xerophthalmia include the

Schirmer's test without anesthesia (considered positive if <5 mm of tears are

collected in 5 minutes) and the Rose Bengal score (considered positive if the

stain intensity score is >4 according to van Bijsterveld's scoring system).2

5. Elevated levels of autoantibodies in the serum. Specifically antibodies

against the sicca syndrome A (SS-A)/RO and sicca syndrome B (SS-B)/LA

antigens because these are elevated in the serum of 80% of patients with

Sjögren syndrome and their absence excludes the diagnosis.2 These

21

antigens have two names (for example SS-A and RO) because they were

discovered by different researchers at different times but then they were

found to be immunologically identical (RO and LA represent the initials of the

first patients in which these antigens were discovered).15

6. Histologic evidence of lymphocytic infiltrate in a salivary gland (at least 2

lymphocytic foci, each with more than 50 lymphocytes per 4 mm2).2 This can

be obtained from an excisional biopsy of a labial minor salivary gland or an

incisional biopsy of the parotid gland.2

The diagnosis of primary Sjögren syndrome is based on the presence of four of the six above listed criteria, or three of the objective criteria listed from 3 to 6.

Secondary Sjögren syndrome is diagnosed in the presence of another autoimmune condition plus one subjective criterion (items 1 and 2) and two objective criteria (items 3 through 6).

Post-irradiation sialadenitis is inflammation of the salivary glands following external beam radiation therapy to the head and neck or radioactive iodine 131

(131I) treatment.16 External beam radiotherapy to the head and neck is used to manage patients with cancers of the oral cavity and pharynx. Patients usually receive 60 to 70 Gray (Gy) in increments of 2 Gy over 6-7 weeks. The radiation results in an inflammatory reaction in the salivary glands that impinges on the ductal structures causing them to obstruct and the gland to swell.16,17 The glandular swelling is often painful and bilateral, and most evident in the parotid glands because they are the most radiosensitive of the salivary glands.2 A decrease in the quantity of saliva ensues due to acinar cell death.16,18 This is

22 followed by alterations in the quality of saliva so that it contains more proteins and electrolytes and less amylase.16,18 Ultimately, the salivary glands undergo atrophy and fibrosis and the loss of salivary flow becomes permanent. Therefore, every effort is made during treatment planning to reduce the total radiation dose to the parotid glands and/or reduce the volume of parotid tissue irradiated. If the parotid glands receive a total dose that is less than their tolerance dose of 25 to

30 Gy, then the damaged acinar cells are likely to be replaced and salivary flow is likely to be restored.19 This reparative process is gradual and may take up to two years.19 On the other hands, if parts of the parotid glands are removed from the treatment field or are shielded and spared the tumouricidal dose, then these parts undergo hyperplasia and an increase in salivary flow is noted approximately six to twelve months following radiation treatment.2

Radioactive iodine 131 is an effective treatment for some thyroid abnormalities because it is efficiently absorbed and concentrated by thyroid cells.20,21 Unfortunately, 131I is also absorbed by salivary gland parenchymal cells and secreted in saliva.20 The disease mechanism for 131I induced sialadenitis is similar to that of external beam radiotherapy induced sialadenitis and involves an inflammatory reaction that causes obstruction and painful swelling of primarily the parotid glands.20 The parotid glands are most sensitive because they are made up primarily of serous cells that concentrate 131I better than the mucous cells that are found in other salivary glands.21 A dose-dependent decrease in salivary flow rate is seen in 69% of patients who receive 100 to 200 mCi of 131I.20 Initially, 131I induced sialadenitis was thought to be a transient condition but more evidence is

23 emerging to support the progressive nature of this condition that leads to fibrosis and atrophy of the salivary glands.18 A sialogram performed in the early stages after irradiation demonstrates areas of parenchymal fill voids where atrophy of the acini has started to occur.2 In later stages, sialograms are not helpful because infusion of a completely fibrotic gland with contrast material is exceedingly difficult. Salivary gland scintigraphy findings also vary depending on the time lapse from treatment.18 Early findings of scintigraphy include normal uptake of TPT but delayed excretion and in later stages even the uptake of TPT is delayed.18 Advanced imaging of the major salivary glands with CT or MRI reveals small and dense fibrotic glands.2

Space occupying masses of the salivary glands can be subdivided into cystic and neoplastic processes.6 Cysts of the salivary glands are rare accounting for less than 5% of all salivary gland masses. They may be subdivided into developmental (branchial, lymphoepithelial, dermoid) and acquired (sialocysts and AIDS related parotid cysts).2,6 Salivary gland tumours are uncommon and represent less than 3% of all head and neck tumours.2,6 Most tumours that affect the salivary glands are benign or low grade malignancies.6

They most commonly affect the parotid glands (80%) followed by the minor salivary glands (10% to 15%), the submandibular glands (5%), and finally the sublingual glands (1%).6 Fortunately, the likelihood of a benign tumour affecting the salivary glands is directly related to the size of the gland; larger glands are more likely to have benign tumours.6 As such, only 20% of tumours that affect the parotid glands are malignant. This percentage jumps to 50% to 60% for the

24

submandibular glands, 60% to 75% for the minor salivary glands, and 90% for

the sublingual glands.6 Pleomorphic adenoma is by far the most common type of

tumour to affect both the major and minor salivary glands (75% of all salivary

gland tumours).6 It arises from the ductal epithelium and contains both epithelial

and mesenchymal components hence it is also termed a benign mixed tumour.6

The most common malignant salivary gland tumour is mucoepidermoid

carcinoma which accounts for approximately 30% of all salivary gland tumours.6

1.1.6 IMAGING OF SALIVARY GLANDS

Diagnostic imaging plays an important role in the management of patients

presenting with signs and symptoms related to the major salivary glands.

Imaging may be useful in assessing the nature of the abnormality, the extent of

involvement, the effects on the adjacent anatomic structures, and possibly, the

causes.

The major salivary glands can be imaged using one or more of the

following techniques: projection radiography (i.e. plain imaging), ultrasound (US),

computed tomography (CT), magnetic resonance imaging (MRI), sialography,

and scintigraphy. Plain films (Figure 5) whether intraoral such as occlusal

radiographs, or extraoral such as panoramic radiographs provide a relatively

quick and inexpensive way to demonstrate calcified sialoliths.2,6 The clinical

applicability of projection radiography, however, is limited because only

moderately sized and fairly dense calcifications can be identified.2

25

Ultrasound (Figure 6) like plain film is widely available and is a relatively safe imaging technique because it does not utilize ionizing radiation.2,6 It is primarily used to guide biopsies, differentiate solid from cystic masses in the superficial portions of the parotid and submandibular glands, and guide choices for further imaging.2,6,22 Recent advances in technology have allowed US to be more specific in interpreting relatively common salivary gland conditions such as

Sjögren syndrome.2 However, its diagnostic accuracy with regards to identifying sialoliths is still low.2,6 The major shortcoming of US is its inability to penetrate deep tissues.2

Computed tomography (Figure 7) is an excellent imaging modality for evaluating the major salivary glands especially when intravenous contrast is administered.6 It is regarded by many as the modality of choice for imaging inflammatory conditions of these glands.2 Computed tomography also has a sensitivity of nearly 100% for detecting masses in the major salivary glands.2

Unfortunately, CT alone cannot differentiate benign from malignant masses because benign masses have capsules that give them a smooth well-defined contour when imaged and low grade malignancies have pseudocapsules that can also give them a smooth well-defined outline.2 Fortunately, when CT findings are combined with clinical findings, the distinction between benign and malignant masses can be made in 90% of cases.2 With regard to obstructive conditions, CT demonstrates large calcified sialoliths with great sensitivity but fails to demonstrate small and non-calcified ones and it fails to show the ductal changes that result from chronic obstruction.2

26

Magnetic resonance imaging (Figure 8) has several advantages over CT.

MRI does not use ionizing radiation, eliminates streak artifacts from dental restorative material, and is better able to differentiate benign from malignant masses because of its superior soft tissue contrast resolution.2,6 Malignancies of the salivary glands for example are more cellular and dense than benign lesions, and thus have low to intermediate signal intensities on all MRI sequences.2 In contrast, benign masses have a higher water content and thus a lower T1 signal

2 intensity and a higher T2 signal intensity. Signal changes in T1 and T2 weighted

MR images are also helpful in cases of inflammation because they reflect the degree of edema versus infiltration by inflammatory cells.2 Magnetic resonance imaging, however, is not the imaging modality of choice for obstructive conditions of the salivary glands because of its low spatial resolution, long acquisition time, and the signal voids that are associated with calcified structures such as sialoliths.2,22

Sialography (Figure 9) is a functional examination of the parotid and submandibular salivary glands that was first performed in 1902.6 It depicts the delicate ductal structures of the salivary glands following the introduction of an iodinated contrast agent through the orifice of the gland duct.6 The gland is then imaged with ionizing radiation (plain film, CT, fluoroscopy).6 This examination is not used for the sublingual or minor salivary glands although sometimes the sublingual gland is incidentally filled during examinations of the submandibular gland.6 When appropriately performed, the contrast material fills the ductal system of the gland giving it an appearance that is similar to that of a branching

27 tree.6 If acinar fill is also achieved, then the tree is said to come into bloom and the appearance is called parenchymal blush.6 Five minutes following the procedure, the gland is re-imaged to assess for retention of the contrast material.6 If the contrast material is not completely cleared from the gland it is indirectly inferred that gland function is reduced and another image at the ten minute time point may be indicated. The procedure is indicated in cases of suspected salivary gland obstruction to evaluate the cause and location of the obstruction and to assess the extent and severity of the resultant changes to the gland.2,6 Rarely, the procedure is used to dilate mild ductal strictures.6

Contraindications of the procedure include active infection of the gland in question because the minimally invasive nature of the procedure may introduce the infectious agent further into the gland.6 The procedure is also contraindicated in cases of acute inflammation because of the associate pain which becomes more intense with injection of the contrast material.6 Other contraindications include an allergy to iodine compounds and an immediately anticipated thyroid function test because some of the iodine in the contrast agent is taken up by the thyroid gland and this may interfere with the results of the test.6 Sialography can also be combined with MRI, A combination that not only eliminates ionizing radiation but also the need for injecting a contrast material into the salivary gland ducts. MR sialography involves giving the patient a secretogogue and then utilizing the patient’s own saliva as a contrast agent. The patient is then imaged using one of many suggested protocols that generally include heavily weighted

2 T2 images and a surface coil. Although the procedure is painless and

28 noninvasive because it eliminates the need for catheterization, it is time consuming and usually complicated by patient movement and swallowing which make producing clinically useful images difficult.2 Therefore, MR sialography is no longer routinely performed.2

Scintigraphy (Figure 10) is also a functional examination of the major salivary glands with the added advantage of being able to examine all the major salivary glands at once.2,6 Unlike the previously mentioned imaging techniques, scintigraphy is a radiologic examination that does not examine the morphologic anatomy but rather the physiologic function of a tissue or organ.6 Scintigraphy is also known as radionuclide imaging because it uses a radioactive molecule that emits gamma rays.6 When injected intravenously, the radiopharmaceutical distributes in the body and is selectively concentrated by certain tissues.2 Then when it starts to decay, a solid state scintillation camera is used to detect gamma emissions.6 Glandular tissues including the thyroid and salivary glands uptake, concentrate, and excrete the radiopharmaceutical technetium-99m (99mTc) pertechnetate (TPT).6 Technetium-99m (99mTc) is a metastable isotope of technetium with a short half-life of 6 hours, and pertechnetate is the water soluble ion that carries and distributes it in the body. In the salivary glands the concentration of TPT reaches a maximum at about 30 to 45 minutes.6 A sialogog

(lemon juice) is then administered to assess the excretory function of the glands.6

Lesions are identified through either an increased, decreased or absent uptake and excretion of TPT.6 Certain salivary gland tumours, namely Warthin’s tumours and oncocytomas characteristically concentrate TPT.2,6 Scintigraphy of the

29 salivary glands like all other nuclear medicine imaging studies has high sensitivity but low specificity which in addition to its low resolution limits its clinical applicability.6

30

B

A

Figure 5: Plain films for imaging the major salivary glands. Panoramic radiograph (A) and asymmetric mandibular occlusal radiograph (B) of the same patient demonstrating a large calcified sialolith in the right submandibular gland duct. Both images can be used to detect calcified sialoliths and to assess the surrounding osseous structures.

Figure 6: Ultrasound (US) image of the right parotid gland. The image demonstrates a solid mass in the superficial lobe of the gland.6 (Copied with permission from Oral Radiology: Principles and Interpretation

Mosby/Elsevier, St. Louis, MO)

31

A B

Figure 7: Computed tomography (CT) images of the left submandibular gland. Soft tissue algorithm axial CT images at the level of the mandible (A) and at the level of the submandibular region (B) demonstrating a well-defined, expansile lesion within the gland with an internal homogeneous low attenuation.

A B

Figure 8: Magnetic resonance images (MRI) of the left parotid gland.

Axial T1 weighted MR image (A) and T2 weighted MR image (B) of the left parotid gland demonstrating a mass in the tail of the gland. The mass has a low T1 signal and a higher T2 signal which is suggestive of a benign neoplasm.

32

Figure 9: Lateral skull radiograph of a left submandibular gland sialogram using plain film.

Figure 10: Scintigraphy of the major salivary glands. Right and left oblique views demonstrate an increased uptake of technetium-99m (99mTc) pertechnetate (TPT) by the right parotid gland (arrowhead) which is highly suggestive of a Warthin’s tumour or an oncocytoma.6 (Copied with permission from Oral Radiology: Principles and Interpretation

Mosby/Elsevier, St. Louis, MO)

33

1.1.7 CONE BEAM COMPUTED TOMOGRAPHY

Cone beam computed tomography (cbCT) was first developed in 1982 for

angiography.8 It was introduced in 1998 for maxillofacial imaging and since that

time, has found many dental applications.8,23 The technology generates a cone

shaped x-ray beam, and hence the name. The x-ray beam is emitted from a

source that is rigidly connected to a two dimensional (2D) detector both of which

are mounted on a rotating gantry that revolves around the patient’s head 360°

during a single scan.8,24 Based on the type of detector, cbCT units are classified

into those that use an image intensifier tube (IIT) charged coupled device (CCD)

combination and those that use a flat panel imager (FPI).24

1.1.7.1 Principle

During image acquisition, multiple x-ray exposures are made at fixed

intervals around the patient.8 The photons recorded by the detector after each

exposure constitute the “raw data” that is fed into a computer algorithm to

produce a single cross sectional projection image (basis image) made up of

picture elements (pixels).8 Each pixel is assigned a grey shade value that

corresponds to the linear attenuation coefficient of the tissue it represents.8 At

the end of a scan, between 150 and 599 basis images are produced, offset from

one another by an angle depending on the location of the x-ray source and

detector. Together these images form multiple sequential projection images

known as the “projection data”.8,23,24 The projection data are fed into

sophisticated viewing software programs to generate a three dimensional (3D)

34 volumetric data set (primary reconstruction) which can be viewed in its entirety from any angle.23,24 The volumetric data set can also be reconstructed into the three orthogonal planes (axial, coronal, sagittal) (secondary reconstruction).23,24

Scan times range between five and forty seconds depending on the cbCT unit used and the protocol setting chosen.23

Figure 11: Illustration demonstrating the basic principle of cbCT. (Copied with permission from Oral Radiology: Principles and Interpretation

Mosby/Elsevier, St. Louis, MO)

1.1.7.2 Image acquisition

Many commercial cbCT units are available, and although they all follow the same basic principles of image acquisition, significant differences exist between the different makes and models. Some units scan the patient in the sitting position while others scan the patient in the standing or supine position.8

Most units use a pulsed x-ray beam to expose the patient but some use a 35 continuous x-ray beam that significantly increases the radiation dose to the patient.8 One method used by some cbCT units to reduce the radiation dose to the patient is called “automatic exposure control” where the peak kilovoltage

(kVp) and milliampere (mA) settings are automatically adjusted depending on the intensity of the detected x-ray beam.8 Alternatively, the kVp and mA settings are adjusted automatically based on the exposure of a scout image, or manually by the operator.8 Field-of-view (FOV) size is another very important factor that affects the radiation dose to the patient because limiting the scan volume significantly reduces the radiation dose to the patient.8 Cone beam CT units may be arbitrarily divided into small FOV (8 cm or less) and large FOV (larger than 8 cm) units. As mentioned earlier, the number of basis images in a single scan can range from 150 to 599.8 Their total number depends on two factors: the rotational speed of the source and the detector and the frame rate.8 The frame rate is the speed with which basis images are acquired and is measured in frames per second.8 Generally, higher frame rates increase the available data for reconstruction, reduce image noise, reduce metallic artifacts but require a longer scan time and consequently deliver higher effective radiation doses to the patient.8

1.1.7.3 Image reconstruction

Image reconstruction is a complex process.8 Typically, an acquisition computer acquires the image data and corrects the basis images for inherent pixel imperfections and uneven exposure.8 The corrected images are then

36 transferred to a processing computer where the remainder of the data processing and image reconstruction takes place.8 The time for image reconstruction varies depending on acquisition factors such as FOV size, as well as hardware and software capabilities.8

1.1.7.4 Image display and optimization

The smallest subunit of a volumetric data set is termed the voxel and, unlike conventional CT, cbCT voxels are isotropic (that is their x, y, and z dimensions are all equal). Depending on the system, voxel sizes can range from

0.07 to 0.4 mm.23 Smaller voxels result in images with greater resolution.24

Voxels are 3D reconstructs of pixels and so they too are assigned grey shade values that represent the x-ray attenuation coefficient of the tissue(s) they represent.8,23 The ability to display attenuation as different shades of grey is termed bit depth.8 Cone beam CT units are capable of producing 12- and 14-bit images.23 Twelve bit images display 212 (4,096) shades of gray and 14 bit images display 214 (16,384) shades of gray.23 However, the display of grey shades is limited by computer monitors which can display only eight bit images (256 shades of gray) at a time.23 To overcome this limitation, software developers use a technique called “windowing and leveling”.23 Windowing allows the data to be visualized eight bits at a time along a spectrum where air and soft tissues (low- attenuation structures) are at one end of the spectrum, and bone and teeth (high- attenuation structures) at the other end.23 Leveling is the adjustment of the image

37 contrast and brightness by the operator to reach a subjective, personal optimum.23

Other display options include multiplanar reformation (MPR), shaded surface display and volume rendering.23 Multiplanar reformation is the process of viewing the data as 2D images of slices or slabs along any straight or curved line.8 Shaded surface display is the process of selecting an attenuation range so that any structures that fall outside this range are not visualized.23 Volume rendering allows the operator to assign a level of transparency to all the structures imaged.23 All cbCT units include viewing software but third party software is also available depending on the task required.23

1.1.7.5 Image artifacts

As the x-ray beam which is polychromatic in nature passes through the object to be imaged, lower energy x-ray photons are attenuated by the object first.8 This results in an increase in the mean energy of the residual x-ray beam which is said to become “harder”.25 The phenomenon of beam hardening results in three types of artifacts: streak, dark bands and cupping artifacts.8,25 Streaks and dark bands occur when the x-ray beam is hardened to different degrees as it passes through different parts of a heterogeneous object at various tube positions.26,27 This type of artifact is common in bony regions of patients and when contrast material is used.26,27 Cupping artifacts result when the x-ray beam passing through the thicker middle portion of an object becomes harder than the beam passing through the thinner edges of the object.26,27 The harder beam is

38 attenuated less and the resultant image appears darker in the center.26,27 Beam hardening software is used by manufacturers to correct for the these artifacts and sometimes overcorrection is attempted to minimize blurring at the bone-soft tissue interface of an image.26,27 In some instances, capping artifacts result and the reverse becomes true with the edges of the image appearing darker than the center.26,27

Patient movement causes artifacts in the form of blurriness of the resultant image.8 To overcome this problem, manufacturers provide head rests and straps to stabilize the patients’ head during a scan.8 Ring artifacts are due to detector imperfections or poor calibration.8 Partial volume averaging artifact is commonly seen in cbCT images.8 This artifact occurs when dense parts of a heterogeneous object protrude partway into the FOV causing shading artifacts to appear.8 Under sampling is another common cbCT artifact that appears as a noisy reconstructed image with streaks when the number of basis images is reduced.8 The divergent nature of the cbCT x-ray beam may also result in artifacts like distortion and peripheral noise.8

1.1.7.6 Advantages, applications, and limitations

One of the most important advantages of cbCT is its high spatial resolution. Resolution is inversely proportional to the voxel size and is influenced by the isotropic nature of cbCT voxels.8 Another important advantage of cbCT is the reduced radiation dose to the patient compared with medical multidetector

CT.8 Extensive dosimetry studies have been conducted and report an effective

39 radiation dose that ranges between 5.3 µSv and 38.3 µSv for one small FOV cbCT unit (Kodak 9000 3D, Carestream Health Inc., Rochester, USA) and between 68 µSv and 1073 µSv for larger FOV cbCT units.25 In comparison, conventional CT examinations of the jaws deliver an effective radiation dose that ranges between 474 µSv and 1410 µSv depending on the protocol chosen.25

These two advantages combined with the reduced scan time, equipment size, and cost compared to conventional CT have made this imaging modality ideal for the maxillofacial complex including investigation of major salivary gland conditions.

Presurgical dental implant site assessment is one of the more common uses of cbCT.8 It is becoming the standard of practice and this is largely due to the availability of software algorithms that allow the practitioner to view, make accurate dimensional measurements, and annotate anatomic structures.8,28

Other applications of cbCT include: localizing impacted teeth, identifying dentoalveolar fractures, assessing the osseous structures of the temporomandibular joint (TMJ), and assessing maxillofacial growth and development.8,24

Cone beam CT like any other imaging modality has its limitations and one of its major limitations is background noise. Background noise in cbCT is primarily due to the divergent x-ray beam exposing a large volume of tissue.8

This results in more Compton interactions which in turn results in the production of more scatter photons that carry non-linear attenuation information.8

Unfortunately, these photons are recorded by the detector and they degrade the

40

quality of the resultant image.8 Another cause of background noise in cbCT is the

inhomogeneity of the x-ray beam and the large size of the area detector which

makes the number of photons reaching a unit area of detector variable and

smaller.8 Poor contrast resolution is another significant limitation of cbCT. This is

also due to the divergent geometry of the x-ray beam and the increased noise.8

Inherent imperfections in flat panel detectors also contribute to the poor soft

tissue resolution seen in cbCT images.8

1.2 SUMMARY

The salivary glands are exocrine glands. There are 3 paired major salivary

glands, the parotid, submandibular and sublingual glands, and numerous minor

salivary glands located throughout the submucosal spaces of the head and neck.

Their sole purpose is the production of saliva which aids in the maintenance of the

healthy well-being of the oral tissues. The salivary glands develop in the early

weeks of intrauterine life in a delicately timed process. Many diseases can affect

the salivary glands but the most common are the obstructive conditions. Imaging

plays an important role in diagnosing diseases of the salivary glands and in

planning management. Many imaging techniques are available for imaging the

salivary glands but each has limitations. Cone beam CT is a relatively new and

promising imaging technique that overcomes many of the inherent limitations of

other imaging techniques and offers many advantages. However, it too has its

limitations and one of these limitations, poor soft tissue resolution, has restricted

its clinical applications.

41

1.3 STATEMENT OF THE PROBLEM

Obstruction is the most common condition to affect the salivary glands.

Imaging plays a major role in identifying the condition and in planning

management. The ideal imaging modality should determine the cause of the

obstruction, the location, as well as the secondary changes in the ductal structures

and parenchyma of affected glands since these findings may significantly influence

the choice of management. Sialography is the examination of choice for

obstructive conditions of the parotid and submandibular glands because of its high

specificity and depiction of the delicate ductal structures of these glands. However,

its success in identifying abnormalities is dependent on the imaging modality to

which it is coupled. Sialography combined with plain films poses an interpretation

challenge because of overlapping structures in the resultant 2D images. The

feasibility of CT for sialography is limited by the significant radiation dose delivered

to the patient and by the anisotropic resolution of the images. Limitations that arise

from coupling sialography with MRI include long acquisition times and low spatial

resolution. Cost and accessibility are further limitations of both CT and MRI. These

limitations are overcome by cbCT, a 3D imaging modality that offers advantages

such as short scan times, relatively low radiation doses, and images with isotropic

voxel resolution.

1.4 AIMS

 Develop and optimize a protocol for cbCT sialography based on radiation dose

delivery to the patient and image quality.

42

 Compare the diagnostic performance of sialography utilizing cbCT and plain

imaging for the parotid and submandibular glands.

1.5 HYPOTHESES

 Varying technical factors associated with cbCT imaging will result in effective

radiation doses equal to or less than those associated with plain film imaging of

the parotid and submandibular glands.

 Varying technical factors associated with cbCT imaging will result in image

quality improvements to cbCT images.

 The diagnostic capability of cbCT sialography of the parotid and submandibular

glands will be superior to that of plain film sialography of the same glands.

1.6 NULL HYPOTHESES

 Varying technical factors associated with cbCT imaging will result in no

changes to the effective radiation doses which will be no different than the

doses associated with plain film imaging of the parotid and submandibular

glands.

 Varying technical factors associated with cone beam CT imaging will result in

no changes to the image quality of cbCT images.

 The diagnostic capability of cbCT sialography of the parotid and submandibular

glands will be no different than those of plain film sialography of the same

glands.

43

2 A COMPARATIVE STUDY OF THE EFFECTIVE RADIATION DOSES FROM CONE BEAM

COMPUTED TOMOGRAPHY AND PLAIN RADIOGRAPHY FOR SIALOGRAPHY.

2.1 INTRODUCTION

Imaging of the major salivary glands has been performed using one of four

techniques: sialography, ultrasound (US), computed tomography (CT), and

magnetic resonance imaging (MRI). Of these methods, sialography has proven to

be the most effective technique to assess salivary gland function and obstructive

conditions of the salivary glands, in particular.6 Sialography was first performed in

1902,8 and depicts the ductal structures of the salivary glands following the

introduction of a contrast agent into the orifice of a salivary gland duct.

Sialography is largely dependent on the imaging modality to which it is

coupled. Traditionally, sialography has been combined with projection radiography

(i.e. plain film), and this has since become the gold standard to which all other

imaging techniques are compared.29 More recently, three dimensional (3D)

depictions of gland ductal anatomy have been possible by combining sialography

with CT or MRI, but these investigations have several limitations including cost

and accessibility. Also, in the case of MRI and single-row CT, prolonged imaging

times may cause the visualization of the uptake of contrast material to be missed

due to its rapid clearance from the gland.30

Today, the rapid acquisition of a 3D image volume using cone beam

computed tomography (cbCT) has enabled us to overcome the temporal

limitations of medical CT and MR image acquisition. Cone beam CT promises to

44

revolutionize the practice of oral and maxillofacial radiology by offering major

advantages such as short scan times and less radiation dose to the patient.31

Consequently, it has found several applications in the field of dentistry such as

localization of impacted teeth and imaging of the temporomandibular joint.12,32

Imaging of the major salivary glands, however, is one application that has not yet

been explored.

As a first step in developing a protocol for 3D cbCT sialography, we

conducted a dose assessment study comparing this novel methodology with two

dimensional (2D) plain film sialography. Dosimetry studies are crucial, especially

when the head and neck area is being examined because of the number of

critically radiosensitive organs that are in the field being imaged.

2.2 OBJECTIVES

 Examine the effect of varying the field-of-view (FOV) size and center, peak

kilovoltage (kVp) setting, and milliampere (mA) setting on the effective radiation

dose (E) using cbCT.

 Calculate and compare E for cbCT imaging of the parotid and submandibular

glands and sialography of the same glands using plain images.

2.3 NULL HYPOTHESES

 There is no difference in E when the following cbCT technical parameters are

varied:

a. FOV size (6”, 9”, 12”) and center (parotid vs. submandibular)

45

b. Peak kilovolt setting (80 kVp, 100 kVp, 120 kVp)

c. Milliampere setting (10 mA and 15 mA)

 There is no difference in E between cbCT and plain film examinations of the

parotid or submandibular glands.

2.4 MATERIALS AND METHODS

A head and neck RANDO®Man (Radiation Analogue Dosimeter) Alderson

phantom (Alderson Research Laboratories, Stanford, CT, USA) was used in this

study. The phantom is a human skull covered with isocyanate rubber which has

tissue radiation attenuation characteristics equivalent to human soft tissues with

respect to both atomic number and tissue density.33 Only the first ten axial slices,

each 2.5 cm in thickness, of the phantom extending from the top of the head to the

level of the clavicles were used. Following the methods of Ludlow et al (2006),34

the absorbed radiation dose was measured at 25 selected locations (Table 2) that

represent critical radiosensitive organs and sites of special interest to dental

imaging.

46

Table 2: The selected locations for measuring the absorbed radiation dose in the head and neck of the RANDO®Man phantom.

Thermoluminescent dosimeter (TLD) chips were placed in these locations to record the absorbed radiation dose.

Organ Location Phantom Level

Brain Pituitary fossa 3

Mid brain 2

Eyes Right/left orbit 4

Right/left eye lens 4

Salivary glands Right/left parotid 6

Right/left submandibular 7

Right/left sublingual 7

Thyroid Surface 9

Midline 9

Pharynx Pharynx 9

Bone marrow Calvarium anterior 2

Calvarium posterior 2

Calvarium left 2

Cervical spine 6

Right/left mandibular body 7

Right/left ramus 6

Skin Right cheek 5

Left back of neck 7

47

Lithium fluoride thermoluminescent dosimeter (TLD-100) chips (Global

Dosimetry Solutions Inc., Irvine, CA, USA), measuring 3 mm x 3 mm x 1 mm, were used to record the absorbed dose at the 25 locations. Unexposed TLD chips were also analyzed for environmental calibration during each exposure of the phantom.

Each measurement was made in triplicate.

Imaging was performed with the CB MercuRay unit (Hitachi Medical

Systems, Tokyo, Japan). The phantom was oriented in the cbCT unit with the left parotid or submandibular salivary gland centered in the image field. The images were acquired using 3 field-of-view (FOV) sizes (12”, 9” and 6”), 3 peak kilovolt settings (120 kVp, 100 kVp and 80 kVp) and 2 milliampere settings (15 mA and 10 mA).

The number of plain radiographs made for a sialography series varied depending on the gland being imaged. Parotid gland examinations included: a panoramic radiograph, two anterior-posterior skull radiographs, and four lateral skull radiographs. For the submandibular gland, the anterior-posterior views were omitted and replaced with one preoperative standard mandibular occlusal radiograph. The panoramic radiographs were made with the Sirona OrthophosDS

(Sirona, Munich, Germany) using 60 kVp, 14 mA, and an exposure time of 14 s; the image receptor was a 12.7 cm x 30.5 cm cassette containing the Kodak Lanex

Medium intensifying screens and Kodak T-Mat G PAN film (Eastman Kodak Co.,

Rochester, NY, USA). The skull and occlusal radiographs were exposed using the

S.S. White Spacemaker x-ray unit (S.S. White, Philadelphia, PA, USA); but the image receptor and the exposure parameters varied for each type of radiograph.

48

For the skull radiographs, the Kodak Directview CR850 PSP system (Kodak

Medical Systems, Rochester, NY, USA) was the image receptor and the exposure parameters were 70 kVp and 15 mA but the exposure time varied by gland such that it was 0.8 s for the parotid gland and 0.5 s for the submandibular gland. The intraoral occlusal radiographs required 0.32 s of exposure time, using 70 kVp and

8 mA; and the image receptor was the size 4 Ultra-speed film (Eastman Kodak Co,

Rochester, NY, USA).

For each radiographic examination or series, effective radiation dose (E) calculations were based on the following equation:35

E (µSv) = Σ(WTHT)= ΣWTDT FT

WT: Weighting factor for tissue T, where the sum over all tissues, ΣWT = 1

HT: Equivalent dose to tissue T in µSv

DT: Average absorbed dose in the volume of tissue T

FT: Fraction of tissue type T irradiated in that view

Tissue weighting factors were based on the recent ICRP 2007 recommendation in

Publication 103.36 The average absorbed radiation dose was calculated as a mean of three independent measurements at the 25 sites in the tissues or organs of interest. Additionally, the fraction of tissue irradiated within each FOV was estimated, and included in the calculation of E, as proposed by Ludlow et al.34

49

2.5 RESULTS

The effective radiation dose (E) changed in direct relationship to changes

in field-of-view (FOV) size and center, peak kilovoltage (kVp) and milliamperage

(mA) setting for cbCT. Specifically, E decreased from 466 µSv for the largest 12”

FOV to 97 µSv for the smallest 6” FOV, when kVp and mA were held constant at

100 kVp and 10 mA. When kVp was decreased from 120 kVp to 100 kVp, E also

decreased from 932 µSv to 683 µSv when the FOV and mA were held constant at

12” and 15 mA. Lastly, when mA was decreased from 15 mA to 10 mA, E

decreased as well from 435 µSv to 275 µSv while FOV and kVp remained constant

at 9” and 100 kVp respectively. Of note is that exposure time for the CB MercuRay

unit (Hitachi Medical Systems, Tokyo, Japan) is constant at 10 seconds. More

importantly, we found that E calculated for the collective series of plain radiographs

made during sialography of the parotid and submandibular glands was comparable

to the E for cbCT examinations centered on the respective glands when the 6”

FOV was used in combination with 80 kVp, 10 mA. These results are summarized

in Figures 12 and 13 which demonstrate the variability for each individual

radiographic technique.

50

1200 932

1000

800

683

600 (µSv)

466

E 435

400 275 256

200 153 145 97 60 65

0

Technique

Figure 12: Variation of effective radiation dose (E) for the parotid gland.

Variation of E with different fields-of-view (FOV) size, milliampere (mA) and peak kilovolt

(kVp) settings. This graph compares the cbCT techniques that were centered on the left parotid gland with the plain film series made during sialography of the same gland.

51

1200 932

1000

800

683

600 (µSv)

466

E 435 421

400 275 261 256 156 200 153 148

0

Technique

Figure 13: Variation of effective radiation dose (E) for the submandibular gland.

Variation of E with different fields-of-view (FOV) size, milliampere (mA) and peak kilovoltage (kVp) settings. This graph compares the cbCT techniques that were centered on the left submandibular gland with the plain film series made during sialography of the same gland.

The reproducibility of the TLD readings was assessed by computing the coefficient of variation and an example of these results is presented for the 12” FOV, 80 kVp and 10 mA setting in Table 3.

52

Table 3: Reproducibility of the thermoluminescent dosimeter (TLD) chips measurements.

The measurements, which were in units of micro-Gray (Gy), were based on cbCT images made with the following technical parameters: 12” FOV, 80 kVp and 10 mA.

Reading Reading Reading SD Mean CV* 1 (µGy) 2 (µGy) 3 (µGy)

Thyroid midline 3.2 2.63 2.89 0.29 2.91 10 %

Thyroid surface 2.42 2.37 2.59 0.12 2.46 5 %

Esophagus 2.76 2.29 2.66 0.25 2.57 10 %

Right mandibular body 2.37 2.45 1.70 0.41 2.17 19 %

Left mandibular body 1.82 1.81 1.32 0.29 1.65 17 %

Right ramus 2.57 2.73 2.11 0.32 2.47 13 %

Left ramus 2.60 2.62 2.13 0.28 2.45 11 %

Cervical spine 1.79 1.73 1.75 0.03 1.76 2 %

Anterior calvarium 2.10 1.63 1.54 0.30 1.76 17 %

Posterior calvarium 1.29 1.26 1.38 0.06 1.31 5 %

Left calvarium 1.51 2.04 1.98 0.29 1.84 16 %

Right parotid gland 2.19 2.43 3.01 0.42 2.54 17 %

Left parotid gland 3.07 3.04 3.28 0.13 3.13 4 %

Right submandibular gland 2.32 2.29 2.27 0.03 2.29 1 %

Left submandibular gland 1.83 2.20 1.98 0.19 2.00 9 %

Right sublingual gland 2.40 2.39 2.18 0.12 2.32 5 %

Left sublingual gland 2.24 2.31 2.17 0.07 2.24 3 %

53

Neck 2.05 3.05 3.31 0.52 3.47 15 %

Cheek 2.78 2.47 2.63 0.16 2.63 6 %

Right lens 3.32 3.43 3.58 0.13 3.44 4 %

Left lens 3.2 3.23 2.92 0.17 3.12 5 %

Pituitary fossa 1.72 1.64 1.52 0.10 1.63 6 %

Midbrain 1.47 1.21 1.58 0.19 1.42 13 %

Right orbit 2.29 2.38 2.29 0.05 2.32 2 %

Left orbit 1.93 2.44 1.67 0.39 2.01 19 %

Mean CV 9 %

*CV: coefficient of variation

2.6 DISCUSSION

The potential radiation hazard from low doses of radiation associated with

diagnostic investigations remains a major concern for both radiologist and patients

alike. In the oral and maxillofacial region, this is especially true because of the

radiosensitive organs in the area being imaged, and because of sporadic reports

that implicate oral and maxillofacial radiography with intracranial pathoses.37 In a

population-based case control study, Longstreth et al found that more than 5 full-

mouth series (10-22 images) performed during a lifetime doubled the risk of

development of intracranial meningioma.37 Consequently, health care providers,

including oral and maxillofacial radiologists, are constantly developing new

technologies and protocols to address the radiation dose concerns of patients

without compromising diagnostic quality or patient care.

54

This study is a first step in the development and application of a novel, potentially improved technique for sialography. The overall goal of our work is to modulate radiation doses to levels that would be comparable to those arising from plain radiography sialography, without compromising the quality of the cbCT images. Using thermoluminescent dosimeter (TLD) measurements on a

RANDO®Man phantom (Alderson Research Laboratories, Stanford, CT, USA), the dependence of effective radiation doses on the exposure factors was estimated for cbCT examinations.

The CB MercuRay system (Hitachi Medical Systems, Tokyo, Japan) allows several technical factors to be controlled by the operator. Holding all other technical factors constant, the effects of varying an individual factor on the effective radiation dose (E) was explored. Reducing the field-of-view (FOV) from the larger size to the next available smaller size resulted in a significant reduction in the calculated E by approximately 40%. This reduction is due to some of the TLD chips no longer being in the primary radiation field; some of the reduction in E may also be due to elimination of scatter radiation. Likewise, reducing the milliampere setting from 15 mA to 10 mA resulted in a 37% reduction in E as is expected due to the reduced output from the x-ray tube. Finally, E decreased by approximately

30% and 60% when the peak kilovolt setting was reduced from 120 kVp to 100 kVp and 80 kVp, respectively. These findings are in general agreement with the results of other published studies.34,38 The significance of these reductions in E, however, is only meaningful if the image quality is not compromised because as the amount of radiation decreases, the amount of noise increases. This tradeoff

55 between amount of radiation and image quality will be address in a future study as a next step in the process of developing a new protocol for sialography using cbCT.

The Palomo et al study,38 like the present study, also examined the influence of different cbCT technical settings on E using a RANDO® phantom and the CB MercuRay cbCT system (Hitachi Medical Systems, Tokyo, Japan). These authors noted a dose reduction of 5% to 10% to the tissues that remained in the path of the direct beam as the FOV decreased from 12” to 9” and 6”. They also achieved a 38% reduction in E by reducing the kVp from 120 kVp to 100 kVp.

Milliampere settings varied markedly (2 mA, 5 mA, 10 mA, and 15 mA) and produced a linear and exponential pattern of dose reduction in the same study.

Consistently, altering the technical parameters significantly reduces the radiation dose, and certainly altering these technical factors should be considered to maintain patient radiation doses as low as reasonably achievable.

Our results are consistent with other dosimetry studies.34,38 Some of the differences we report in E are likely related to variations in the methodology of measuring the absorbed radiation dose and in the calculations of E. Two prominent differences in the methodology are the centering of the image field that we utilized as well as the number of times a single TLD chip was exposed. In the current study, the image field was asymmetrically centered on the salivary gland of interest

(either the left parotid or left submandibular salivary gland). In previous studies, the image field was centered in the midline of one or both jaws.34,38,39 Because this study is the first of its kind to calculate E for a specific application of cbCT, imaging

56 the major salivary glands, we believed it to be more appropriate to localize the image field where we did. We firmly believe that this technical modification has led to a more accurate estimate of E for cbCT examinations of the parotid and submandibular glands.

Regarding the number of exposures, the TLD chips in the present study were exposed only once as was done in the Palomo et al study.38 In most other similar studies the TLD chips were exposed a minimum of three times, after which the measured absorbed radiation doses were divided by the number of exposures.31,34,39 We believe that exposing the TLD chips only once allowed for a more realistic simulation of the patient situation since patients will undergo only one cbCT scan during the procedure. It also allowed us to truly examine the reproducibility of the dose measurement, which was determined by calculating the coefficient of variation, the mean of which was calculated to 9% for the 12” FOV,

80 kVp, and 10 mA cbCT protocol.

The effective radiation dose was calculated according to the ICRP definition but, as per Ludlow et al,34 it was necessary to estimate the fraction of irradiated tissue in each FOV. A unique feature of this study is that the effect of the variation of the percentage contribution of each tissue with changes in the FOV size and image field center was taken into account. For example, the fraction of brain irradiated in the 12” FOV centered on the left parotid gland was 100% but decreased to 50% in the 9” FOV and decreased even further to 10% in the smallest 6” FOV. On the other hand, it was estimated that only 5% of the brain was irradiated in the 6” FOV when the FOV was centered on the submandibular gland.

57

Tailoring the fraction of tissue irradiated for each FOV size and center for this imaging task may have yielded more meaningful dose results.

The calculated thyroid effective radiation dose was by far the largest contributor to the overall E in all examinations centered on the submandibular gland, whether using cbCT or plain radiographs as the imaging modality. In fact, E calculated for the thyroid contributed 71% and 76% of the total E for cbCT and plain radiograph examinations, respectively, when centered on the submandibular gland. Because of the anatomic proximity of the two glands, it is inevitable that the thyroid will receive more radiation dose during examinations of the submandibular gland. This may be a source of concern because of the relative high radiosensitivity of the thyroid, especially in children. Fortunately, obstructive conditions of the salivary glands are very rare in children and adolescents,40 and it is unlikely that an individual from that age group will require a sialogram procedure.

As for the risk of thyroid cancer in adults from diagnostic radiation exposure, the data are still inconclusive and no studies have been able to prove a causal relationship or even a statistically significant association.41,42 Nevertheless, the inconclusive nature of the data creates a dilemma for physicians and dentists interested in imaging the submandibular gland. This dilemma is an excellent example of where risk versus benefit judgment comes into play; that is, the excess risk of imaging versus the anticipated benefit to improved patient care and management. Other tissues that contributed significantly to the overall calculated

E, especially in examinations centered on the parotid gland were the salivary glands and the bone marrow.

58

Based on the findings of this study, a preliminary protocol for cbCT sialography has been developed. Following the introduction of radiographic contrast, a lateral skull plain image is made to ensure adequate filling of the gland with contrast material. This is then followed by cbCT image acquisition using the

6” FOV, and x-ray tube factors of 80 kVp and 10 mA. After the completion of the cbCT scan, another lateral skull plain radiograph is made five minutes after removal of the catheter to assess contrast material clearance as this is regarded as an indirect indicator of gland function and saliva production. The 2 lateral skull radiographs are made with the Kodak Directview CR850 PSP system (Kodak

Medical Systems, Rochester, NY, USA) using 70 kVp, 15 mA, and 0.8 s exposure time. One of the initial cases that were performed according to this protocol is presented in Figure 14. The cbCT images demonstrate the secondary ductal structures of the submandibular gland that are not readily apparent on the two dimensional (2D) plain image due to extravasation of contrast material into the gland capsule.

In conclusion, the calculated effective radiation doses from cbCT examinations centered on the parotid and submandibular glands were comparable to E from plain radiography sialography of the same glands when a smaller FOV was chosen in combination with lower kVp and mA settings (6” FOV, 80 kVp, and

10 mA). Having acquired the dosimetric data for site-specific imaging using cbCT, a future goal is to optimize the exposure parameters for cbCT sialography by proposing kVp and mA settings for the CB MercuRay unit (Hitachi Medical

59

Systems, Tokyo, Japan) that will balance the quality of the images and the radiation dose to the patient.

60

(a) (b)

(c) (d)

Figure 14: Sialogram of left submandibular gland.

(a) Lateral skull plain radiograph of the gland following contrast administration. This image was made prior to the cbCT scan to insure adequate fill of the gland with contrast material, and it demonstrates the lack of visibility of the secondary and tertiary ductal structures due to extravasation of the contrast material into the gland capsule. (b)

Reformatted sagittal cbCT image of the same gland with the secondary and tertiary ducts clearly visible. Maximum intensity projection (MIP) cbCT images in the coronal plane (c) and in the axial plane (d) demonstrating the three dimensional (3D) and multiplanar capabilities of cbCT.

61

3 OPTIMIZATION OF EXPOSURE PARAMETERS FOR CONE BEAM COMPUTED TOMOGRAPHY

SIALOGRAPHY

3.1 INTRODUCTION

In a previous study we demonstrated the wide range of radiation doses

that can be delivered to the patient from cone beam computed tomography (cbCT)

scans simply by varying three technical parameters: field-of-view (FOV) size, peak

kilovoltage (kVp) setting, and milliamperage (mA) setting.43 Based on the results of

the dosimetry study, we proposed a preliminary protocol for sialography using

cbCT. The recommended protocol entailed centering the gland of interest in a 6”

FOV and using exposure factors of 80 kVp with 10 mA.44 However, this protocol

was based primarily on minimization of dose and did not consider the effect of

varying the technical parameters on image quality. The purpose of the present

study was to further optimize the protocol by maximizing the quality of images

while delivering radiation doses to the patient that are as low as reasonably

achievable.

Radiographic image quality is defined as the amount of information within

the image that allows the radiologist to make a diagnostic decision with a particular

level of certainty.45 It is therefore believed that increasing the image quality

increases the certainty of the diagnostic decision; most often this can be achieved

simply by increasing the exposure technique such as choosing greater kVp or mA

settings. However, higher exposure techniques come at the expense of greater

radiation dose to the patient.46 Therefore, it is crucial when developing a new

62 imaging protocol to consider both radiation dose and image quality and balance the trade-off between them to produce images that are diagnostically adequate while minimizing radiation exposure to the patient.

Recently there has been interest in addressing the issue of image quality for cbCT. In an in vitro study, Liang et al. compared the image quality and visibility of anatomic structures in a dry mandible between five cbCT units and one multislice CT (MSCT) system using a subjective image classification system.47

Thirteen different scan protocols were used, and five independent dentist observers were asked to rate the visibility of eleven anatomic structures of the mandible on a five-point scale.47 Although they found great variability among the different cbCT systems, they concluded that the image quality was comparable to

MSCT even though MSCT had less image noise.47 This study did not investigate the trade-off between image quality and patient dose and no recommendations were made for a specific cbCT protocol.

Similarly, in 2008 Kwong et al. subjectively evaluated the quality of images of cadaver heads and dry skulls made with the CB MercuRay unit (Hitachi Medical

Systems, Tokyo, Japan) taken at different exposure settings.48 Three FOVs were examined (12”, 9”, and 6”) in addition to two kVp settings (100 kVp and 120 kVp) and four mA settings (2 mA, 5 mA, 10 mA, and 15 mA). They also examined the effect of filtering the x-ray beam with copper.48 Image quality was defined as: “the ability of the image to answer our [the authors’] diagnostic question”; this was determined by having thirty observers from various dental disciplines fill out a diagnostic quality questionnaire.48 For the 6” FOV images we are interested in,

63

Kwong’s study showed that the image quality was affected by altering the kVp and

mA settings but not by adding a copper filter.48 Images were considered to be of

superior diagnostic quality when greater kVp and mA settings were chosen.48

Although the subjective findings for the 6” FOV images are consistent with our

objective findings, once again the issue of patient radiation dose was not

addressed.

In this study we are interested in maximizing the detection of the

difference between the signal from an iodinated contrast agent injected into a

salivary gland ductal system and the signal from surrounding normal tissue. This

signal detection task can be quantified by the metric, signal-difference-to-noise-

ratio (SDNR). SDNR describes the relative magnitude of useful information to that

of the noise that impairs its detection.

A common method employed to optimize a radiographic imaging

technique is to maximize the ratio of image SDNR to the radiation dose to the

patient while maintaining some required level of SDNR.49 We used this approach

in the present study to optimize the protocol for cbCT sialography based on the

results of an exploration of how SDNR varies with kVp and mA settings. We also

report on an evaluation of the sensitivity of image signal to the iodine concentration

in the contrast agent.

3.2 OBJECTIVES

 Examine the effect of varying the peak kilovolt (kVp) setting, milliampere (mA)

setting, and iodine concentration in the contrast agent on the signal-difference-

to-noise ratio (SDNR) of cbCT images. 64

 Compare the relative tradeoff between SDNR and the effective radiation dose

(E) for cbCT when kVp and mA settings are varied.

 Propose an optimized protocol for cbCT sialography.

3.3 NULL HYPOTHESES

 There is no difference in SDNR when the following cbCT parameters are

varied:

a. Peak kilovolt setting (60 kVp, 80 kVp, 100 kVp, 120 kVp)

b. Milliampere setting (10 mA and 15 mA)

c. Iodine concentration in contrast agent (120, 140 160, 180 mg I/ml)

 There is no difference in the tradeoff between SDNR and E when the following

cbCT parameters are varied:

a. Peak kilovolt setting (60 kVp, 80 kVp, 100 kVp, 120 kVp).

b. Milliampere setting (10 mA and 15 mA)

3.4 MATERIALS AND METHODS

An imaging phantom was constructed using a round (20 cm diameter)

water filled Plexiglas container. A dry, human mandible was immersed alongside

four iodine contrast phantoms containing variable concentrations of iodine within

this container. The iodine phantoms (1 cm X 1 cm X 4 cm) are solid radiographic

test objects composed of iodobenzene embedded in epoxy resin.50 At the x-ray

energies used in this study the epoxy resin has an x-ray attenuation that is the

same as water, and this was confirmed by imaging a phantom containing only

65 epoxy (0 mg I/ml) immersed in water for each imaging technique. The iodine phantoms imaged with the mandible contained iodine concentrations of 180, 160,

140, and 120 mg I/ml. Figure 15a is a cropped photograph of the imaging phantom and 15b is the corresponding axial cbCT image of the same area of the phantom acquired with 80 kVp and 10 mA x-ray tube factors.

66

120 mg I/ml

140 mg I/ml

160 mg I/ml

180 mg I/ml

(a) (b)

Figure 15: Photograph (a) and axial cbCT image (b) of the imaging phantom.

The images show the immersed mandible and the iodine contrast phantoms arranged adjacent to one another. In the photograph, the mandible is seen resting on an object with wells that functioned to support the mandible and hold the iodine cubes in place.

The iodine cubes are solid radiographic test objects composed of iodobenzene embedded in epoxy resin. They contained iodine concentrations of 180, 160, 140, and

120 mg I/ml. The image was acquired using 80 kVp and 10 mA and edge artifacts are noted along the edges of the square shaped iodine phantoms.

67

The CB MercuRay unit (Hitachi Medical Systems, Tokyo, Japan) was used to image the phantom. All the images were acquired in a 6” FOV but the kVp and mA settings were varied in the technique combinations outlined in Table 4. Sample images produced by different exposure factors are displayed in Figure 16. For each technique combination, three scans were made on three separate occasions to account for cbCT system variability. Then the raw unprocessed DICOM images were uploaded into

ImageJ (National Institutes of Health, Bethesda, MD, USA) for analysis. Using the same axial slice from each scan, equal sized regions of interest (ROI), 3.5 mm in diameter, were chosen in the center of each iodine phantom and in an adjacent area that contained only background water while avoiding areas with image artifacts as demonstrated in Figure 17.

Table 4: The different combinations of operational parameters that were used for the cbCT scans.

10 mA 15 mA

60 kVp 60 kVp 10mA 60kVp 15 mA

80 kVp 80 kVp 10mA 80 kVp 15 mA

100 kVp 100kVp 10mA 100 kVp 15 mA

120 kVp 120kVp 10mA 120 kVp 15 mA

68

60 kVp, 10 mA 80 kVp, 10 mA 100 kVp, 10 mA 120 kVp, 10 mA Figure 16: Four example cbCT images.

The images were made with the same mA setting of 10 but different kVp settings that varied from 60 to 120. The images demonstrate the effect of changing the kVp on the perceived image noise with the image on the far right made with the highest kVp setting displaying the least noise.

Figure 17: Cone beam CT image showing the regions-of-interest (ROI).

The one outlined with black is the ROII in the iodine phantom and the one outlined in white is the ROIW in an adjacent area with only background water.

69

The signal difference (SD) was calculated by subtracting the mean pixel value

(MPV) recorded in an adjacent ROI with only background water (ROIW) from that

6 recorded in an iodine phantom (ROII).

SD = MPV in ROII - MPV in adjacent ROIW (1)

Noise for each iodine sample measurement was defined as the standard deviation (σ)

6 of the pixel values recorded in the adjacent ROIW.

Noise = σ (ROIW) (2)

Then the pixel signal-difference-to-noise ratio (SDNRp) was calculated as the ratio of

Equation 1 to Equation 2.6

SDNRp = SD/Noise

Finally a figure-of-merit (FOM), which is a numerical expression representing the efficiency of a given system or procedure, was calculated to relate the image quality

51 to the radiation dose risk. It was computed as the SDNRp squared divided by the effective radiation doses (E) for the parotid salivary gland. The effective doses were either calculated in our previous dosimetry study or calculated in the same manner for the technique combinations used in this study and are listed in Table 5.44 The FOM values are reported in inverse micro Sieverts (µSv)-1.

2 FOM = SDNRp /E

The reason the SDNR was squared in the calculation of FOM is because the SDNR is proportional to the square root of the dose, or in other words the SDNR squared is proportional to the dose.

70

Table 5: The effective radiation doses that were used to calculate the figure-of-merit

(FOM) for the different technique combinations.

Technique Effective dose (µSv)

60 kVp, 10 mA 27

60 kVp, 15 mA 33

80 kVp, 10 mA 60

80 kVp, 15 mA 71

100 kVp, 10 mA 97

100 kVp, 15 mA 145

120 kVp, 10 mA 120

120 kVp, 15 mA 167

Statistical analysis was performed using the SAS software Version 9.1 (SAS

Institute Inc., Cary, NC, USA). The paired t-test was used to compare the SDNR and

FOM for all the combinations of exposure techniques. The alpha value (p) was set at

0.05.

3.5 RESULTS

The pixel signal-difference-to-noise ratio (SDNRp) was calculated for the iodine concentration routinely used in our clinic (180 mg I/ml) and was found to range between

2.3 for the technique using 60 kVp and 10 mA and 13.3 for the highest exposure using

120 kVp and 15 mA. By applying the paired t-test, a statistically significant difference was noted between the images that were made with 60 kVp and the images that were

71 made with 80 kVp, 100 kVp, and 120 kVp. This difference was noted regardless of the mA setting. In addition, a statistically significant difference in SDNRp was found between the images generated with 10 mA and 15 mA but this was only true for the 60 kVp and

120 kVp techniques. These results are outlined in Figure 18.

* 18.0 * *p< 0.05 16.0

14.0

12.0

p 10.0

8.0 10 mA SDNR 15 mA 6.0 9.0 11.0 11.2 12.1 12.4 13.3

4.0

2.0 2.3 3.3 0.0 60 kVp 80 kVp 100kVp 120 kVp Technique * *

Figure 18: Variation of pixel signal-difference-to-noise ratio (SDNRp) with different kVp and mA settings.

The error bars represent the maximum and minimum values for each individual technique. The graph highlights the statistically significant differences that were found among the various techniques (*).

72

The effect of the iodine concentration on the image SDNRp is demonstrated in

Figure 19. The SDNRp ranged from 5.8 for the 120 mg I/ml concentration to 9.0 for the

180 mg I/ml concentration when 80 kVp was chosen with 10 mA. No statistically significant difference was noted among the concentrations when the paired t-test was applied.

12

10

8

p

6 SDNR

4

2

0 120 mg I/ml 140 mg I/ml 160 mg I/ml 180 mg I/ml Iodine concentration

Figure 19: Variation of pixel signal-difference-to-noise-ratio (SDNRp) relative to iodine concentrations in the phantom.

Four concentrations are shown 120, 140, 160, and 180 mg I/ml; these were imaged using 80 kVp and 10 mA. The error bars represent the maximum and minimum values of SDNRp for each concentration. A linear fit to the data is shown by the solid line.

73

The calculated figure-of-merit (FOM) for the different technique combinations are plotted in Figure 20. SDNRp was used to calculate the FOM. The technique with the greatest FOM value is the one that employs 80 kVp and 15 mA.

3.5

3.0

1 -

2.5

(µSv)

E /

2 2.0

) p 10 mA 1.5 15 mA

1.0 1.7 1.3 FOM=(SDNR 1.4 0.5 0.3 1.0 1.1 0.2 1.3

0.0 60 kVp 80 kVp 100kVp 120 kVp Technique

Figure 20: Calculated figure-of-merit (FOM).

FOM was calculated for 8 different combination techniques using 60 kVp, 80 kVp, 100 kVp and 120 kVp and two mA settings (15 and 10). The error bars represent the maximum and minimum values for each individual technique.

74

3.6 DISCUSSION

Production of diagnostic images involves a complex interplay of many

different parameters. A solid understanding of these parameters, how they interact,

and how they influence both image quality and radiation dose is crucial in the

process of developing new imaging techniques. Therefore, the protocol we

propose for three dimensional (3D) sialography using cbCT is based on an

extensive evaluation of the parameters that can be adjusted by the operator and

their effect on both radiation dose and image quality.

The calculated pixel signal-difference-to-noise ratio (SDNRp) increased in

proportion to peak kilovoltage (kVp) when the milliamperage (mA) was held

constant. This was expected because as the kVp increases, so does the x-ray

beam energy, the flux emitted from the tube, the x-ray beam penetrability, and thus

the number of x-ray photons reaching the detector. With greater numbers of x-ray

photons per unit area of image receptor, the noise decreases throughout the

image, which in turn increases the SDNRp. However, in our experimental data the

positive relationship between SDNR and kVp is exaggerated by another source of

image noise, spatial non-uniformity. An inverse cupping artifact was present in our

images, which is sometimes known as “capping”.26 This artifact occurs when there

is overcompensation for a cupping artifact; an image artifact caused by beam

hardening. The capping was more pronounced in the images acquired at lower

kVp, where the beam is less penetrating or “softer”. Therefore, the SDNRp could

be improved at the lower kVp settings by appropriate corrections for spatial non-

uniformity (i.e. flat-fielding). A positive relationship was also noted between

75 increases in mA and SDNRp, where, within the observed range of SDNRp

variability, the SDNRp increased by a factor of 1.5 when mA was increased by a factor of 1.5. This relationship indicates that quantum noise is likely the dominant factor affecting image performance for each technique combination considered here. These quantitative results are consistent with the trends observed in the subjective image quality ratings published by Kwong et al.48

Figure-of-merit (FOM) values were influenced by the choice of kVp and mA. At the lower kVp settings of 60 and 80, a direct relationship was noted between FOM and mA but at the higher kVp settings of 100 and 120, an inverse relation was demonstrated because the dose increased significantly more than the

SDNRp. The only FOM values that were significantly different than the others were those at 60 kVp. This indicates that among the other examined techniques, where image quality was adequate, the one that should be adopted as a clinical protocol for sialography is the one which imparts the lowest effective radiation dose. This technique is the one that utilizes 80 kVp with 10 mA. These technique factors are optimized specifically for the CB MercuRay unit (Hitachi Medical Systems, Tokyo,

Japan), which has a limited range of choices of kVp settings (60, 80, 100, and 120) and of mA settings (10 and 15). Further refinement of the sialography protocol could be made following the same approach used in this work for other cbCT systems with different imaging technique parameters.

Suomalainen et al. published an extensive study that evaluated the radiation dose and image quality of four cbCT scanners and compared them to two multislice CT (MSCT) scanners.44 Using appropriate phantoms, radiation doses

76 and contrast values were measured. Then radiation doses were calculated and reported as effective radiation doses.44 The contrast-to-noise-ratio (CNR) was used as an indicator of image quality, and the modulation transfer function (MTF) quantity was used to determine the resolving power of each system.44 The authors concluded that despite the large variation in results, cbCT scanners provide adequate image quality with smaller effective radiation doses as compared to

MSCT.44 However, the authors were quick to emphasize the importance of optimizing imaging factors for the different examinations.44 It is our opinion that this recommendation can be accomplished only by optimizing these parameters for specific clinical applications of cbCT, and by objectively measuring the trade-off between image quality and radiation dose as we have done in this study for cbCT sialography.

Omnipaque® (Iohexil injection 39%, General Electric Healthcare Canada

Inc., Mississauga, ON, Canada) is a low osmolar, nonionic, iodinated contrast agent that is produced in five concentrations: 140, 180, 240, 300, and 350 mg I/ml for different indications of use. At our institution and for the indication of sialography, the 180 mg I/ml concentration is used. Therefore, in this study, we examined the effect of the two smaller commercially available concentrations (140 and 180 mg I/ml) in addition to two intermediate concentrations (120 and 160 mg

I/ml) in order to fully understand the impact of the iodine concentration on SDNRp for cbCT sialography. Greater concentrations of the contrast agent were deemed unnecessary because the injection is locally confined to the ductal structures of the salivary glands as opposed to vascular injection, where the agent quickly becomes

77 diluted by distribution throughout the whole body. An increase in SDNRp was noted with the increase in iodine concentration but there was no statistically significant difference among the different concentrations for the technique using 80 kVp and

10 mA. This relation is due to the substantial signal difference provided by the attenuation of iodine in the salivary ducts.52

To our knowledge there are no other studies in the English literature that examine the effect of varying the iodine concentration in contrast agents on the quality of the resultant images for sialography studies. However, a similarity can be drawn to studies of CT angiography. Unfortunately, these studies vary in their results from demonstrating no significant effect of the iodine concentration53 to showing a statistically significant difference54,55 on vascular enhancement. The results of these studies are complicated by many other variables such as imaging techniques and injection parameters.55 One particular study by Wang et al. examined the effects of two iodine concentrations of the same contrast agent on image quality and side effects for dynamic CT of the neck.56 They found that both concentrations produced images of excellent quality but the lower concentration resulted in fewer immediate minor complications.56 In the current study, we demonstrated a positive linear trend between the iodine concentration and SDNRp, as indicated by the linear fit to the data in Figure 18. This relationship is expected because the signal difference will increase proportionally to the amount of iodine present. However, no statistical differences in SDNRp were noted among the four concentrations examined; the highest of which (180 mg I/ml) is the concentration currently used at our institution for sialography. The likelihood of complications

78 from contrast media in relation to sialography procedures is minimal because of the localization of the contrast material in the salivary gland ducts; nevertheless, it would be more reasonable to use the smaller commercially available concentration of the contrast agent, which is 140 mg I/ml.

In conclusion, we have developed an optimized protocol for cbCT sialography using the CB MercuRay unit (Hitachi Medical Systems, Tokyo, Japan).

The protocol involves centering the salivary gland of interest in a 6” FOV and choosing a kVp of 80 with 10 mA. Our future goal is to examine the diagnostic efficacy of this optimized cbCT sialography technique in a clinical setting and to compare it to the standard of practice which is plain film sialography.

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4 A COMPARATIVE STUDY OF THE DIAGNOSTIC CAPABILITIES OF 2D PLAIN RADIOGRAPHY

AND 3D CONE BEAM COMPUTED TOMOGRAPHY FOR SIALOGRAPHY

4.1 INTRODUCTION

Obstructive conditions of the major salivary glands are the most common

abnormalities affecting nearly 1% of the population. From an imaging standpoint,

the major salivary glands can be imaged using one of four techniques: ultrasound

(US), computed tomography (CT), magnetic resonance imaging (MRI), and

sialography.7 Ultrasound offers many advantages because it is inexpensive, widely

available, and safe.57 However, US does not demonstrate all calculi accurately or

ductal damage caused by obstruction and inflammation.57 CT has a greater

sensitivity for sialoliths, but it cannot demonstrate small sialoliths. Moreover, it

cannot demonstrate ductal damage.57 MRI, unlike US and CT, can demonstrate

changes in the ductal structures but calcified sialoliths may be overlooked because

of the signal void associated with calcified structures.57

Sialography is a functional examination of the major salivary glands that

involves the injection of a radiopaque contrast agent into the ductal system of the

gland prior to imaging. It is the only examination that demonstrates the fine,

delicate anatomy of the ductal system, and most accurately visualizes sialoliths

and strictures, two of the most common causes of obstruction.2,7 These capabilities

make sialography the most suitable examination for investigation of obstructive

conditions of the parotid and submandibular salivary glands. The capabilities of

sialography are, however, restricted by the limitations of the imaging modalities to

which it is coupled. Plain imaging has been used extensively with sialography, 80 however the 2D images that are generated may have limited diagnostic capability.

Sialography has also been combined with medical CT but the anisotropic voxel resolution may not demonstrate the fine anatomy of the gland ductal structures.30

Sialography has also been combined with fluoroscopy but this modality delivers relatively significant doses of radiation to the patient.58

Recently, we and others have begun using cone beam CT (cbCT) as the imaging tool for sialography. Cone beam CT overcomes many of the shortcomings of other imaging modalities and as isotropic voxel resolution. Previously, we have demonstrated our ability to achieve comparable effective radiation doses between plain imaging and cbCT sialography using the CB MercuRay system (Hitachi

Medical Systems, Tokyo, Japan), by centering the gland of interest in a 6” field-of- view (FOV) and using x-ray tube settings of 80 peak kilovoltage (kVp) and 10 milliamperage (mA).44 Specifically, a parotid CBCT examination using the above mentioned settings resulted in an effective radiation dose of 60 µSv compared to

65 µSv for the plain image sialography series, for the submandibular gland, the effective radiation dose from CBCT was 148 µSv while from plain image sialography it was 156 µSv.44 Moreover, we were able to confirm adequate image quality when using these technical factors in a previous in-vitro study using a sialography phantom.43

The purpose of this study is to compare the diagnostic capabilities of cbCT sialography with sialography using plain images. We hypothesize that cbCT sialography will have similar or greater diagnostic capabilities than sialography with plain imaging with regard to the visualization of normal gland structures such as

81

the primary duct, the identification of abnormal findings such as sialoliths, and

finally, image interpretation.

4.2 OBJECTIVES

 To compare the abilities of cbCT sialography and plain film sialography in:

o Visualizing the primary and secondary ducts and the parenchyma of the

parotid and submandibular glands.

o Detecting abnormal findings in the same glands.

o Interpreting the sialographic examinations.

 To assess the reliability of cbCT sialography relative to plain film sialography.

 To assess the reproducibility of cbCT sialography findings.

4.3 NULL HYPOTHESIS

 There is no difference in the abilities of cbCT sialography and plain film

sialography in:

o Visualizing the primary and secondary ducts and the parenchyma of the

parotid and submandibular glands.

o Detecting abnormal findings in the same glands.

o Interpreting the sialographic examinations.

 There is no difference in the reliability of cbCT sialography relative to plain film

sialography.

 Cone beam CT sialography findings are not reproducible.

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4.4 MATERIALS AND METHODS

Fourty-seven (47) subjects were recruited into this prospective clinical

study over a two year time period from January, 2009 to December, 2010. Subject

inclusion criteria were adults over 18 years of age with a suspected obstructive

condition of a parotid or submandibular gland as determined by history and clinical

examination. Exclusion criteria included acute inflammation of the major salivary

gland of interest, known or suspected allergy to iodinated contrast agents, or an

immediately anticipated thyroid function test. For each subject, a clinical

examination was performed and the following clinical data were collected prior to

the sialography procedure: subject age, gender, medical history, chief complaint,

subject self-assessment of pain presence and pain quality, swelling, abnormal

taste, mouth dryness and provoking stimulus. As well, extra- and intra-oral

examinations were performed to determine the presence of a swelling, and salivary

quantity and quality (clear or cloudy). Ethical approval was obtained from the

University of Toronto Research Ethics Board (appendix 1) and dictated that each

subject should sign and receive a copy of the consent form (appendix 2).

Sialography was performed by a resident in oral and maxillofacial

radiology closely supervised by a faculty member certified as a specialist in oral

and maxillofacial radiology. The orifice of the primary duct of the salivary gland

under examination was dilated with a series of metal probes, and this was followed

by canulation of the primary duct with a 24G (Pajunk Medizintechnologie,

Geisingen, Germany) or 30G catheter (Cook, Bloomington, IN, USA). Between 1

mL and 10 mL of Omnipaque® 180 mg I/ml (Iohexil injection 39%, General Electric

83

Healthcare Canada Inc., Mississauga, ON, Canada) were injected slowly into the duct of the gland until the subject reported maximum tolerance to a feeling of pressure in the gland. A lateral skull plain image was then made using the GE focus system (General Electric Corporation, Henry Schein Ash Arcona, Niagara- on-the-Lake, ON, Canada) and a photostimulable phosphor (PSP) sensor (CR850,

Carestream, Rochester, NY, USA) to confirm optimal fill of the ductal structures of the gland prior to the cone beam computed tomography (cbCT) image acquisition.

If contrast fill was deemed inadequate, additional contrast was injected and another lateral skull plain image was made.

Cone beam CT imaging was performed with the CB MercuRay cbCT unit

(Hitachi Medical Systems, Tokyo, Japan) using a 6” field-of-view (FOV), 80 peak kilovoltage (kVp) and 10 milliamperage (mA) with the occlusal plane of the dentition parallel to the floor, and the imaging volume centered on the gland of interest. Five minutes following catheter removal, a second lateral skull plain image was made to evaluate contrast clearance from the gland. The two lateral skull plain images represented the two-dimensional (2D) part of the study, and these were used for comparison with the cbCT images. This protocol allowed us to acquire and then compare the images of the same gland in the same subject using both modalities.

Three certified specialists in oral and maxillofacial radiology reviewed the images after undergoing a calibration exercise prior to image analysis. The calibration exercise included a review of twelve archived cases of sialography performed with plain images, with the aim of standardizing structural appearances

84 of the gland and the definitions of descriptive terms. Prior to review by the oral and maxillofacial radiologists, all images were anonymized. The three observers reviewed the plain and cbCT sialographic images for each subject separately with a wash out period of at least one week. As all the images were digitally-acquired, they were viewed using the CBWorks 2.0 software (CyberMed, Seoul, Korea) on a

19 inch Dell® Ultrasharp 1907 flat panel LCD screen with a maximum resolution of

1280 X 1024 pixels in a dimly lit room. The observers were permitted to enhance the images by manipulating the brightness and contrast as they chose. As well, they were permitted to review the 3D renderings of each cbCT image dataset in their entirety. The reviewing oral and maxillofacial radiologists were blinded to the clinical data and were asked to make observations with respect to the features listed in Table 6. Agreement between two of the three oral and maxillofacial radiologists was used to determine the presence or absence of an imaging finding.

No attempt was made to reconcile disagreements. As well, one of the oral and maxillofacial radiologists reviewed twenty randomly selected cases (including both plain and cbCT images) twice to determine intra-observer reliability.

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Table 6: List of the radiographic features and findings that were reviewed.

Radiographic feature Radiographic finding

Normal structures: Primary duct Visualization Presence of abnormalities Secondary duct Visualization Presence of abnormalities Parenchyma Visualization Presence of abnormalities Abnormal features: Sialoliths Number Size Location Strictures Number Size Location Ductal dilatation Severity Location Acinar pooling Number Distribution Size Mass Location Borders Internal structure Effect on surrounding structures Interpretation Normal Inflammatory (sialadenitis/sialodochitis) Autoimmune Other

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Statistical analysis was performed using the SAS software Version 9.1 (SAS

Institute Inc., Cary, NC, USA). Descriptive statistics were performed for the clinical data and for the radiographic features listed in Table 1, and McNemar’s Chi Square test was used to determine differences between the two imaging modalities with regard to the same outcomes. Because there is no gold standard (i.e. histopathological confirmation) for this work, unbiased estimates of “accuracy”, “sensitivity”, and “specificity” cannot be calculated and therefore the terms should not be used.59 Instead, the same numerical calculations were made, but the estimates are called “overall percent agreement” instead of “accuracy”, “positive percent agreement” instead of “sensitivity”, and

“negative percent agreement” instead of “specificity”.59 This modification reflects that the estimates are not of accuracy but of agreement of the new test (CBCT) with the non- reference standard (plain radiographs).59

“Overall percent agreement” = the number of cases agreed upon by both imaging modalities/ the total number of cases.

“Positive percent agreement” = the number of cases that both imaging modalities agreed upon as demonstrating the radiographic feature or findings/ the total number of cases that demonstrated the radiographic feature or finding on plain images.

“Negative percent agreement” = the number of cases that both imaging modalities agreed upon as not demonstrating the radiographic feature or finding/ the total number of cases that did not demonstrate the radiographic feature or finding on plain images.

Comparison was performed between the two imaging modalities for visualization of normal structures, identification of abnormal findings, and interpretation. Cohen’s kappa was used to calculate inter- and intra-observer agreement and the Landis and Koch

87 guidelines were used to interpret them. The null hypothesis was rejected when the alpha (p) value was less than 0.05.

4.5 RESULTS

The 47 subjects ranged in age from 21 years to 87 years with a mean of

48 years. Gender distribution was approximately equal with 27 females (57.4%)

and 20 males (42.6%). The majority of subjects (29 cases, 61.7%) were healthy

with non-contributory medical histories. Sixteen subjects (34.0%) reported a non-

contributory health ailment. Two subjects had received previous radioactive iodine

treatment.

In total, 32 parotid glands and 15 submandibular glands were examined.

Referral to our clinic for sialography was primarily from oral and maxillofacial

surgeons (25 cases, 53.2%), followed by oral and maxillofacial pathologists (14

cases, 29.8%), general dentists (6 cases, 12.8%), and otolaryngologists (2 cases,

4.3%). All subjects were symptomatic, and intermittent swelling was the most

common chief complaint of 32 subjects (68.1%). Three subjects (6.4%)

experienced only a single episode of swelling. With regard to pain, most subjects

(26, 55.3%) reported pain. Fourteen subjects (29.8%) reported dull pain and 8

subjects (17.0%) reported sharp pain. Four other subjects (8.5%) reported

“discomfort” and 21 subjects (44.7%) reported no pain. The majority of subjects

denied any abnormal taste in the mouth or dryness, only 29.8% and 21.3%

reported these symptoms respectively. Twenty subjects (42.6%) could relate their

symptoms of swelling and/or pain to meal time, while three subjects (6.4%) noticed

88 their symptoms to be worse in the morning. One subject claimed tongue movement was the provoking stimulus. At the time of the examination, saliva could be easily expressed from the gland of interest in the majority of subjects (31 cases, 66.0%).

For 13 subjects (27.7%) saliva was difficult to expel, and for three subjects (6.4%) we were unable to expel any saliva from the gland of interest. In the majority of subjects (46 cases, 97.9%), saliva was clear. Cloudy saliva was found in only one case (2.1%). None of the subjects in this study suffered any adverse reactions to the contrast agent or a complication following the procedure.

The two imaging modalities agreed on the interpretation of 39 out of 47 subjects. Of these, four subject image sets (8.5%) were interpreted as being within the range of normal and 35 (74.5%) were interpreted as abnormal. The majority of the image sets (29 cases), however, were interpreted as being consistent with changes secondary to inflammation (sialodochitis and sialadenitis). Two image sets were interpreted as an autoimmune condition (Sjögren syndrome) and two others as space occupying tumours. One image set was interpreted as gland fibrosis and another as sialadenosis. These findings are listed in Table 7.

The abnormal findings listed in Table 6 were identified by the observers more frequently on cone beam CT (cbCT) images than on plain images and are summarized in Table 7. The only exception to this was strictures which were identified more frequently on the plain images. The most common location for sialoliths and strictures was the primary duct. Solitary sialoliths were identified more often than multiple sialoliths, and these ranged in size from 1.0 mm to 24.0 mm. Solitary strictures were identified more commonly on cbCT while multiple

89 strictures were identified more frequently on plain imaging. Ductal dilatation was the most common abnormal finding identified on both plain images (57.4%) and cbCT images (70.2%). The primary and secondary ductal structures were more commonly involved and the severity of ductal dilatation was evaluated to be severe in most cases as accessed on both cbCT and plain imaging. As well, the globular collections of contrast material seen in acinar pooling were most often described as non-uniform in distribution and size as they ranged from 0.1 mm to 6.5 mm on both cbCT and plain imaging.

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Table 7: Radiologic interpretation and identification of features as determined by the reviewers.

Primary outcome (Interpretation) Cone beam CT (%) Plain film (%) Both modalities (%) Normal 06/47 (12.8) 10/47 (21.3) 04/47 (08.5) Abnormal 41/47 (87.2) 37/47 (78.7) 35/47 (74.5) Inflammation (sialadenitis, sialodochitis) 33 (80.5) 30 (81.1) 29 (82.9) Autoimmune (Sjögren syndrome) 2 (04.9) 2 (05.4) 02 (05.7) Gland fibrosis 2 (04.9) 1 (02.7) 01 (02.9) Sialadenosis 1 (02.4) 2 (05.4) 01 (02.9) Tumour 3 (07.3) 2 (05.4) 02 (05.7) Secondary outcomes Visualization of primary duct 46/47 (97.9) 46/47 (97.9) 45/47 (95.7) Visualization of secondary ducts 43/47 (91.5) 42/47 (89.4) 39/47 (83.0) Visualization of parenchyma 39/47 (83.0) 21/47 (44.7) 19/47 (40.4)

Presence of sialoliths 22/47 (46.8) 15/47 (31.9) 15/47 (31.9) Number: Single 15 (68.2) 10 (66.7) Multiple 7 (31.8) 5 (33.3) Location: Primary duct 15 (68.2) 10 (66.7) Secondary ducts 5 (22.7) 5 (33.3) 1ry and 2ry ducts 2 (09.1) 0 (00.0)

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Presence of strictures 19/47 (40.4) 25/47 (53.2) 19/47 (40.4) Number: Single 11 (57.9) 6 (24.0) Multiple 8 (42.1) 19 (76.0) Location: Primary duct 9 (47.4) 12 (48.0) Secondary ducts 3 (15.8) 5 (20.0) 1ry and 2ry ducts 7 (36.8) 8 (32.0) Presence of ductal dilatation 33/47 (70.2) 27/47 (57.4) 25/47 (53.2) Severity: Mild 7 (21.2) 7 (26.0) Moderate 4 (12.1) 9 (33.3) Severe 22 (66.7) 11 (40.7) Location: Primary 10 (30.3) 8 (29.6) Secondary 2 (06.0) 2 (07.4) 1ry and 2ry ducts 21 (63.7) 17 (63.0) Presence of acinar pooling 9/47 (19.1) 4/47 (08.5) 01/47 (02.1) Size (mm): 0.1-6.5 0.2- 5.0 Distribution: Homogenous 2 (22.2) 1 (25.0) Heterogeneous 7 (77.8) 3 (75.0) * McNemar’s chi square test

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The overall percent agreement (“accuracy”) between the two imaging modalities for visualization of the primary duct was high (95.7%). As the gland structures became finer and more delicate (i.e. secondary ducts and parenchyma), the overall agreement between the two imaging modalities decreased to 85.1% and 53.2%, respectively. Differences for visualization of the parenchyma were statistically significant (p< 0.001) with more cases visualized on cbCT (39 cases,

83.0%) than plain images (21 cases, 44.7%). Inter-observer agreement for both plain imaging and cbCT ranged from “moderate to very good” for visualization of the primary and secondary ducts, and ranged from “fair to moderate” for visualization of the parenchyma. Intra-observer agreement was “good” for visualization of the normal structures (plain image 0.71, cbCT 0.79). These findings are summarized in Table 8.

With regard to the identification of abnormal findings (Table 8), the positive percent agreement (“sensitivity”) between the two imaging modalities was 100% for the identification of sialoliths and the negative percent agreement (“specificity”) was 100% for the identification of strictures. Both of these findings were statistically significantly different (p<0.05) between the two imaging modalities. Inter-observer agreement for all the abnormal findings listed in Table 1 ranged from “moderate to very good” for cbCT and “fair to very good” for plain images while intra-observer agreement was “good” for both imaging modalities (plain image 0.73, cbCT 0.75).

Overall percent agreement between the two imaging modalities was similar (83.0%) for normal and abnormal glands. The positive percent agreement was higher (96.7%) for changes secondary to inflammation whereas the negative percent agreement was higher (94.6%) for normal salivary glands. Inter-observer agreement for interpretation ranged from “fair to good” for plain imaging and “good to very good” for cbCT. Furthermore, intra-observer agreement was “good” (plain image 0.80 and cbCT 0.78). These findings are outlined in Table 8.

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Table 8: Overall percent agreement and positive and negative percent agreements for cone beam CT and plain imaging sialography.

Overall % Positive % Negative % Cohen’s kappa Outcomes p* agreement agreement agreement (inter-observer)

Primary outcome

Interpretation cbCT: 0.73 - 0.90

plain film: 0.39 - 0.75

Normal 83.0 40.0 94.6 0.3

Abnormal

Inflammatory 89.4 96.7 76.5 0.4

Secondary outcomes

Visualization of cbCT: 0.52 - 1.00 95.7 97.8 00.0 0.5 primary duct plain film: 0.56 - 0.97

Visualization of cbCT: 0.61 - 0.83 85.1 92.9 20.0 1.0 secondary ducts plain film: 0.63 - 0.83

Visualization of 53.2 90.5 23.1 <0.001 cbCT: 0.22 - 0.58

parenchyma plain film: 0.35 - 0.60

cbCT: 0.62 - 0.84 Presence of sialoliths 85.1 100.0 78.1 0.02 plain film: 0.75 - 0.88

cbCT: 0.82 - 0.91 Presence of strictures 87.2 76.0 100.0 0.04 plain film: 0.34 - 0.64

Presence of ductal cbCT: 0.82 - 1.00 78.7 92.6 60.0 0.1 dilatation plain film: 0.77 - 0.91

Presence of acinar cbCT: 0.63 - 0.73 76.6 25.0 81.4 0.2 pooling plain film: 0.44 - 0.65

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4.6 DISCUSSION

Sialography was first performed in 190212, and is regarded as the gold

standard for depicting the delicate ductal structures of the major salivary

glands7,60,61 and identifying non-calcified sialoliths and ductal strictures.2,7 The

purpose of this study was to determine whether sialography performed with cone

beam computed tomography (cbCT) is superior to sialography performed with plain

imaging.

Interpretation was our primary outcome and we found the overall percent

agreement (“accuracy") between the two imaging modalities to be the same for

interpreting the examinations as normal or abnormal. We also noted that the

positive percent agreement (“sensitivity”) was higher for changes seen secondary

to inflammation and the negative percent agreement (“specificity”) was higher for

normal salivary glands. The high positive percent agreement (96.7%) for the

identification of abnormal glands, particularly those demonstrating changes

secondary to inflammation suggests that inflammatory changes can be confidently

ruled out if these changes are not seen on cbCT images. In contrast, the high

negative percent agreement (94.6%) for normal glands suggests that if an

abnormal finding is detected on cbCT images, then disease can be confidently

ruled in. Figure 21 is an example of a case that was interpreted by all three

observers as normal on plain imaging but was interpreted as demonstrating

changes secondary to sialodochitis when the cbCT images were reviewed.

(a) (b) (c)

Figure 21: Plain and cbCT images of a left submandibular gland sialogram.

This is a case of a 26 year old female that came to our clinic complaining of a single episode of painful swelling in the area of the left submandibular salivary gland. Image

(a) is the lateral skull plain film radiograph that was made following contrast administration. All three observers agreed on the interpretation of normal when this image was reviewed. The observers dismissed the area of dilatation in the proximal part of the primary duct (red arrow) as a point of branching rather than abnormal. Images (b) and (c) are maximum intensity projection (MIP) cbCT images in the sagittal and axial planes respectively. These images demonstrate that the area of ductal dilatation is not due to branching and were thus interpreted by all three observers as changes secondary to sialodochitis.

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Sialadenitis of the major salivary glands especially the chronic type is a relatively common condition with approximately two-thirds of cases reportedly being due to ductal obstruction.2,62-64 Ductal obstruction in turn, may have as primary causes calculi, strictures and fibromucinous plugs, and as secondary causes mass lesions that may impinge on the ductal structures and cause them to occlude. In this study, sialoliths were the most common cause of obstruction identified on both cbCT (46.8%) and plain (31.9%) images. These findings are consistent with the work of Ngu et al (2007), who reported that the most common cause of ductal obstruction (73.2%) was salivary calculi, followed by strictures

(22.6%) and mucous plugs (4.2%). Of note was our finding that more sialoliths were identified on cbCT images than on plain images. Dreiseidler et al suggested that 2D plain images have limited success in identifying sialoliths because of overlapping anatomical structures.65 Moreover, Som and Curtin, estimate that approximately 20% of submandibular gland sialoliths and 40% of parotid gland sialoliths are missed on plain images due to low calcium content.2 Figure 22 is an example of one such sialolith that was missed on plain imaging because of overlapping structures but identified on cbCT.

99

(a) (b) (c)

Figure 22: Plain and cbCT images of a left parotid gland sialogram.

This is a case of a 52 year old female that was referred to our clinic to investigate episodes of intermittent painful swellings in the area of the left parotid gland. Image (a) is the lateral skull plain film radiograph that was made following contrast administration and demonstrates severe sialectasia of the primary and secondary ductal structures but with no obvious cause. Images (b) and (c) are MIP cbCT images of the same gland in the sagittal and the axial planes respectively identifying a cause for the sialectasia, a non-calcified sialolith immediately proximal to the duct orifice (red arrow).

100

Solitary sialoliths are more common than multiple sialoliths, and these are more commonly found in the primary ducts of glands.2 Our data are in agreement with these findings. The high positive percent agreement (100%) between the cbCT and plain imaging datasets suggests that if no sialoliths are detected on cbCT images, then they can be confidently ruled out.

Strictures, like sialoliths, are most often single and more commonly found in the primary duct.7 In the current study, the cbCT results support these findings.

However, more strictures were identified on plain images and they were more often described as multiple on plain imaging. The high negative percent agreement

(100%) of these data suggests that if a stricture is identified on cbCT images, then an obstruction can be confidently ruled in.

Ductal obstruction, regardless of cause, results in the classic painful meal time swelling of the affected gland that is frequently described in the literature and was the most common complaint of subjects in this study.2,64,66 Upon imaging of the affected gland, sialectasia of the ductal structures is the most prominent feature as is demonstrated in the literature and was confirmed in this study.2,64

Cone beam CT sialography, is a novel investigation, and there are few case reports in the literature. Drage and Brown reported two cases in females in their sixth decade of life with classic symptoms of salivary obstruction.67 The authors indicated that the primary duct, secondary ducts, and obstruction(s) were easily identified in both cases. Although the diagnostic capabilities of cbCT sialography were not compared to any other form of imaging, radiation doses delivered to the patients were addressed. Using rough estimates, the authors

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concluded that cbCT sialography delivered a radiation dose equal to fluoroscopic

sialography, but higher than plain image sialography.67 Our earlier work indicates

that this may not be the case. Indeed, the choice of using lower peak kilovolt and

milliampere settings may lower the patient radiation dose without compromising

image quality at all.6,7 Of note is that different iodine concentrations in the contrast

agent were used for the two cases (300 and 370 mg I/ml respectively) and by

observation, the authors concluded that a lower concentration of iodine (180 or 240

mg I/ml) might have been better.67 This conclusion is in general agreement with

our earlier in vitro work on image quality that demonstrated that the lowest

commercially available iodine concentration (140 mg I/ml) is adequate for cbCT

sialography.43

We achieved “moderate to very good” inter-observer agreement in

visualization of the normal gland structures and in identifying abnormal findings as

the three observers were all certified specialists in oral and maxillofacial radiology

with extensive training in sialography and advanced imaging interpretation. The

“fair to moderate” agreement for visualization of the parenchyma is not surprising

since the parenchymal appearance can vary depending on many factors such as

the degree of damage of the terminal acini, the amount of contrast injected, and

the amount of pressure used during injection. It is also encouraging that for

interpretation, the inter-observer agreement was greater for cbCT images than for

plain images.

In conclusion, our results which are based on image interpretation indicate that CBCT sialography may be better than plain film sialography in visualizing the

102 delicate structures of the parotid and submandibular salivary glands, identifying sialoliths and single ductal strictures, as well as differentiating normal salivary glands from those with secondary inflammatory changes.

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5 GENERAL DISCUSSION

In this series of studies, we have developed a novel technique for imaging

the parotid and submandibular salivary glands using sialography combined with

cone beam computed tomography (cbCT). This combination was chosen to make

the greatest use of the advantages of each examination, and to overcome many of

the shortcomings of other imaging modalities routinely used to image the major

salivary glands. These other imaging modalities are ultrasound, computed

tomography and magnetic resonance imaging. Ultrasound is a relatively

inexpensive and widely available imaging modality, however, it has limited

penetrability and therefore its application is limited to examining superficial

structures and guiding future imaging directions. Computed tomography and

magnetic resonance imaging are three dimensional (3D) imaging modalities with

high spacial and contrast resolution however their cost and accessibility have

limited their clinical applicability.

Ensuring that radiation doses are kept as low as reasonably achievable,

quantifying the radiation dose to patients is a crucial first step in the process of

developing a novel imaging technique. This is especially important in the head and

neck area because of the radiosensitive organs in the area being imaged.

Currently, plain imaging of the salivary glands following contrast introduction is the

standard of practice for sialography. Therefore, it was important early on to ensure

that the effective radiation dose (E) for cbCT sialography would be comparable to

doses that patients are currently receiving with plain imaging. Given that the

104 multiple cbCT technical parameters of image acquisition can be varied and controlled by the operator, dose calculations can also vary widely.

Our first study used thermoluminescent dosimeter (TLD) chips (Global

Dosimetry Solutions Inc., Irvine, CA, USA) placed in predefined strategic locations throughout the head and neck of a RANDO®Man radiologic phantom (Alderson

Research Laboratories, Stanford, CT, USA). The imaging system we used, the

Hitachi CB MercuRay (Hitachi Medical Systems, Tokyo, Japan) allows the operator to control the position and size of the field-of-view (FOV), x-ray tube voltage and x- ray filament current. Centering the FOV on either the parotid or submandibular salivary glands, we found significant dose reductions upward of 40% when the

FOV size decreased from 12” to 9”, and from 9” to 6”, with all other factors being equal. This reduction is due, primarily, to some of the TL dosimeters no longer being in the primary radiation field and a reduction of scatter radiation. A second factor that we manipulated was x-ray tube peak kilovoltage (kVp). Reducing kVp resulted in a decrease in E by approximately 30% and 60% when kVp was reduced from 120 kVp to 100 kVp, and then from 100 kVp to 80 kVp, respectively.

With respect to x-ray filament current, when this setting was reduced from 15 mA to 10 mA, all other factors being equal, we found a 37% reduction in E. These findings are in general agreement with the results of other published studies and demonstrate that altering the technical parameters can significantly reduce the radiation dose. Indeed, altering these technical factors should be considered to keep patient radiation doses as low as reasonably achievable.34,38

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Some of the differences in the reported E between our study and other dosimetry studies are likely related to variations in the methodology of measuring the absorbed dose and in the calculations of the effective dose. Two prominent differences in the methodology relate to our decision to center the image FOV and to expose TLD chips, one chip per exposure. In our study, the image FOV was asymmetrically centered on the salivary gland of interest. In other studies, the image FOV was centered in the anatomic midline of one or both jaws.34,38,39

Because this study was the first of its kind to calculate the effective dose for a specific application of cbCT, imaging the major salivary glands, we believed it to be more appropriate to localize the image field where we did, that is, asymmetrically.

We firmly believe that this technical modification has led to a more accurate estimate of E for cbCT examinations of the parotid and submandibular glands. As a result of asymmetric FOV positioning, the percentage contribution of each tissue changed in each FOV. For example, the fraction of brain irradiated in the 12” FOV centered on the left parotid gland was 100% but decreased to 50% in the 9” FOV and decreased even further to 10% using the smallest 6” FOV. On the other hand, it was estimated that only 5% of the brain was irradiated in the 6” FOV when the

FOV was centered on the submandibular gland. Tailoring the estimated fraction of irradiated tissue according to FOV size and centering may have yielded more meaningful dose results.

Regarding the number of TLD exposures, some investigators exposed their TLD chips a minimum of three times, after which the measured absorbed doses that were recorded were divided by the number of exposures.31,34,39 We

106 believe that exposing the TLD chips only once allowed for a more realistic simulation of the patient situation since patients will undergo only one cbCT scan during the procedure. It also allowed us to truly examine the reproducibility of the dose measurement, which was determined by calculating the coefficient of variation, the mean of which was calculated to 9% for the 12” FOV, 80 kVp, and 10 mA cbCT protocol.

The calculated thyroid effective radiation dose was by far the largest contributor to the overall E in all examinations centered on the submandibular gland, whether cbCT or plain radiographs were employed as the imaging modality.

Because of the anatomic proximity of the two glands, it is inevitable that the thyroid will receive more radiation dose during examinations of the submandibular gland.

This may be a source of concern because of the relative high radiosensitivity of the thyroid, especially in children. Fortunately, obstructive conditions of the salivary glands are very rare in children and adolescents,40 and it would be rare that an individual from that age group will require a sialogram procedure. As for the risk of thyroid cancer in adults from diagnostic radiation exposure, the data are still inconclusive and no studies have been able to prove a causal relationship or even a statistically significant association.41,42 Nevertheless, the inconclusive nature of the data creates a dilemma for physicians and dentists interested in imaging the submandibular gland. This dilemma is an excellent example where risk versus benefit judgment comes into play; that is, the excess risk of imaging versus the anticipated benefit to improved patient care and management.

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Radiation dose control is, however, just one factor to consider when evaluating a new imaging technique. Equally important is a consideration of how changing the technical factors that limit dose, affect the quality of the resulting image. For the task of quantifying image quality, we began by calculating the metric, signal-difference-to-noise ratio (SDNR), a relative measure of true image signal to background noise. Not unexpectedly, we found that SDNR increased in proportion to kVp when the mA was held constant because the number of x-ray photons reaching the detector increased. With greater numbers of x-ray photons per unit area arriving at the image receptor, the background image noise decreased. However, in our experimental data, the positive relationship between

SDNR and kVp was exaggerated by another source of image noise, spatial non- uniformity. An inverse cupping artifact was present in our images, which is sometimes known as “capping”.26 This artifact occurs when there is overcompensation for a cupping artifact; an image artifact caused by beam hardening. The capping was more pronounced in the images acquired at lower kVp, where the beam is less penetrating or “softer”. Therefore, the SDNR could be improved at the lower kVp settings by appropriate corrections for spatial non- uniformity (i.e. flat-fielding). A positive relationship was also noted between increases in mA and SDNR, where, within the observed range of SDNR variability, the SDNR increased by a factor of 1.5 when mA was increased by a factor of

1.5. This relationship indicates that quantum noise is likely the dominant factor affecting image performance for each technique combination considered here.

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These quantitative results are consistent with the trends observed in the subjective image quality ratings published by Kwong et al.48

Image artifacts in computed tomography (CT) represent discrepancies between the attenuation coefficient of an object and its CT number in a reconstructed image.26 There are four categories of artifacts: physics-based

(related to the physical process of data acquisition), patient-based (related to patient movement or the presence of radiopaque dental materials), scanner-based

(which result from imperfections in scanner function), and reconstruction-based.27

As artifacts degrade image quality, every effort should be made to minimize or eliminate them as part of the optimization process of any imaging technique or protocol. Three artifacts that affected the quality of the cbCT images of our sialography phantom were identified: dark streak, partial volume, and capping artifacts. Dark streak artifacts occur when the x-ray beam is hardened to different degrees as it passes through different parts of a heterogeneous object at various tube positions. This type of artifact is common in bony regions of patients and when contrast material is used as was the case in this study. Partial volume artifacts are commonly seen in cbCT images. These artifacts occur when dense parts of a heterogeneous object protrude partway into the FOV causing shading artifacts to appear. Cupping artifacts result when the x-ray beam passing through the thicker middle portion of an object becomes harder than the beam passing through the thinner edges of the object. The harder beam is attenuated less and the resultant image appears darker in the center. Beam hardening software is used by manufacturers to correct for this artifact and sometimes overcorrection is

109 attempted to minimize blurring at the bone-soft tissue interface of an image. In some instances, capping artifacts result and the reverse becomes true with the edges of the image appearing darker than the center. Therefore, in some instances, capping artifacts represent an overcompensation to correct for cupping artifacts. The three types of artifacts identified in our images are from the physics- based category, and two of these, dark streaks and capping artifacts, are related to beam hardening. Understanding when and why artifacts occur in cbCT images will allow us to better interpret anomalies identified on cbCT images.

The ability to detect the 3.5 mm diameter region-of-interest (ROI) we used in this study was deemed adequate according to the measured SDNRRose and the threshold specified by the Rose criterion.68 However, in sialography the structures of interest are significantly smaller. The main duct of the parotid gland ranges in diameter between 0.1 mm and 2.0 mm at different points along its course, and for the submandibular gland, the main duct diameter ranges between 0.2 mm and 3.0 mm.69 We can estimate the ability to detect these smaller structures by calculating the SDNRRose at these smaller feature sizes. As an example, SDNRRose for a duct diameter of 0.2 mm imaged with a 6” FOV and using the technical parameters of

80 kVp and 10 mA and a pixel size of 0.2 mm means that a structure of 0.2 mm

diameter occupies just 1 pixel. Under these conditions, SDNRRose= N  SDNRp =

SDNRp= 9 where N is the number of pixels in the region of interest, which is above the Rose criterion cut-off point of five. However, using this same method of analysis, we would find that a 0.2 mm diameter duct would not be reliably visible if

110 the kVp was lowered to 60, while holding all of the other parameters constant, since the SDNRRose= 2.3 in this case.

For the task of imaging technique optimization, we calculated a metric called the figure-of-merit (FOM), which is the ratio of image SDNR to radiation dose. Figure-of-merit values are influenced by kVp and mA. At lower kVp settings of 60 kVp and 80 kVp, a direct relationship was noted between FOM and mA. At higher kVp settings (100 kVp and 120 kVp), an inverse relation was demonstrated because the dose increased significantly more than the SDNR. The only FOM values that were significantly different than the others were those at 60 kVp. This indicates that among the other examined techniques where image quality was adequate, the one that should be adopted as a clinical protocol for sialography is the one which imparts the lowest E.

Suomalainen et al. published an extensive study that evaluated the radiation dose and image quality of four cbCT scanners and compared them to two multislice CT (MSCT) scanners.70 Using appropriate phantoms, radiation doses and contrast values were measured. The contrast-to-noise-ratio (CNR) was used as an indicator of image quality, and the modulation transfer function (MTF) quantity was used to determine the resolving power of each system.70 The authors concluded that despite the large variation in results, cbCT scanners provide adequate image quality with smaller effective doses as compared to MSCT.70

However, the authors were quick to emphasize the importance of optimizing imaging factors for the different examinations.70 It is our opinion that this recommendation can be accomplished only by optimizing these parameters for

111 specific clinical applications of cbCT, and by objectively measuring the trade-off between image quality and radiation dose as we have done in this study for cbCT sialography.

Omnipaque® (Iohexil injection 39%, General Electric Healthcare Canada

Inc., Mississauga, ON) is a low osmolar, nonionic, iodinated contrast agent that is produced in five concentrations: 140, 180, 240, 300, and 350 mg I/mL for different indications of use. At our institution and for the indication of sialography, the

180mg/mL iodine concentration is used. In this study, we examined the effect of the two smaller commercially available concentrations (140 and 180 mg I/mL) in addition to two intermediate concentrations (120 and 160 mg I/mL) in order to fully understand the impact of the iodine concentration on SDNR for cbCT sialography.

Greater concentrations of the contrast agent were deemed unnecessary because the injection is locally confined to the ductal structures of the salivary glands as opposed to vascular injection, where the agent quickly becomes diluted by distribution throughout the whole body. An increase in SDNR was noted with the increase in iodine concentration but there was no statistically significant difference among the different concentrations for the technique using 80 kVp and 10 mA. This relation is due to the substantial signal difference provided by the attenuation of iodine in the salivary ducts.52

To our knowledge there are no other studies in the English literature that examine the effect of varying the iodine concentration in contrast agents on the quality of the resultant images for sialography studies. However, a similarity can be drawn to studies of CT angiography. Unfortunately, these studies vary in their

112 results from demonstrating no significant effect of the iodine concentration53 to showing a statistically significant difference54,55 on vascular enhancement. The results of these studies are complicated by many other variables such as imaging techniques and the injection parameters.55 One particular study by Wang et al. examined the effects of two iodine concentrations of the same contrast agent on image quality and side effects for dynamic CT of the neck.56 They found that both concentrations produced images of excellent quality but the lower concentration resulted in fewer immediate minor complications.56 In the current study, we demonstrated a positive linear trend between the iodine concentration and SDNRp, as indicated by the linear fit to the data in Figure 18. This relationship is expected because the signal difference will increase proportionally to the amount of iodine present. However, no statistical differences in SDNRp were noted among the four concentrations examined; the highest of which (180 mg I/mL) is the concentration currently used at our institution for sialography. The likelihood of complications from contrast media in relation to sialography procedures is minimal because of the localization of the contrast material in the salivary ducts; nevertheless, it would be more reasonable to use the commercially available smaller concentration of the contrast agent, which is 140 mg I/ml.

Based on the findings of the dosimetry and image quality studies, the following protocol for cbCT sialography was proposed. Following the introduction of contrast material into the primary duct of the salivary gland of interest, a lateral skull plain image is made to ensure adequate fill of the ducts with contrast material. This is then followed by cbCT image acquisition of the gland centered in a

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6” FOV and using exposure factors of 80 kVp and 10 mA. After the completion of the cbCT scan, another lateral skull plain radiograph is made five minutes after removal of the catheter to assess contrast material clearance, an accepted indirect indicator of gland function and saliva production. The two lateral skull radiographs are made with the Kodak Directview CR850 PSP system (Kodak Medical Systems,

Rochester, NY) using 70 kVp, 15 mA, and 0.8 s exposure time. It is estimated that a patient undergoing this cbCT sialography examination will receive an effective radiation dose that ranges between 76 µSv for a parotid gland examination (16

µSv for the 2 lateral plain radiographs and 60 µSv for the cbCT examination) and

170 µSv for a submandibular gland examination (22µSv for the 2 lateral conventional radiographs and 148 µSv for the cbCT scan). The estimated effective radiation doses are comparable with the estimated E for a plain film sialography

(parotid 65 µSv and submandibular 156 µSv).

The final step in our project of developing a novel 3D sialography technique for the parotid and submandibular salivary glands using cbCT was to apply the protocol clinically, and to examine its diagnostic efficacy by comparing it with two dimensional (2D) plain film sialography. Given that subject received both

2D and 3D imaging with sialography on the same day allowed us to perform these comparisons with relative ease.

Three certified specialists in oral and maxillofacial radiology were used as observers and asked to review the 2D and 3D image series separately, with a wash out period of at least one week. The parotid and submandibular salivary glands under examination were reviewed by the observers in three parts: the

114 primary duct, the secondary ducts and the parenchyma. Observers were able to visualize the primary duct equally well with both modalities in 45 out of 47 cases.

For the more delicate secondary ducts, imaging agreement decreased to 39 of 47 cases. The observers reported a greater ability to visualize the delicate secondary ducts and the parenchyma of the glands on cbCT images. This is likely largely due to the image processing features permitted by cbCT image data that allowed multi- planar viewing, 3D rendering, and elimination of superimposing structures, which is a major limitation in the 2D plain images.

Interpretation was our primary outcome and we found the overall percent

agreement (“accuracy") between the two imaging modalities to be the same for

interpreting the examinations as normal or abnormal. We also noted that the

positive percent agreement (“sensitivity”) was higher for changes seen secondary

to inflammation and the negative percent agreement (“specificity”) was higher for

normal salivary glands. The high positive percent agreement for the identification

of abnormal glands, particularly those demonstrating changes secondary to

inflammation suggests that inflammatory changes can be confidently ruled out if

these changes are not seen on cbCT images. In contrast, the high negative

percent agreement for normal glands suggests that if an abnormal finding is

detected on cbCT images, then disease can be confidently ruled in.

Sialadenitis of the major salivary glands especially the chronic type is a relatively common condition with approximately two-thirds of cases reportedly being due to ductal obstruction.2,62-64 Ductal obstruction in turn, may have as primary causes calculi, strictures and fibromucinous plugs, and as secondary

115 causes mass lesions that may impinge on the ductal structures and cause them to occlude. In this study, sialoliths were the most common cause of obstruction identified on both cbCT (46.8%) and plain (31.9%) images. These findings are consistent with the work of Ngu et al (2007), who reported that the most common cause of ductal obstruction (73.2%) was salivary calculi, followed by strictures

(22.6%) and mucous plugs (4.2%). Of note was our finding that more sialoliths were identified on cbCT images than on plain images. Dreiseidler et al suggested that 2D plain images have limited success in identifying sialoliths because of overlapping anatomical structures.65 Moreover, Som and Brandwein-Genster, estimate that approximately 20% of submandibular gland sialoliths and 40% of parotid gland sialoliths are missed on plain images due to low calcium content.2

Solitary sialoliths are more common than multiple sialoliths, and these are more commonly found in the primary ducts of glands.2 Our data are in agreement with these findings. The high positive percent agreement between the cbCT and plain imaging datasets suggests that if no sialoliths are detected on cbCT images, then they can be confidently ruled out.

Strictures, like sialoliths, are most often single and more commonly found in the primary duct.7 In the current study, the cbCT results support these findings.

However, more strictures were identified on plain images and they were more often described as multiple on plain imaging. The high negative percent agreement of these data suggests that if a stricture is identified on cbCT images, then an obstruction can be confidently ruled in. Whereas the identification of strictures on

116 plain images may have been overestimated and confused with areas of duct branching or bending.

Ductal obstruction, regardless of cause, results in a cascade of events that starts with saliva build-up proximal to the duct opening. The build-up intensifies during meal times when copious volumes of saliva are quickly produced, but meet resistance at the obstruction. This results in the classic painful meal time swelling that is frequently described in the literature and was the most common complaint of subjects in this study.2,64,66 In most cases the obstruction rarely occludes the duct completely, and saliva eventually finds its way around the obstruction and into the mouth prompting the relief of the patients’ symptoms. If the obstruction is not removed or dislodged, the process may result in chronic distention of the ducts beyond the obstructive point. Many patients seek professional help at this point and when imaged, sialectasia of the ductal structures is the most prominent feature as is described in the literature and was demonstrated in this study.2,64 Within the now dilated ducts, saliva may stagnate and become an inviting environment for retrograde bacterial infections. Imaging of the gland at this point may demonstrate globular collections of contrast material that represent contrast pooling. These collections are characteristically heterogeneous in size and distribution, and may appear not unlike the globular collections encountered in autoimmune diseases which are comparatively more homogenous in size and distribution.2,8,64 Although these changes can be seen in both minor and major salivary glands, approximately

83% of these appearances have been reported to involve the parotid and submandibular glands, with the submandibular glands being the most commonly

117 affected.12,65 The reason for the higher prevalence of obstructions in the submandibular gland ducts is believed to be related to the longer, more tortuous, path of the major duct, and the nature and consistency of submandibular saliva which has a higher mucous content making it thicker and more likely to form a mucous plug. In this study, parotid examinations were more common than submandibular ones. In another series, parotid examinations were performed more frequently than submandibular ones.71 A possible explanation for parotid gland examinations being more common than submandibular ones despite the higher occurrence of obstructions in the submandibular gland may be related to the presenting symptoms. Obstructive conditions commonly present as a facial swelling, and the developing facial asymmetry may be more noticeable to patients, making them more likely to seek professional help.

The imaging findings that have been discussed thus far influence not only the interpretation of the images, but as well, management. Many management options have become available, and several of these are minimally invasive and radiologically guided such as basket retrieval for sialoliths and balloon ductoplasty for ductal strictures.9,11 Their success, however, depends on having adequate and accurate information provided by diagnostic imaging. Therefore, it is imperative that imaging reports include a detailed description of any causes of obstruction, their nature, number, location, and effect on the glandular structures. This increased need for detailed diagnostic information highlights the importance that diagnostic imaging plays not only in diagnosis, but in patient management, as well.

And indeed, the additional information provided by cbCT images, such as the type

118 of obstruction and its exact location in the three orthogonal planes, will no doubt influence the management of patients.

Due to the novelty of cbCT sialography, only one similar publication was found in the English literature; a report of 2 cases by Drage and Brown who used sialography and performed their imaging using the i-CAT unit (Imaging Science

International, Hatfield, PA).67 Both cases were of females in their sixth decade of life with classic symptoms of salivary obstruction. In the first case, a single sialolith, which the authors indicated would have been very difficult to identify on plain images, was identified in the right submandibular gland. The second case involved a sialolith and a stricture in the right parotid gland, both of which were managed with minimally invasive, radiographically-guided, interventional procedures.67 The authors claim that the primary duct, secondary ducts, and obstruction(s) were easily identified in both cases.67 Although the diagnostic capabilities of cbCT sialography were not compared to any other form of imaging, radiation doses delivered to the patients were addressed. Using rough estimates, but with no hard data, the authors surmised that cbCT sialography delivered a radiation dose equal to fluoroscopic sialography, and higher than plain image sialography.67 Of note is that different iodine concentrations in the contrast agent were used for the two cases (300 and 370 mg I/mL, respectively) and by observation, the authors concluded that a lower concentration of iodine (180 or 240 mg I/mL) might have been better.67 Although there is a lack of a reputable dataset from these 2 cases, their supposition is in general agreement with our earlier work that demonstrates

119

that the lowest commercially available iodine concentration (140 mg I/ml) may be

adequate for cbCT sialography.43

We achieved “moderate to very good” inter-observer agreement in

visualization of the normal gland structures and in identifying abnormal findings as

the three observers were all certified specialists in oral and maxillofacial radiology

with extensive training in sialography and advanced imaging interpretation. The

“fair to moderate” agreement for visualization of the parenchyma is not surprising

since the parenchymal appearance can vary depending on many factors such as

the degree of damage of the terminal acini, the amount of contrast injected, and

the amount of pressure used during injection. It is also encouraging that for

interpretation, the inter-observer agreement was greater for cbCT images than for

plain images.

5.1 CONCLUSION

We have successfully developed a novel technique for imaging the parotid

and submandibular salivary glands using sialography combined with cone beam

computed tomography (cbCT) based on an extensive evaluation of the technical

factors that can be adjusted by the operator and their effect on both radiation

doses delivered to the patient and image quality. The protocol which was specific

for the Hitachi CB MercuRay unit (Hitachi Medical Systems, Tokyo, Japan)

recommends placing the major salivary gland of interest in the center of a 6” FOV

and imaging using 80 kVp and 10 mA. The diagnostic efficacy of the novel

technique was also examined clinically and compared to 2D plain film sialography

which is the standard of practice. The results were overwhelmingly promising as 120 they demonstrated that 3D cbCT sialography was superior to plain film sialography in visualizing the delicate structures of the salivary gland such as the parenchyma.

Cone beam CT sialography may also be better at identifying sialoliths and single ductal strictures (the two most common causes of obstruction), as well as differentiating normal salivary glands from those with secondary inflammatory changes.

The role of diagnostic imaging is no longer limited to providing an interpretation which will contribute to the diagnosis. Diagnostic imaging now plays a pivotal role in the overall management of patients. Therefore existing and new imaging technologies and protocols must undergo an extensive evaluation of their efficacy. In diagnostic imaging there is a well-established hierarchical model for assessing efficacy that starts with technical efficacy (i.e. assessment of the resultant image quality).72 Then the accuracy, sensitivity, and specificity of interpreting the images is addressed in the second level which is the diagnostic accuracy efficacy.72 The third level studies the diagnostic thinking efficacy, that is the influence of the radiographic interpretation on the clinicians’ diagnosis.72 Level four addresses the effect of the imaging information on the management plan

(therapeutic efficacy) and level five addresses the effect of the information on the patient outcome (patient outcome efficacy).72 The final level is an analysis of the societal costs and benefits of the diagnostic imaging technique (societal efficacy).72

The three studies presented in this thesis have successfully addressed the first two levels of the diagnostic imaging hierarchy. Further studies are needed to address the remaining four levels of diagnostic efficacy.

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5.2 FUTURE DIRECTIONS

The cbCT sialography protocol recommended in this study is specific for

the Hitachi CB MercuRay cbCT scanner (Hitachi Medical Systems, Tokyo, Japan).

Future studies following the same approach used in this work could be applied to

other cbCT systems to address the applicability of this novel combination to other

cbCT machines and to optimize the protocol for those specific units.

One of the limitations of the current study was the lack of a gold standard

which restricted our ability to determine the diagnostic accuracy of cbCT

sialography. Ideally, future diagnostic efficacy studies should try to incorporate a

gold standard such as correlating the imaging findings with the surgical or

histopathological findings. Future studies should also address the remaining levels

of diagnostic efficacy mentioned earlier. “Diagnostic thinking efficacy” can be

determined by studying the influence of the imaging findings and interpretation on

the post-imaging diagnosis of the clinician. Determining whether the imaging

results helped chose the line of management or changed the management plan

will address the “therapeutic efficacy” of cbCT sialography. Correlating the imaging

results with the management outcome in terms of morbidity to the patient and

quality of life will ascertain the “patient outcome efficacy”. Finally, the “societal

efficacy” of cbCT sialography can be established by studying the critical balance

between the cost of the procedure and its benefits from a societal point of view.

In the present studies we examined the different commercially available

concentrations of iodine in one contrast agent which is manufactured primarily for

intravenous use. Our data demonstrated a trend that supports the adequacy of

122 lower concentrations of iodine in the contrast agent especially when used locally as is the case for sialography. Future studies should examine a wider range of lower iodine concentrations in contrast agents and their effect on image quality for specific local indications such as sialography. This will hopefully prompt producing companies to manufacture contrast agents with lower concentrations of iodine that are more appropriate for local rather than intravenous use.

Cone bean CT sialography was superior to plain film sialography in identifying sialoliths. However, the level of calcification of the sialolith was not addressed in this study. An excellent future direction would be to conduct a study that specifically answers the question of whether cbCT sialography is superior to other imaging modalities in identifying non-calcified sialoliths which are usually difficult to detect and diagnose using even the most sophisticated imaging techniques.

Additionally, future studies could explore the possibility of canulating and imaging not only the gland in question but also the contra-lateral gland in an attempt to provide a comparative study. This can be easily achieved by increasing the FOV size and centering the image field symmetrically on the patient’s midline to include both glands. This of course will result in greater radiation exposure to the patient but the diagnostic yield may outbalance this increase in risk.

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COPYRIGHT ACKNOWLEDGEMENT

From: Gould, Laura (ELS-OXF) [[email protected]] Sent: October-12-11 10:30 AM To: Fatima Jadu Subject: RE: Permission to use copyrighted material in my PhD thesis.

Dear Ms Jadu

Ten Cate's Oral Histology: Development, Structure, and Function by Antonio Nanci; 3 figures only Head and Neck Imaging by Peter Som and Hugh Curtin; 2 figures only Oral Radiology: Principles and Interpretation by Stewart C. White and Michael J. Pharoah; 3 figures only

As per your email below, we hereby grant you permission to reprint the below mentioned material at no charge in your thesis, in print and on the University of Toronto web site subject to the following conditions:

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“This article was published in Publication title, Vol number, Author(s), Title of article, Page Nos, Copyright Elsevier (or appropriate Society name) (Year).”

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4. Reproduction of this material is confined to the purpose for which permission is hereby given.

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6. This includes permission for the Library and Archives of Canada to supply single copies, on demand, of the complete thesis. Should your thesis be published commercially, please reapply for permission.

Yours sincerely

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135

Appendix 1: Research ethics board approval letter

136

Appendix 2: Patient consent form

Title of Research Project: Development and application of a technique for three-dimensional sialography using cone beam computed tomography (cbCT).

Investigator(s): 1. Principal investigator

Dr. Fatima Jadu DDS, MSc Dipl ABOMR PhD candidate Division of Oral and Maxillofacial Radiology

Faculty of Dentistry, University of Toronto 124 Edward Street, Division of Oral and Maxillofacial Radiology Toronto, ON M5G 1G6 416-979-49-32 x 4040

2. Faculty Supervisor

Dr. Ernest Lam DMD, PhD, FRCD(C) Associate Professor Division of Oral and Maxillofacial Radiology

Faculty of Dentistry, University of Toronto 124 Edward Street, Division of Oral and Maxillofacial Radiology Toronto, ON M5G 1G6 416-979-49-32 x 4385

Purpose of the Research: The purpose of this study is to compare the diagnostic performance of cbCT sialography with plain film sialography with respect to its ability to depict salivary gland anatomy and function.

Description of the Research: Subject population

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Adult patients referred to the Special Procedures Clinic in the Discipline of Oral and Maxillofacial Radiology at the Faculty of Dentistry, University of Toronto for a sialographic procedure.

Inclusion criteria: individuals with a suspected salivary gland obstructive condition as determined by a pre-sialography clinical examination of the patient.

Exclusion criteria: subjects with acute inflammation of the salivary gland of interest, subjects with known or suspected allergy to iodinated contrast agents, subjects with an immediately anticipated thyroid function test and patients under the age of 18 years.

Collected data

The data that will be collected for each patient prior to the sialography procedure is listed in the Materials and Methods section page 92. These data will be collected in the clinic by the Principal Investigator at the time of clinical examination.

Sialography procedure

A thorough explanation of the sialographic procedure and its possible complications will be given to each patient prior to consenting to the examination. Upon approval, the procedure will be performed by a Resident in Oral and Maxillofacial Radiology at the Faculty of Dentistry, University of Toronto. The resident will be closely supervised by the Principal Investigator or a faculty member, all of whom are certified specialists in Oral and Maxillofacial Radiology. Sialography procedures are routinely performed in the Special Procedure clinic and the supervising faculty members are experienced in the performance of this procedure.

The procedure will start by canulating the major duct of the salivary gland followed by insertion of a 24G or 30G catheter (Pajunk, Medizintechnologie, Geisingen, Germany or Cook, Bloomington, IN). Between 1 mL and 6 mL Omnipaque® (Iohexil injection 39%, General Electric Healthcare Canada Inc., Mississauga, ON) will be injected slowly into the primary duct of the gland until the patient reports maximum tolerance to the feeling of pressure in the gland of interest. A lateral skull plain radiograph will be made using the GE focus system (General Electric Corporation, Henry Schein Ash Arcona, Niagara- on-the-Lake, ON) to confirm optimal fill of the gland being examined prior to the cbCT scan. If fill of the gland is inadequate, additional contrast will be injected and another lateral skull plain radiograph will be made. The patient will then be placed in the CB MercuRay cone beam CT unit (Hitachi Medical Systems, Tokyo, Japan) with the occlusal plane of the dentition parallel to the floor, the midsagittal plane perpendicular to the floor, and the gland of interest centered in the image field. Imaging will be performed using a 6” field-of-view, and x-ray tube factors of 80 kVp and 10 mA. Five minutes following catheter removal a final lateral skull plain image will be made to evaluate

138 contrast clearance from the gland. The lateral skull plain image demonstrating adequate contrast fill and the postoperative lateral skull plain image will represent the “conventional” part of the study and will be used for comparison with the cbCT images. By following this protocol, it will be possible to compare the two imaging modalities relative to the same patient and same salivary gland under investigation. Variables related to the patient and the gland will be standardized without unnecessarily repeating the procedure or exposing the patient to additional doses of radiation.

The results of the sialographic examination will be reported to the patient at the completion of the examination. As well, a digital copy of the radiographic images that were obtained for the patient will be couriered to the referring physician accompanied by a radiographic report stating the findings of the examination.

Image analysis

The conventional plain images and cbCT images for each patient will be reviewed independently by 3 certified oral and maxillofacial radiologists. As the images are all digitally-acquired, they will be reviewed at one of the three computer workstations in the oral radiology department where the observers will have the advantage of enhancing the images by manipulating their brightness and contrast; as well as reviewing the 3D renderings in their entirety. The reviewing radiologists will be blinded to the clinical data and will be required to fill out the form outlines in Table 6 (in the Materials and Methods section on page 96) for each image series. The presence or absence of a particular radiographic feature will be based on agreement of 2 of the 3 radiologists, and there will be no attempt to reconcile disagreement. As well, one of the radiologists will review the series twice so that intra-observer reliability may be determined. Image analysis will be done twice during the course of this project; half way through the study during year 1, and again at the end of the study.

Potential Harm, Injuries, Discomforts or Inconvenience: Sialographic procedures are minimally invasive and carry two possible risks: hypersensitivity reaction to the contrast agent and infection. These adverse effects are very rare especially when the appropriate precautions are taken. During the procedure, every effort is made to minimize the risk of developing one or both of these potential complications. A strict aseptic technique is always followed during the procedure as a standard of practice. The risk of developing a hypersensitivity reaction is very low in sialography. This risk is usually minimized further by using small amounts (2 to 6 mL) of an ionic agent that is less likely to provoke an allergic reaction. Screening of patients for a potential contrast agent-related hypersensitivity reaction is elicited during the initial review of the patient’s medical history. In the event that a hypersensitivity reaction does occur, the clinic is fully equipped with the proper medications and materials to deal with medical emergencies, and the staff are trained in this aspect.

139

With respect to radiation doses, we have recently completed a dosimetric study comparing the effective radiation doses from a 2D plain radiography sialographic examination with a 3D cbCT examination using an Alderson RANDO® phantom with lithium fluoride (LiF) dosimeters placed in 25 locations in the phantom. A sialographic examination of the parotid salivary gland includes a panoramic radiograph, 2 anterior- posterior skull and 4 lateral skull views, while a submandibular salivary gland examination includes a panoramic radiograph, a mandibular intra-oral occlusal radiograph and 4 lateral skull radiographs. We compared the effective doses from these 2 studies with cbCT studies where we varied field-of-view (FOV) size (6”, 9”, 12”), killovoltage (kV) (80 kVp, 100 kVp, 120 kVp) and milliamperage (mA) (10 mA, 15 mA). The results were presented recently at the 2008 meeting of the American Academy of Oral and Maxillofacial Radiology in Pittsburgh, PA. Our results found that the effective doses for plain radiograph parotid, plain film submandibular and cbCT examinations of these glands were comparable when using the 6” FOV for the cbCT examination at 80 kVp and 10 mA:

Parotid gland (plain radiograph): 60 microSievert (µSv) Parotid gland (cbCT): 65 µSv

Submandibular gland (plain radiograph): 156 µSv Submandibular gland (cbCT): 148 µSv

Potential Benefits: By agreeing to participate in this study, patients undergoing cbCT sialography will greatly benefit from the 3D imaging of their gland. We hypothesize that 3D imaging of the gland ductal structures will provide more detailed diagnostic information than conventional 2D imaging techniques, by allowing multi-planar viewing of the gland and by eliminating superimpositions of adjacent anatomic structures. We believe that the additional information obtained by this technique will aid the treating physician or dentist in choosing the most appropriate management option for the patient, and improve the quality of patient care.

Alternatives: If you elect at any time not to participate in this study, an alternative sialographic examination using plain radiography will be offered.

Confidentiality: Confidentiality will be respected and no information that discloses the identity of the subject will be released or published without consent unless required by law. Patient

140 data will be anonymized with the identities of the patients known only to the Principle Investigator.

Participation: Participation in research is voluntary. If you choose to participate in this study you can withdraw at any time. Should you choose to withdraw, your data will be removed from the database. There will be no consequences with respect to your future care in the Faculty.

Contact: If you have any questions about this study, please contact:

Dr. Fatima Jadu DDS, MSc Dipl ABOMR PhD candidate Division of Oral and Maxillofacial Radiology

Faculty of Dentistry, University of Toronto 124 Edward Street, Division of Oral and Maxillofacial Radiology Toronto, ON M5G 1G6 416-979-49-32 x 4040

If you have any complaints or concerns about how you have been treated as a research participant, please contact:

Zaid Gabriel Research Ethics Officer, Health Sciences [email protected] or 416-946-5806

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CONSENT:

By signing this form, I agree that:

The study has been explained to me. Yes No All my questions were answered. Possible harm and discomforts and possible benefits (if any) of this study have been explained to me. I understand that I have the right not to participate and the right to stop at any time. I understand that I may refuse to participate without consequence to continuing care at the Faculty. I have a choice of not answering any specific questions I am free now, and in the future, to ask any questions about the study I have been told that my personal information will be kept confidential I understand that no information that would identify me, will be released or printed without asking me first. I understand that I will receive a signed copy of this consent form.

I hereby consent to participate.

______Signature Date

Name of Participant and Age: ______

Telephone #: ______

Name of person who obtained consent: ______

______Signature Date

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